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9 Interesting Facts of Glanzmann Thrombasthenia
- Glanzmann thrombasthenia is a rare bleeding disorder caused by defective platelet membrane glycoprotein IIb/IIIa (integrin αIIbβ3), resulting in failure of platelets to aggregate in response to stimuli
- Characterized by a lifelong tendency for mucocutaneous bleeding with an elevated risk of fatal bleeding episodes
- Symptoms, which often manifest shortly after birth or in early childhood, include bruising, purpura, epistaxis, and gingival bleeding; severe bleeding may occur after minor trauma or surgery, and menorrhagia develops at menarche
- Diagnosis is based on presence of platelet count within reference range, prolonged bleeding time, prolonged platelet function analysis time, failure of platelets to aggregate on light transmission aggregometry, glycoprotein receptor deficiency and/or dysfunction on flow cytometry, and/or confirmation of specific genetic mutations
- Treatment is not required on a regular basis but rather only when necessary (eg, to control spontaneous bleeding episodes, after injury, before surgical procedures)
- Local measures (eg, compression, nasal packing, fibrin sealants, gelatin sponges, topical thrombin) alone or in conjunction with antifibrinolytic therapy (eg, tranexamic acid) are indicated for initial treatment of bleeding episodes
- Tranexamic acid is also indicated to control menorrhagia and for prophylaxis before dental extractions and other minor surgical procedures
- Platelet transfusion or recombinant factor VIIa are indicated for bleeding that is not controlled by use of local measures and antifibrinolytics, life-threatening bleeding (eg, head bleeding, massive gastrointestinal bleeding), and prophylaxis before major surgical procedures
- Allogeneic hematopoietic stem cell transplant is last-resort curative therapy for patients with severe recurrent bleeding episodes and/or platelet alloimmunization and whose disorder is refractory to platelet transfusions
Pitfalls
- Glanzmann thrombasthenia is rare and its diagnosis can be challenging; the risk of overlooking the disease is relatively high
- Glanzmann thrombasthenia is a rare bleeding disorder caused by a quantitative or qualitative defect of platelet membrane glycoprotein IIb/IIIa (also known as integrin αIIbβ3), a fibrinogen receptor required for platelet aggregation
- Platelets fail to aggregate in response to stimuli because the receptor is missing or nonfunctional, which results in disrupted platelet function and diminished clot retraction
- Characterized by a lifelong bleeding tendency with elevated risk of fatal bleeding episodes
- Hereditary (by autosomal recessive inheritance) or acquired through autoimmunization or alloimmunization
- Estimated incidence is 1:1,000,000
- Incidence can be as high as 1:200,000 in areas where marriage between close family members is common
Classification
- Classification is based on cause (inherited or acquired); inherited form is further classified according to level of integrin αIIbβ3 expression
- Inherited Glanzmann thrombasthenia
- Type I, characterized by less than 5% of residual αIIbβ3
- Found in approximately 75% of patients
- Features include:
- Absent platelet aggregation
- Normal platelet agglutination
- Absent clot retraction
- Absent α-granule pool fibrinogen (platelet fibrinogen content)
- Prolonged bleeding time
- Type II, characterized by 5% to 20% of residual αIIbβ3
- Found in approximately 15% of patients
- Features include:
- Absent platelet aggregation
- Normal platelet agglutination
- Diminished clot retraction
- Subnormal α-granule pool fibrinogen
- Prolonged bleeding time
- Variant-type, characterized by more than 20% of residual αIIbβ3
- Found in approximately 10% of patients
- Features include:
- Absent platelet aggregation
- Normal platelet agglutination
- Variable clot retraction
- Variable α-granule pool fibrinogen
- Prolonged bleeding time
- Type I, characterized by less than 5% of residual αIIbβ3
- Acquired Glanzmann thrombasthenia
- Seen in association with platelet transfusion and a number of hematologic conditions
- Caused by autoantibodies attacking platelet αIIbβ3 or isoantibodies inhibiting proper function
- Characterized by normal platelet glycoprotein expression but a moderate to severe bleeding tendency with rapid onset
- Inherited Glanzmann thrombasthenia
Clinical Presentation
History
- Spontaneous and unpredictable bleeding episodes are the hallmark of the disease
- Bleeding phenotype is heterogeneous, ranging from mild to severe
- Symptoms often manifest shortly after birth, and most cases are diagnosed before age 5 years
- Common symptoms include:
- Epistaxis (79.2%)
- Most common presentation in children; often caused by digital manipulation
- Gingival bleeding (61.9%)
- Purpura or petechiae (43.1%)
- Purpura can manifest in neonates shortly after birth
- Ecchymoses (43.1%)
- Subcutaneous hematoma
- Muscle hematoma
- Epistaxis (79.2%)
- Severe bleeding after minor trauma or surgery may occur
- After menarche, menorrhagia is common in females (73.6%)
- Incidence of bleeding decreases with age; symptomatic children may have improved hemostasis when they reach adulthood
Physical examination
- Examination findings may include:
- Ecchymoses
- Purpura or petechiae
- Pallor due to anemia
- Active bleeding from nose or gingiva
Causes
- Inherited Glanzmann thrombasthenia is caused by genetic mutations resulting in a quantitative or qualitative defect of platelet membrane glycoprotein IIb/IIIa (integrin αIIbβ3), which leads to faulty platelet aggregation and diminished clot retraction
- Acquired Glanzmann thrombasthenia is caused by autoantibodies attacking platelet glycoprotein IIb/IIIa or the production of isoantibodies inhibiting proper platelet function
Risk factors and/or associations
Age
- Disease is generally diagnosed before age 5 years
Sex
- Slightly higher predominance in females compared with males (58% versus 42%)
Genetics
- Inherited in an autosomal recessive manner
- Caused by mutation in ITGA2B gene (at locus 17q21.31), which encodes glycoprotein subunit IIb, or in ITGB3 gene (at locus 17q21.32), which encodes glycoprotein subunit IIIa
- Multiple mutations have been reported; mutations have been found more commonly in ITGA2B than in ITGB3
- Homozygosity of the same mutation is often a result of consanguineous marriage
- Compound heterozygosity for different mutations can be inherited from each parent
- Homozygous or heterozygous mutations at either locus determine severity of Glanzmann thrombasthenia
- Only patients who are either homozygous or compound heterozygous for αIIbβ3 mutations present bleeding symptoms
- Severe hemorrhagic symptoms occur only in those patients who are homozygous
- Patients with simple heterozygosity are asymptomatic and often have no family history of bleeding
- Only patients who are either homozygous or compound heterozygous for αIIbβ3 mutations present bleeding symptoms
- Multiple mutations have been reported; mutations have been found more commonly in ITGA2B than in ITGB3
Ethnicity/race
- More common among ethnic groups with higher incidences of consanguinity
- French Romany (Manouche community) represent 150 cases out of 300 in France
- Iraqi Jews
- Some Arab populations (eg, Palestinian Arabs)
Other risk factors/associations
- Acquired Glanzmann thrombasthenia is secondary to a variety of conditions
- Frequent platelet transfusion (increased risk of platelet alloimmunization)
- Hematologic conditions (association is rare for all conditions)
- Immune thrombocytopenic purpura
- Non-Hodgkin lymphoma
- Multiple myeloma
- Myelodysplastic syndrome
- Hairy cell leukemia
- Acute lymphoblastic leukemia
- Systemic lupus erythematosus
- Antithrombotic therapies with glycoprotein IIb/IIIa antagonists (eg, abciximab, eptifibatide, tirofiban) for treatment of acute coronary events
- Can trigger a transient Glanzmann thrombasthenia–like state
Diagnostic Procedures
Primary diagnostic tools
- Glanzmann thrombasthenia is often overlooked, and despite its rarity it must be included in the differential diagnosis for patients with history of bruising or bleeding episodes and signs of mucocutaneous bleeding
- Diagnosis is based on:
- Presence of platelet count within reference range
- Prolonged bleeding time
- Prolonged platelet function analysis time
- Failure of platelets to aggregate on light transmission aggregometry
- Glycoprotein receptor deficiency and/or dysfunction on flow cytometry
- Confirmation of specific genetic mutations
Laboratory
- CBC with differential
- Hemoglobin level may be within reference range or low, with evidence of iron deficiency anemia
- Platelet count is within reference range (typically on lower end of reference range) and morphology is normal
- Coagulation studies
- Prothrombin time and activated partial thromboplastin time are within reference ranges
- Bleeding time test
- Prolonged bleeding time is suggestive but is insufficient alone to diagnose condition
- Platelet function analysis
- High sensitivity for Glanzmann thrombasthenia but is not specific for it; test can be performed instead of bleeding time test
- Measures platelet closure time when citrated whole blood is passed through collagen-based filters under a high shear flow
- Closure time is prolonged in Glanzmann thrombasthenia
- Light transmission aggregometry
- Gold standard diagnostic tool for assessing platelet function; indicated in all patients with suggestive clinical presentation
- Tests platelet aggregation in response to various platelet agonists
- Performed by adding different agonists (eg, adenosine diphosphate, collagen, epinephrine, arachidonic acid, ristocetin, thrombin receptor–activating peptide, thromboxane A₂ mimetic) to centrifuged platelet-rich plasma samples and monitoring subsequent platelet changes (eg, shape, lag phase, percent and slope of aggregation, deaggregation)
- In Glanzmann thrombasthenia, primary platelet aggregation response is reduced or absent in response to all agonists except ristocetin
- Highly specific for Glanzmann thrombasthenia; however, time consuming and requires experienced laboratory personnel
- May also be difficult to obtain platelet-rich plasma from patients with thrombocytopenia and from pediatric patients
- Flow cytometry
- Uses monoclonal antibodies anti-CD41 (specific for the glycoprotein IIb/integrin αIIb subunit) and anti-CD61 (for the glycoprotein IIIa/integrin β3 subunit) to measure variation in density of platelet receptor
- Markedly decreased levels or absence of CD41 and CD61 identify a deficient or nonfunctional IIb/IIIa (αIIbβ3) receptor, a result consistent with diagnosis of Glanzmann thrombasthenia
- Also particularly useful for diagnosing acquired Glanzmann thrombasthenia; only test that can characterize both functional effect and molecular target of patient’s autoantibody
- Genetic mutation analysis
- Targets the 45 exons encoding glycoprotein IIb/IIIa, along with splice sites of ITGA2B and ITGB3 genes
- Identification of known mutations associated with disease confirms diagnosis
Differential Diagnosis
Most common
- Von Willebrand disease
- Inherited bleeding disorder caused by either a quantitative or qualitative defect of von Willebrand factor; classified as type 1, type 2, or type 3 disease (most severe), according to the spectrum of mutations
- Shared feature is excessive mucocutaneous bleeding (ranging from mild to severe) causing epistaxis, menorrhagia, bruising, and bleeding after minor surgery
- Unlike in Glanzmann thrombasthenia, bleeding history generally becomes more apparent with age
- Differentiating features include musculoskeletal/joint bleeding (37%-42% of patients with type 3 disease), thrombocytopenia (present in some types), and presence of abnormal coagulation parameters
- Differentiated by molecular genetic testing identifying the responsible mutations and assays measuring the levels of specific molecular markers
- Assess level of von Willebrand factor, which maybe within reference range (50-200 units/dL) in type 1 disease to virtually absent in type 3 disease
- Assess level of factor VIII, which is decreased (2-20 units/dL; reference range, 50-150 units/dL) in type 3 disease
- Positive family history is also required for most diagnoses
- Hemophilia
- Inherited bleeding disorder affecting coagulation and characterized by deficiency or dysfunction of factor VIII (in hemophilia type A, the most common) or factor IX (in hemophilia type B)
- An acquired form caused by development of autoantibodies against coagulation factors (most commonly factor VIII) has also been described
- Similar features include spontaneous bleeding episodes of variable frequency and severity; typical presentation includes episodes of recurrent epistaxis (bilateral), excessive bruising with subcutaneous hematoma, and menorrhagia at onset of menarche
- Bleeding episodes may be more frequent in childhood and adolescence than in adulthood
- Differentiating features include frequent spontaneous joint or deep-muscle bleeding (hemarthrosis), intracranial bleeding in the absence of major trauma, prolonged oozing or renewed bleeding after initial bleeding stops, and poor wound healing after surgery or trauma
- Additionally, it rarely affects females (X-linked recessive inheritance)
- Diagnosed on the basis of:
- Low factor VIII clotting activity in the presence of a von Willebrand factor level (hemophilia A) within reference range
- Low factor IX clotting activity and identification of pathogenic variants in F9, the gene encoding factor IX, by molecular genetic testing (hemophilia B)
- Bernard-Soulier syndrome
- Rare inherited bleeding disorder affecting megakaryocyte/platelet lineage (also known as hemorrhagiparous thrombocytic dystrophy)
- The main shared clinical feature is an increased bleeding tendency leading to purpura, epistaxis, menorrhagia, and gingival and gastrointestinal bleeding
- Differentiating features include presence of giant platelets, thrombocytopenia, and lack of platelet aggregation response to ristocetin only
- Differentiated by morphologic analysis that shows very large and rounded platelets (main volume, 11-16 μm³; diameter, 4-10 μm), reduced platelet counts (typically ranging from 20 × 10⁹/L to 100 × 10⁹/L), and flow cytometry analysis using a panel of specific monoclonal antibodies (eg, anti-CD42) to confirm diagnosis
- Afibrinogenemia
- Rare bleeding disorder resulting from mutations in any of the 3 genes that encode the 3 polypeptide chains of fibrinogen
- An acquired form caused by frequent hemodilution and use of clotting factors has also been described
- Shared features include spontaneous bleeding from mucosal surfaces (eg, epistaxis, gingival bleeding, menorrhagia), bleeding after minor trauma, and excessive bleeding during medical procedures
- Differentiating features include presence of musculoskeletal bleeding/hemarthrosis (in approximately 50% of patients, and more frequent than mucosal bleeding), as well as umbilical cord bleeding (associated with up to 85% of congenital cases)
- Diagnosis is based on presence of abnormal coagulation parameters, undetectable functional fibrinogen, and absence or trace amounts of immunoreactive fibrinogen
- Inherited factor VII deficiency
- Rare inherited bleeding disorder characterized by reduced factor VII activity caused by the mutation A294V in the F7 gene (which encodes for factor VII)
- Similar features include mucocutaneous hemorrhage (eg, epistaxis, menorrhagia, bleeding gums) and/or postsurgical hemorrhagic complications, frequently reported in the late-onset/mild form, which is also the most common
- Differentiating features include hemarthrosis with possible progression towards chronic arthropathy and severe joint degeneration, as well as rare occurrence of life-threatening intracerebral hemorrhage, generally occurring during the first weeks or months of life (observed only in the severe form; 10%-20% incidence)
- Diagnosed on the basis of demonstrated reduction of factor VII activity level in plasma (only values less than 30% are symptomatic)
Treatment Goals
- Prevent and control bleeding episodes
Disposition
Register all patients with a 24-hour center capable of handling diagnosis and treatment
Admission criteria
Admit all patients with severe blood loss requiring transfusion
In all pregnant patients with disease, admit in preparation for delivery, given severe hemorrhagic risk
- Platelet transfusion is administered before delivery and sometimes for at least a week postpartum
Criteria for ICU admission
- Patients at risk of fatal hemorrhage (eg, during labor and delivery) require ICU care
Recommendations for specialist referral
- Refer all patients to a hematologist specializing in Glanzmann thrombasthenia
Treatment Options
Treatment is not required on a regular basis but rather only when necessary (eg, to control spontaneous bleeding episodes, after injury, before surgical procedures)
Treat bleeding episodes with local measures alone or in conjunction with antifibrinolytic therapy initially
- Local measures include compression, nasal packing, fibrin sealants, gelatin sponges, and topical thrombin (can be combined if necessary)
- Sufficient to resolve mild to moderate bleeding episodes (eg, epistaxis, gingival bleeding, minor trauma or wound)
- Antifibrinolytic therapy (eg, tranexamic acid) can be added to local measures if these alone are not able to resolve bleeding
- Also indicated to control menorrhagia and for prophylaxis before dental extractions and other minor surgical procedures
- Caution is recommended in patients who are at high risk of thrombosis and who are undergoing procedures
- Avoid in case of hematuria because of an increased risk of blood clot formation in the urinary tract
Treat with platelet transfusion and recombinant factor VIIa if bleeding is severe or persists despite use of local measures and antifibrinolytics
- Platelet transfusion
- Standard treatment of bleeding that is not controlled by use of local measures and antifibrinolytics and life-threatening bleeding (eg, head bleeding, massive gastrointestinal bleeding); also used prophylactically before major surgical procedures
- Estimated that at least 75% of patients with Glanzmann thrombasthenia require platelet transfusion at least once in their lifetime
- HLA-matched platelets are recommended to avoid platelet alloimmunization and subsequent therapeutic failure of platelet transfusion
- If HLA-matched platelets are not available, patients should receive leukocyte-reduced platelets, as this has also been found to reduce rate of alloimmunization
- Determine patient’s HLA type at diagnosis; continue monitoring for HLA and antiplatelet antibodies regularly during treatment
- Recombinant factor VIIa
- Used alone or as adjunct to antifibrinolytic agents for more severe bleeding and for surgical prophylaxis
- Highly effective and low-risk option for bleeding that is refractory to platelet transfusion
Curative therapy may be used in rare cases
- Hematopoietic stem cell transplant
- Curative treatment for patients with severe recurrent bleeding episodes and/or platelet alloimmunization and whose disorder is refractory to platelet transfusions
- However, transplant is associated with significant risks; it is used only in patients with persistent and life-threatening hemorrhagic episodes that cannot be controlled with other therapies (and after careful risk/benefit assessment)
- Gene therapy
- Currently experimental but offers prospect for future cure
Drug therapy
- Thrombin for topical hemostasis
- Thrombin (Recombinant) Topical solution; Infants, Children, and Adolescents: Apply topically to surface of bleeding tissues only; amount required depends upon size and number of bleeding sites and method of application.
- Thrombin (Recombinant) Topical solution; Adults: Apply topically to surface of bleeding tissues only; amount required depends upon size and number of bleeding sites and method of application.
- Antifibrinolytics
- Tranexamic acid
- Menorrhagia
- Tranexamic Acid Oral tablet; Children and Adolescent females 12 to 17 years of reproductive potential: 1,300 mg PO 3 times daily for 5 days during monthly menstruation.
- Tranexamic Acid Oral tablet; Adult females of reproductive potential: 1,300 mg PO 3 times daily for 5 days during monthly menstruation.
- Prophylaxis before dental extractions and other minor surgical procedures
- Tranexamic Acid Oral tablet; Adults: 25 mg/kg/dose PO 3 times daily for 5 to 7 days.
- First dose should be given 2 hours before procedure
- Menorrhagia
- Tranexamic acid
- Recombinant factor VIIa
- Nonsurgical bleeding
- Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Infants, Children, and Adolescents: 90 mcg/kg/dose IV every 2 to 6 hours until hemostasis is achieved.
- Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Adults: 90 mcg/kg/dose IV every 2 to 6 hours until hemostasis is achieved.
- Perioperative bleeding
- Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Infants, Children, and Adolescents: 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery, then every 2 to 6 hours postoperatively. Higher doses of 100 to 140 mcg/kg can be used in refractory patients.
- Factor VIIa (Recomb)(Murine)(Bovine)(Hamster) Solution for injection; Adults: 90 mcg/kg/dose IV immediately before surgery, then every 2 hours during surgery, then every 2 to 6 hours postoperatively. Higher doses of 100 to 140 mcg/kg can be used in refractory patients.
- Literature describes use of 90 to 140 mcg/kg for minor surgery; in major surgery, dosages can be further increased until hemostasis is secured.
- Nonsurgical bleeding
Nondrug and supportive care
Counsel patients about self-treatment with local measures to manage minor bleeding episodes (eg, epistaxis, gingival bleeding, minor trauma or wound)
- Teach how bleeding can be stopped by applying pressure and/or by taking an oral antifibrinolytic; however, advise to seek prompt medical attention if bleeding persists
- Advise patients to avoid contact sports to reduce the risk of trauma-induced bleeding episodes
- Advise patients to avoid antiplatelet drugs such as aspirin and other NSAIDs
- Counsel patients about importance of good oral hygiene and recommend regular dental visits to reduce risk of gingival bleeding
Recommend use of oral contraceptive pills to control menorrhagia
Provide iron supplementation, if necessary, for women with menorrhagia
Vaccinate against hepatitis B owing to risks associated with multiple blood product transfusions
Procedures
Allogeneic hematopoietic stem cell transplant
General explanation
- Transfusion of healthy stem cells from an HLA-matched donor into patient to restore hematopoietic cell lines—including normally functioning platelets—that have been eradicated by chemotherapy or radiation
- Immunosuppressive medication is administered after procedure to reduce rejection risk
Indication
- Persistent and life-threatening hemorrhagic episodes that cannot be controlled with other therapies; often due to platelet alloimmunization
- Decision to transplant must be weighed against the intense morbidity associated with immunosuppression and complications of the procedure
Contraindications
- Significant comorbidities
- Impaired cardiac, pulmonary, hepatic, and/or renal function
- Infection (eg, hepatitis, HIV)
- Unavailability of a matched sibling donor
- However, identification of an appropriate donor matched at 10/10 or 9/10 relevant HLA alleles is possible for an increasing number of patients, as a result of the higher number of registered unrelated donors worldwide
Complications
- Severe hemorrhage during the peritransplant period; may be precipitated by:
- Routine procedures such as central venous catheter placement
- Mucosal disruption associated with chemotherapy conditioning
- Thrombocytopenia resulting from the conditioning regimen
- Delayed engraftment or nonengraftment
- Infections
- Malignancies
- Acute and chronic graft-versus-host disease
- Intolerance to immunosuppressive medications
- Sinusoidal obstruction syndrome (venoocclusive disease of liver)
- Infertility
- Hypothyroidism
- Iron overload
Special populations
- Pregnant patients
- Increased risk of developing primary and secondary intrapartum and postpartum hemorrhage
- Increased risk of fetal bleeding
- Treatment guidelines recommend prophylaxis for vaginal delivery in patients with Glanzmann thrombasthenia with either platelet transfusions or recombinant factor VIIa in combination with an antifibrinolytic
Monitoring
- In all premenopausal patients with the condition, monitor for iron deficiency associated with menorrhagia
- In all pregnant patients with the condition, monitor for platelet isoantibodies throughout pregnancy
Complications
- Postpartum hemorrhage (7.7%)
- Other bleeding complications
- Postsurgical, posttraumatic, or caused by medical procedures
- Dental extraction or deciduous teeth eruption and removal (37.6%)
- Circumcision bleeding
- Bleeding from vaccination
- Miscellaneous
- Gastrointestinal bleeding (22.9%)
- Hematuria
- Hemarthrosis
- Hemorrhoidal bleeding
- Bleeding after minor trauma
- Hemoperitoneum
- Ruptured ovarian follicle or cyst
- Central nervous system bleeding
- Subconjunctival bleeding
- Cephalohematoma
- Hemopericardium
- Intrahepatic hematoma
- Muscle hematoma
- Postsurgical, posttraumatic, or caused by medical procedures
- Iron deficiency is particularly frequent in females (a consequence of menorrhagia) and can lead to anemia
- Complications associated with platelet transfusion
- Allergic and immune reactions (the most serious ones consist of anaphylaxis and transfusion-related acute lung injury)
- Platelet immunization
- Blood-borne pathogen transmission
- Thromboembolic events associated with the use of recombinant factor VIIa are rare but potentially life-threatening
Prognosis
- Prognosis is generally favorable with adequate supportive care
- Mortality rate is relatively low
- Overall morbidity and mortality have been difficult to estimate owing to rarity of disease
- Disease has a limited effect on the daily life of most affected adults
- Most require certain adaptations, including avoidance of NSAIDs and activities that may lead to trauma (eg, contact sports), as well as maintenance of optimal oral hygiene
- Mortality rate is relatively low
- Prognosis is poorer for patients whose disorder becomes refractory to platelet transfusions
- Death from hemorrhage is rare, unless associated with trauma or other disease (eg, cancer)
Screening
At-risk populations
- Persons with known family history of the disease
Screening tests
- Carrier testing and prenatal diagnosis are possible if specific genetic mutation has been identified in an affected family member
References
1: Poon MC et al: New insights into the treatment of Glanzmann thrombasthenia. Transfus Med Rev. 30(2):92-9, 2016