Glanzmann Thrombasthenia

Etiology

GT is an autosomal recessive disorder with mutations involving chromosome 17q21, specifically the ITGA2B or ITGB3 genes.[2][4][5] Mutations of either gene can cause GT, and hundreds of mutations have been reported. GT results when a patient is homozygous for the same mutation or is a compound heterozygote for 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 alpha IIb beta3 integrin expression. [6]

Acquired GT 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-alpha IIb beta3 antibody in a patient with systemic lupus erythematosus. [8] These cases are rare, and GT mostly commonly refers to the inherited form, which is otherwise described in this article.

Epidemiology

The prevalence of GT is estimated to be about 1:1,000,000 in the general population.[2] In certain areas, such as those with high 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.[9][6] Some patients may have mild symptoms and are never identified as having GT, so the actual prevalence may be higher than reported.[6] Studies show that females are slightly more frequently affected than males. GT is commonly encountered in children and young adults but can affect any age.[2]

Pathophysiology

The alpha IIb beta3 integrin, formerly known as GPIIb-IIIa, is the platelet’s fibrinogen receptor. When platelets are activated, the alpha IIb beta3 integrin shifts into its active configuration to allow fibrinogen binding. As platelets bind the fibrinogen, they aggregate and provide primary hemostasis. Without functioning fibrinogen receptors, or without enough of them, bleeding can be spontaneous or occur with an injury.[2][7] Additionally, platelets in GT are not as efficient at generating thrombin, an essential part of converting fibrinogen to fibrin.[3] Secondary hemostasis occurs when cross-linked fibrin stabilizes the platelet plug, and is thus also affected by GT.[6]

Histopathology

GT is a platelet disorder, and platelets are identified on blood smears. In general, the platelets of a patient with GT appear normal, but rare mutations can result in platelets that are of unequal size.[4][5] Isolated families with GT have been identified as having large and relatively few platelets, a condition known as macrothrombocytopenia.[3]

History and Physical

When evaluating a patient for potential Glanzmann thrombasthenia, his or her bleeding and bruising history is 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 are menorrhagia and gingival bleeds [2] Gastrointestinal bleeding is less frequently reported, and some cases of GT are undiagnosed until an invasive procedure.[4][10] Most patients with GT are diagnosed at an early age, with symptoms often appearing within the first year of life. Bleeding can occur after circumcision and can even require transfusion,[2], but some patients will have an improvement in their symptoms by adulthood. The use of a bleeding assessment tool may be beneficial to help identify abnormalities.[11] 

A voluntary Glanzmann thrombasthenia registry enrolled patients with GT, and their data indicates that the first symptoms occurred at a median age of 1one year and a mean of 5.6 years. Of the enrollees, 85% were diagnosed with GT by 14 years of age.[3]

Physical examination is focused on identifying bleeding and its sequelae, such as ecchymoses.[11] As epistaxis is a common manifestation of GT, 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 offered guidance on the diagnosis of GT and other inherited platelet function disorders (IPFD). According to their algorithm, if the patient has clear clinical bleeding abnormalities, preliminary laboratory tests may include a complete blood count (CBC), activated partial thromboplastin time (PTT), prothrombin time, and assessments for von Willebrand disease such as von Willebrand Factor (vWF) antigen, ristocetin cofactor activity, and factor VIII coagulant activity. These tests help rule out more common causes of bleeding, and they are generally normal in GT and other IPFD. Further evaluation consists of platelet function studies or next-generation sequencing. Screening may include a blood smear, light transmission aggregometry (LTA), platelet granule release assessment, and flow cytometry to analyze platelet surface glycoproteins.

LTA, the gold standard test, reveals altered platelet aggregation with agonists other than ristocetin.[7] Flow cytometry typically shows defective expression of alpha IIb beta 3 integrin, although some cases with defective integrins may demonstrate normal expression.[11] The integrin components are identified as CD41 (alpha IIb) and CD61 (beta 3). CD42b, a glycoprotein important in binding vWF, should be normally expressed.[2] Of note, the platelet function analyzer (PFA) test was not recommended by the ISTH. The PFA test simulates damaged endothelium and measures the platelet plug formation time, which is prolonged in GT.[7]

Secondary tests may include clot retraction, which is impaired in GT. Molecular genetic tests are included in the ISTH guidance for cases that remain undiagnosed after other laboratory studies. Gene mutations in ITGA2B or ITGB3 are identified in GT.[11]

Treatment / Management

As with many bleeding disorders, a tiered management system exists for GT. For mild bleeding episodes, initial treatment may include local pressure, cauterization, sutures, or ice therapy.[3][9][6] Some providers also use antifibrinolytic agents, such as tranexamic acid, which can be used as a mouthwash for gingival bleeding.[9][6] 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 the bleeding is unresponsive or incompletely responds to local measures, or if the patient is undergoing surgery, platelets and/or recombinant activated clotting factor VII (rFVIIa) may be required.[3] Platelet transfusion as surgical prophylaxis and as the treatment for moderate to severe bleeding is standard for GT.[6] Recombinant FVIIa binds to activated platelets and creates a thrombin burst, helping fibrinogen conversion to fibrin and subsequent hemostasis. Recombinant FVIIa is approved in the United States for patients with GT with platelet refractoriness. In Europe, rFVIIa is additionally approved for patients with platelet antibodies. For the treatment of surgical bleeds, rFVIIa alone can be highly effective. Its efficacy has led to its frequent off-label use for surgical procedures and bleeding.[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 vs. non-operative procedures, and children may require more rFVIIa than adults.[3] In select patients, however, rFVIIa may be ineffective.[7]

Female patients may require menorrhagia management and should be screened for iron deficiency. Antifibrinolytics are the initial treatment for menorrhagia, although continuous hormone supplementation is a common preventative management technique.[7] Menarche may require a blood transfusion, and in those cases, immediate treatment with high-dose estrogen followed by continuous oral contraceptives could be considered.[5] Surgical management with endometrial ablation or hysterectomy can be performed for women not interested in preserving fertility. For pregnant GT patients planning to deliver vaginally, guidelines recommend some form of prophylaxis, such as an anti-fibrinolytic or rFVIIa. Operative guidelines also recommend rFVIIa as prophylaxis for Cesarean sections.[7]

Preventative management and symptomatic treatment work well for many patients. In select patients with GT with an extremely poor quality of life, curative treatment by way of hematopoietic stem cell transplant has been effective.[6] Transplant comes with its risks, and careful assessment of the clinical scenario with its potential risks and benefits is essential.[3][5]

Differential Diagnosis

Patients with GT with bleeding initially have a broad differential, including thrombocytopenia and acquired platelet dysfunction (such as NSAID 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 GT with platelets can result in anti-HLA antibodies as well as antibodies against integrin alpha IIb beta 3. Treatment with HLA-compatible platelets can be beneficial, and immunoadsorption techniques for anti-alpha IIb beta 3 are available. Patients with GT can experience the same reactions (i.e., anaphylaxis or transfusion-related acute lung injury) as other patients receiving blood products and need to be treated accordingly.[3]

Treatment with rFVIIa can result in thromboembolic complications, although this is rare in patients with inherited bleeding disorders.[6]

Prognosis

GT is a severe bleeding disorder, and life-threatening or fatal bleeding can occur spontaneously or with invasive procedures, severe trauma, or as a consequence of childbirth.[3][6] The broad mutational causes of GT yield many clinical presentations that range in severity. Patients can do well with healthcare team preparation and coordination, such as the 52-year-old man with GT who had a successful open aortic valve replacement.[10] In general, GT bleeding episodes are not as life-threatening as those associated with inherited coagulation disorders.[2]

Complications

Patients with GT and chronic mild bleeding may develop iron deficiency anemia, but the majority of GT complications are related to its treatment rather than the disease itself.[6]

Approximately 17% of patients with GT who receive leukocyte-reduced platelets develop anti-HLA antibodies, and that percentage increases significantly if the platelets are not leukocyte-reduced. Of the patients who develop anti-HLA antibodies, roughly half are refractory to future platelet transfusions. Patients with certain mutations may develop antibodies to the surface antigens of the alpha IIb beta 3 integrin.[3][6] Patients with GT can also develop anti-platelet antibodies. Anti-platelet antibodies can cross the placenta, and studies of pregnant women with GT and anti-platelet antibodies have demonstrated a spectrum of fetal effects ranging from thrombocytopenia to neonatal death secondary to intracranial hemorrhage.[7][12]