Hypercoagulable State

Hypercoagulable State 

Hypercoagulable state is an inherited or acquired condition associated with an increased risk of thrombosis.

A classification of hypercoagulable state is described in the below table.

Classification of Hypercoagulable State

HereditaryMixedAcquired
Loss of Function
Antithrombin deficiencyHyperhomocysteinemiaPrevious venous thromboembolism
Protein C deficiencyObesityPregnancy, puerperium
Protein S deficiencyCancer
Drug-induced:
Heparin-induced thrombocytopenia
Prothrombin complex concentrates
l-Asparaginase
Hormonal therapy
Gain of Function
Factor V LeidenPostoperative
Prothrombin FII G20210AMyeloproliferative disorders
Elevated factor VIII, IX, or XI

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Synonym of Hypercoagulable State

  • Thrombophilia

Incidence, Prevalence, Predominant Sex and Age

Significant variations in the prevalence rates and thrombotic risks for hypercoagulable states are reported.

This may reflect geographic variation in the prevalence of genetic defects, different populations, or the presence of other unidentified thrombophilic risk factors.

When thrombosis occurs, it is often associated with an acquired risk factor (e.g., surgery, pregnancy, oral contraceptive [OC] use).

Hypercoagulable Conditions

Prevalence in General Population (%)Prevalence in Population with Thrombosis (%)A/V EventsRelative Risk of Thrombosis
FVL mutation5% of whites; rare in nonwhites12%-40%VHeterozygous: 3-7; homozygous: 80
Prothrombin G20210A mutation3% of whites; rare in nonwhites6%-18%V3
AT deficiency0.02%1%-3%V20-50
PC deficiency0.2%-0.4%3%-5%V7-15
PS deficiency0.03%-0.1%1%-5%V5-11
Antiphospholipid antibody syndrome1%-2%5%-21%V + A2-11

A, Arterial; AT, antithrombin; FVL, factor V Leiden; PC, protein C; PS, protein S; V, venous.

What increases the Risk of Hypercoagulable State?

Here are the conditions which increases the Risk of Hypercoagulable State.

Family history of thrombosis, increasing age, tobacco use, immobility, surgery, prior history of deep vein thrombosis (DVT) pregnancy, hormone replacement therapy, trauma, connective tissue disease, underlying malignancy, medications (megestrol acetate, tamoxifen, oral contraceptives).

Potential prothrombotic states are summarized in the below table.

Potential Prothrombotic States

Congenital
Deficiency of anticoagulants
AT-III, protein C or protein S, plasminogen
Resistance to cofactor proteolysis
Factor V Leiden
High levels of procoagulants
Prothrombin 20210 mutation
Damage to endothelium
Acquired
Obstruction to flow indwelling lines
Pregnancy
Polycythemia/dehydration
Immobilization
Injury
Trauma, surgery, exercise
Inflammation
IBD, vasculitis, infection, Behçet syndrome
Hypercoagulability
Malignancy
Antiphospholipid syndrome
Nephrotic syndrome
Oral contraceptives
l-Asparaginase
Rare Other Entities
Congenital dysfibrinogenemia
Acquired
Paroxysmal nocturnal hemoglobinuria
Thrombocythemia
Vascular grafts

AT-III, Antithrombin III; IBD, inflammatory bowel disease.

From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.

Genetics

  • •Most people with a genetic defect will not have thrombotic disease.
  • •Approximately half of patients with unprovoked thrombosis have an identifiable inherited thrombophilia. There is a low risk of recurrent thrombosis in patients with a single genetic defect. Multiple genetic defects are not uncommon (1% to 2% prevalence in patients with idiopathic venous thromboembolism [VTE]); a strong synergistic effect occurs when multiple defects are present.

Physical Findings & Clinical Presentation

  • •Inherited thrombophilia is usually associated with VTE, most commonly DVT.
  • •Some acquired thrombophilias are associated with arterial thrombosis. 
  • •Pregnancy complications.
  • •Medical conditions associated with increased risk of thrombosis.

What are the causes of Hypercoagulable State?

  • •Thrombosis is often a multifactorial process with genetic, environmental, and acquired factors. The below tables describe causes of acquired and inherited deficiencies in antithrombin, protein C, and protein S.
  • •All thrombotic factors ultimately lead to blood flow stasis, endothelial damage, or change in blood constituents to cause thrombosis. These three components of thrombosis are known as Virchow’s triad.
  • •Thrombotic risk increases with use of OCs or hormone replacement therapy (HRT) and during the pregnancy/postpartum period.
  • •Adverse pregnancy outcomes may be caused by thrombosis of the uteroplacental circulation.

Types of Inherited Antithrombin Deficiency

Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TypeAntigenActivity (No Heparin)Activity (with Heparin)
ILowLowLow
II (active site defect)NormalLowLow
II (heparin-binding site defect)NormalNormalLow

Causes of Acquired Antithrombin Deficiency

Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Decreased SynthesisIncreased ConsumptionEnhanced Clearance
Hepatic cirrhosisMajor surgeryHeparin
Severe liver diseaseAcute thrombosisNephrotic syndrome
l-AsparaginaseDisseminated intravascular coagulation
Severe sepsis
Multiple trauma
Malignancy
Prolonged extracorporeal circulation

Types of Inherited Protein C Deficiency

Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TypeAntigenActivity
ILowLow
IINormalLow

Types of Inherited Protein S Deficiency

Hoffman R et al: Hematology: basic principles, and practice ed 7, Philadelphia, 2018, Elsevier.

TypeTotal Protein SFree Protein SProtein S Activity
ILowLowLow
IINormalNormalLow
IIINormalLowLow

Differential Diagnosis

Inherited

Factor V Leiden (FVL) mutation:

  • •Autosomal-dominant mutation with low penetrance
  • •Causes activated protein C resistance (APCR); 90% of APCR is caused by FVL mutation
  • •Most common inherited thrombophilia; accounts for 40% to 50% of cases
  • •OC use in heterozygous carriers is associated with an eightfold increased risk of VTE compared with noncarriers and a thirty-fivefold increased risk of VTE compared with noncarriers not using OCs
  • •May be associated with cardiovascular disease in select high-risk subgroups

Prothrombin G20210A mutation:

  • •Autosomal-dominant mutation with low penetrance
  • •OC use in heterozygous carriers is associated with a sixteenfold increased risk of VTE compared with noncarriers not using OCs
  • •May be associated with cardiovascular disease in select high-risk subgroups and young patients with ischemic stroke
  • •Causes increased mRNA accumulation and protein synthesis, leading to elevated prothrombin plasma concentrations

Protein C, protein S, antithrombin (AT) deficiency:

  • •Autosomal-dominant inheritance; many mutations identified for each of these conditions
  • •Decreased level (type I deficiency) or abnormal function (type II deficiency)
  • •First episode of thrombosis is usually in young adults

Protein C and protein S:

  • •Homozygous condition is very rare; usually associated with lethal thrombosis in infancy
  • •Associated with warfarin-induced skin necrosis, which occurs secondary to depletion of vitamin K–dependent anticoagulant factors sooner than procoagulant factors in the first few days of therapy

AT deficiency:

  • •Most thrombogenic of the inherited thrombophilias; 50% lifetime risk of thrombosis.
  • •Homozygous condition is very rare, probably not compatible with normal fetal development.
  • •Arterial thrombosis can occur rarely.
  • •Can cause heparin resistance.

Other possible causes: Non-O blood group, dysfibrinogenemia, elevated thrombin-activatable fibrinolysis inhibitor, elevated factor IX and factor XI levels

Acquired

Antiphospholipid antibody syndrome (APS):

  • •Most common cause of acquired thrombophilia
  • •Can present as arterial or venous thrombosis, recurrent pregnancy loss, and adverse pregnancy outcomes
  • •Thromboembolic events occur in up to 30% of population; high risk of recurrent thrombosis (up to 70% reported)
  • •See “ Antiphospholipid Antibody Syndrome ” for more information

Conditions associated with increased risk of thrombosis:

  • •Prior thrombosis
  • •Trauma
  • •Medical illness: Heart failure, respiratory failure, infection, diabetes mellitus, obesity, nephrotic syndrome, inflammatory bowel disease
  • •Chronic hemolysis–paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, sickle cell anemia
  • •Pregnancy (sixfold increased risk of VTE), postpartum, OC use (fourfold increased risk, higher risk with third-generation OCs), transdermal contraceptive patch, HRT (twofold increased risk), tamoxifen, raloxifene
  • •Immobilization, travel
  • •Surgery (especially orthopedic), central venous catheters
  • •Hyperviscosity syndromes
  • •Myeloproliferative neoplasms
  • •Malignancy: Disease or treatment related
  • •Heparin-induced thrombocytopenia and thrombosis
  • •Smoking

Workup

  • •History (presence of conditions or use of medications predisposing to thrombosis, family history of thrombosis), physical examination, laboratory tests, imaging studies. Routine investigations to evaluate a patient with thrombosis are summarized in the box.
TestAbnormalityDiagnostic Information
Complete blood countElevated hematocrit
Increased white count
Increased platelet count
Leukopenia
Thrombocytopenia
Myeloproliferative disorder (e.g., essential thrombocythemia, polycythemia vera); may be found in paroxysmal nocturnal hemoglobinuria; if associated with heparin administration, consider heparin-induced thrombocytopenia
Blood filmLeukoerythroblastic changesUnderlying neoplasm invading bone marrow
Liver function testsAbnormal testsMay point to malignancy
Renal functionImpaired renal functionAssess prior to anticoagulation with heparin, low-molecular-weight heparin or new oral anticoagulants
UrinalysisProteinuriaNephrotic syndrome; may be associated with venous thromboembolism or renal vein thrombosis
PT and aPTTProlonged PT and aPTTTo enable safe anticoagulation to proceed if required
Need to exclude lupus anticoagulant

aPTT, Activated partial thromboplastin time; PT, prothrombin time.

TestAbnormalityDiagnostic Information
Complete blood countElevated hematocrit
Increased white count
Increased platelet count
Leukopenia
Thrombocytopenia
Myeloproliferative disorder (e.g., essential thrombocythemia, polycythemia vera); may be found in paroxysmal nocturnal hemoglobinuria; if associated with heparin administration, consider heparin-induced thrombocytopenia
Blood filmLeukoerythroblastic changesUnderlying neoplasm invading bone marrow
Liver function testsAbnormal testsMay point to malignancy
Renal functionImpaired renal functionAssess prior to anticoagulation with heparin, low-molecular-weight heparin or new oral anticoagulants
UrinalysisProteinuriaNephrotic syndrome; may be associated with venous thromboembolism or renal vein thrombosis
PT and aPTTProlonged PT and aPTTTo enable safe anticoagulation to proceed if required
Need to exclude lupus anticoagulant

aPTT, Activated partial thromboplastin time; PT, prothrombin time.

  • Age-appropriate cancer screening.
  • •No consensus exists regarding screening for thrombophilia; few cost-effectiveness or outcomes data are available. Thrombophilia screening is probably overused, as results usually do not change management.
  • •Thrombophilia screening is not recommended for primary prevention of VTE; some advocate testing prior to OC use or pregnancy in women with a strong family history of thrombosis or thrombophilia. The above box summarizes recommendations regarding when to perform a thrombophilia screen. Essential tests for thrombophilia screening are described in the below box.

When to Perform a Thrombophilia Screen

Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Clinical Scenario

  • •First episode of unprovoked venous thromboembolism in individuals younger than 40 yr of age
  • •Thrombosis in an unusual site (e.g., cerebral or mesenteric thrombosis)
  • •Two or more first-degree relatives with unprovoked thrombosis
  • •Three or more early pregnancy losses, or one or more fetal deaths after 10 wk gestation
  • Essential Tests for Thrombophilia ScreeningHoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.APC, Activated protein C; Ig, immunoglobulin.
    • •Basic coagulation screen
      • 1.International normalized ratio (INR): To exclude warfarin effect—warfarin will lower protein C and S levels
      • 2.Activated partial thromboplastin time (aPTT): To exclude heparin effect—heparin will lower antithrombin levels
    • •Functional assay for antithrombin (with heparin to detect type II defects)
    • •Functional assay for protein C
    • •Functional assay for protein S (immune assays for total and free protein S)
    • •APC resistance assay: With genetic test for factor V Leiden for confirmation of abnormal results
    • •Genetic test for FIIG 20210A gene mutation
    • •Anticardiolipin and β2-glycoprotein-1 antibodies (IgG and IgM) and lupus anticoagulant assay
  • •Screening not recommended if VTE was associated with an identified risk factor. A possible exception is thrombosis associated with pregnancy, the postpartum period, or with OC use.
  • •Reasonable to pursue workup for VTE with weak triggers, a strong family history, and female family members of childbearing age; consider testing for FVL, prothrombin G20210A mutation, protein C, protein S, and AT deficiency. Consider testing for APS if extensive DVT or pulmonary embolism (PE).
  • •Unprovoked VTE:
    • 1.Screen individuals for APCR, prothrombin G20210A mutation, protein C, protein S, AT deficiency, and APS if any of the following are present: <50 yr of age at first episode of thrombosis + strong family history of thrombosis or female family member of childbearing age, thrombosis in unusual anatomic location (cerebral veins or splanchnic veins; if splanchnic veins, consider testing as well for myeloproliferative neoplasms [MPN] and paroxysmal nocturnal hemoglobinuria [PNH]).
    • 2.Screen all others for APS.
  • •Arterial thrombosis: Screen for APS.
  • •note: Routine screening for factor VIII level or hyperhomocysteinemia is not recommended.

Timing of Workup

  • •Ideally >3 wk after discontinuation of vitamin K antagonists (VKA) and >2 days after discontinuation of direct oral anticoagulant (DOAC) (except for APS, which requires prolonged anticoagulation).
  • •note: Acute thrombosis, anticoagulation, pregnancy, and many medical conditions can affect the results and must be considered in the timing and interpretation of the workup.

Laboratory Tests

  • •Initial workup: CBC with peripheral smear, electrolytes, calcium, creatinine, blood urea nitrogen (BUN), liver function tests, prothrombin time/partial thromboplastin time, prostate-specific antigen (in men aged >50 yr), urinalysis.
  • •note: Genetic counseling and written informed consent should be obtained before genetic testing. Abnormal nongenetic tests should be repeated after 6 wk to decrease false-positive results.
  • •APC-resistance assay tests for factor V Leiden mutation. Presence of lupus anticoagulant causes false positives. Follow-up positive result with a confirmatory genetic test.
  • •Prothrombin G20210A mutation testing.
  • •AT, protein C, and protein S deficiency: Functional assays are initial tests, then follow up positive result with antigenic assay to determine the type of deficiency. Note that antigenic assays for protein S should measure free and total levels. The functional assays for protein C and S deficiency testing may be falsely low in the presence of APCR or elevated factor VIII level and falsely high if lupus anticoagulant is present.
  • •APS: Any one of the following found elevated on two occasions at least 12 wk apart: Lupus anticoagulant, anticardiolipin antibodies, or anti–B2-glycoprotein-I antibodies.

Imaging Studies

Chest radiograph and other tests as appropriate to diagnose thrombosis and rule out associated conditions

How is Hypercoagulable State treated?

Nonpharmacologic Therapy

OC/HRT use and smoking should be avoided.

Prophylaxis

  • •Prophylactic anticoagulation in high-risk situations.
  • •Patients with AT deficiency may benefit from antithrombin concentrates in high-risk situations.
  • •Pregnancy prophylaxis: Timing and intensity of therapy is based on the patient’s risk (genetic or acquired defect and clinical history). Women with thrombophilia and recurrent adverse pregnancy outcomes may benefit from prophylaxis with heparin (low-molecular-weight heparin most commonly used) and low-dose aspirin.

Acute General Treatment

Initial therapy is the same as for individuals with and without thrombophilia, with exceptions for protein C, AT, and APS deficiency as detailed in the following.

Venous thrombosis:

  • •DOACs such as Xa inhibitors (rivaroxaban and apixaban) have been FDA-approved for treatment in acute DVT and are currently recommended as first-line therapy. They have been found to be noninferior to warfarin, appear easier to use with fewer drug interactions, and have a trend toward less major bleeding.
  • •In patients unable to take DOACs, begin low-molecular-weight heparin (LMWH) and warfarin simultaneously. Continue heparin for at least 5 days and until international normalized ratio (INR) is therapeutic for 2 consecutive days; continue warfarin for at least 3 mo. Aim for INR of 2 to 3. Unfractionated heparin (UH) or fondaparinux (factor Xa inhibitor) may be used as alternatives to LMWH. LMWH is preferred over UH (except in patients with massive pulmonary embolism, increased risk of bleeding, or renal failure) because of equivalent or superior effectiveness and a better safety profile.
  • •Thrombophilia is not associated with a higher risk of recurrent VTE during warfarin therapy, with the exception of cancer patients in whom LMWH for 3 to 6 mo is associated with lower rates of recurrence than warfarin therapy.
  • •In pregnancy, anticoagulate with heparin throughout pregnancy and for at least 6 wk postpartum. Minimum duration of anticoagulation should be 6 mo. LMWH is preferred over UH. Warfarin may be used postpartum.
  • •Consider thrombolysis or thrombectomy in patients with massive pulmonary embolism or large proximal lower extremity DVT.

Protein C deficiency:

  • •Warfarin-induced skin necrosis: Discontinue warfarin, give vitamin K, and start heparin anticoagulation. Consider protein C replacement with protein C concentrate or fresh frozen plasma. Warfarin may be restarted at a low dose (2 mg daily for 3 days and increase by 2 to 3 mg daily until target INR is reached). Continue heparin for at least 5 days and until warfarin-induced anticoagulation is achieved.

AT deficiency:

  • •AT concentrates may be used if difficulty achieving anticoagulation (heparin resistance), severe thrombosis, or recurrent thrombosis despite adequate anticoagulation.

APS:

  • •Warfarin is superior to rivaroxaban in patients with APS. The RAPS trial randomized patients with APS to receive either rivaroxaban or warfarin and found significantly higher rates of thrombosis in the rivaroxaban group. A subsequent trial noted increased endogenous thrombin potential (a marker of less effective anticoagulation) in APS patients switched to rivaroxaban following initial VKA therapy compared to those continued on warfarin. This study was not powered to assess clinical efficacy.

Arterial thrombosis:

  • •Anticoagulation and evaluation for thrombolysis or surgery

Chronic Treatment

  • •Optimal duration of anticoagulation remains unknown. Length of therapy may be individualized by assessing the risk of recurrence. Residual thrombosis (on ultrasonography) or elevatedd-dimer levels after completion of anticoagulation are associated with an increased risk of recurrence. With these findings, consider prolonging anticoagulation.
  • •Must consider risk and benefit; risk of major bleeding 2% to 3% annually in general population on anticoagulation but higher in the elderly (7% to 9% per yr). Long-term anticoagulation is usually not indicated given the low risk of recurrent thrombosis for most conditions and the bleeding risk associated with anticoagulation.
  • •Indefinite anticoagulation considered if any of the following:
    • 1.Life-threatening thrombosis or thrombosis at an unusual site
    • 2.More than a single genetic defect
    • 3.Presence of AT deficiency or APS
    • 4.Unprovoked DVT or PE with low bleeding risk
    • 5.>1 Provoked DVT or PE with low bleeding risk
  • •Patients with active cancer may benefit from indefinite anticoagulation.

Disposition

Depends on underlying condition

Referral

Hematology, maternal-fetal medicine, obstetric medicine

Pearls & Considerations

  • •Women with thrombophilic defects but no prior history of venous thromboembolism, or family history of the same, likely do not require antepartum prophylaxis or postpartum treatment, but definitive data are lacking. A summary of these recommendations is provided in the below table.

Management of Women with a History of Venous Thrombosis during Pregnancy and the Puerperium

Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Clinical HistoryThrombophiliaAntepartumPostpartum 
Prior VTE due to a transient risk factorNoSurveillanceYes
Prior VTE due to pregnancy or estrogensYes or noProphylactic LMWHYes
Prior idiopathic VTEYes or noProphylactic LMWHYes
Recurrent VTEYes or noTreatment dose LMWHResume long-term anticoagulation
No prior VTEPositive family historyAntithrombin deficiency; homozygous FII G20210A; or Factor V Leiden; or dual heterozygosity for both mutationsProphylactic or intermediate dose LMWHYes

LMWH, Low-molecular-weight heparin; VTE, venous thromboembolism.

a Postpartum prophylaxis involves a 6-wk course of prophylactic doses of LMWH or dose-adjusted warfarin (target INR: 2.0 to 3.0).

  • DOACs and warfarin therapy effectively reduce the risk of recurrent VTE; when therapy is discontinued VTE risk increases.
  • •Warfarin is preferred over DOAC for APS patients based on the data showing rivaroxaban to be inferior to warfarin in this population.
  • •Previous episode of VTE is a major risk factor for recurrence regardless of the presence of thrombophilia. Risk is greatest in the first 2 yr after thrombosis. 20% of all patients with unprovoked VTE have recurrence within 5 yr.
  • •Genetic risk factors for thrombosis in nonwhites remain largely unknown.
  • •Interpreting workup: Many medical conditions cause acquired abnormalities.
    • 1.Acute thrombosis may be associated with lupus anticoagulant, increased anticardiolipin antibodies, and elevated factor VIII levels
      • a.Heparin therapy: Antithrombin levels decrease by up to 30%; can affect lupus anticoagulant testing depending on available assay
      • b.Warfarin therapy: Cannot measure protein C and protein S (levels and function decrease); antithrombin levels may increase; can affect lupus anticoagulant testing
      • c.Acute thrombosis: Antithrombin level, protein C, and protein S levels may be falsely lowered
    • 2.Protein C, protein S, and antithrombin levels decrease with surgery, liver disease, disseminated intravascular coagulation, and chemotherapy. Protein C level also decreases with severe infection but levels increase with age and hyperlipidemia. Protein S and antithrombin levels also decrease with nephrotic syndrome, pregnancy, and estrogen therapy (HRT, OCs)
    • 3.APCR is increased with pregnancy, estrogen therapy (HRT, OCs), and certain cancers; elevated factor VIII level and antiphospholipid antibodies can cause APCR

Prevention

Risk of postthrombotic syndrome decreases if compression stockings are worn for at least 1 yr, starting in the first month after the DVT.

Patient & Family Education

  • National Blood Clot Alliance
  • 120 White Plains Road, Suite 100
  • Tarrytown, NY 10591

Suggested Readings

  • Andrade D., et al.: 15th International Congress on Antiphospholipid Antibodies Task Force on Antiphospholipd Syndrome Treatment Trends Report. In Erkan D., Lockshin M. (eds): Antiphospholipid syndrome., ed 1 2017. Springer International Publishing, pp. 317.
  • Baglin T., et al.: Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149: pp. 209-220.
  • Connors J.M.: Thrombophilia testing and venous thrombosis. New Engl J Med 2017; 377: pp. 1177-1187.
  • Couturaud F., et al.: Factors that predict thrombosis in relatives of patients with venous thromboembolism. Blood 2014; 124: pp. 2124-2130.
  • Kearon C., et al.: Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149: pp. 315-352.
  • Kunk P.R.: Direct oral anticoagulants in hypercoagulable states. J Thromb Thrombolysis 2017; 43 (1): pp. 79-85.

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