Glanzmann Thrombasthenia

Etiology

Glanzmann thrombasthenia is an autosomal recessive disorder caused by mutations in the ITGA2B or ITGB3 gene on chromosome 17q21.[2][4][5] Mutations in either gene can cause Glanzmann thrombasthenia, and hundreds of mutations have been reported. Glanzmann thrombasthenia develops when a patient is homozygous for 1 mutation or compound heterozygous for 2 different mutations.[3] The various genetic alterations can lead to different levels of function and expression of the alpha IIb beta3 integrin.[2] The Manouche mutation has no αIIbβ3 integrin expression.[6]

Acquired Glanzmann thrombasthenia is due to an autoantibody against the platelet fibrinogen receptor. Many hematologic conditions can lead to antibody formation, such as multiple myeloma. [7] One case report describes an anti-αIIbβ3 antibody in a patient with systemic lupus erythematosus.[8] Acquired cases are rare, and Glanzmann thrombasthenia most commonly refers to the inherited form described throughout this article.

Epidemiology

The prevalence of Glanzmann thrombasthenia is estimated to be about 1:1,000,000 in the general population.[2] In certain areas, such as regions with high rates of consanguinity, the prevalence is roughly 1:200,000 or higher.[3][6] Pakistan and the Canadian provinces Newfoundland and Labrador are some of the areas with a high prevalence.[6][9] Some patients may have mild symptoms and remain undiagnosed; therefore, the actual prevalence may be higher than reported.[6] Results from studies showed that female individuals are affected slightly more often than male individuals. Glanzmann thrombasthenia is commonly diagnosed in children and young adults but may occur at any age.[2]

Pathophysiology

The αIIbβ3 integrin, formerly known as glycoprotein IIb/IIIa, is the platelet fibrinogen receptor. When platelets are activated, the αIIbβ3 integrin changes to an active conformation that permits fibrinogen binding. Fibrinogen binding enables platelet aggregation and formation of the primary hemostatic plug. Without functioning fibrinogen receptors, or with insufficient receptor expression, bleeding may occur spontaneously or after injury.[2][7] Additionally, platelets in Glanzmann thrombasthenia are less efficient at generating thrombin, which is essential for converting fibrinogen to fibrin.[3] Cross-linked fibrin stabilizes the platelet plug during secondary hemostasis; therefore, this process may also be impaired in Glanzmann thrombasthenia.[6]

Histopathology

Glanzmann thrombasthenia is a platelet disorder, and platelets can be evaluated on peripheral blood smears. In general, platelets from patients with Glanzmann thrombasthenia appear normal, but rare mutations can result in platelets of unequal sizes.[4][5] Reports of isolated families with Glanzmann thrombasthenia describe large platelets and reduced platelet counts, a finding known as macrothrombocytopenia.[3]

History and Physical

When evaluating a patient for potential Glanzmann thrombasthenia, the bleeding and bruising history provides a common starting point. Additionally, a family history of bleeding can be an important aid in diagnosis. Epistaxis is particularly prevalent in children,[3] and other common manifestations include heavy menstrual bleeding and gingival bleeding.[2] Gastrointestinal bleeding is less frequently reported, and some patients with Glanzmann thrombasthenia remain undiagnosed until they undergo an invasive procedure.[4][10] Most patients with Glanzmann thrombasthenia receive a diagnosis at an early age, with symptoms often appearing within the first year of life. Bleeding can occur after circumcision and may require a transfusion,[2] but some patients experience improvement in symptoms during adulthood. A bleeding assessment tool may help identify abnormal bleeding patterns.[11] 

A voluntary Glanzmann thrombasthenia registry enrolled patients with the disorder, and results from the registry indicated that the first symptoms occurred at a median age of 1 year and a mean age of 5.6 years. Among enrolled patients, 85% were diagnosed with Glanzmann thrombasthenia by 14 years of age.[3] Physical examination should focus on identifying bleeding and its sequelae, such as ecchymoses.[11] Because epistaxis is a common manifestation of Glanzmann thrombasthenia, the nasal cavity should be carefully inspected.[4][7]

Evaluation

The Subcommittee on Platelet Physiology, part of the International Society on Thrombosis and Haemostasis (ISTH), has provided guidance on the diagnosis of Glanzmann thrombasthenia and other inherited platelet function disorders. According to the ISTH diagnostic algorithm, if a patient has clear clinical bleeding abnormalities, preliminary laboratory tests may include a complete blood count, activated partial thromboplastin time, prothrombin time, and tests for von Willebrand disease, such as von Willebrand factor antigen, ristocetin cofactor activity, and factor VIII coagulant activity. These tests help exclude more common causes of bleeding and generally yield reference-range results in patients with Glanzmann thrombasthenia and other inherited platelet function disorders. Further evaluation includes platelet function studies or next-generation sequencing. Screening may include a peripheral blood smear, light transmission aggregometry, platelet granule release testing, and flow cytometry for analysis of platelet surface glycoproteins.

Light transmission aggregometry is the gold standard test and demonstrates impaired platelet aggregation in response to all agonists except ristocetin.[7] Flow cytometry typically shows defective expression of the αIIbβ3integrin, although some dysfunctional integrins may have reference-range expression levels.[11] The integrin components are identified as cluster of differentiation 41, corresponding to αIIb, and cluster of differentiation 61, corresponding to β3. Cluster of differentiation 42b, a glycoprotein involved in binding von Willebrand factor, should have reference-range expression.[2] Notably, the International Society on Thrombosis and Haemostasis did not recommend platelet function analyzer testing. This test simulates damaged endothelium and measures platelet plug formation time, which is prolonged in Glanzmann thrombasthenia.[7]

Secondary tests may include clot retraction, which is impaired in Glanzmann thrombasthenia. Molecular genetic testing is recommended in the International Society on Thrombosis and Haemostasis guidance for patients who remain without a diagnosis after other laboratory studies. Pathogenic variants in the ITGA2B or ITGB3 gene may confirm Glanzmann thrombasthenia.[11]

Treatment / Management

As with many bleeding disorders, a tiered treatment approach is used for Glanzmann thrombasthenia. For mild bleeding episodes, initial treatment may include local pressure, cauterization, sutures, or ice therapy.[3][9][6] Some clinicians also use antifibrinolytic agents, such as tranexamic acid, which can be used as a mouthwash for gingival bleeding.[6][9] After the failure of synthetic nasal packing and conventional therapies, successful treatment with salt pork packing and concomitant antibiotics has been reported.[4](B2)

If bleeding does not respond or responds incompletely to local measures, or if the patient is undergoing a surgical procedure, platelets or recombinant activated factor VII may be required.[3] Platelet transfusion is standard surgical prophylaxis and treatment for moderate to severe bleeding in patients with Glanzmann thrombasthenia.[6] Recombinant activated factor VII binds to activated platelets and generates a thrombin burst, promoting the conversion of fibrinogen to fibrin and subsequent hemostasis. Recombinant activated factor VII is approved in the US for patients with Glanzmann thrombasthenia and platelet refractoriness. In Europe, recombinant activated factor VII is additionally approved for patients with platelet antibodies. For the treatment of surgical bleeding, recombinant activated factor VII alone can be highly effective. Its efficacy has contributed to frequent off-label use during surgical procedures and for bleeding episodes.[3] Data from the Glanzmann Thrombasthenia Registry suggest that treatment with rFVIIa with or without antifibrinolytics is as effective as or more effective than treatment with platelets with or without antifibrinolytics.[6] Dosing is adjusted for operative and nonoperative procedures, and children may require higher doses of recombinant activated factor VII than adults.[3] In select patients, however, rFVIIa may be ineffective.[7]

Women may require treatment for heavy menstrual bleeding and should undergo screening for iron deficiency. Antifibrinolytics are the initial treatment for heavy menstrual bleeding, although continuous hormonal therapy is commonly used for prevention.[7] Bleeding at menarche may require blood transfusion; in these patients, clinicians may consider immediate treatment with high-dose estrogen followed by continuous oral contraceptives.[5] Endometrial ablation or hysterectomy may be considered for women who do not wish to preserve fertility. For pregnant patients with Glanzmann thrombasthenia who plan a vaginal delivery, guidelines recommend prophylaxis with an antifibrinolytic agent or recombinant activated factor VII. Guidelines for cesarean delivery also recommend recombinant activated factor VII prophylaxis.[7]

Preventive care and symptomatic treatment are effective for many patients. In select patients with Glanzmann thrombasthenia and a severely impaired quality of life, hematopoietic stem cell transplant has provided curative treatment.[6] Hematopoietic stem cell transplant carries substantial risks; therefore, careful assessment of the clinical circumstances and potential benefits and harms is essential.[3][5]

Differential Diagnosis

Patients with Glanzmann thrombasthenia who present with bleeding have a broad differential diagnosis, including thrombocytopenia and acquired platelet dysfunction, such as that caused by nonsteroidal anti-inflammatory drug use. Hermansky-Pudlak syndrome, von Willebrand disease, and Bernard-Soulier syndrome should also be considered.[6] Other platelet function disorders, such as gray platelet syndrome, Medich platelet syndrome, and Scott syndrome, are possible but less likely.[11]

Pertinent Studies and Ongoing Trials

Gene editing and gene transfer for GT are in experimental stages. [3][6]

Toxicity and Adverse Effect Management

Treatment of patients with Glanzmann thrombasthenia using platelet transfusions can result in antibodies against human leukocyte antigens (HLA) and the αIIbβ3 integrin. Treatment with HLA-compatible platelets can be beneficial, and immunoadsorption techniques targeting anti-αIIbβ3 antibodies are available. Patients with Glanzmann thrombasthenia may experience transfusion reactions, including anaphylaxis or transfusion-related acute lung injury, and should receive appropriate treatment.[3] Additionally, recombinant activated factor VII treatment may cause thromboembolic complications, although these events are rare among patients with inherited bleeding disorders.[6]

Prognosis

Glanzmann thrombasthenia is a severe bleeding disorder, and life-threatening or fatal bleeding may occur spontaneously, during invasive procedures, after severe trauma, or during childbirth.[3][6] The wide range of pathogenic variants associated with Glanzmann thrombasthenia results in clinical presentations of varying severity. Patients can have favorable outcomes with careful preparation and coordination by the healthcare team, as demonstrated by a 52-year-old man with Glanzmann thrombasthenia who underwent successful open aortic valve replacement.[10] In general, bleeding episodes associated with Glanzmann thrombasthenia are less likely to be life-threatening than bleeding associated with inherited coagulation disorders.[2]

Complications

Patients with Glanzmann thrombasthenia and chronic mild bleeding may develop iron deficiency anemia, but most complications of Glanzmann thrombasthenia result from treatment rather than from the disorder itself.[6] Approximately 17% of patients with Glanzmann thrombasthenia who receive leukocyte-reduced platelet transfusions develop antibodies against human leukocyte antigens, and the rate increases substantially when platelets are not leukocyte reduced. Among patients who develop these antibodies, roughly half become refractory to future platelet transfusions. Patients with certain mutations may also develop antibodies against surface antigens of the αIIbβ3 integrin.[3][6] Additionally, patients with Glanzmann thrombasthenia may develop antiplatelet antibodies that can cross the placenta. Results from studies of pregnant women with Glanzmann thrombasthenia and antiplatelet antibodies demonstrated fetal and neonatal complications ranging from thrombocytopenia to neonatal death caused by intracranial hemorrhage.[7][12]