Acquired Inhibitors of Coagulation 

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Acquired Inhibitors of Coagulation 

Description

  • acquired inhibitors of coagulation are autoantibodies that deplete or inhibit activity of target coagulation factors(1,2)
  • inhibitors of factor VIII (acquired hemophilia A) and inhibitors of von Willebrand factor (von Willebrand syndrome) are most common, but other coagulation factors may rarely be targeted(1,2)
  • autoantibodies against coagulation factors develop in persons with previously normal coagulation factor function; this is in contrast to alloantibodies which develop in patients with inherited deficiencies of coagulation factors (for example, inherited hemophilia A and hemophilia B) after treatment with exogenous coagulation factor concentrates(5)
  • often associated with autoimmune disorders and neoplastic conditions, though sporadic cases do occur(2)
  • bleeding is a clinical manifestation of acquired inhibitors of coagulation; severity of bleeding can vary, ranging from asymptomatic to severe, limb-threatening, or life-threatening bleeding(1,2,3,4)
  • this topic will not discuss
    • acquired von Willebrand syndrome; see Acquired Von Willebrand Syndrome for additional information
    • development of inhibitors in patients with hemophilia receiving treatment; see Medication Management of Acute Bleeding in Hemophilia A Patients With Inhibitors or Medication Management of Acute Bleeding in Hemophilia B Patients With Inhibitors for additional information

Also Called

  • acquired hemophilia A (inhibition of factor VIII)
  • acquired hemophilia B (inhibition of factor IX)

Epidemiology

Who Is Most Affected

  • acquired hemophilia A
    • frequency increases with age and is more common in adults > 65 years old; reported median age of onset 74-78 years(2)
    • incidence similar between female and male individuals, except between ages 20 and 40 years when women are more commonly affected due to cases associated with pregnancy(2)
    • rare in children(2,3)
  • inhibitors to factor V is more common in older adults, but can occur at any age(1)

Incidence/Prevalence

  • autoantibodies against all coagulation factors have been reported but inhibitors directed against factor VIII are the most common, followed by factor V(5)
  • inhibitors to factor VIII (acquired hemophilia A [AHA])
    • reported incidence of AHA 1.5 per million per year(1,2)
    • pregnancy-associated AHA reported in 1 out of 350,000 deliveries in the United Kingdom and 20 cases over 15 years in Italy(1,2)
    • estimated incidence of acquired hemophilia A of 1.5/million/year in children and adults in United Kingdom from 2001-2003
      •  based on population-based cohort study
      • 172 children and adults (median age 78 years) with AHA from United Kingdom from 2001 to 2003 were evaluated
      • incidence of AHA 1.48/million/year (calculated from population of 58 million in United Kingdom)
      • 3 pregnant women had AHA (2% of all patients)
      • out of 150 patients evaluated, 63% did not have underlying conditions; among the others, underlying conditions included
        • autoimmune or collagen vascular disease in 17%
        • malignancy in 15%
        • dermatologic conditions in 3%
        • pregnancy in 2%
      • Reference – Blood 2007 Mar 1;109(5):1870full-text
    • estimated incidence of acquired hemophilia A 0.65 per million per year in Finland from 2006 to 2019
      •  based on retrospective cohort study
      • 55 patients (median age 76 years, 51% female) diagnosed with AHA between 2006 and 2019 in Finland were assessed
      • estimated median incidence of AHA 0.65 per million per year, with no increase in annual incidence over time
      • causes identified
        • autoimmune disease in 25%
        • malignancy in 7%
        • postpartum in 4%
        • infection in 2%
      • 62% had no underlying disease
      • Reference – Haemophilia 2024 Jun 28 early online
    • estimated incidence of AHA 2.4 per million per year in Hong Kong from 2012 to 2021 (Thromb Res 2024 Jan;233:138)
  • inhibitors to other acquired coagulation factors
    • acquired inhibitors to other coagulation factors such as fibrinogen and factors II, V, VII, IX, X, XI, and XIII are rare(1,2,5)
    • about 150 cases of inhibitors to factor V have been described(5)
      • most cases have been attributed to exposure to bovine thrombin that contain traces of bovine factor V
      • with more wide spread use of recombinant human thrombin during surgery, risk of developing factor V inhibitors has become very low
    • incidence of acquired inhibitors to other coagulation factors is unclear because only sporadic cases have been described (Hematology Am Soc Hematol Educ Program 2019 Dec 6;2019(1):80full-text)

Risk Factors

  • inhibitors to factor VIII (acquired hemophilia A [AHA])
    • about half of the cases are idiopathic with no obvious underlying risk factors(2,3)
    • autoimmune disorders
      • reported to be associated with 9.4%-17% of AHA cases(3)
      • autoimmune disorders include
        • rheumatoid arthritis (most common)(2,3,4)
        • systemic lupus erythematosus (SLE)(1,2,4)
        • temporal arteritis(4)
        • ulcerative colitis(4)
        • Sjogren syndrome(4)
        • Goodpasture syndrome(4)
        • multiple sclerosis(4)
        • myasthenia gravis(4)
        • graft-versus-host disease(4)
        • autoimmune thyroid disorders(4)
        • autoimmune hemolytic anemia(4)
    • malignancy
      • reported to be associated with 6.4%-18.4% of AHA cases(3)
      • malignancies include(4)
        • chronic lymphocytic leukemia
        • multiple myeloma
        • Waldenstrom macroglobulinemia
        • non-Hodgkin lymphoma
        • myelodysplastic syndrome
        • myelofibrosis
        • monoclonal gammopathy of undetermined significance (MGUS)
        • erythroleukemia
        • solid tumors such as lung, prostate, pancreas, colon, stomach, melanoma, breast, kidney, cervix, head, and neck
    • infections(3)
    • dermatologic conditions
      • pemphigoid(1,4)
      • psoriasis(4)
    • medications
      • interferon-alpha(3,4)
      • antibiotics(2,4)
      • phenytoin(4)
      • sulfonylureas(4)
      • methyldopa(4)
      • depot thioxanthene(4)
      • non-steroidal anti-inflammatory drugs(4)
      • fludarabine(4)
      • clopidogrel(4)
    • vaccinations
    • pregnancy
      • especially puerperium(2,4)
      • transplacental crossing of maternal antibody has been reported (rare)(3)
    • acute hepatitis B/acute hepatitis C(4)
    • chronic pulmonary obstructive disease (COPD)(4)
    • asthma(4)
  • risk factors associated with development of inhibitors to other coagulation factors
    • other acquired coagulation inhibitors are also associated with autoimmune disease and malignancy or idiopathic(1,2,5)
    • inhibitors to factor V
      • about two-thirds of cases reported to develop after topical bovine thrombin or fibrin glue application containing traces of bovine factor V; use of recombinant human thrombin in hemostatic agents has reduced incidence of antibody development(1,2)
      • other conditions/risk factors include
        • autoimmune disorders(2)
        • malignancies(1,2)
        • surgical intervention (unclear how many of these cases are due to use of topical bovine thrombin or fibrin glue containing traces of bovine factor V)(2)
        • antibiotics, especially beta-lactams and aminoglycosides(1,2)
        • blood transfusions(2)
    • inhibitors to fibrinogen
    • inhibitors to factor II (prothrombin)
      • may be idiopathic(5)
      • risk factor for factor II inhibition include application of topical preparations of bovine thrombin or fibrin glue; use of recombinant human thrombin in topical hemostatic agents has greatly reduced risk of antibody formation(1)
      • other conditions/risk factors include
        • autoimmune disorders such as SLE and rheumatoid disease ((1), Hematology Am Soc Hematol Educ Program 2019 Dec 6;2019(1):80full-text)
        • monoclonal gammopathies or polyclonal increase in immunoglobulin(1)
        • antiphospholipid antibody syndrome(1)
          • commonly associated with antiprothrombin antibodies in factor II inhibition
          • hypoprothrombinemia-lupus anticoagulant syndrome caused by some lupus anticoagulants resulting in low factor II, though often transient
    • inhibitors to factor VII
    • inhibitors to factor IX
      • may be idiopathic(5)
      • risk factors are similar to those for AHA(1)
      • frequently associated with autoimmune disorders or postpartum(5)
    • inhibitors to factor X
      • may be idiopathic(5)
      • factor X deficiency typically associated with amyloidosis, with only occasional reports of acquired factor X deficiency caused by inhibitor to factor X(1)
      • occasionally reported in association with malignancies, autoimmune disorders, or drug exposure(5)
    • inhibitors to factor XI
      • usually associated with underlying collagen vascular disease, such as SLE(1)
      • less commonly associated with hematologic malignancy, autoimmune gastrointestinal diseases, or phenothiazines(1)
    • inhibitors to factor XIII – risk factors include

Etiology and Pathogenesis

Causes

  • autoantibodies against coagulation factors develop in persons with previously normal coagulation factor function; this is in contrast to alloantibodies which develop in patients with inherited deficiencies of coagulation factors (for example, inherited hemophilia A and hemophilia B) after treatment with exogenous coagulation factor concentrates(5)
  • development of acquired inhibitors may be triggered by underlying conditions such as autoimmune and malignant disorders, but some inhibitors develop in the absence of apparent underlying condition(1,2)
  • see Risk Factors for additional information on underlying conditions, clinical settings, and medications that may trigger development of acquired inhibitors
  • characteristics of inhibitors to various coagulation factors
    • type IgG4-polyclonal immunoglobulins targeting several functional epitopes of clotting factors(2)
    • factor VIII (acquired hemophilia A) – IgG autoantibodies (predominantly IgG1 and IgG4); rarely IgM or IgA (2,3,4)
    • factor V – IgG autoantibodies(5)
    • fibrinogen – IgG, IgA, or IgM autoantibodies(5)
    • prothrombin – IgG autoantibodies(5)
    • factor VII – IgG autoantibodies(5)
    • factor IX – IgG4 autoantibodies(5)
    • factor X – IgG autoantibodies(5)
    • factor XI – IgG autoantibodies(5)
    • factor XIII – IgG autoantibodies against A or B factor XIII subunits(5)

Pathogenesis

Coagulation Factors and the Coagulation Cascade
  • Coagulation cascade – Intrinsic, extrinsic, and common pathways of the coagulation cascade.Copyright ©2021 EBSCO Information Services.
  • clotting cascade and the coagulation factors
    • the clotting cascade involves sequential activation of series of coagulation factors (serine proteases) that normally circulate in the plasma as inactive enzymes (zymogens)
    • upon vessel injury
      • initiation of the coagulation cascade (extrinsic pathway) leads to slow increase in thrombin and amplification of active forms of other coagulation factors, resulting in further accumulation of thrombin
      • platelet are recruited to sites of injury by adhering to von Willebrand factor/collagen matrix and are activated; activate platelets
        • secrete granular contents
        • aggregate further via their surface glycoproteins (integrins)
        • help generate thrombin after developing a procoagulant surface
        • form contracted thrombus with fibrin
      • accumulating thrombin also contributes to activation of platelets that have adhered to site of injury
    • the activation of platelets and fibrin polymerization ultimately result in a clot that prevents excessive blood loss after vascular injury
    • Reference – Crit Rev Biochem Mol Biol 2015;50(4):326full-text, Physiol Rev 2013 Jan;93(1):327full-text
    • initiation of the cascade involves 2 pathways
      • extrinsic pathway
        •  mechanism for triggering blood clotting that functions in normal hemostasis and likely involved in most types of thrombosis
        • triggered by tissue factor expressed in the vascular wall or activated circulating monocytes; vascular injury or monocyte activation leads to activation of factor VII (factor VIIa), which then activates factor IX (cross-talk with intrinsic pathway) and factor X (of the common pathway)
      • intrinsic
        • triggered when plasma comes in contact with negatively charged surfaces such as glass test tubes
        • does not contribute to normal hemostasis but thought to contribute to thrombotic disease and monitored by activated partial thromboplastin time
        • initiated by conversion of factor XII to factor XIIa, followed by subsequent stepped conversions of factor XI and IX to their active forms
      • References – Crit Rev Biochem Mol Biol 2015;50(4):326full-text, Physiol Rev 2013 Jan;93(1):327full-text
    • both pathways then converge on to the common pathway, leading to
    • normal coagulation factor activity varies between 50% and 150% of activity of circulating clotting factors from normal pooled plasma
      • clotting can still occur even if coagulation factors are significantly low
      •  in patients with one-factor deficiency (such as factor VIII or IX), > 30% of activity is typically required for hemostasis
      •  in patients with multiple factor deficiency (for example, after trauma, synthetic liver dysfunction, and vitamin K deficiency), > 40% of activity of each deficient factor may be needed for normal hemostasis
      • Reference – Fung MK, Grossman BJ, Hilyer CD, Westhoff CM, eds. Technical manual of American Association of Blood Banks (AABB). 18th ed. Bethesda, MD: AABB; 2014

Table

Table 1: Coagulation Factor Half-lives and Percent Needed for Hemostasis

FactorBiological Half-lifePercent Activity Needed for Normal Hemostasis in Isolated Deficiency States
I3-6 days12%-50%
II2-5 days10%-25%
V5-36 hours10%-30%
VII2-5 hours> 10%
VIII8-12 hours30%-40%
IX18-24 hours15%-40%
X20-42 hours10%-40%
XI40-80 hours20%-30%
XIII12 days< 5%

Citation: Reference – Fung MK, Grossman BJ, Hilyer CD, Westhoff CM, eds. Technical manual of American Association of Blood Banks (AABB). 18th ed. Bethesda, MD: AABB; 2014.

Acquired Inhibitors of Coagulation
  • acquired inhibition of coagulation is caused by immune-mediated depletion or inhibition of activity of endogenous coagulation factor by autoantibodies (acquired inhibitors)(1,2)
  • kinetics of coagulation factor inactivation by acquired inhibitors
    • usually, kinetics of inactivation are second order or exponential, with rapid initial inactivation, followed by slower phase or period of equilibrium in which factor activity can still be measured(2,5)
      • inhibitors that display second-order kinetics of inhibition (for example, inhibitors to factor VIII) produce nonlinear inactivation profile when coagulation factor activity is plotted against plasma concentration and do not completely block coagulation factor activity even at highest concentration of inhibitor plasma in vitro
      • Bethesda assay, used to quantify in vitro inhibitor activity, can underestimate in vivo potency due to this complex reaction kinetics and may complicate treatment choices and monitoring
    • rarely, immunoglobulins show first-order kinetics where factor inactivation is directly proportional to concentration of antibody or to duration of incubation(2,5)
      • characterized by linear inactivation profile when coagulation factor activity is plotted against plasma concentration
      • completely neutralizes coagulation activity at high plasma concentrations in vitro
      • more commonly observed with alloantibodies that develop in congenital hemophilias
  • development of select inhibitors and their mechanism of action
    • inhibitors of factor VIII
      • autoantibodies to factor VIII appear to bind to regions A2, A3, and C2 domains of the protein, interfering with its interaction with factor IXa, phospholipids, and von Willebrand factor(4)
      • autoantibodies may develop due to breakdown of peripheral immune tolerance mechanisms that regulate normal immune response to factor VIII(4)
        • factor VIII-specific CD4 T cells may play an important role; both Th1 (stimulating production of IgG1 antibodies) and Th2 (stimulating production of IgG4) cells are implicated in production of antibodies against factor VIII
          • predominance of Th2 driven IgG4 antibody production correlates with higher inhibitor activity and failure to eradicate inhibitor
          • predominance of Th1 driven IgG1 antibody production correlates with more successful eradication of inhibitor with immunosuppressive therapy
        • in addition, lack of recognition of immunodominant CD4 epitopes on factor VIII A3 and C2 domains also likely to contribute to inhibitor development
      • breakdown of immune tolerance mechanisms may be a result of combination of environmental and genetic factors (for example, human leukocyte antigen class II alleles and single polymorphism of cytotoxic T lymphocyte antigen 4 gene)(4)
      • acquired inhibitors follow second order kinetics for factor VIII inhibition(2,4)
    • inhibitors of factor V
      • historically, development of factor V inhibitors has been attributed to exposure to bovine thrombin (frequently used as topical hemostatic agents in vascular, orthopedic, and neurosurgical procedures) that contains trace amounts of bovine factor V(5)
      • bovine factor V thought to elicit an immune response that results in development of antibodies that cross-react with endogenous human factor V(5)
      • topical human thrombin is considered safe with regards to factor V development, though development of factor V autoantibody has been reported(5)
      • use in surgical settings now mostly restricted to both recombinant bovine and recombinant human thrombin, greatly reducing the risk of developing factor V inhibitors (5)
    • inhibitors of fibrinogen
      • inhibitors of fibrinogen associated with clinically significant bleeding are extremely rare, but there are reports of non-clinically significant bleeding associated with these antibodies(5)
      • low levels of inhibitors can be detected in normal individuals and high inhibitor levels have been reported in patients with various disorders and in pregnant or peripartum persons, especially in those who are Rh-immunized and with complicated pregnancy (compared to nonpregnant persons) (5)
      • it has been hypothesized that in pregnant persons, rapid fibrinogen turnover and expression of neoantigens on fibrin fragments predispose to development of autoantibodies against fibrinogen(5)
      •  autoantibodies complex with fibrinogen or fibrin, inhibiting fibrin polymerization; polyclonal antibodies may inhibit fibrinopeptide release or affect factor XIIIa stabilization(1)
    • inhibitors of prothrombin (factor II)
      • antibodies usually develop in patients exposed to topical preparations of bovine thrombin or fibrin glue during major surgery and react mainly with bovine coagulation factors(1,5)
      • in some cases, antibovine thrombin antibodies cross-react with endogenous human thrombin and may also cross-react with factor V(5)
    • inhibitors of factor VII – IgG autoantibody that has been isolated have shown binding at light chain of factor VII protein, which may disrupt the interaction with phospholipid membranes or to tissue factor(5)
    • inhibitors of factor XIII
      • autoantibodies to factor XIII (tetrameric protein complex consisting of 2 copies of subunit A and B each) may target the factor XIII zymogen, interfering with activation of factor XIII by thrombin or with transamidase activity, or altering its binding sites on fibrinogen(1,5)
      • most of the autoantibodies identified to date recognize the subunit A of factor XIII(5)

History and Physical

Clinical Presentation

Clinical Presentation of Acquired Hemophilia A (AHA)

  • in half of cases, inhibitor onset occurs in presence of disorders or clinical conditions associated with development of autoantibodies including solid or hematologic neoplasms, autoimmune diseases, pregnancy, drugs, and dermatologic diseases(2)
  • presence of acquired inhibitors should be suspected in patients presenting with recent onset of abnormal bleeding, especially in the absence of family or personal history of bleeding(1)
  • severity of bleeding can vary, ranging from asymptomatic to severe, limb-threatening, or life-threatening bleeding(1,2,3,4)
  • bleeding manifestations are generally more severe than those with congenital hemophilia with or without inhibitors(2)
  • severe and life-threatening bleeding is common in patients with AHA, with need for hemostatic and transfusion treatment reported in 70%-90% and fatal in 5%-10%(1, 2,4)
  • factor VIII levels are not predictive of severity of bleeding due to second-order kinetics of anti-factor VIII antibodies; significant bleeding may occur despite modest reduction in factor VIII activity(3)
  • hemarthroses (joint bleeding) is rare compared to congenital hemophilia (1,2,3)
  • bleeding may occur
    • spontaneously (reported in > 70%)(1,2,3)
    • after minor trauma(2)
    • after invasive procedures such as placement of venous catheters, endoscopic investigations, intramuscular injections, and arterial blood sampling(2)
    • with surgical interventions(2)
    • peripartum; presents at median 3 months postpartum but may occur up to a year following delivery(1,4)
    • in association with anticoagulation and antiplatelet agent use(1)
      •  bleeding is often assumed to be caused by these agents and diagnosis can be delayed
      • excessive bruising or unexpected bleeding in patients on anticoagulants or antiplatelet agents should be further investigated for acquired inhibitors to factor VIII
  • patients may experience ≥ 1 type of bleeding at presentation and/or at relapse(4); sites of bleeding include
    • subcutaneous bleeding/bruising (most common; reported in > 80%), including vast ecchymoses and subcutaneous hematomas(1,2,4)
    • mucosa, including epistaxis, bleeding gums, metrorrhagia, hematemesis, melena, or gastrointestinal bleeding; gastrointestinal bleeding reported in > 20%(2,3,4)
    • muscle (reported in 40%)(1,2,4)
    • retroperitoneal, genitourinary, and other sites (reported in < 10%)(1,2,3,4)
    • intracranial bleeding (rare)(1,3)
  • fatal bleeding is usually associated with gastrointestinal bleeding, but may also occur with intracranial, retroperitoneal, or postoperative bleeding (among other types of bleeding)(1,2,4)
  • compartment syndromes and critical compression of nerves and blood vessels may be seen, leading to bleeding in critical sites (larynx, nerves, and vessels)(1,2)

Clinical Presentation of Other Acquired Inhibitors

  • presence of acquired inhibitors should be suspected in patients presenting with recent onset of abnormal bleeding, especially in the absence of family or personal history of bleeding(1)
  • available information on clinical presentation is mainly anecdotal; each patient should be assessed individually(1)
  • many patients may remain asymptomatic despite significant abnormalities on laboratory testing(1)
  • acquired inhibitors of factor V
    • usually occur in older people and have been reported in association with beta-lactam or aminoglycoside antibiotics, surgical intervention, blood transfusions, malignancies, and autoimmune diseases(1,2)
    • approximately two-thirds of the cases have developed following topical bovine thrombin or fibrin glue application; hemorrhagic complications usually occur after repeated exposures to bovine thrombin products(1,2)
    • bleeding manifestations are similar to those of inherited thrombophilias(1)
    • other bleeding manifestations include
    • severity of bleeding can vary considerably, ranging from mild epistaxis or gingival bleeding to life-threatening retroperitoneal bleeding(1,5)
    • severity of bleeding may or may not correlate with factor V levels(1,5)
    • some patients are asymptomatic with no bleeding, even in the setting of surgery, despite abnormal laboratory findings(1)
    • most patients with bovine thrombin-induced autoantibodies reported no bleeding complications and presence of autoantibodies are frequently transient(5)
    • a case of hypercoagulable state has been reported due to inhibitor blocking factor Va cleavage sites, causing severe activated protein C resistance(1)
  • acquired inhibitors of fibrinogen
    • antibodies to fibrinogen associated with clinical bleeding but there are reports of nonclinically relevant antibodies(5)
    • bleeding may be recurrent, severe, and spontaneous, and associated with high mortality(1)
    • bleeding manifestations may present as gastrointestinal, genitourinary, pulmonary, intraperitoneal, intracranial bleeding, often in combination with soft tissue hematomas and ecchymoses(1)
  • acquired inhibitors of prothrombin/thrombin (factor II/factor IIa) – some patients are asymptomatic with no bleeding despite abnormal laboratory findings(1)
  • acquired inhibitors of factor VII(1)
    • associated with use of antithymocyte globulin in aplastic anaemia, use of penicillins, cephalosporins and interleukin-2, septicemia, pancreatitis, and malignancy, such as multiple myeloma
    • patients may present with severe bleeding including intracranial hemorrhage
    • hemarthroses are uncommon in both congenital and autoimmune factor VII deficiency
  • acquired inhibitors of factor IX – associated with diseases similar to those underlying acquired FVIII inhibitors; bleeding manifestations are similar to those of acquired hemophilia A(1)
  • acquired inhibitors of factor X(1)
    • although acquired factor X deficiency is usually associated with amyloidosis, there are occasional reports of acquired factor X deficiency caused by an inhibitor to factor X
    • most commonly presents with gastrointestinal bleeding and hematuria
    • other bleeding manifestations include ecchymoses, mucosal bleeds, and hemarthrosis
    • severity of bleeding may or may not correlate with factor X levels, but all cases with factor X activity < 1 unit/dL reported to have active bleeding
  • acquired inhibitors of factor XI
    • autoimmune antibodies to factor XI typically associated with underlying collagen vascular disease, such as systemic lupus erythematosus, but have less frequently been reported in association with hematologic malignancy, autoimmune disorders, gastrointestinal diseases, or use of phenothiazines(1)
    • bleeding manifestations are unpredictable and often absent(1)
    • fetal loss and thrombosis have also been reported (Hematology Am Soc Hematol Educ Program 2019 Dec 6;2019(1):80full-text)
  • acquired inhibitors of factor XIII
    • bleeding pattern more severe than congenital factor XIII deficiency and may include hemarthroses, hematoma, menorrhagia, surgical bleeding, poor wound healing, and recurrent miscarriages(1)
    • patients may present with increased bruising and soft tissue bleeding(5)
    • intracranial hemorrhage may be common(1,5)

History

Medication History

  • ask about history of anticoagulants, antiplatelet agents, and other medications that may increase risk of bleeding(2)
  • ask about intake of medications associated with development of inhibitors such as antibiotics, phenytoin, amiodarone, non-steroidal anti-inflammatory drugs, and others; see Risk Factors for additional information

Past Medical History

  • ask about conditions known to increase development of inhibitors to coagulation factors such as malignancies and autoimmune disorders; see Risk Factors for additional information(2)
  • negative personal history for bleeding symptoms important for diagnosis(2)

Family History (FH)

  • ask about family history of bleeding disorders to help rule out congenital bleeding disorders(2)
  • negative family history for bleeding symptoms important for diagnosis(2)

Diagnosis

Making the Diagnosis

  • suspect presence of acquired inhibitors of coagulation in patients with recent onset of abnormal or unexpected bleeding, often severe, either spontaneous or after minor trauma especially in the absence of family or personal history of bleeding, and abnormal coagulation test result that does not correct with mixing study
  • consider diagnosis of acquired hemophilia A if presenting with
    • recent-onset and unexpected bleeding without personal and family history of bleeding
    • isolated prolonged activated partial thromboplastin time not corrected by addition of normal plasma in a 1:1 mixing study and incubation for ≥ 2 hours at 37 degrees C (98.6 degrees F)
  • consider presence of acquired inhibitors against functional epitopes of other clotting factors if presenting with
    • recent-onset and unexpected bleeding without personal and family history of bleeding
    • prolonged prothrombin time and/or activate partial thromboplastin time and/or thrombin time that are not correct by the addition of normal plasma, in a 1:1 mixing test and incubation for ≥ 2 hours at 37 degrees C (98.6 degrees F)
  • exclude other causes of bleeding such as congenital bleeding disorders, congenital and acquired coagulation factor deficiencies, and bleeding due to anticoagulants and antiplatelet therapies
  •  diagnosis of acquired coagulation factor inhibitors and differentiating them from other coagulation abnormalities require a series of coagulation screening tests

Table

Table 2: Expected Coagulation Screening Test Abnormalities in Patients With Acquired Coagulation Inhibitors

Coagulation InhibitorPTaPTTTTAdditional Tests
Factor VIIINormalProlongedNormalNormal VWF:RCo and VWF:Ag
Factor VProlongedProlongedNormalProlonged dilute Russell viper venom time not corrected by excess phospholipid
FibrinogenProlongedProlongedProlongedProlonged reptilase time and reduced Clauss fibrinogen
Factor II (prothrombin/thrombin)Prolonged for prothrombinProlonged for prothrombinNormal for prothrombin; Prolonged for thrombinNormal reptilase time for thrombin
Factor VIIProlongedNormalNormalNot applicable
Factor IXNormalProlongedNormalNot applicable
Factor XProlongedProlongedNormalProlonged dilute Russell viper venom time not corrected by excess phospholipid; Normal fibrinogen
Factor XINormalProlongedNormalNot applicable
Factor XIIINormalNormalNormalNormal fibrinogen; clot solubility test and thromboelastogram may be abnormal

Citation: Abbreviations: aPTT, activated partial thromboplastin time; PT, prothrombin; TT, thrombin time; VWF:RCo, von Willebrand factor-ristocetin co-factor; VWF:Ag, von Willebrand factor-antigen.References – Br J Haematol 2013 Sep;162(6):758, Blood Transfus 2015 Jul;13(3):498full-text, Am J Hematol 2017 Jul;92(7):695full-text, Semin Thromb Hemost 2012 Jul;38(5):433, Semin Thromb Hemost 2012 Jul;38(5):447.

Differential Diagnosis

  • lupus anticoagulant – associated with inhibitors of coagulation, but not clinical bleeding(1)
  • acquired inhibitors of each of the coagulation factors is a differential diagnosis to one another(1,2,5)
  • acquired von Willebrand syndrome caused by acquired inhibitors against von Willebrand factor(1,2)
  • congenital bleeding disorders including(1,2,4,5)
    • hemophilia A – congenital deficiency or absence of factor VIII
    • hemophilia B – congenital deficiency or absence of factor IX
    • von Willebrand disease
  • other acquired or congenital coagulation factor deficiencies(1,2,5)
  • other conditions of impaired primary hemostasis
    • bleeding pattern in acquired hemophilia A more similar to defects in primary hemostasis than coagulation defects(4)
    • conditions associated with thrombocytopenia
    • conditions associated with platelet dysfunction(4)
    • disseminated intravascular coagulation(1)
  • other causes of bleeding including

Testing Overview

  • presence of acquired inhibitors should be suspected in patients presenting with recent onset of abnormal bleeding, especially in the absence of family or personal history of bleeding(1)
  • if acquired inhibitor of coagulation is suspected, refer to specialist laboratory for testing (UKHCDO Grade 2C)(1)
  • in patients with abnormal bleeding, exclude anticoagulant therapy as potential cause; thrombin time and anti-Xa assays may be useful(1,2)
  • perform screening tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT), Clauss fibrinogen, and complete blood count(1,2,3)
    • if only aPTT is prolonged, measure thrombin time to exclude heparin-induced prolongation and perform immediate mixing study
    • if only PT is prolonged, perform mixing studies and exclude warfarin intake
    • if both PT and aPTT are prolonged, exclude oral direct anticoagulant and warfarin intake, and perform D-dimer test to exclude disseminated intravascular coagulation as well as immediate mixing
      • if PT and aPTT correct, perform factor activity assays including factor II, V, and X first; if assay results are low/non-parallel, perform incubated mixing study plus relevant inhibitor assay
      • if PT and aPTT does not correct
        • consider factor II, V, and X assays first and look for low/non-parallel results
        • perform relevant inhibitor assays
        • consider lupus anticoagulant (may coexist with factor inhibition)
    • if screening tests are normal with positive bleeding history, consider thrombin test, platelet function studies, and consider possible mild factor deficiency

Principles of Inhibitor Testing

General Considerations

  • consider investigating patients with recent bleeding, if indicated, for acquired inhibitors of coagulation and refer to specialist laboratory (UKHCDO Grade 2C)(1)
  • blood test typically shows abnormal coagulation screening tests that do not correct with normal plasma either with immediate or incubated mix(1)
  • pattern of abnormality on screening test depends on specificity of inhibitor(1)
  • diagnosis confirmed by assays of specific factor activity and inhibitors; Bethesda assay for factor VIII, or for other factors, modification of Bethesda assay(1)
  • Nijmegen modification of Bethesda assay (titration of inhibitor) should be included in all cases to improve assay sensitivity(1)
  • inhibition of one factor may interfere with assay of other coagulation factors; serial dilution results in correction of non-specifically reduced factors(1,2)
  • acquired inhibitors may coexist with lupus anticoagulant, which may be causing artefactually prolonged clotting times(1)
  • recommendations from professional organizations
    • United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) recommendations for diagnosis of acquired inhibitors of coagulation(1)
      • consider acquired hemophilia A (AHA) if acute or recent onset of bleeding is accompanied by unexplained prolonged activated partial thromboplastin time (aPTT) (UKHCDO Grade 1C)
      • consider acquired inhibitors for other clotting factors if acute or recent onset of bleeding is accompanied by unexplained prolonged screening tests (prothrombin time [PT], aPTT, or thrombin time [TT]) that fail to correct with normal plasma (UKHCDO Grade 2C)
      • consider using algorithms in coagulation laboratories that ensure timely and appropriate investigation of abnormal coagulation screening tests, especially of isolated prolonged aPTT (UKHCDO Grade 2C)
      • laboratories should urgently inform clinicians of potential significance of abnormal results (UKHCDO Grade 2C)
    • Italian Association of Hemophilia Centers (AICE) recommendations for diagnosis of AHA and acquired inhibitors of other clotting factors(2)
      • consider AHA in case of recent-onset, unexpected bleeding in patient without personal and family history of bleeding, who exhibits isolated prolonged aPTT not corrected by addition of normal plasma in 1:1 mixing test following incubation for ≥ 2 hours at 37 degrees C (98.6 degrees F) (AICE Grade 1B)
      • consider acquired inhibitors against functional epitopes of other clotting factors in case of recent-onset unexpected bleeding in patient without personal and family history of bleeding, who showed prolonged PT and/or aPTT and/or TT not correct by addition of normal plasma in 1:1 mixing test following incubation for ≥ 2 hours at 37 degrees C (98.6 degrees F) (AICE Grade 1B); if screening tests are normal, presence of factor XIII inhibitors should be ruled out by specific testing
      • laboratory diagnosis of acquired inhibitors should be made by specialized coagulation laboratories, that work in close collaboration with centers with expertise in diagnosis and treatment of congenital hemophilia and other inherited bleeding disorders (AICE Grade 1B)
      • ensure that laboratories are able to quickly perform mixing test with normal plasma and assays of clotting factor levels even in emergency context (AICE Grade 1B)
    • International acquired hemophilia A (AHA) recommendations on diagnosis of patients with AHA

Initial Blood Tests

  • routine blood tests include
    • complete blood count(1,5)
    • coagulation tests
      • includes prothrombin time (PT), and activated partial thromboplastin time (aPTT)(1,5)
        • these tests may be performed to screen symptomatic patients
        • prolongations of these tests may indicate presence of an inhibitor
      • PT
        • sensitive to deficiencies of factors of the extrinsic and common pathways including fibrinogen and factors II, V, VII, and X
        • prolonged by presence of vitamin K antagonists and direct oral anticoagulants, especially dabigatran and rivaroxaban, and to a lesser extent apixaban
        • prolongation does not necessarily reflect bleeding risk
        • Reference – Am J Hematol 2020 Jan;95(1):117full-text
        • CLINICIANS’ PRACTICE POINT: Lupus anticoagulant can prolong PT, although less common seen than aPTT.
      • aPTT
        • sensitive to deficiencies of factors of the intrinsic and common pathways of coagulation, including factor II, V, VIII, IX, X, XI, and XII, and fibrinogen
        • also sensitive to presence of lupus anticoagulant
        • prolongation of aPTT can also occur as a result of treatment with unfractionated heparin, vitamin K antagonists, and direct oral anticoagulants, especially dabigatran, and to a lesser extent rivaroxaban and apixaban
        • prolongation does not necessarily reflect bleeding risk
        • Reference – Am J Hematol 2020 Jan;95(1):117full-text
  • additional tests to perform may include
    • thrombin time (TT)
    • reptilase time
      • similar to TT, except that the coagulation cascade is initiated by addition of snake venom (Bothrops atox)
      • unlike TT, reptilase time is not affected by presence of heparin
      • Reference – Lab Med 2017 Nov 8;48(4):295
    • D-dimer assay to exclude disseminated intravascular coagulation(1,5)
    • Clauss fibrinogen test (functional test) – may be reduced if inhibitors against fibrinogen or fibrin polymerization are present ((1,5), Favaloro EJ, Lippi G, eds. Hemostasis and Thrombosis: Methods and Protocols. New York, NY: Humana Press, Springer Nature; 2017)

Follow-Up Coagulation Tests

Mixing Studies
  • use of mixing studies
  • performing mixing test
    • coagulation tests that showed prolongation during initial screening is performed using mix of patient plasma and normal plasma at ratio of 1:1
    • usually performed as immediate mix where patient plasma is mixed with normal plasma and immediately re-tested
    • in some cases, results may only become apparent after incubation
      • for example, in the case of inhibitors to factor VIII, inhibitor activity is time and temperature sensitive and initially overwhelmed by donor factor VIII; inhibitory effects are observed only after some time and at temperatures above ambient room temperature
      • no correction of activated partial thromboplastin time (aPTT) after ≥ 2 hours of incubation suggests presence of factor VIII inhibitor
    • can be applied to most routine coagulation tests including prothrombin time, aPTT, thrombin time, and Russell viper venom time
    • in general, mixing tests that correct abnormal prolongation of coagulation tests suggest factor deficiencies, where as clotting times that fail to normalize suggest presence of inhibitors (inhibitors will inhibit factors in normal plasma)
    • Reference – Am J Hematol 2020 Jan;95(1):117full-text
  • limitations of the assay
    • assay works best when single factor deficiencies are present; chance of false non-correction increases when multiple factor deficiencies are present, for example, in the setting of liver dysfunction, disseminated intravascular coagulation, or vitamin K deficiency
    • mixing test may mask presence of mild inhibitor due to dilutional effects
    • not useful if patient is known to be on anticoagulant therapy
      • mixing studies will result in correction of coagulation test abnormality in patients who are on vitamin K antagonist therapy
      • non-correction will result in patients on direct oral anticoagulants and other anticoagulants such as heparin (unless mixing brings heparin levels to within neutralizing ability of a particular agent)
    • Reference – Am J Hematol 2020 Jan;95(1):117full-text
Inhibitor Assay
  • Bethesda assay
    • standardized quantitation of inhibitors in factor VIII neutralization assay
    • original Bethesda method
      • patient plasma mixed with equal volume of normal plasma pool and incubated for 2 hours at 37 degrees C (98.6 degrees F)
      • at same time, control mixture consisting of equal volume of normal plasma pool with imidazole buffer is prepared
      • after 2 hours, factor VIII coagulant activity (FVIII:C) of each mixture is compared and percentage of residual factor VIII activity is calculated
      • Bethesda unit/mL is determined by interpolating percent residual activity against Bethesda units using a theoretical inhibitor graph
        • requires residual factor VIII activity to be between 25% and 75%
        • otherwise appropriate patient plasma will need to be diluted to determine the Bethesda units (after correcting for dilution factor)
        • if inhibitor has type II kinetics (for example, inhibitors to factor VIII), take lowest dilution of patient plasma to inactivate close to 50% of factor VIII activity in incubation mixture and calculate Bethesda unit
      • 1 Bethesda unit defined as amount of inhibitor that results in 50% of residual factor VIII coagulant activity
    • Nijmegen modification (Nijmegen-Bethesda method)
      • used to improve stability of factor VIII in incubation mixtures and prevent artificial deterioration of factor VIII concentration
      • normal plasma pool and control mixtures buffered to pH 7.4 using 0.1 mol/L imidazole
      • source of immuno-depleted factor VIII-deficient plasma used in place of imidazole buffer to dilute normal plasma pool to maintain similar protein concentration in control and test incubations
    • procedure can be modified to detect inhibitors to other coagulation factors; procedure is essentially the same as above except that immuno-depleted plasma used in Nijemgen-Bethesda method will lack factor of interest and the activity assay will be for that specific factor
    • there is lack of consensus for lower limit cutoff for the Nijmegen-Bethesda assay; widely used cutoff for negative result is 0.5-0.6 Bethesda units/mL, corresponding to about 70% residual factor activity for full strength plasma
    • References – (2,3),Methods Mol Biol 2013;992:321
  • enzyme-linked immunosorbent assay (ELISA) for detection of inhibitors to human factor VIII
    • useful if lupus anticoagulant suspected to interfere with positive Bethesda assay or if recombinant porcine factor VIII has already been administered (Haematologica 2020 Jul;105(7):1791full-text)
    • ELISA has high specificity to detect factor VIII antibodies in patients with congenital or acquired hemophilia A (level 1 [likely reliable] evidence)
      •  based on diagnostic cohort study
      • 239 patients (497 samples) with congenital hemophilia A or acquired hemophilia A (AHA) were evaluated with ELISA for factor VIII antibodies
        • 140 patients (291 samples) had severe inherited hemophilia A (baseline FVIII:C < 1 unit/dL)
        • 85 patients (129 samples) had non-severe inherited hemophilia A (baseline FVIII:C 1-40 units/dL)
        • 14 patients (77 samples) had AHA (acute or recent onset of bleeding with unexplained prolonged aPTT not correcting upon mixing studies and low FVIII:C)
      • all patients were included in analysis
      • reference standard was Nijmegen-Bethesda assay
      • Nijmegen-Bethesda was positive in 28 patients (63 samples); prevalence of 11.8% of patients (12.7% of samples)
      • diagnostic performance of ELISA for detection of factor VIII antibodies
        • sensitivity 77.8%
        • specificity 94%
        • positive predictive value 65.3%
        • negative predictive value 96.7%
      • Reference – Thromb Haemost 2015 Oct;114(4):804
    • ELISA with threshold of 15 arbitrary units/mL may have high specificity and sensitivity to detect or rule out presence of factor VIII antibodies (level 2 [mid-level] evidence)
      •  based on diagnostic case-control study
      • 102 adults (mean age 71 years) with AHA enrolled in Acquired Hemophilia Working Group of the German, Austrian and Swiss Thrombosis and Hemostasis Society (GTH)-AH 01/2010 study were matched to 102 controls
      • reference standard was Nijmegen-Bethesda assay in which all adults with AHA had inhibitor ≥ 0.6 Bethesda unit
      • diagnostic performance of ELISA with threshold at 15 arbitrary unit/mL (IgG above 99th percentile of normal controls) for detection of factor VIII antibodies
        • sensitivity 99%
        • specificity 99%
      • Reference – J Thromb Haemost 2016 May;14(5):940full-text
Coagulation Factor-Specific Activity Assays
  • factor VIII assay
    • one-stage assay
      • based on activated partial thromboplastin time (aPTT) and ability of patient sample to correct prolonged aPTT of factor VIII-deficient plasma relative to known calibrator
      • also used to measure levels during replacement therapy
      • 100 units/dL or 100% of normal is the mean activity present in general population
      • assay generally performed at 2-3 dilutions to ensure parallelism with standard curve; non-parallelism may be observed if inhibitors are present (for example, acquired inhibitors and lupus anticoagulant) which can cause lowering of results than expected from the standard curve at lower dilutions
    • chromogenic factor VIII coagulant activity assay
      • less commonly used; an alternative to one-stage assay, used in some specialized hemophilia reference centers and considered to better reflect severity of disease in patients with inherited hemophilia A
      • based on same principle as manual two-stage coagulation factor VIII coagulant activity assay
        • factors II, VII, IX, and X are removed from patient plasma before dilution and mixed with other factors (that is, phospholipid, factors IXa, X, and V, calcium, and small amount of thrombin)
        • activated factor Xa generated in first stage, which is then measured in second stage by addition of chromogenic substrate that is cleaved by factor Xa, resulting in change in color
        • chromogen released reflects amount of factor Xa generated, which is proportional to amount of factor VIII activity in sample
      • as with one-stage assay, non-parallelism in activity when compared to standard curve suggests presence of inhibitory activity
    • with both assays, activity may be underestimated by presence of
      • heparin in sample (> 0.2 units/mL)
      • direct oral anticoagulants
    • Reference – Favaloro EJ, Lippi G, eds. Hemostasis and Thrombosis: Methods and Protocols. New York, NY: Humana Press, Springer Nature; 2017
  • activity analysis of other coagulation factors
    • factors VII, IX, X, and XI activity
    • factor XIII activity assay
      • 3 methods available; all based on transglutaminase activity of factor XIII that occurs in the fibrin cross-linking process
        • ammonia release assay
          • most common assay that involves measurement of ammonia released by thrombin and calcium-activated factor XIII from glutamine containing peptide substrate
          • ammonia release is spectrophotometrically measured by NAD(P)H-dependent glutamate dehydrogenase reaction
        • other assays include amine incorporation assay and isopeptidase assay
      • References – Int J Lab Hematol 2018 Feb;40(1):3, Favaloro EJ, Lippi G, eds. Hemostasis and Thrombosis: Methods and Protocols. New York, NY: Humana Press, Springer Nature; 2017
Lupus Anticoagulant Testing
  • lupus anticoagulants block phospholipid-dependent clotting assays by interfering with assembly of prothrombinase complex and paradoxically lead to increased risk of thrombosis, not bleeding (Obstet Gynecol 2012 Dec;120(6):1514)
  • acquired inhibitors may coexist with lupus anticoagulant, which may be causing apparent reduction in coagulation factor activity levels(1)
  • principles of lupus anticoagulant testing
    • screening – use 2 tests based on different principles
      • dilute Russell viper venom time (DRVVT) should be the first test considered
      • second test should be a sensitive aPTT (low phospholipids concentration and preferably silica as activator)
      • combination of DRVVT and aPTT reported to have high detection rates for LA
    • to obtain maximal amount of information, if screening test is prolonged, perform mixing test and confirmation test simultaneously
      • mixing test
        • usually performed using tests used during screening
        • pooled normal plasma mixed with patient plasma 1:1
      • confirmatory test
        • must be performed by increasing the concentration of phospholipid in screening tests
        • bilayer or hexagonal (II) phase phospholipid should be used to increase the concentration of phospholipids
    • Reference – J Thromb Haemost 2020 Nov;18(11):2828
  • interpretation of lupus anticoagulant testing (in patients not taking anticoagulants)
    • LA should be considered as positive if 1 of the 2 tests (DRVVT or aPTT) gives a positive result in the 3 steps (J Thromb Haemost 2020 Nov;18(11):2828)
    • primary criteria for LA detection include
      • prolonged phospholipid-dependent clotting assay
      • failure of mixing studies to correct abnormality
      • shortening of coagulation time in presence of high aPL concentrations
      • absence of specific coagulation factor inhibitors
      • Reference – Autoimmun Rev 2017 Feb;16(2):173
    • screening
    • mixing test
      • if prolongation is corrected after mixing test, lupus anticoagulant can be ruled out; consider clotting factor deficiency
      • if prolongation is not corrected, add phospholipids (confirmatory test)
      • Reference – N Engl J Med 2018 May 24;378(21):2010
    • confirmatory test
      • if prolongation shortens significantly after addition of phospholipids, lupus anticoagulant is confirmed
      • significant shortening of prolongation defined as one of the following
        • a ratio of clotting time before addition of phospholipids to clotting time after addition of phospholipids of > 1.3
        • percentage correction ([screen – confirm]/screen × 100) > 99th centile
      • if prolongation is not shortened, LA is not confirmed; consider presence of inhibitor
      • References – N Engl J Med 2018 May 24;378(21):2010, J Thromb Haemost 2020 Nov;18(11):2828
  • limitations of lupus anticoagulant testing
    • LA tests
      • sensitive to VKAs or therapeutic doses of unfractionated heparin (UFH)
      • results of tests performed close to a thromboembolic event should be interpreted with caution as patients may be treated with full doses of unfractionated heparin and/or VKA
      • acute phase reactants such as factor VIII may be increased during an inflammatory illness, which can shorten aPTT results and elevated C-reactive protein can interfere with phospholipid in the reagent
      • Reference – J Thromb Haemost 2020 Nov;18(11):2828
    • mixing tests
      • improve specificity but they introduce a dilution factor and may result in weak LA samples to appear negative; in the absence of any other causes of prolonged clotting time, if screen and confirmatory tests on undiluted plasma shows positive results, such samples should be considered LA positive (Br J Haematol 2012 Apr;157(1):47)
      • coagulation time of mixing test could also be prolonged because of the presence of heparin or inhibitors to coagulation factors; prothrombin time/INR, aPTT, thrombin time, and fibrinogen level should be checked to determine anticoagulation intake or presence of coagulopathy (J Thromb Haemost 2020 Nov;18(11):2828)
    • sensitive to vitamin K antagonists, therapeutic doses of unfractionated heparin, or direct oral anticoagulants (Br J Haematol 2012 Apr;157(1):47, J Thromb Haemost 2020 Nov;18(11):2828)
    • results of tests performed during pregnancy should be interpreted with caution
      • LA positivity may increase or decrease during pregnancy
      • LA testing may be reliable during first trimester, but repeat LA testing should be performed post-delivery; no optimal time established but after ≥ 6 weeks, or ideally, after 3 months post-delivery
      • Reference – J Thromb Haemost 2020 Nov;18(11):2828
Other Coagulation Tests
  • to help differentiate factor VIII inhibitor (factor VIII activity < 50%) from acquired von Willebrand disease, consider von Willebrand factor-ristocetin co-factor (VWF:RCo) and von Willebrand factor-antigen (VWF:Ag) testing(3)
    • if low VWF:RCo, suspect acquired von Willebrand disease
    • if anti-human factor VIII is > 0.6 Bethesda units/mL with normal VWF:RCo and VWF:Ag, suspect acquired hemophilia A

Testing According to Specific Inhibitors

Diagnosis of Factor VIII Inhibition (Acquired Hemophilia A [AHA])

  • general diagnostic principles
    • key diagnostic includes prolonged aPTT not corrected by normal plasma (mixing test) with normal PT(1,2,3)
    • TT is normal(4)
    • inhibitors are time and temperature dependent so mixing studies with normal plasma show inhibition on incubation that is not present immediately after mixing(1,2)
      •  aPTT of mixtures of the patient’s plasma and normal plasma in different proportions (volume/volume ratios 1:4, 1:1, and 4:1) should determined before and after incubation at 37 degrees C (98.6 degrees F) for ≥ 2 hours
      • in patients with AHA, aPTT of mixture is abnormally prolonged after incubation, whereas it can be corrected immediately after mixing
    • enzyme-linked immunosorbent assay (ELISA) and chromogenic factor VIII assays may be used as lupus anticoagulant do not interfere(1)
    • pattern of inactivation is non-linear and may lead to inhibitor potency being underestimated(1)
    • usual to report dilution that most closely inhibits half the factor VIII after 2 hours(1)
    • quantify porcine factor VIII inhibitor titer if considering recombinant porcine factor VIII as treatment option (patients with anti-porcine titer of > 20 Bethesda units were excluded in trial evaluating efficacy of recombinant porcine factor VIII); inhibitor assay is the same as Bethesda assay but uses recombinant porcine factor VIII as substrate instead of normal human plasma (Haematologica 2020 Jul;105(7):1791full-text)
  • testing algorithm for AHA(2,3)
    • if prolonged aPTT, exclude therapeutic anticoagulants including heparin, direct thrombin inhibitor, and warfarin as a cause of prolongation
      • if factor VIII assay is available, check factor VIII activity
        • if factor VIII activity is < 50%, measure anti-human factor VIII inhibitor level, von Willebrand factor-ristocetin co-factor (VWF:RCo), and von Willebrand factor-antigen (VWF:Ag)
          • if low VWF:RCo, suspect acquired von Willebrand disease
          • if anti-human factor VIII level is > 0.6 Bethesda units/mL, normal VWF:RCo and VWF:Ag, suspect AHA and begin treatment
        • if factor VIII activity is ≥ 50%, measure factor IX and factor XI activity and lupus anticoagulant
          • if lupus anticoagulant is detected and factor IX and factor XI activities are normal, suspect lupus anticoagulant
          • if factor IX or factor XI activities are low without lupus anticoagulant (very rare), suspect factor IX or factor XI inhibitor and measure inhibitor levels on Bethesda assay
    • if factor VIII assay is not available, perform aPTT mixing study with ≥ 2 hours incubation at 37 degrees C (98.6 degrees F)
      • if aPTT fails to correct within normal range, suspect inhibitor and perform factor VIII, IX, and XI assays; if reduced factor VIII, perform inhibitor titration with Bethesda assay and Nijmegen modification to diagnose AHA
      • if aPTT corrects to normal range, suspect factor deficiency, and measure factor VIII, IX, XI, and XIII activity

Diagnosis of Factor V Inhibition

Diagnosis of Fibrinogen Inhibition

  • suspect antibodies against fibrin or fibrinogen polymerization with(1,2)
    • prolongation of PT
    • prolongation of aPTT
    • prolongation of TT
    • prolongation of reptilase time
    • reduced Clauss fibrinogen
  • mixing studies with normal plasma demonstrate prolonged and uncorrected TT and presence of inhibitor can be confirmed by modified Bethesda assay(1,2)
  • reduced clot formation may be seen on thromboelastography or thromboelastometry(1)
  • investigate for paraprotein because inhibitors affecting fibrin polymerization have been reported with monoclonal gammopathies(1)

Diagnosis of Factor II (Prothrombin and Thrombin) Inhibition

  • suspect antibodies against prothrombin with(1,2)
    • prolongation of PT and aPTT that does not correct with mixing study of normal plasma
    • normal TT
  • suspect antibodies against thrombin with prolonged TT and normal reptilase time(1)
  • Clauss fibrinogen assay usually normal due to higher concentration of thrombin reagent and higher dilution of test plasma than in TT(1)
  • exclude effects of EDTA and anticoagulants (heparin, thrombin inhibitors, and anti-Xa agents)(5)
  • factor II level will be low and inhibitor titer estimated in modified Bethesda assay(1)
  • ELISA may be performed for antiprothrombin antibodies(1)

Diagnosis of Factor VII Inhibition

Diagnosis of Factor IX Inhibition

Diagnosis of Factor X Inhibition

  • suspect factor X inhibition with(1,2)
  • dRVVT may be prolonged and does not correct with normal plasma and phospholipid, which suggests lupus anticoagulant is unlikely(1)
  • factor X activity will be low and titer of antibody can be estimated from Bethesda assay(1)
  • factor X deficiency as a result of increased absorption due to systemic amyloidosis differs from factor X inhibition by autoantibodies in that, in deficiency due to amyloidosis(1)
    • PT and aPTT correct with normal plasma
    • there will be no evidence of an inhibitor
    • other coagulation factors such as factor VII, IX, and V and von Willebrand factor may be reduced
  • exclude effects of EDTA, and anticoagulants (heparin, thrombin inhibitors, and anti-Xa agents)(5)

Diagnosis of Factor XI Inhibition

Diagnosis of Factor XIII Inhibition

  • suspect factor XIII inhibition with(1)
    • PT, aPTT, TT, and fibrinogen level that may be normal
    • thromboelastogram and clot solubility test may be abnormal
  • factor XIII level < 3% in plasma factor XIII assays based on ammonia release or amine incorporation(1)
  • neutralizing antibodies can be detected with mixing studies, although binding assays needed to detect non-neutralizing antibodies(1)
  • immunological assays may show normal factor XIII levels(1)
  • inhibitory antibodies and nonimmunological inhibitors of factor XIIIa can be detected, in vitro, with mixing tests using patient plasma or purified IgG fraction to inhibit cross-linking of alpha chains of fibrin in normal plasma(1)

Management

Management Overview

  • manage all patients at specialized centers for hemophilia and other bleeding disorders with expertise in treatment and laboratory monitoring of patients with inhibitors against any coagulation factors (UKHCDO Grade 2C; AICE Grade 1B)(1,2)
  • goals for management of patients with acquired inhibitors to coagulation factors include(3)
    • bleeding control (if present/significant)
    • eradication of inhibitor
    • treatment of underlying condition (if applicable)
  • management of bleeding
    • red blood cell transfusions as needed
    • patients with inhibitors to factor VIII (acquired hemophilia A [AHA])
      • severe bleeding requires prompt hemostatic control; however, some bleeds, such as subcutaneous bleeds can be managed conservatively
      • if initial treatment of bleeding is required, offer 1 of the bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate [aPCC]) as initial treatment without delay (UKHCDO Grade 1B; AICE Grade 1B; International AHA Grade 1B); suggested dosing for
        • recombinant factor VIIa: 90 mcg/kg IV boluses every 2-3 hours until hemostasis is achieved (doses > 90 mcg/kg not recommended except as rescue therapy due to increased risk of thrombosis)
        • aPCC (FEIBA): 50-100 units/kg IV boluses every 8-12 hours to maximum of 200 units/kg/day
      • if first bypassing agent fails, consider switching treatment to the other bypassing agent (UKHCDO Grade 2C; AICE Grade 2C); also consider emicizumab (if patient has been given emicizumab, aPCC should be avoided due to increased risk of development of thrombotic microangiopathy)
      • offer recombinant porcine factor VIII as another option for initial treatment of bleeding, if available (International AHA Grade 1B); suggested dose 200 units/kg IV, followed by further doses to maintain trough levels at > 50%
      • if both bypassing agents and recombinant porcine factor VIII have been tried and are unsuccessful, consider factor VIII concentrate with plasmapheresis and immunoadsorption (UKHCDO Grade 2B; AICE Grade 2B; International AHA Grade 1B)
      • consider tranexamic acid with or without other hemostatic agents for bleeding, particularly mucosal bleeding (UKHCDO Grade 2C; AICE Grade 2B); however, tranexamic acid is contraindicated in setting of urinary tract bleeding (AICE Grade1B)
      • consider desmopressin to increase factor VIII levels, although it may be contraindicated in some patients due to comorbidities
      • clinical evaluation should include hemoglobin and hematocrit assessment and imaging (ultrasound or computed tomography) as appropriate to assess bleeding
      • appropriate duration of treatment is not established but hemostasis often achieved within 24 hours to 72 hours and further treatment to prevent recurrence of bleeding may be beneficial
      • do not expose patients to invasive procedures unless essential due to risk of uncontrollable bleeding
    • patients with inhibitors to coagulation factors other than factor VIII
      • consider not offering treatment for patients who are asymptomatic despite significant laboratory abnormalities (UKHCDO Grade 2C)
      • management of bleeding varies by specificity of factor inhibition and level of inhibitor(2)
      • high doses of purified concentrates of deficient factor may neutralize antibody in cases of acquired inhibitors to factors VII, IX, XI, or XIII or fibrinogen, particularly at low titer(2)

Table

Table 3: Management of Bleeding in Patients With Inhibitors to Coagulation Factors Other Than Factor VIII

FactorsFirst-LineSecond-LineOther OptionsNot Likely Efficacious
Factor VPlatelets with or without fresh frozen plasmaFresh frozen plasma and immunoadsorptionaPCCRecombinant factor VIIa
FibrinogenFibrinogen concentrateFibrinogen concentrate and immunoadsorptionCryoprecipitate with or without immunoadsorptionRecombinant factor VIIa, aPCC, or fresh frozen plasma
Factor II (prothrombin/thrombin)aPCC or PCCaPCCaPCC or PCC and immunoadsorptionRecombinant factor VIIa or fresh frozen plasma
Factor VIIaPCCRecombinant factor VIIa or factor VII concentrateRecombinant factor VIIa, factor VII concentrate and immunoadsorption or PCC with or without immunoadsorptionFresh frozen plasma
Factor IXRecombinant factor VIIa or aPCCAlternative bypassing agentFactor IX concentrate with or without immunoadsorptionFresh frozen plasma
Factor XaPCCPCCaPCC or recombinant factor VIIa and immunoadsorptionRecombinant factor VIIa
Factor XIRecombinant factor VIIa or aPCCAlternative bypassing agentFactor XI concentrate with or without immunoadsorptionNot Mentioned
Factor XIIIFactor XIII concentrateFactor XIII concentrate and immunoadsorptionCryoprecipitate with or without immunoadsorptionRecombinant factor VIIa, aPCC, or fresh frozen plasma

Citation: Abbreviations: aPCC, activated prothrombin complex concentrate; PCC, prothrombin complex concentrate.Reference -Br J Haematol 2013 Sep;162(6):758

    • monitor factor levels closely to adjust dose and administration intervals and to ensure that adequate hemostasis is achieved(2)
    • if unresponsive to first-line treatment, consider early switch to second-line treatment (AICE Grade 2C)
  • eradication of acquired inhibitors
    • treatment of condition that triggered development of inhibitor such as cancer or and cessation of causative drugs should be a priority because this can result in resolution or reduction of inhibitor (AICE Grade 2C)(2); see list of risk factors associated with development of inhibitors to coagulation factors
    • in some cases, inhibitor may disappear spontaneously (common if inhibitor is pregnancy- or drug-related or in children, but it is not always predictable); watch and wait policy is an option in such cases(2)
    • combined immunosuppressive therapy (IST) is usually initiated in patients with AHA, whether idiopathic or secondary to cancer or autoimmune disease, due to risk of life-threatening bleeding if inhibitor persists(2)
    • patients with inhibitors to factor VIII (AHA)
      • IST is generally recommended for all adults with AHA; this is irrespective of presence of bleeding, inhibitor titer, or identification of underlying disease
      • start IST as soon as diagnosis confirmed (UKHCDO Grade 1B; AICE Grade 1B)
      • common IST strategy consists of initial immunosuppression with prednisolone 1 mg/kg/day either alone or in combination with cyclophosphamide 1-2 mg/kg/day orally (UKHCDO Grade 1B; AICE Grade 1B)
      • rituximab 375 mg/m2 IV/week for 4 weeks (or 100 mg/week for 4 weeks) plus corticosteroid regimen (prednisone 1 mg/kg/day orally or dexamethasone 40 mg/day orally for 4-7 days) can also be considered as first-line therapy
      • consider rituximab 375 mg/m2 IV alone once per week for 4 weeks as first-line therapy if standard immunosuppression is contraindicated (UKHCDO Grade 2B; AICE Grade 2B)
      • if no response in 3-5 weeks, consider second-line therapies such as
      • in female patients of reproductive age, avoid cyclophosphamide and other alkylating agents, if possible (UKHCDO Grade 2B; AICE Grade 2C)
      • do not offer IV immunoglobulins (UKHCDO Grade 1B; AICE Grade 1B; International AHA Grade 2C)
      • consider extending observation in patients who do not achieve remission with first-line IST but have continued improvement of factor VIII activity and inhibitor titer
      • risk of thromboembolism
        • monitoring factor VIII levels during eradication therapy is important as part of evaluation for risk of thromboembolism
        • risk of thromboembolism may be increased in some patients due to older age, pre-existing comorbidities, and immobilization, in addition to risk from hemostatic treatment with activated coagulation factor concentrates
        • assess risk of venous thrombosis and consider thromboprophylaxis (mechanical and/or pharmacologic) if appropriate (UKHCDO Grade 2B; AICE Grade 2C), especially at a time when the inhibitor has presumably been eradicated and when factor levels can be significantly higher than normal, adding to further risk; monitor for bleeding symptoms and coagulation parameters closely when initiating thromboprophylaxis
    • patients with inhibitors to other coagulation factors
      • IST not always required for asymptomatic patients despite significant inhibitor levels; in most cases, resolution of coexisting condition may lead to spontaneous remission of inhibitor (UKHCDO Grade 2C; AICE Grade 2C)
      • for patients with bleeding, consider IST similar to that of AHA (UKHCDO Grade 2C; AICE Grade 2C)
      • if IST is not indicated or antibody persists, consider IV immunoglobulin especially if inhibitor is an IgG (AICE Grade 2C)
  • follow-up after inhibitor eradication (patients with AHA)
  • special considerations
    • in pregnant patients
      • hemostatic treatment is similar to that given to nonpregnant patients, except that caution should be used with bypassing agents in postpartum period due to risk of venous thromboembolism
      • inhibitor eradication is also similar except that cytotoxic and alkylating drugs should be avoided if possible (UKHCDO Grade 2B; AICE Grade 2C)
    • in patients needing invasive procedures
      • perform invasive procedures only if unavoidable and keep venipuncture to minimum (UKHCDO Grade 1C; AICE Grade 1B)
      • consider coagulation screen, preferably for specific factor for which inhibitors had developed, prior to procedures (UKHCDO Grade 2C; AICE Grade 2C
      • prophylactic use of bypassing agents or recombinant porcine factor VIII for minor or major invasive procedures in patients with AHA (International AHA Grade 1B)
      • consider plasmapheresis and/or immunoadsorption prior to procedure (AICE Grade 2C)

Management Strategies According to Specific Coagulation Factor Inhibitor

Management of Patients With Inhibitors to Factor VIII (Acquired Hemophilia A)

Management of Bleeding
  • in patients with acquired hemophilia A (AHA), bleeding may be severe and will require prompt hemostatic control; however, some bleeds such as subcutaneous bleeds, can be management conservatively with wait and watch approach (1)
  • transfuse red blood cells as needed (Hematol Oncol Clin North Am 2017 Dec;31(6):1045)
  • there is lack of correlation between factor VIII activity or inhibitor titer and bleeding phenotype; decision to treat clinically relevant bleeding should not be based on inhibitor titer or factor VIII activity alone (Haematologica 2020 Jul;105(7):1791full-text)
  • no standardized laboratory tests are available for monitoring hemostatic response(1,3)
  • hemostatic efficacy mainly relies on clinical assessment; alternative hemostatic agent should be considered after 12-24 hours (3)
  • clinical evaluation should include hemoglobin and hematocrit assessment, activated partial thromboplastin time, and imaging (ultrasound, computed tomography) as appropriate to assess bleeding(3,4)
  • appropriate duration of treatment is not established but hemostasis often achieved within 24 hours to 72 hours and further treatment to prevent recurrence of bleeding may be beneficial(4)
  • recommendations from professional organizations
    • United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) recommendations(1)
      • if indicated, treat bleeding without delay using 1 of the bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate [aPCC]) (UKHCDO Grade 1B); however not all bleeds need hemostatic treatment and many subcutaneous bleeds can be managed conservatively
      • if initial bypassing agent is ineffective, consider treatment with the other bypassing agent at early stage (UKHCDO Grade 2C)
      • recombinant factor VIIa doses > 90 mcg/kg are not suggested, except as rescue therapy, because of increased risk of thrombosis (UKHCDO Grade 2C)
      • consider factor VIII replacement combined with plasmapheresis and immunoadsorption for severe bleeding or if first-line therapy is unsuccessful (UKHCDO Grade 2B)
      • consider tranexamic acid for all bleeds (contraindicated in renal bleeding), especially those involving mucosal surfaces (UKHCDO Grade 2C)
      • once in remission, assess risk of venous thrombosis and provide thromboprophylaxis if indicated (UKHCDO Grade 2C)
    • Italian Association of Hemophilia Centers (AICE) recommendations(2)
      • not all patients require hemostatic agents and may only require wait and watch approach (AICE Grade 2C)
      • in patients with AHA and clinically significant bleeding, offer bypassing agent (aPCC or recombinant factor VIIa) as first-line treatment (AICE Grade 1B)
      • if initial bypassing agent is ineffective, consider switching to treatment with alternative bypassing agent at early stage (AICE Grade 2C)
      • use of factor VIII concentrates and desmopressin should be reserved for patients with measurable factor VIII plasma levels and low inhibitor titers (AICE Grade 2C)
        • initial dose of factor VIII should be sufficient to overcome inhibitor and provide adequate hemostatic level
        • evaluate adequacy of treatment by measuring factor VIII activity after administration of initial dose and by subsequent regular monitoring of factor VIII activity (at least daily)
        • regular monitoring can also help detect development of anamnestic response
      • for mucosal bleeding
        • consider tranexamic acid alone or with other hemostatic agents (AICE Grade 2B); however urinary tract bleeding is a contradiction (AICE Grade1B)
        • tranexamic acid should be used with caution if given concurrently with activated clotting factor concentrates, in particular with aPCC in older adults or in those with comorbidities associated with high risk of thromboembolism (AICE Grade 2B)
      • in patients with AHA who require rapid bleeding control who do not adequately respond to either type of bypassing agent or who require urgent surgery or invasive procedures, consider plasmapheresis and/or immunoadsorption in combination with high dose of factor VIII concentrates (AICE Grade 2B)
    • International AHA recommendations
    • guidance from professional organizations above were published prior to availability of emicizumab (approved for use in congenital hemophilia A); consider emicizumab as an option in patients who fail one of the bypassing agents (recombinant VIIa or PCC)
Inhibitor Eradication
  • goal of inhibitor eradication is to reduce risk of bleeding by shortening time to achieve remission of AHA (Haematologica 2020 Jul;105(7):1791full-text)
  • severity of bleeding at presentation is not a good predictor of future bleeding; patients remain at risk of fatal bleeding until inhibitor is eradicated(1,3,4)
  • some soft tissue bleeding managed without hemostatic therapy can progress into compartment syndrome; close monitoring and prompt eradication of inhibitor is important(3)
  • immunosuppressive therapy (IST) is generally recommended for all adults with AHA; this is irrespective of presence of bleeding, inhibitor titer, or identification of underlying disease(3,4)
  • role of IST in pediatric patients is not well established(3)
  • there is no standard definition for remission; examples of definitions used
    • Italian Association of Hemophilia Centers (AICE) defines complete response to eradication therapy as persistent undetectable inhibitor (< 0.6 Bethesda units/mL) with normal plasma levels of factor VIII (> 70%) (AICE Grade 2B)(2)
    • United Kingdom surveillance study defined complete remission as normal factor VIII and inhibitor undetectable after IST is discontinued or reduced to doses used prior to AHA without relapse (Blood 2007 Mar 1;109(5):1870full-text)
    • Acquired Hemophilia Working Group of the German, Austrian and Swiss Thrombosis and Hemostasis Society (GTH) defined
      • partial remission as factor VIII level restored to > 50% and no bleeding after stopping hemostatic treatment for ≥ 24 hours
      • complete remission as partial remission plus negative inhibitor test, prednisolone tapered to < 15 mg/day, and discontinuation of any other IST
      • Reference – Blood 2015 Feb 12;125(7):1091full-text, editorial can be found in Blood 2015 Feb 12;125(7):1052
  • recommendations from professional organizations
    • UKHCDO recommendations(1)
      • start IST as soon as diagnosis confirmed (UKHCDO Grade 1B)
      • administer IST with prednisolone 1 mg/kg/day either alone or combined with cyclophosphamide 1-2 mg/kg/day orally (UKHCDO Grade 1B)
      • consider rituximab as first-line therapy if standard IST is contraindicated, but rituximab may have limited efficacy if used alone (UKHCDO Grade 2B)
      • if no response in 3-5 weeks, consider second-line therapies (UKHCDO Grade 2B)
      • IV immunoglobulin (IVIG) as treatment for inhibitor eradication is not recommended (UKHCDO Grade 1B)
      • follow up at least monthly for first 6 months due to common relapses (UKHCDO Grade 2B)
      • in female patients of reproductive age, avoid cyclophosphamide and other alkylating agents, if possible (UKHCDO Grade 2B)
    • AICE recommendations(2)
      • start IST as soon as possible, ideally immediately after diagnosis (AICE Grade 1B)
      • offer first-line treatment with prednisone 1-2 mg/kg/day either alone or with oral cyclophosphamide 1-2 mg/kg/day (AICE Grade 1B)
      •  in female patients of reproductive age, use of cyclophosphamide and other alkylating agents should be avoided (AICE Grade 2C)
      • in patients with contraindications to standard immunosuppressive drugs, consider rituximab 375 mg/m2 IV once per week for 4 doses total as first-line therapy (AICE Grade 2B)
      • if lack of response to first-line treatment in 8-12 weeks
      • do not offer IVIG (AICE Grade 1B)
      • once factor VIII levels have normalized, monitor factor VIII levels monthly for first 6 months, and subsequently every 3 months or less frequently afterwards, or as needed
    • International AHA recommendations
      • administer IST in all patients; however use caution in patients who are frail (International AHA Grade 1B)
      • consider prognostic markers (such as factor VIII activity or inhibitor titer, if available) to individualize IST (International AHA Grade 2B)
      • in patients with factor VIII activity ≥ 1 unit/dL and inhibitor titer ≤ 20 Bethesda unit, consider corticosteroids alone for 3-4 weeks
      • in patients with factor VIII activity < 1 unit/dL or inhibitor titer > 20 Bethesda unit, consider corticosteroids with rituximab or cytotoxic agent as first-line treatment
      • in patients who do not achieve remission with first-line IST but have continued improvement of factor VIII activity and inhibitor titer, consider extending observation (International AHA Grade 2B)
      • for second-line therapy, administer rituximab or cytotoxic agent (whichever was not used as first-line) (International AHA Grade 1B)
      • dosing (International AHA Grade 2B)
        • for corticosteroid therapy, consider prednisone or prednisolone at 1 mg/kg/day orally for maximum of 4-6 weeks (followed by tapering)
        • for rituximab, consider 375 mg/m2 per week for maximum of 4 cycles
        • for cytotoxic agent, consider cyclophosphamide 1.5-2 mg/kg/day orally for maximum of 6 weeks or mycophenolate mofetil 1 g/day for 1 week followed by 2 g/day
      • use of high-dose human factor VIII for immune tolerance induction is not suggested (International AHA Grade 2C)
      • do not offer IVIG for inhibitor eradication (International AHA Grade 1B)
      • after complete remission, follow-up with factor VIII activity monitoring monthly during first 6 months, every 2-3 months up to 1 year, and every 6 months afterwards (International AHA Grade 1B)
      • in patients with pregnancy-associated AHA, same approach to inhibitor eradication can be considered as those who are not pregnant, but use of cytotoxic agents should be carefully considered because of the potential of these drugs to reduce fertility and cause embryotoxicity (International AHA Grade 2C)
      • offer thromboprophylaxis based on American Society of Hematology (ASH) guidelines if factor VIII activity returned to normal levels; if indicated, start antiplatelet therapy or oral anticoagulants after normal factor VIII activity is achieved (International AHA Grade 1C); see Venous Thromboembolism (VTE) Prophylaxis for Medical Patients for ASH guidance on venous thromboembolism prophylaxis in hospitalized and nonhospitalized medical patients
      • Reference – Haematologica 2020 Jul;105(7):1791full-text

Management of Patients With Inhibitors to Other Coagulation Factors

Management of Bleeding
  • management of bleeding in patients with acquired inhibitors against coagulation factors other than factor VIII mainly depends on type and level of inhibitor present(2)
  • in some cases, inhibitors can be neutralized by using high doses of purified factor concentrates of deficient factor especially if inhibitor titer is very low; factor concentrate may be an option in patients with inhibitors of fibrinogen or factor VII, IX, XI, or XIII(2)
  • not all patients require hemostatic agents; some can be managed with wait and watch approach (AICE Grade 2C)(2)
  • transfuse red blood cells as needed (Hematol Oncol Clin North Am 2017 Dec;31(6):1045)
  • in patients with acquired inhibitor against a clotting factor other than factor VIII that is unresponsive to first-line treatment, consider early switch to second-line treatment (AICE Grade 2C)(2)
  • in patients with severe bleeding who fail to respond to first-line treatment or require urgent surgery or invasive procedures, consider plasmapheresis and/or immunoadsorption (AICE Grade 2C)(2)
  • no standardized laboratory tests available for monitoring hemostatic response(1,3)
  • hemostatic efficacy mainly relies on clinical assessment; alternative hemostatic agent should be considered after 12-24 hours (3)
  • clinical evaluation should include hemoglobin and hematocrit assessment and imaging (ultrasound, computed tomography) as appropriate to assess bleeding(3,4)
  • appropriate duration of treatment is not established but hemostasis often achieved within 24 hours to 72 hours and further treatment to prevent recurrence of bleeding may be beneficial(4)
  • patients with inhibitors to factor V
    • UKHCDO recommendations (UKHCDO Grade 2C)(1)
    • AICE recommendations(2)
      • consider FFP and transfusion of platelet concentrates as main therapeutic options
      • alternatively, consider aPCC, especially in patients at high risk of cardiovascular complications, given additional risk from circulatory overload if large volumes of plasma is transfused (AICE Grade 2C)
  • patients with inhibitors of fibrinogen
    • UKHCDO recommendations (UKHCDO Grade 2C)(1)
      • first-line treatment includes fibrinogen concentrate
      • second-line treatment includes fibrinogen concentrate and immunoadsorption
      • other options include cryoprecipitate with or without immunoadsorption
      • recombinant factor VIIa, aPCC, and FFP unlikely to be of benefit
    • AICE recommendation – in patients with acquired antifibrinogen inhibitor, consider fibrinogen concentrate as first-line treatment and monitor frequently during treatment to determine levels of fibrinogen achieved (AICE Grade 2C)(2)
  • patients with inhibitors to factor II (prothrombin)
    • UKHCDO recommendations (1)
      • treatment options (UKHCDO Grade 2C)
        • first-line treatment includes aPCC or PCC
        • second-line treatment includes aPCC
        • other options include PCC or aPCC and immunoadsorption
        • recombinant factor VIIa or FFP unlikely to be of benefit
      • if PCC is used, levels of prothrombin and factors VIII, IX, and X levels should be monitored
      • hemostatic therapy can be used in combination with plasmapheresis in resistant cases
    • AICE recommendation – consider treatment with aPCC that can overwhelm the inhibitor and provide sufficient hemostatic activity; alternatively, consider PCC (AICE Grade 2C)
  • patients with inhibitors to factor VII
    • UKHCDO recommendations (UKHCDO Grade 2C)(1)
      • first-line treatment includes aPCC (activates coagulation without need for factor VII)
      • second-line treatment includes recombinant factor VIIa and factor VII concentrate (if available)
      • other options include recombinant factor VIIa, factor VII, and immunoadsorption, or PCC with or without immunoadsorption
      • FFP unlikely to be of benefit
    • AICE recommendations(2)
      • consider aPCC as first-choice (AICE Grade 2C)
      • if ineffective, especially in patients with low inhibitor titers, consider recombinant factor VIIa or plasma-derived factor VII concentrate
      • initial dose should be sufficient to overcome the inhibitor and provide adequate hemostasis
      • factor VII level should be monitored closely and adjust dose and frequency until effective hemostasis has been achieved
  • patients with inhibitors to factor IX
    • UKHCDO recommendations (UKHCDO Grade 2C)(1)
      • first-line treatment includes recombinant factor VIIa or aPCC
      • second-line treatment includes alternative bypassing agent
      • other options include factor IX concentrate with or without immunoadsorption
      • FFP unlikely to be of benefit
    • AICE recommendations(2)
      • consider bypassing agent (aPCC or recombinant factor VIIa) as treatment of choice (AICE Grade 2C)
      • other options include factor IX and factor XI concentrates, particularly in patients with low-titer inhibitor or inadequate response to bypassing agent
      •  factor levels should be monitored carefully in order to adjust dose and frequency of administration so that neutralizing effect of inhibitor can be overcome and effective hemostasis can be achieved (AICE Grade 2C)
  • patients with inhibitors to factor X
    • UKHCDO recommendations(1)
      • treatment options (UKHCDO Grade 2C)
        • first-line treatment includes aPCC
        • second-line treatment includes PCC
        • other options include aPCC or PCC plus immunoadsorption
        • recombinant factor VIIa unlikely to be of benefit
      • close monitoring of factors II, VII, IX, and X levels is needed to ensure adequate levels of factor X while avoiding excessively high levels of factors II, VII, and IX
    • AICE recommendations (AICE Grade 2C)(2)
      • consider treatment with aPCC that can overwhelm the inhibitor and provide sufficient hemostatic activity
      • alternatively, consider PCC
  • patients with inhibitors to factor XI
    • UKHCDO recommendations (UKHCDO Grade 2C)(1)
      • first-line treatment includes recombinant factor VIIa or aPCC
      • second-line treatment includes alternate bypassing agent
      • other options include factor XI concentrate with or without immunoadsorption
    • AICE(2)
      • consider bypassing agent (aPCC or recombinant factor VIIa) as treatment of choice (AICE Grade 2C)
      • other options include factor IX and factor XI concentrates, particularly in patients with low-titer inhibitor or inadequate response to bypassing agent
      •  factor levels should be monitored carefully in order to adjust dose and frequency of administration so that neutralizing effect of inhibitor can be overcome and effective hemostasis can be achieved (AICE Grade 2C)
  • patients with inhibitors to factor XIII
    • UKHCDO recommendations (UKHCDO Grade 2C)(1)
      • first-line treatment includes factor XIII concentrate
      • second-line treatment includes factor XIII concentrate and immunoadsorption
      • other options include cryoprecipitate with or without immunoadsorption
      • recombinant factor VIIa, aPCC, or FFP unlikely to be of benefit
    • AICE recommendation – consider large doses of plasma-derived or recombinant factor XIII concentrates and carefully monitor plasma levels to adjust doses to achieve effective hemostasis (AICE Grade 2C)(2)
Inhibitor Eradication
  • for eradication of inhibitor to coagulation factors other than factor VIII, treatment with immunosuppressive agents only indicated for frequent or severe bleeding using same regimens as for AHA(2)
  • recommendation from professional organizations
    • UKHCDO recommendations(1)
      • asymptomatic patients with acquired factor inhibitors (other than factor VIII) may not require treatment because some inhibitors are transient and others do not cause clinical bleeding, despite significant laboratory abnormalities (UKHCDO Grade 2C)
      • in patients with clinical bleeding, consider immunosuppression to eradicate inhibitor with same regimens used for inhibitors to factor VIII (UKHCDO Grade 2C)
    • Italian Association of Hemophilia Centers (AICE) recommendations(2)
      • IST is not always indicated since many inhibitors are transient and do not cause significant bleeding; ‘wait and watch’ approach may be appropriate in certain settings where resolution of coexisting conditions (for example, malignant or autoimmune disease) may lead to spontaneous remission of inhibitor (AICE Grade 2C)
      • if bleeding symptoms present, treat with immunosuppression as in AHA (AICE Grade 2C)
      • if IST is not indicated or antibody persists, consider high-dose IVIG especially if inhibitor is an IgG (AICE Grade 2C)
        •  duration of treatment can be assessed by infusion of IVIG (1 g/kg/day for 2 days or 400 mg/kg/day for 5 days) measuring factor VIII level at ≥ 1, 7, and 15 days after end of first cycle of treatment
        • treatment usually administered at intervals of about 21 days (dose can be as low as 1 g/kg/day), especially in patients in whom risk of bleeding remains high (for example, patients with gastrointestinal bleeding due to angiodysplasia)

Hemostatic Therapies

Bypassing Agents

Introduction
  • bypassing agents include recombinant factor VIIa and activated prothrombin complex concentrate (aPCC)(1,2,3)
    • either bypassing agents can be used as first-line therapy for treatment of bleeding in patients with acquired hemophilia A (AHA) or patients with acquired inhibitors to factors IX or XI
    • aPCC is first-line treatment for bleeding in patients with acquired inhibitors of factors II, VII, or X
  • treatment strategies and dosing of these agents are mainly based on experience of their use in patients with inherited hemophilia with inhibitors, despite considerable differences in patient population (patients with acquired inhibitors are likely to be older and/or with comorbidities) and type of bleeding events(2)
  • after initial control of bleeding has been achieved, period of treatment at reduced dose and frequency is often required to prevent recurrence and should be evaluated on individual basis(1)
  • if one bypass agent does not elicit desired response, a switch to the other bypass agent should be considered and the change performed early to avoid persistent bleeding that can lead to disabling consequences or life-threatening situations(2)
  • challenges of using bypassing agents
    • no laboratory measures to monitor under- or overdosing(3)
    • thromboembolic risk
      • treatment with either recombinant factor VIIa or aPCC is associated with arterial and venous thrombosis; risk appears to be higher in patients with AHA compared to patients with congenital hemophilia A(1)
      • while risk of thromboembolism exists, treatment should not be withheld given benefit of early control of severe bleeding which outweighs risk of thrombosis(1,4)
      • careful considerations should be given to minor bleeds, for example subcutaneous bleeds, which often resolve spontaneously(1)
      • recombinant factor VIIa and aPCC should not be administered together except in life- or limb-threatening bleeding unresponsive to individual bypassing agent(1)
      • in patients with AHA, remission is associated with high factor VIII levels; patients should be assessed for other risk factor of venous thromboembolism and treated with appropriate thromboprophylaxis, if indicated(1)
Recombinant Factor VIIa
  • recombinant factor VIIa
    • recombinant factor VIIa complexes with tissue factor exposed at sites of vascular injury, and then activates remainder of coagulation cascade via factor X
    • alternatively, recombinant factor VIIa may bind to activated platelets, which helps mediate activation of factor X at sites of tissue injury
    • activation of factor Xa leads to burst of thrombin generation, initiating fibrin clot formation
    • Reference – Semin Thromb Hemost 2016 Mar;42(2):125
  • NovoSeven RT – FDA approved for treatment of bleeding episodes and perioperative management in adults with AHA (FDA DailyMed 2020 July 10 )
  • example dosing strategy
    • International AHA recommended dosing: 90 mcg/kg IV boluses every 2-3 hours until hemostasis is achieved (International AHA Grade 1B) (Haematologica 2020 Jul;105(7):1791full-text)
    • reported initial doses used have ranged from 70 mcg/kg to 120 mcg/kg every 2-3 hours(2,3)
    • dose escalation should be considered with caution and only in exceptional cases where severe bleeding is unresponsive to conventional dose(1)
  • warning and precautions
    • risk of serious arterial and venous thrombotic events
      • risk factors associated with increased thrombotic events may include
        • concomitant treatment with activated or nonactivated prothrombin complex concentrates (PCCs)
        • older patients with acquired hemophilia receiving other hemostatic agents
        • history of cardiac disease, vascular disease, or predisposition to thrombotic events
        • liver disease, postoperative patients, neonates, and those at risk for disseminated intravascular coagulation
      • avoid
        • simultaneous use of PCCs
        • concomitant administration with coagulation factor XIII
    • hypersensitivity reactions to contents in product including trace amounts of proteins from manufacturing may occur
    • adverse reactions
      • most common serious adverse reactions in setting of clinical trials are thrombotic events: thrombotic adverse reactions reported in 4% of patients with acquired hemophilia
      • other than thrombosis, severe adverse reactions reported include pain, reduced therapeutic response, cerebrovascular disorder, angina pectoris, disseminated intravascular coagulation, anaphylactic shock, and abnormal liver function
    • References –
Activated Prothrombin Complex Concentrate (aPCC)
  • plasma-derived prothrombin complex concentrate which contains mixture of vitamin K-dependent coagulation factors potentially providing bypassing activity by boosting coagulation activity of prothrombinase complex (J Thromb Haemost 2012 Aug;10(8):1478full-text)
  • aPCC (FEIBA) (off-label)
    • composed mostly of nonactivated factors II, IX, and X, and activated factor VII (factor VIIa) as well as small amounts of proteins C and S
    • aPCC administration induces thrombin generation on tissue factor presenting cells and activated platelets, bypassing the coagulation cascade, and initiates fibrin clot formation
    • thrombin-mediated feedback then results in activation of other coagulation proteins to further activate platelets
    • nonactivated and procoagulant enzyme components of aPCC directly and indirectly amplify thrombin generation on activated platelet surfaces
    • due to long half-life of nonactivated factors, circulating substrate levels are increased, leading to long-lasting hemostasis that helps prevent recurrence of bleeds
    • Reference – FDA DailyMed 2020 Mar 5, Arch Pathol Lab Med 2015 Dec;139(12):1568full-text
  • suggested dosing
  • warnings and precautions
    • risk of thromboembolic events
      • repeated infusions of aPCC can cause accumulation of other clotting factors and potentially increase risk of thromboembolic events(1,2)
      • increased risk in patients with (benefit should be weighed against risk)
        • disseminated intravascular coagulation
        • advanced atherosclerotic disease
        • crush injuries
        • septicemia
        • concomitant treatment with recombinant factor VIIa
        • concomitant treatment with emicizumab (increased risk of thrombotic microangiopathy)
        • Reference – FDA DailyMed 2020 Mar 5
    • other adverse events may include
      • hypersensitivity reactions (including anaphylaxis)
      • possible transmission of viruses as well as variant Creutzfeldt-Jacob disease, and in theory, Creutzfeldt-Jacob disease agent
      • anemia, diarrhea, nausea, and vomiting (reported among patients with congenital hemophilia A or B)
      • Reference – FDA DailyMed 2020 Mar 5
Evidence for Bypassing Agents
  • bypassing agents (recombinant factor VIIa or aPCC) may achieve higher rate of bleeding control compared to factor VIII or desmopressin in adults with AHA (level 2 [mid-level] evidence)
    •  based on cohort study
    • 288 adults (median age 73 years) with AHA and ≥ 1 bleeding episode who received hemostatic therapy enrolled in the European Acquired Hemophilia Registry (EACH2) between 2003 and 2008 were evaluated
    • hemostatic therapy included
      • bypassing agent in 219 adults (recombinant factor VIIa in 159 adults and aPCC in 60 adults)
      • other hemostatic therapy in 69 adults (factor VIII in 55 adults and desmopressin in 14 adults)
    • some patients also received ancillary antifibrinolytic treatment
    • propensity score for likelihood of receiving bypassing agent or other hemostatic therapy was calculated for each patient based on demographic and clinical factors (such as age, sex, inhibitor titer, cause of bleeding, bleeding site, and severity of bleeding)
    • 60 adults on bypassing agent and 60 adults on other therapy were included in propensity-matched analysis
      • severity of bleeding
        • 96 adults presented with severe bleeding (defined as hemoglobin level < 8 g/dL [80 g/L], drop by > 2 g/dL [20 g/L], or life- or limb threatening, central nervous system, deep muscle, or retroperitoneal bleeding)
        • 24 adults presented with nonsevere bleeding
      • median factor VIII activity 2 units/dL in bypassing agent group and 3 units/dL in other hemostatic therapy group
      • inhibitor titer 9.3 units/mL in bypassing agent group and 8 units/mL in other hemostatic therapy group
    • bleeding control in 93.3% of bypassing agent group vs. 68.3% in other hemostatic therapy group in propensity score-matched analysis (p = 0.003)
    • Reference – Blood 2012 Jul 5;120(1):39full-text
  • complete or improved resolution of initial bleeding reported in 81% of adults with AHA who received recombinant factor VIIa and 100% of adults who received aPCC (level 3 [lacking direct] evidence)
    •  based on case series
    • 82 adults (median age 76 years) with AHA enrolled in Surveillance des Auto antiCorps au cours de l’Hémophilie Acquise (SACHA) registry between September 2001 and September 2005 were followed for 1 year
    • no underlying conditions identified in 55%; in other cases, underlying conditions/setting associated with AHA included postpartum, autoimmune disease, and malignancy
    • at presentation
      • most adults had ≥ 1 bleeding site
        • most common bleeding manifestations (reported in > 20 adults) included diffuse subcutaneous hematomas, localized subcutaneous bruises, and muscular hematoma
        • other bleeding manifestations included macroscopic hematuria, hemarthrosis, mucosal bleeding, gastrointestinal bleeding, and intracranial hemorrhage
      • median factor VIII activity 2%; median anti-factor VIII inhibitor level 16 Bethesda units/mL
    • 79 adults required red blood cell transfusion before and/or after study inclusion and 77 adults received immunosuppressive treatment after inclusion
    • 38 adults (46%) received hemostatic therapy for initial bleed
      • 82% of patients received recombinant factor VIIa (mean total dose 0.8 mg/kg given over mean 4.7 days)
      • 18% of patients received aPCC (mean total dose 620 units/kg given over mean 12.8 days)
    • at 1 month, complete or improved resolution of initial bleeding in 81% of patients who received recombinant factor VIIa and 100% of patients who received aPCC
    • 27 adults died during study with 20 deaths occurring within first 3 months (overall mortality 33%)
      • 3 patients died of fatal bleeding
      • 10 patients died of sepsis
      • other causes of death included myocardial infarction (1 adult), ischemic stroke (1 adult), general deterioration, cardiac failure, and concomitant disease
    • recurrent bleeding occurred in 26 adults during 1-year follow-up
    • Reference – Haemophilia 2013 Jul;19(4):564

Coagulation Factor Concentrates

Factor VIII
Human Factor VIII Concentrate
  • most patients with AHA are resistant to human factor VIII concentrates, even when inhibitor titer is low; response reported to be unpredictable and Bethesda assay is not a good predictor of factor VIII recovery(1)
  • human factor VIII is usually rapidly neutralized to a low level, which can be followed by slower reduction in factor VIII, resulting in low level of residual activity that may last for several hours(1)
  • human factor VIII concentrate may be considered in patients with low-titer inhibitor (< 5 Bethesda units/mL) to neutralize inhibitor and increase circulating factor VIII(2)
  • if used, factor VIII dose should be sufficient to overcome inhibitor and provide adequate hemostasis; large initial dose is likely to be needed with regular boluses or continuous infusion(1,3)
  • factor VIII activity should be controlled within 15-30 minutes after factor VIII concentrate infusion(2)
  • monitoring treatment
    • routine one-stage factor VIII coagulation assays can be used to measure factor VIII levels after treatment with human concentrates(3)
    • monitor factor VIII levels daily to check if dose of factor VIII concentrate is sufficient for hemostatic control and to monitor for development of anamnestic response(2)
    • factor VIII levels should be obtained with turnaround of 1-2 hours to be clinically useful in guiding subsequent treatment; this may not be feasible in many settings(3)
    • if poor response, consider early switch to another product(1)
    • however, note that factor VIII level measurement is not a good readout for clinical response(1)
    • activated partial thromboplastin time (aPTT), a commonly available assay, normalizes when factor VIII levels reach > 30%-50%, but is not suited to detect supra-therapeutic levels and therefore, not a suitable surrogate marker to guide treatment(3)
  • several commercial plasma-derived or recombinant factor VIII products available; see Clotting Factor Concentrates in Factor Concentrates and Other Plasma Products for information on available products
  • factor VIII plus immunoadsorption or therapeutic plasma exchange
    • treatment with human factor VIII is usually less effective than bypassing agents unless combined with immunoadsorption(1)
    • immunoadsorption is achieved by filtering patient’s plasma through sepharose column with bound recombinant protein A or polyclonal antibodies against human immune globulin(2,4)
    • therapeutic plasma exchange can help remove inhibitors, resulting in transient drop in inhibitor titer to enable treatment with human factor VIII(4)
    • immunoadsorption or plasma exchange result in reduction of circulating factor VIII inhibitors sufficient enough to ensure adequate hemostasis with factor VIII replacement, even in patients with higher titer inhibitors(1,2,4)
      • high-dose of factor VIII (for example, 100 units/kg/day) together with immunoadsorption may induce rapid control of severe bleeding, even in presence of high factor VIII inhibitor titers
      • useful in patients who require surgery or if bypassing agent is ineffective
    • immunoadsorption is not widely available(1,2)
Porcine Factor VIII Concentrate
  • in patients with AHA, inhibitor titer to porcine factor VIII is typically about 5%-10% of the human titer; porcine factor VIII may achieve hemostasis in cases where human factor VIII treatment was ineffective(1)
  • increase in porcine factor VIII inhibitor titer reported with administration of porcine factor VIII in some patients and may reduce response to subsequent treatments(3)
  • monitoring treatment
    • International AHA recommends close monitoring of factor VIII activity during treatment with porcine factor VIII concentrate (International AHA Grade 1B) (Haematologica 2020 Jul;105(7):1791full-text)
    • baseline and post-infusion factor VIII level should be used to help guide dosing and treatment intervals(3)
    • factor VIII levels should be obtained with turnaround of 1-2 hours to be clinically useful in guiding subsequent treatment; this may not be feasible in many settings(3)
    • activated partial thromboplastin time (aPTT), a commonly available assay, normalizes when factor VIII levels reach > 30%-50%, but is not suited to detect supra-therapeutic levels and therefore, not a suitable surrogate marker to guide treatment(3)
  • recombinant porcine factor VIII (Obizur)
    • approved for treatment of bleeding in patients with AHA in United States, Canada, and Europe(3)
    • International AHA recommended dosing: 200 units/kg, followed by further doses to maintain trough levels at > 50% (International AHA Grade 1B) (Haematologica 2020 Jul;105(7):1791full-text)
    • package insert dosing for patients with AHA
      • for minor and moderate bleeding (for example, superficial muscle/no neurovascular compromise, or joint bleeding)
        • target factor VIII level 50%-100% (50-100 units/dL)
        • initial dose is 200 units/kg IV; titrate subsequent doses to maintain recommended trough levels and based on individual response
        • repeat dose every 4-12 hours; frequency may be adjusted based on clinical response and measured factor VIII levels
      • for major bleeding (for example, moderate-to-severe intramuscular bleeding, retroperitoneal, gastrointestinal, or intracranial bleeding)
        • target factor VIII level
          • 100%-200% (100-200 units/dL) to treat an acute bleed
          • 50%-100% (50-100 units/dL) after acute bleed is controlled, if required
        • initial dose 200 units/kg; titrate subsequent doses to maintain recommended trough levels and based on individual response
        • repeat dose every 4-12 hours; frequency may be adjusted based on clinical response and measured factor VIII levels
      • Reference – FDA DailyMed 2021 Apr 27
  • porcine factor VIII reported to achieve control of serious bleeding in 86% of adults with AHA (level 3 [lacking direct] evidence)
    •  based on uncontrolled trial
    • 29 adults (median age 70 years) with AHA with serious bleed (for example, bleeding threatening vital organ function, requiring blood transfusion, impacting major joint, or compromising muscle viability or neurovascular integrity) were treated with recombinant B-domain-deleted porcine factor VIII
    • porcine factor VIII dosing
      • initial dose: single 200 units/kg dose
      • subsequent doses adjusted according to target factor VIII trough level (evaluated 10-20 minute pre- and post-infusion and repeated every 2-3 hours post-infusion)
        • within first 24 hours, dosing adjusted to achieve
          • target factor VIII trough level > 80% for bleeds of particular concern (for example, severe mucosal, intracranial, retro- or intra-abdominal, genitourinary, neck, traumatic, or postoperative bleeding)
          • target factor VIII trough level > 50% for all other bleeds
        • after 24 hours, dosing adjusted to achieve post-infusion trough factor VIII level ≥ 50% for all bleeds
    • co-existing comorbidities in 13 adults, including malignancies, autoimmune disorder, and infections; no underlying comorbidities identified in 16 adults
    • at baseline, factor VIII activity ranged from 0%-30%; 7 adults had received prior hemostatic treatment and all adults received immunosuppressive therapy during study
    • 24 adults (86%) had primary bleeding controlled effectively (stopped or significantly reduced) with porcine factor VIII at final treatment dosing (median duration of treatment 6.5 days)
    • median cumulative dose for effective hemostatic treatment 460 units/kg with 3.5 infusions
    • 7 deaths reported during study
      • 3 deaths due to bleeding (1 intestinal and 2 intracranial) but none considered related to treatment or due to treatment failure
      • 3 deaths due to sepsis
      • 1 death due to renal failure (patient had history of renal insufficiency)
    • no patients developed thrombotic events, allergic reactions, or thrombocytopenia
    • Reference – Haemophilia 2015 Mar;21(2):162
Fibrinogen Concentrate and Cryoprecipitate
  • fibrinogen concentrate is considered first-line therapy for bleeding in patients with inhibitors that affect fibrinogen function or fibrin polymerization; may be used in combination with plasma exchange and immunoadsorption(1)
  • cryoprecipitate may be considered if fibrinogen concentrate is not available, but high volume of infusion is likely needed(1)
  • cryoprecipitate has also been used in patients with inhibitors to factor XIII (may be considered with or without immunoadsorption)(1)
  • commercially available fibrinogen concentrate in the United States is RiaSTAP approved for treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency such as afibrinogenemia and hypofibrinogenemia (FDA DailyMed 2021 Jun 15)
Factor VII
Factor IX
  • factor IX concentrate may be an option to manage bleeding at high doses for patients with acquired inhibitors to factor IX but is not likely to be efficacious compared to first-line therapies (bypassing agents)(1)
  • several commercial plasma-derived or recombinant factor IX products are available; see Clotting Factor Concentrates in Factor Concentrates and Other Plasma Products for information on available products
Factor XI
Factor XIII
  • large doses of factor XIII concentrate are indicated as first-line therapy for bleeding in patients with inhibitors to factor XIII, potentially in combination with plasma exchange and immunoadsorption(1,2)
  • available factor XIII replacement therapy includes
    • plasma-derived factor XIII concentrate (Corifact) and recombinant factor XIII (Tretten), both approved for routine prophylactic management and perioperative management of surgical bleeding in patients with congenital factor XIII deficiency but not for acquired inhibitors to factor XIII
    • hypersensitivity reactions and injection site pain are common adverse events
    • References – FDA DailyMed 2020 Aug 18, FDA DailyMed 2020 June 30
  • factor XIII concentrate (50-150 units/kg) reported to achieve adequate hemostasis in 10 out of 11 patients with inhibitors to factor XIII in systematic review of case reports (J Thromb Thrombolysis 2013 Jul;36(1):109)
  • initial treatment of severe bleeding with factor XIII concentrate 35 units/kg in combination with tranexamic acid and recombinant factor VIIa reported to result in resolution of bleeding; continued treatment with factor XIII concentrate 1,250 units every 4 days in combination with prednisone and mycophenolate mofetil reported to maintain hemostasis at follow-up of > 3 years in 65-year-old adult with acquired inhibitor to factor XIII in case report (Thromb Haemost 2013 Mar;109(3):479)
Prothrombin Complex Concentrate (PCC)
  • 4-factor PCCs (Kcentra) contain mixture of plasma coagulation factors including factors II, VII, IX, and X, and natural anticoagulants protein C and protein S (FDA DailyMed 2020 Sep 15)
  • PCC is a treatment option for bleeding in patients with inhibitors to factors II, VII, and X(1)
  • if used, levels of specific coagulation factor level should be monitored closely(2)
  • repeated infusions of PCC can cause accumulation of other clotting factors and potentially increase risk of thromboembolic events(1,2)

Other Hemostatic Medications

  • desmopressin
    • desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is synthetic analogue of hormone 8-arginine vasopressin, an antidiuretic hormone
    • desmopressin has limited utility in patients with acquired inhibitors of coagulation factors(3)
    • however, desmopressin may be considered in patients with AHA and measurable factor VIII activity to help increase factor VIII activity without inducing amnestic response(2)
    • desmopressin should be reserved for minor bleeding in patients with low inhibitor titers (< 2 Bethesda units/mL) and factor VIII levels > 5 units/mL(1,3)
    • clinical response reported to be unpredictable and hemostatic efficacy may not be as high as that seen with bypassing agents(1)
    • contraindications and precautions
      • contraindicated in patients with
        • moderate to severe renal impairment (creatinine clearance < 50 mL/minute)
        • hyponatremia or history of hyponatremia
      • should be used with caution in patients
        • with coronary artery insufficiency and/or hypertensive cardiovascular disease due to potentially slight increase in blood pressure or temporary fall in blood pressure and a compensatory increase in heart rate
        • with conditions associated with fluid and electrolyte imbalance such as cystic fibrosis, heart failure, and renal disorders due to increased risk of hyponatremia
        • during pregnancy due to limited safety data; should be used only if clearly needed
        • who are nursing; unknown if the drug is excreted in milk
      • Reference – FDA DailyMed 2020 Aug 14
    • adverse events
      • may lead to tachyphylaxis (loss of response after several consecutive doses)(2)
      • fluid retention, heart failure, and severe hyponatremia may occur; higher risk of adverse events associated with older age ((3), Haematologica 2020 Jul;105(7):1791full-text)
    • desmopressin reported to induce hemostatic effect in 75.7% of patients with AHA, most of whom received another hemostatic therapy (level 3 [lacking direct] evidence)
      •  based on systematic review of case reports and case series
      • systematic review of 6 case series and 9 case reports evaluating efficacy of desmopressin in 37 patients (median age 65 years, age range 12-83 years) with AHA
      • in 26 evaluable cases, AHA was idiopathic in 42.3%, occurred postpartum in 23.1%, and was associated with bronchial asthma in 15.4%
      • at baseline, median inhibitor titer was 5.3 Bethesda units/mL and median factor VIII activity was 5%
      • desmopressin was used for non-life-threatening hemorrhages or for coverage of minor surgical, invasive, or dental procedures
      • most common dosing for desmopressin 0.3 mcg/kg IV (administered in 87.5% of patients); median doses administered were 2
      • out of 26 evaluable cases, 57.7% also received other hemostatic therapy
      • hemostasis achieved in 75.7%
      • increase in factor VIII activity to median 24.7%
      • Reference – Blood Transfus 2011 Oct;9(4):377full-text
  • tranexamic acid
    • tranexamic acid may be useful as adjunct therapy for non-severe mucosal bleeding when used together with other hemostatic agents; however it is contraindicated if patient has urinary tract bleeding due to potential for iatrogenic urinary tract obstruction(1,2,3)
    • topical tranexamic acid useful for oral or skin bleeding(1,3)
    • there is some concern with concomitant use of tranexamic acid and activated prothrombin complex (aPCC), but complications reported to be very rare; if being used together, use caution, especially in older adults with presence of comorbidities that are known to be associated with increased risk of thrombosis(1,2)
    • combination of tranexamic acid and aPCC reported to induce good or excellent hemostatic response without adverse events in 91% of patients with inherited hemophilia A with inhibitors or AHA (level 3 [lacking direct] evidence)
      •  based on case series
      • 11 adults (age range 19-79 years) with inherited hemophilia A with inhibitors (6 adults) or AHA (1 adult) received tranexamic acid 10 mg/kg IV or 20 mg/kg orally every 6-8 hours and aPCC 50-100 units/kg every 8 hours (not exceeding 200 units/day) for total of 11 treatment episodes
      • treatment episodes included 3 bleeding episodes and 8 episodes to cover for surgery
      • 10 adults (91%) had good or excellent hemostatic effect (rating based on consensus statement on assessment of hemostatic outcome for surgery in hemophilia A patients without inhibitors)
      • in 1 adult with AHA, treatment was indicated for extensive muscle bleeding and fasciotomy and achieved excellent hemostatic outcome
      • no adverse events reported
      • Reference – Haemophilia 2012 Jul;18(4):544
  • emicizumab
    • humanized monoclonal antibody that binds to and bridges factor IXa and factor X to restore function of missing factor VIII activity needed for effective hemostasis; approved for use in patients with congenital hemophilia A (FDA DailyMed 2021 Mar 8)
    • use of activated prothrombin complex concentrates (aPCC) should be avoided in patients receiving emicizumab
      • thrombotic microangiopathy has been reported when aPCC was administered with patients with congenital hemophilia receiving emicizumab; patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury without severe deficiencies in ADAMTS13 activity
      • due to long half-life of emicizumab, interaction with aPCC may last for up to 6 months after last dose
      • Reference – FDA DailyMed 2021 Mar 8
    • emicizumab after treatment with bypassing agent reported to achieve hemostatic control in adults with AHA (level 3 [lacking direct] evidence)
      •  based on case series
      • 12 adults (median age 74 years) with newly diagnosed AHA received emicizumab 3 mg/kg subcutaneously every week for 2-3 doses followed by 1.5 mg/kg every 3 weeks (median 5 doses given) after treatment with bypassing agent
      • co-existing comorbidities present in all adults, including malignancies, autoimmune disorder, infection, lung disease, and metabolic syndrome
      • at baseline, median initial factor VIII activity < 1% and median inhibitor titer 22.3 Bethesda unit/mL
      • severity of bleeding
        • 8 adults presented with severe bleeding (drop in hemoglobin levels by > 2 g/dL [20 g/L], need ≥ 2 red blood cell transfusions, or life-, organ- or limb-threatening)
        • 4 adults presented with nonsevere bleeding
      • all patients had comorbidities preventing intensive immunosuppressive therapy (old age or comorbid conditions) but received reduced-intensity immunosuppression with corticosteroids and/or rituximab
      • initial hemostatic therapy with bypassing agent included aPCC in 3 adults (but switched to recombinant factor VIIa due to poor response or adverse events), and recombinant factor VIIa in 7 adults; first dose of emicizumab given median 3 days after initial hemostatic therapy
      • after administering emicizumab, improvement in bleeding in all patients within median of 3 days with no breakthrough bleeding reported after first dose
      • no fatality from bleeding or thromboembolism reported
      • Reference – Blood 2021 Jan 21;137(3):410, editorial can be found in Blood 2021 Jan 21;137(3):294

Transfusion Therapy

  • red blood cell transfusion in patients who are bleeding
    • bleeding should be controlled and this may involve surgery, endoscopy, or interventional radiology-based therapies
  • platelet transfusion
  • plasma transfusion
    • fresh frozen plasma (FFP) not indicated in most cases of acquired inhibitors of coagulation due to impracticality of sustaining sufficient volume to neutralize inhibitor and provide hemostatic levels without risk of circulatory overload(1,2)
    • however, plasma transfusion can be administered in patients with factor V along with platelet transfusion(1,2)
      • in cases of unresponsive bleeds, high volumes of FFP and plasmapheresis with immunoadsorption or bypassing agents may be needed (activated prothrombin complex concentrate may be preferred over recombinant factor VIIa in this case)
      • Italian Association of Hemophilia Centers (AICE) suggests solvent/detergent virally-inactivated FFP if available (but in-house viral inactivation methods are not suggested due to lack of standardization in coagulation factor concentrations)

Medications for Eradication of Inhibitors

Immunosuppressive Therapy (IST)

Introduction
  • patients with acquired hemophilia A (AHA)
    • IST to eradicate acquired inhibitors should be initiated as soon as diagnosis is made to reduce risk of bleeding(1)
    • choice of IST should take into consideration presence of comorbidities and patients should be monitored closely for infections(1)
    • inhibitor titer and factor VIII activity levels should be monitored at least weekly during IST until inhibitor becomes undetectable and factor VIII level is normalized(3)
    • tapering of therapy should be started when inhibitor is undetectable and factor VIII is rising(3)
    • common first-line IST regimen is corticosteroid alone or corticosteroids combined with cytotoxic agent(1)
      • in case of failure of first-line therapy (lack of factor level increase and fall in inhibitor titer after about 3-5 weeks), second-line therapy should be considered
      • options include calcineurin inhibitor or rituximab
    • there is no standard definition for remission; examples of definitions used
      • Italian Association of Hemophilia Centers (AICE) defines complete response as persistent undetectable inhibitor (< 0.6 Bethesda units/mL) with normal plasma levels of factor VIII (> 70%) (AICE Grade 2B)(2)
      • United Kingdom surveillance study defined complete remission as normal factor VIII and inhibitor undetectable after IST is discontinued or reduced to doses used prior to AHA without relapse (Blood 2007 Mar 1;109(5):1870full-text)
      • Acquired Hemophilia Working Group of the German, Austrian and Swiss Thrombosis and Hemostasis Society (GTH) defined
        • partial remission as factor VIII level restored to > 50% and no bleeding after stopping hemostatic treatment for ≥ 24 hours
        • complete remission as factor VIII level restored to > 50% and no bleeding after stopping hemostatic treatment for ≥ 24 hours plus negative inhibitor test, prednisolone tapered to < 15 mg/day, and discontinuation of any other IST
        • Reference – Blood 2015 Feb 12;125(7):1091full-text, editorial can be found in Blood 2015 Feb 12;125(7):1052
    • if patient was given rituximab as first-line therapy and fails to respond, treatment with corticosteroids, cytotoxic agents, or calcineurin inhibitors should be considered(1)
    • in resistant cases, administration of factor VIII, immunosuppression and immunoadsorption, and higher intensity combination cytotoxic agents may be considered(1)
    • IST reported to achieve remission in about 60%-80% of patients after median 5-6 weeks(3)
    • relapse reported to occur in 10%-20% of patients with AHA; patients should be informed about signs and symptoms of recurrence and report bleeding or increased bruising immediately(1,3)
  • for inhibitor eradication other than inhibitors to factor VIII, treatment with immunosuppressive agents only indicated for frequent or severe bleeding using same regimens as for AHA(2)
  • adverse events reported to be common with IST, including
    • infection (resulting in deaths in some cases)(1,2)
    • neutropenia(1,2)
    • diabetes mellitus(1,2)
    • psychiatric illness(1,2)
    • hypertension, osteoporosis, and cataract development following corticosteroids use in older adults(2)
Corticosteroids
  • corticosteroids with or without cytotoxic agent
    • suggested dosing options
      • prednisone 1-2 mg/kg/day for 4-6 weeks as monotherapy or in combination with cyclophosphamide 1-2 mg/kg/day orally for maximum 5 weeks; commonly used strategy with successful inhibitor eradication reported in patients with AHA(1,2)
      • dexamethasone 40 mg orally daily for 4-7 days as monotherapy or in combination with cyclophosphamide 1-2 mg/kg orally daily (or 5 mg/kg IV every 3-4 weeks)(3)
      • prednisone or prednisolone at 1 mg/kg/day orally for maximum of 4-6 weeks (followed by tapering) with or without cytotoxic agent (cyclophosphamide 1.5-2 mg/kg/day orally for maximum of 6 weeks or mycophenolate mofetil 1 g/day for 1 week followed by 2 g/day) (Haematologica 2020 Jul;105(7):1791full-text)
    • corticosteroid monotherapy unlikely to take effect within 3 weeks in patients with factor VIII activity < 1 unit/dL or inhibitor titer > 20 Bethesda units/mL at baseline(3)
    • addition of cyclophosphamide may achieve higher response and shorter time to remission but is associated with more adverse events(1,2,3)
      • cyclophosphamide and other cytotoxic agents should be used with caution, especially in older adults
      • monitor for marrow suppression (white blood cells and platelets), and infection
      • avoid cyclophosphamide and other alkylating agents in female patients of reproductive age
    • corticosteroid treatment can also be considered in combination with rituximab (375 mg/m2 IV per week for 4 weeks; alternatively 100 mg/week for 3 weeks)(3)
    • monitor for adverse events including elevated glucose levels, infection, or psychiatric disorders(3)
  • rates of remission achieved with corticosteroid based treatment
    • GTH immunosuppressive treatment protocol reported to induce partial remission in 84% and complete remission in 61% of adults with AHA (level 3 [lacking direct] evidence)
      •  based on uncontrolled trial
      • 102 adults (median age 74 years) with AHA treated with immunosuppressive regimen developed by Acquired Hemophilia Working Group of the German, Austrian and Swiss Thrombosis and Hemostasis Society (GTH) were followed for mean 262 days
      • no underlying conditions or idiopathic identified in 67%; in other cases, underlying conditions/setting associated with AHA included postpartum, autoimmune disease, and malignancy
      • at baseline, median factor VIII activity 1.4 units/dL and median inhibitor level 19 Bethesda units/mL
      • all but 1 adult (who died prior to treatment) initiated immunosuppressive treatment
      • GTH immunosuppressive regimen
        • start with prednisolone alone during weeks 1-3 (given to 101 adults)
        • if partial response is not achieved, cyclophosphamide added to prednisolone during weeks 4-6 (given to 35 adults)
        • if partial response is still not achieved, rituximab plus prednisolone given during week 7 (given to 12 adults)
        • as soon as partial remission was achieved, cyclophosphamide and rituximab were discontinued (if applicable) and prednisolone tapered over 6 weeks
      • 85 adults (83%) achieved partial remission, defined as factor VIII activity > 50 units/dL, and no active bleeding after stopping hemostatic agent for > 24 hours, after median 31 days
      • 62 adults (60.8%) achieved complete remission, defined as partial remission plus negative inhibitor test, prednisolone tapered to < 15 mg/day, and any other immunosuppressive therapies stopped, after median 79 days
      • recurrence after partial remission, prior to achieving complete remission, in 22%; 95% of these adults achieved second partial remission after increasing corticosteroid dose according to protocol and 11% achieved complete remission
      • 1-year overall survival 68%; common causes of death included
        • infections in 19 patients
        • cardiovascular disorders in 6 patients
        • underlying disorder in 3 patients
        • bleeding in 3 patients
      • Reference – GTH-AH 01/2010 study (Blood 2015 Feb 12;125(7):1091full-text)
    • IST reported to induce 98% complete remission at 1 year in adults with AHA (level 3 [lacking direct] evidence)
      •  based on case series
      • 82 adults (median age 76 years) with AHA enrolled in Surveillance des Auto antiCorps au cours de l’Hémophilie Acquise (SACHA) registry between September 2001 and September 2005 were followed for 1 year
      • no underlying conditions identified in 55%; in other cases, underlying conditions/settings associated with AHA included postpartum, autoimmune disease, and malignancy
      • at presentation
        • most adults had ≥ 1 bleeding site
          • most common bleeding manifestations (reported in > 20 adults) included diffuse subcutaneous hematomas, localized subcutaneous bruises, and muscular hematoma
          • other bleeding manifestations included macroscopic hematuria, hemarthrosis, mucosal bleeding, gastrointestinal bleeding, and intracranial hemorrhage
        • median factor VIII activity 2%; median anti-factor VIII inhibitor titer 16 Bethesda units/mL
      • 38 adults (46%) received hemostatic therapy for initial bleed; 79 adults required red blood cell transfusion before and/or after study inclusion
      • 77 adults (94%) received IST including
        • corticosteroids alone in 22 adults
        • corticosteroids plus cytotoxic agents in 47 adults
        • corticosteroids plus rituximab in 5 adults
        • immunoglobulin therapy in 3 adults
      • complete remission (defined as inhibitor titer < 0.6 Bethesda units/mL, normal factor VIII activity [50 units/dL], and without bleeding symptoms) in
        • 34% of 74 adults at 1 month
        • 61% of 59 adults at 3 months
        • 87% of 54 adults at 6 months
        • 98% of 51 adults at 1 year
      • 27 adults died during study with 20 deaths occurring within first 3 months (overall mortality 33%)
        • 3 patients died of fatal bleeding
        • 10 adults died of sepsis
        • other causes of death included myocardial infarction (1 adult), ischemic stroke (1 adult), general deterioration, cardiac failure, and concomitant disease
      • recurrent bleeding occurred in 26 adults during 1-year follow-up
      • Reference – Haemophilia 2013 Jul;19(4):564
  • evidence for addition of cytotoxic agent to corticosteroid therapy
    • corticosteroids plus cyclophosphamide associated with higher rate of stable complete remission and shorter time to complete remission compared to corticosteroid alone in adults with AHA (level 2 [mid-level] evidence)
      •  based on cohort study
      • 331 adults (mean age 75 years) with AHA identified from European Acquired Hemophilia Registry (EACH2) between 2003 and 2008 who received IST were evaluated
        • no underlying conditions identified or idiopathic in 64%; in other cases, underlying conditions/settings associated with AHA included postpartum, autoimmune disease, and malignancy
        • at diagnosis, mean inhibitor titer 15 Bethesda units/mL and mean factor VIII activity 2 units/dL
      • IST included
        • corticosteroids and cyclophosphamide in 83 patients (25%)
        • corticosteroids alone in 142 patients (43%)
        • rituximab-based regimen in 51 patients (15%)
        • other regimens or not reported in 55 patients (17%)
      • complete remission (defined as undetectable inhibitor, factor VIII activity ≥ 70 units/dL after end of immunosuppression) in
        • 80% of adults on corticosteroids plus cyclophosphamide
        • 58% of adults on corticosteroids alone
        • 61% of adults on rituximab-based regimens
      • at median 149 days follow-up among patients with complete remission, relapse in
        • 12% of adults on corticosteroids plus cyclophosphamide
        • 18% of adults on corticosteroids alone
        • 3% of adults on rituximab-based regimens
      • propensity score for likelihood of receiving corticosteroid plus cyclophosphamide or corticosteroid alone was calculated for each patient based on demographic and clinical factors (such as age, sex, inhibitor titer, etiology, and weight)
      • 70 adults on corticosteroid alone and 70 adults on corticosteroid plus cyclophosphamide were included in propensity-matched analysis
      • in propensity-matched analysis, compared to corticosteroid alone, corticosteroid plus cyclophosphamide associated with
        • higher rate of stable complete remission (complete remission until follow-up) (odds ratio 3.25, 95% CI 1.51-6.96)
        • shorter time to negative inhibitor, normal factor VIII activity, and time to complete remission (hazard ratio 2.11, 95% CI 1.38-3.21)
      • adverse events
        • ≥ 1 adverse events reported in (no p value reported)
          • 41% of adults on corticosteroids and cyclophosphamide
          • 25% of adults on corticosteroids alone
          • 37% of adults on rituximab-based regimens
        • adverse events included infection, neutropenia, diabetes, and psychiatric disorders
      • Reference – Blood 2012 Jul 5;120(1):47full-text
    • addition of cytotoxic agents to corticosteroid therapy may not shorten time to complete remission or improve duration of survival in patients with AHA (level 2 [mid-level] evidence)
      •  based on population-based cohort study
      • 172 children and adults (median age 78 years) with AHA identified in United Kingdom between 2001 and 2003 were evaluated
      • AHA was idiopathic in 63%; in other cases, AHA-associated conditions included malignancy, autoimmune diseases, and pregnancy
      • 30% of patients had severe factor VIII level deficiency (≤ 1 unit/dL)
      • baseline inhibitor titer
        • 0-10 Bethesda units/mL in 6.2%
        • 11-100 Bethesda units/mL in 80.6%
        • 101-1,000 Bethesda units/mL in 11.1%
      • 95% of 151 patients with data available received IST including
        • corticosteroids alone in 26.5%
        • corticosteroids plus cytotoxic agents in 60.9%
        • cytotoxic agents alone in 5.3%
      • 65.8% of 149 patients with bleeding received ≥ 1 hemostatic therapy
      • fatal bleeding in 9.1% of 143 patients with data available at median 19 days
      • 71% of 144 patients with follow-up data achieved complete remission (CR) defined as normal factor VIII activity, and immunosuppression stopped or reduced to doses used before hemophilia developed without relapse
      • comparing corticosteroids plus cytotoxic agents vs. corticosteroids alone
        • CR in 78% vs. 76% (no p value reported)
        • time to CR 39 days vs. 49 days (not significant)
        • median overall survival 975 days vs. 767 days (not significant)
      • of patients who achieved CR, 20% of patients had relapse; median time to relapse 7.5 months after stopping immunosuppression (among 11 patients for whom data was available)
      • most common nonbleeding morbidities among 112 patients with available data included sepsis (33%) and neutropenia (12%)
      • Reference – Blood 2007 Mar 1;109(5):1870full-text
Rituximab
  • monoclonal antibody against CD20(2)
  • can be administered as monotherapy or in combination with other therapies(2)
  • first-line therapy options
    • rituximab 375 mg/m2 IV/week for 4 weeks (or 100 mg/week for 4 weeks) plus 1 of the following corticosteroid regimen(3)
      • prednisone 1 mg/kg/day orally
      • dexamethasone 40 mg/day orally for 4-7 days
    • rituximab 375 mg/m2/week for 4 weeks may be indicated as first-line monotherapy in patients with contraindications to standard immunosuppressive drugs; rituximab not recommended as monotherapy unless other immunosuppressive agents are contraindicated(2,3)
  • as second-line therapy, rituximab 375 mg/m2 IV per week for 4 weeks with corticosteroids with or without cyclophosphamide can be administered in patients who do no respond to first-line treatment within 3-5 weeks(1)
  • evidence for rituximab for eratdication of inhibitors in patients with AHA
    • no randomized trials found evaluating efficacy and safety of rituximab for eradication of inhibitors in patients with AHA in Cochrane review (Cochrane Database Syst Rev 2021 Aug 23;8:CD011907)
    • rituximab reported to induce complete remission in 58% of adults with AHA (level 3 [lacking direct] evidence)
      •  based on case series
      • 22 adults (age range 19-88 years) with AHA received rituximab 375 mg/m2 IV once per week for 4 weeks
      • additional IST administered if factor VIII inhibitor titer was not controlled adequately, at clinician discretion
      • AHA were idiopathic in 8 adults; in other cases, AHA-associated conditions included malignancy, autoimmune diseases, infection, and postpartum
      • complete remission defined as factor VIII activity > 70 units/dL or undetectable factor VIII inhibitor titer (< 0.4 Bethesda units/mL)
      • 8 adults who received rituximab alone were available for analysis; complete remission in 7 adults (58.3%)
      • among patients who achieved complete remission or partial remission, factor VIII inhibitor titer was 22 Bethesda units/mL (patients who were given multiple lines of therapy and achieved complete remission had initial inhibitor titer of 834 Bethesda units/mL)
      • no adverse events reported
      • Reference – J Thromb Haemost 2011 Jul;9(7):1429full-text
    • rituximab reported to induce complete remission in 78.6% of children and adults with AHA (level 3 [lacking direct] evidence)
      •  based on literature review of published studies, abstracts, and observation
      • 43 children and adults (median age 70 years) with AHA who received rituximab 375 mg/m2/week (most patients received 4 cycles of treatment)
      • at baseline, median inhibitor titer levels were 30 Bethesda units/mL
      • 21 patients (50%) were previously treated for inhibitor eradication
      • complete remission defined as complete disappearance of the antibody and normalization of factor VIII activity
      • complete remission in 78.6%
      • median time to complete remission 8.3 weeks
      • 2-year complete remission in 66%
      • Reference – Haematologica 2007 Jan;92(1):66, commentary can be found in Blood Transfus 2016 May;14(2):255
    • case reports suggest mixed results with lower rituximab dosing
      • rituximab 100 mg IV per week for 4 weeks induced remission in 88-year-old adult with AHA in case report (Hematology 2014 Dec;19(8):483)
      • rituximab 100 mg IV reported to improve factor VIII activity and lower inhibitor titer after 2 weeks, but ultimately resulted in fatal retroperitoneal hemorrhagic event prior to administration of fourth dose in 82-year-old adult with AHA in case report (J Am Geriatr Soc 2016 Aug;64(8):1744)
Other ISTs
  • calcineurin inhibitors
    • some cases of remission reported with use of cyclosporine A following failed first-line therapy(1)
    • cyclosporine or tacrolimus reported to induce sustained response in 91% of adults with AHA (level 3 [lacking direct] evidence)
      •  based on case series
      • 11 adults (median age 71 years) with AHA received cyclosporine 5 mg/kg or tacrolimus 0.3 mg/kg plus methylprednisone IV 1 g/day on days 1-3 and prednisone orally 1 mg/kg day onwards
      • at baseline, median inhibitor titer 6 Bethesda units/mL and median factor VIII activity 1%
      • AHA was idiopathic in 72.7%; in other cases, AHA-associated conditions included malignancy and monoclonal gammopathy of uncertain signification
      • sustained response defined as negative for inhibitor and with stable factor VIII level > 50% for median follow-up of 14 months
      • 91% achieved sustained response in median 3 weeks
      • 1 patient presented with hypertensive posterior progressive encephalopathy which improved after drug withdrawal
      • 5-year overall survival 54.5% (deaths were caused by complications of morbidities or immunosuppressants, not from bleeding)
      • Reference – Haemophilia 2012 Sep;18(5):789
  • factor VIII immune tolerance induction
    • involves treatment with factor VIII together with immunosuppressive agents; rarely used(1,2)
    • infusion of exogenous factor VIII thought to increase susceptibility of inhibitor producing B cell clones to cytotoxic agents(4)
    • limited evidence to support immune tolerance as treatment strategy to treat patients with AHA(1)
    • examples of treatment regimen
      • combination of immunoadsorption, factor VIII, and immunosuppression (cyclophosphamide and corticosteroid) (Bonn-Malmӧ protocol), mainly used in Europe; immunoadsorption columns are not available in United States(1,2)
      • daily infusion of factor VIII 30 units/kg/day for 1 week, 20 units/kg/day for second week, and 15 units/kg/day for third week combined with IV cyclophosphamide at 200 mg/day (total does 2-3 g) and systemic methylprednisolone 100 mg/day for first week, followed by gradual tapering in following 2 weeks (Budapest protocol)(1,2,4)
      • 3 weekly infusions of factor VIII combined with vincristine, cyclophosphamide, and corticosteroids(1)
    • Bonn-Malmӧ protocol reported to induce 90% complete remission in adults with severe AHA (level 3 [lacking direct] evidence)
      •  based on case series
      • 67 adults (mean age 62 years) who received treatment for AHA were evaluated
      • all adults presented with muscle bleeding associated with compartment syndrome and 65 adults presented with life-threatening bleeding; other bleeding manifestations included gastrointestinal bleeding, retroperitoneal bleeding, retropharyngeal bleeding, and hematuria
      • at initial diagnosis, mean inhibitor titer was 457 Bethesda unit/mL and mean factor VIII activity < 2.4%
      • 17 adults (25%) had underlying conditions including autoimmune disease, malignancy, and pregnancy
      • 60 adults received Bonn-Malmӧ treatment (treatment cycles [from day 1 to day 7] repeated as needed) which consisted of
        • large volume immunoadsorption (apheresis and immunoadsorption over polyvalent anti-human immunoglobulin coated column; performed with 2.5-3 times total plasma volume on days 1-5)
        • IV immunoglobulin 0.3 g/kg/day on days 5-7 days
        • immunosuppression with cyclophosphamide 1-2 mg/kg/day and prednisolone 1 mg/kg/day from day 1 until remission (dose reduction)
        • high-dose factor VIII 100 units/kg (up to 200 units/kg in patients with body mass index > 40 kg/m2) every 6 hours; optional dose reduction based on clinical signs and level of recovery (for example, 50%-80% of factor VIII residual activity after 4-6 hours) throughout treatment cycle
      • 27 adults also received recombinant factor VIIa after diagnosis to achieve immediate reduction in bleeding
      • among adults who received Bonn-Malmӧ treatment
        • 54 adults (90%) achieved complete remission (defined as normal factor VIII activity without factor substitution and undetectable inhibitor titer levels ≥ 12 months follow-up period)
        • 6 adults (10%) achieved partial remission (defined as factor VIII recovery by up to 30% and/or a reduction of inhibitor titer to < 5 Bethesda unit/mL without further bleeding); 4 of these adults had underlying cancer and 2 adults did not complete treatment due to catheter occlusion
      • Reference – Haemophilia 2010 May;16(102):95

IV Immune Globulin (IVIG)

  • limited evidence to support use of IVIG as adjunct inhibitor eradication therapy in patients with acquired inhibitors of coagulation as (1,2)
  • however, in patients with inhibitors other than factor VIII, if immunosuppressive therapy is contraindicated or antibody persists (especially antibodies of IgG class), treatment with IVIG can be considered(2)
    •  duration of treatment determined by infusion of IVIG (1 g/kg/day for 2 days or 400 mg/kg day for 5 days) measuring factor VIII level at ≥ 1, 7, and 15 days after end of first cycle of treatment
    • treatment usually administered at intervals of about 21 days (dose can be as low as 1 g/kg/day), especially in patients in whom risk of bleeding remains high (for example, patients with gastrointestinal bleeding due to angiodysplasia)

Thromboprophylaxis

  • in patients with acquired hemophilia A, monitoring factor VIII levels during eradication therapy is important as part of evaluation for risk of thromboembolism(2)
  • risk of thromboembolism may be increased in some patients due to older age, pre-existing comorbidities, and immobilization, in addition to risk from hemostatic treatment with activated coagulation factor concentrates(2)
  • thromboprophylaxis should be considered, especially at a time when the inhibitor has presumably been eradicated and when factor levels can be significantly higher than normal, adding further to risk(2)
  • CLINICIANS’ PRACTICE POINT: If thromboprophylaxis is indicated, use caution and monitor for bleeding symptoms and coagulation parameters closely.
  • both United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) and Italian Association of Hemophilia Centers (AICE) suggest pharmacologic thromboprophylaxis in patients at increased risk
    • UKHCDO recommendation – when factor VIII level is normal, assess for risk of venous thrombosis and consider thromboprophylaxis, if appropriate (UKHCDO Grade 2B)(1)
    • AICE recommendation – in patients with risk factors for thromboembolism, consider mechanical and/or pharmacologic thromboprophylaxis, particularly in case of excessively high levels of factor VIII during or at end of eradication therapy (AICE Grade 2C)(2)
  • additional considerations for anticoagulation(3)
    • nonbleeding patients who are hospitalized with endogenous factor VIII level > 50 units/dL should receive thromboprophylaxis
    • in patients who were previously taking aspirin or anticoagulants, treatments may be restarted when factor VIII activity is consistently > 50 units/dL

Additional Considerations for Management in Specific Patient Populations

Pregnancy-Associated Acquired Inhibitors Coagulation

  • pregnancy-associated acquired hemophilia A (AHA) may resolve spontaneously(1,2,3)
  • treatment of bleeding in pregnant patients with AHA is similar to treatment of AHA in patients who are not pregnant; but caution is required when using bypassing agents in postpartum period due to risk of venous thromboembolism(1)
  • inhibitor eradication
    • corticosteroids alone should be considered as first-line therapy to avoid potential bleeding complications in mother and neonate(3)
    • immunosuppressive treatment for inhibitor eradication should account for age of patient and potential side effects in female patient of reproductive age or during lactation; avoid cyclophosphamide and other alkylating agents(1,2,3)
    • rituximab may also be used in this setting but limited evidence showing improved efficacy compared to other treatment modalities(3)
  • relapse in subsequent pregnancies is uncommon, but patients should be informed of the possibility(1,2)
  • hemostatic agents reported to achieve resolution of bleeding in 87% and immunosuppressive therapy (IST) reported to induce complete remission in 74% of patients with pregnancy-related AHA (level 3 [lacking direct] evidence)
    •  based on case series
    • 42 adults with pregnancy-related AHA (median age at diagnosis 34 years) enrolled in the European Acquired Hemophilia Registry (EACH2) between 2003 and 2008 were evaluated
      • median factor VIII level at presentation 2.5 units/dL
      • median factor VIII inhibitor titre 7.8 Bethesda unit/mL
    • at presentation, most pregnant patients had ≥ 1 bleeding site
      • most bleeding manifestations were subcutaneous (45%)
      • other bleeding manifestations included mucosal (43%), musculoskeletal or retroperitoneal (33%), and hemarthrosis (5%)
    • 41 bleeding episodes reported
      • 25 bleeding episodes were severe (symptomatic bleeding in critical area or organ or bleeding causing drop in hemoglobin of ≥ 2 g/dL [20 g/L] or leading to transfusion of ≥ 2 units of red cells per day or a hemoglobin < 8 g/dL [80 g/L]) and 16 bleeding episodes were nonsevere
      • cause of bleeding was reported to be spontaneous in 24 patients (45%), peripartum and postpartum in 15 patients (34%), postsurgical in 4 patients (9%), 1 of which was attributed to delivery, and traumatic in 1 patient (2%)
    • median time to abnormal bleeding episode was 77 days from delivery
    • hemostatic therapy given in 23 out of 41 adults (56%) with bleeding episodes including
      • recombinant factor VIIa in 12 patients
      • activated prothrombin complex concentrates (aPCC) in 5 patients
      • factor VIII concentrates alone in 1 patient and combined with aPCC in 1 patient
      • desmopressin in 1 patient
      • antifibrinolytics in 1 patient
    • bleeding episodes resolved in 87% of 23 patients (89% of bleeding episodes that were treated with bypassing agent)
    • IST given in 95% of patients including (as first-line IST)
      • prednisone in 32 patients
      • dexamethasone in 1 patients
      • unspecified corticosteroids in 6 patients
    • 74% of patients achieved complete remission with first-line IST, defined as factor VIII >70 units/dL, negative inhibitor assay, and termination of immunosuppressive treatment, at mean 96 days after initiation of therapy
    • 86% of patients in remission at median follow-up 406 days
    • Reference – BJOG 2012 Nov;119(12):1529

Patients With Inhibitors of Coagulation Factor Requiring Procedures

  • avoid invasive procedures if possible; even minor procedures may result in uncontrollable bleeding in patients with inhibitors to factor VIII(1)
  • patients with acquired hemophilia A (AHA) at high risk of bleeding such as those undergoing recent surgery or recent delivery, or those with peptic ulcers, require prophylactic hemostatic therapy; however, hemostasis cannot be guaranteed and life-threatening bleeding may occur(1,3)
  • recommendations from professional organizations
    • United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) recommendations (1)
      • perform invasive procedures only if unavoidable and keep venipuncture at minimum (UKHCDO Grade 1C)
      • patients with past history of AHA should have coagulation screen, preferably factor VIII level assayed before any invasive procedures (UKHCDO Grade 2C)
    • Italian Association of Hemophilia Centers (AICE) recommendations(2)
      • avoid invasive procedures in patients with suspected acquired inhibitor until diagnosis is clarified (AICE Grade 1B)
      • in patients with previous acquired inhibitor, always consider assaying for factor affected by inhibitor before surgery or any invasive procedures (AICE Grade 2C)
      • in patients with acquired inhibitor against any clotting factor who require urgent surgery or invasive procedures, consider plasmapheresis and/or immunoadsorption (AICE Grade 2C)
    • International AHA recommends prophylactic use of bypassing agents or recombinant porcine factor VIII for minor or major invasive procedures in patients with AHA (International AHA Grade 1B) (Haematologica 2020 Jul;105(7):1791full-text)
  • recombinant factor VIIa reported to achieve adequate hemostasis in 75-year-old adult with chronic myelomonocytic leukemia and acquired inhibitors to factor XI requiring therapeutic puncture to manage bulky pleural effusion as a result of acute pneumonia in case report (Blood Coagul Fibrinolysis 2001 Oct;12(7):551)

Follow-Up

  • in patients with acquired hemophilia A, after inhibitor eradication
    • United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) recommends monitoring factor VIII levels at least monthly for first 6 months (UKHCDO Grade 2B)(1)
    • International Acquired Hemophilia A recommends follow-up with factor VIII activity monitoring monthly during first 6 months, every 2-3 months up to 1 year, and every 6 months afterwards (International AHA Grade 1B) (Haematologica 2020 Jul;105(7):1791)
    • after remission is achieved, continue to monitor patient for ≥ 12 months because of significant risk of recurrence (AICE Grade 1C)(2)
    • check factor VIII levels in subsequent years in patients who need to have surgery or invasive procedures at high risk of bleeding(1,2)

Complications

  • bleeding
    • bleeding is a complication and clinical manifestation of acquired inhibitors of coagulation; severity of bleeding can vary ranging from asymptomatic to severe, limb-threatening or life-threatening bleeding(1,2,3,4)
    • severity of bleeding can also vary according to specific coagulation factor inhibitor; for example severe and life-threatening bleeding is common in patients with acquired hemophilia A (AHA)(1,2,4)
    • patients may experience ≥ 1 type of bleeding; in patients with AHA, subcutaneous bleeding/bruising is most common, occurring in > 80% of patients(1,2,4)
    • see History and Physical for additional information on various bleeding manifestations associated with acquired inhibitors of coagulation
  • thrombosis
    • treatment for hemostasis may lead to thromboembolism in patients with high risk (such as older age, pre-existing comorbidities, and immobilization, in addition to risk from hemostatic treatment with activated coagulation factor concentrates)(2)
    • consider thromboprophylaxis, especially at a time when the inhibitor has presumably eradicated and factor levels can be significantly higher than normal, adding to further risk(1,2)
    • see Thromboprophylaxis for additional information on thromboprophylaxis strategies in patients with acquired inhibitors of coagulation
    • for information on treatment of thrombotic complications see
      • Pulmonary Embolism Treatment
      • Management of Deep Vein Thrombosis (DVT)
      • Acute Ischemic Stroke
      • Thrombolytics for ST-Elevation Myocardial Infarction (STEMI)

Prognosis

  • survival
    • severity of bleeding at presentation not predictive of severity of future bleeding and fatal bleeding may still occur until inhibitors are eradicated(1,2,3)
    • fatal bleeding is usually associated with gastrointestinal blood loss, but may also occur with intracranial, retroperitoneal, or postoperative bleeding(1,4)
    • immunosuppressive therapy (IST) increases risk of infections, especially in older adults; death from sepsis has been reported in patients with acquired hemophilia A (AHA)(3)
    • 44% all-cause mortality and 24% acquired hemophilia A (AHA)-related mortality reported at 2 years in patients with AHA in Finland, with majority of deaths occurring within 3 months of diagnosis
      •  based on population-based retrospective cohort study
      • 55 patients (median age 76 years, 51% female) diagnosed with AHA between 2006 and 2019 in Finland were assessed
        • 100% had bleeding (severe bleeding in 93%) at diagnosis
        • median time from first reported symptom to diagnosis 7 days
        • 62% had no underlying disease
      • 78% received hemostatic therapy (mainly recombinant activated factor VII or activated prothrombin complex concentrate)
      • 98% received IST, including steroid monotherapy or combination therapy with steroids plus azathioprine, cyclophosphamide, or rituximab
      • AHA-related mortality defined as death due to bleeds, IST-related infection, or hemostatic therapy-related thrombotic events
      • clinical remission defined as normalization of factor VIII level (twice > 50 units/dL) and discontinuation of IST
      • median follow-up of 26 months
      • outcomes
        • all-cause mortality 35% at 3 months, 36% at 12 months, and 44% at 24 months
        • AHA-related mortality 20% at 3 months, 22% at 12 months, and 24% at 24 months
        • clinical remission in 71%
        • median time to remission 56 days
      • causes of death included fatal bleeding (29%), IST-related infection (21%), IST-unrelated infection (8%), cardiac event (8%), hemostatic therapy-related thrombosis (4%), and malignancy (4%)
      • all patients who did not achieve clinical remission died within 2 years of diagnosis
      • Reference – Haemophilia 2024 Jun 28 early online
    • 55% mortality reported at 2 years in patients with acquired hemophilia A (AHA) in Hong Kong, with 50% of deaths due to immunosuppressive therapy-related sepsis and 13% due to AHA-related bleeding
      •  based on retrospective cohort study
      • 165 patients (median age 80 years, 53% female, 100% Chinese) diagnosed with AHA between 2012 and 2021 in Hong Kong were assessed
      • 72% had major bleeding, and 28% had minor bleeding
      • 80.6% received ≥ 1 line of hemostatic agent, most commonly recombinant factor VIIa (37%), tranexamic acid (27%), and anti-inhibitor coagulant complex (22%)
      • 93.9% received ≥ 1 line of immunosuppressive therapy, most commonly steroids alone (52.7%) and steroids plus cyclophosphamide (28.5%)
      • outcomes at mean follow-up of 2 years
        • mortality 55%
        • median overall survival 2.3 years
        • complete remission rate 54%
        • median time to complete remission 244 days
      • of 91 deaths, 49.5% were due to immunosuppressive therapy-related sepsis, 13.2% due to AHA-related bleeding, and 9.9% due to malignancy
      • Reference – Thromb Res 2024 Jan;233:138
    • 27.9% mortality at median 75 days after presentation with fatal bleeding reported in 17.2% and death from IST complications reported in 16.1% of all deaths in adults with AHA
      •  based on cohort study
      • 501 adults (median age 73 years) with AHA enrolled in the European Acquired Hemophilia Registry (EACH2) between 2003 and 2008 were evaluated
      • AHA were idiopathic in 52%; associated conditions included malignancy, autoimmune diseases, and pregnancy
      • at diagnosis, median factor VIII activity 2 units/dL (< 50 units/dL in all adults) and median inhibitor titer 12.8 Bethesda units/mL
      • 474 patients had bleeding at presentation (94.7%), mostly spontaneous bleeds, but some cases were caused by trauma, surgery, or associated with peripartum period
        • severe bleeding (defined as hemoglobin level < 8 g/dL [80 g/L], drop by > 2 g/dL [20 g/L], or life- or limb-threatening, central nervous system, deep muscle, or retroperitoneal bleeding) in 70.3% of bleeding cases
        • mild bleeding in 28.9% of bleeding cases
      • 70.5% of patients with bleeding at presentation (85% of those with severe bleeding events and 14.4% of those with mild bleeding events) received ≥ 1 hemostatic therapy
      • 95% of patients also received IST
      • out of 312 evaluable adults, mortality 27.9% at median follow-up of 75 days; cause of death included ≥ 1 of the following (% of deaths)
        • fatal bleeding in 17.2%
        • IST complications in 16.1%
        • underlying disease in 46%
        • other causes/unknown in 37.9%
      • Reference – J Thromb Haemost 2012 Apr;10(4):622full-text
    • factor VIII activity < 1 unit/dL, malignancy, and World Health Organization (WHO) performance status > 2 each associated with poorer overall survival in adults with AHA
      •  based on prospective cohort study
      • 102 adults (median age 74 years) with AHA treated with immunosuppressive regimen developed by Acquired Hemophilia Working Group of the German, Austrian and Swiss Thrombosis and Hemostasis Society (GTH) were followed for mean 262 days
      • GTH immunosuppressive regimen involves initial treatment with prednisolone, followed by addition of cyclophosphamide or rituximab as needed
      • idiopathic or no underlying conditions identified in 67%; in other cases, underlying conditions/setting associated with AHA included postpartum, autoimmune disease, and malignancy
      • at baseline, median factor VIII activity 1.4 units/dL and median inhibitor concentration 19 Bethesda units/mL
      • all but 1 adult (who died prior to treatment) initiated immunosuppressive treatment
      • 85 adults achieved partial remission, defined as factor VIII activity > 50 units/dL, and no active bleeding after stopping hemostatic agent for > 24 hours, after median 31 days
      • 62 adults achieved complete remission, defined as partial remission plus negative inhibitor test, prednisolone tapered to < 15 mg/day, and any other ISTs stopped, after median 79 days
      • 1-year overall survival 68%; common causes of death included
        • infections in 19 patients
        • cardiovascular disorders in 6 patients
        • underlying disorder in 3 patients
        • bleeding in 3 patients
      • in multivariable analysis, factors significantly associated with poorer overall survival included
        • factor VIII activity at baseline < 1 unit/dL (odds ratio [OR] 2.4, 95% CI 1.1-5.22)
        • malignancy (OR 2.91, 95% CI 1.12-7.52)
        • WHO performance status > 2 (OR 3.38, 95% CI 1.55-7.37)
      • Reference – GTH-AH 01/2010 study (Blood 2015 Feb 12;125(7):1091full-text)
  • recurrence/relapse
    • relapse reported to occur in 10%-20% of patients with AHA; patients should be informed about signs and symptoms of recurrence and report bleeding or bruising early(1,3)
    • in patients with pregnancy-associated AHA, relapse in subsequent pregnancies is uncommon, but patients should be informed of the possibility(1,2)
    • 8.5% relapse rate reported in 165 Chinese patients (median age 80 years, 53% female) diagnosed with AHA between 2012 and 2021 in Hong Kong (Thromb Res 2024 Jan;233:138)
    • 15% relapse rate reported in patients diagnosed with acquired hemophilia A in Finland between 2006 and 2019
      •  based on population-based retrospective cohort study
      • 55 patients (median age 76 years, 51% female) diagnosed with AHA between 2006 and 2019 in Finland were assessed
      • 100% had bleeding (severe bleeding in 93%) at diagnosis
      • 78% received hemostatic therapy (mainly recombinant activated factor VII or activated prothrombin complex concentrate)
      • 98% received IST, including steroid monotherapy (31%), steroid plus azathioprine (29%), steroid plus cyclophosphamide (22%), steroid plus rituximab (7%), and steroid plus rituximab plus azathioprine or cyclophosphamide (9%)
      • clinical remission defined as normalization of factor VIII level (twice > 50 units/dL) and discontinuation of IST
      • relapse defined as factor VIII level < 50 units/dL after remission
      • median follow-up of 26 months
      • clinical remission rate 71% overall
        • 100% with steroid plus rituximab
        • 88% with steroid plus azathioprine
        • 60% with steroid plus rituximab plus azathioprine or cyclophosphamide
        • 58% with steroid plus cyclophosphamide
        • 65% with steroid monotherapy
      • relapse rate 15% overall (median time to relapse 527 days)
        • 25% with steroid plus rituximab
        • 19% with steroid plus azathioprine
        • 0% with steroid plus rituximab plus azathioprine or cyclophosphamide
        • 0% with steroid plus cyclophosphamide
        • 24% with steroid monotherapy
      • Reference – Haemophilia 2024 Jun 28 early online
    • relapse in 20% of patients with AHA who had achieved complete remission with IST
      •  based on population-based cohort study
      • 172 children and adults (median age 78 years) with AHA identified in United Kingdom between 2001 and 2003 were evaluated
      • AHA idiopathic in 63%; in other cases, AHA-associated conditions included malignancy, autoimmune diseases, and pregnancy
      • 30% of patients had severe factor VIII level deficiency (≤ 1 unit/dL)
      • baseline inhibitor titer
        • 0-10 Bethesda units/mL in 6.2%
        • 11-100 Bethesda units/mL in 80.6%
        • 101-1,000 Bethesda units/mL in 11.1%
      • 65.8% of 149 patients with bleeding received ≥ 1 hemostatic therapy
      • 95% of 151 patients with data available received IST
      • 71% of 144 patients with follow-up data achieved complete remission defined as normal factor VIII activity, and immunosuppression stopped or reduced to doses used before hemophilia developed without relapse
      • 71% of patients achieved complete remission defined as normal factor VIII, and immunosuppression stopped or reduced to doses used before hemophilia developed without relapse
      • of patients who achieved complete remission, 20% had relapse
      • Reference – Blood 2007 Mar 1;109(5):1870

Prevention and Screening

Prevention

  • not applicable

Screening

  • presence of acquired inhibitors should be suspected in patients presenting with recent onset of abnormal bleeding, especially in the absence of family or personal history of bleeding(1)
  • see Diagnosis for information on coagulation screening tests and diagnosis of acquired inhibitors of coagulation

Guidelines and Resources

Guidelines

International Guidelines

United States Guidelines

  • National Hemophilia Foundation (NHF) Medical and Scientific Advisory Counsil (MASAC) recommendations on products licensed for the treatment of hemophilia and other bleeding disorders can be found at MASAC 263 2020 Sep 3

United Kingdom Guidelines

  • United Kingdom Haemophilia Center Doctors’ Organization (UKHCDO) guideline on diagnosis and management of acquired coagulation inhibitors can be found in Br J Haematol 2013 Sep;162(6):758

European Guidelines

Review Articles

  •  to search MEDLINE for (Acquired Inhibitors of Coagulation) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

  • DynaMed Editors have not identified patient education materials that meet our criteria for inclusion (freely accessible, non-promotional, topic-specific). We will continue to search for acceptable materials and welcome your suggestions.

References

General References Used

  1. W Collins P, Chalmers E, Hart D, et al; United Kingdom Haemophilia Centre Doctors’ Organization. Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO. Br J Haematol. 2013 Sep;162(6):758-73.
  2. Franchini M, Castaman G, Coppola A, et al; AICE Working Group. Acquired inhibitors of clotting factors: AICE recommendations for diagnosis and management. Blood Transfus. 2015 Jul;13(3):498-513full-text.
  3. Kruse-Jarres R, Kempton CL, Baudo F, et al. Acquired hemophilia A: Updated review of evidence and treatment guidance. Am J Hematol. 2017 Jul;92(7):695-705full-text.
  4. Coppola A, Favaloro EJ, Tufano A, Di Minno MN, Cerbone AM, Franchini M. Acquired inhibitors of coagulation factors: part I-acquired hemophilia A. Semin Thromb Hemost. 2012 Jul;38(5):433-46.
  5. Franchini M, Lippi G, Favaloro EJ. Acquired inhibitors of coagulation factors: part II. Semin Thromb Hemost. 2012 Jul;38(5):447-53.

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