Glanzmann's Thrombasthenia

Prolonged
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Diagnosis and reasoning

Epistaxis is a frequent complaint in primary care, and in most cases is benign and self-limiting; however, in an important minority of patients, it may potentially herald serious disease. As this symptom can be due to a variety of both local and systemic etiologies, a detailed history and examination followed by targeted investigations is key to achieving a timely diagnosis. Considering this 4 year old boy, note the extended history of epistaxis, along with postoperative bleeding, and easy bruising; this is most suggestive of a disorder of hemostasis, although there is insufficient information to guess at whether this might be a primary or secondary hemostatic defect. His examination is unremarkable, while there is no family history of bleeding disorders; thus, the next step should be a panel of basic hematological studies, including a complete blood count (CBC), peripheral blood smear, and coagulation profile. The CBC is within normal parameters, excluding thrombocytopenia; furthermore, the peripheral smear shows the platelets to be of normal size and morphology, excluding disorders such as May-Hegglin anomaly, grey platelet syndrome, or a platelet storage pool deficiency. The coagulation profile reveals a normal prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT); this essentially excludes coagulation disorders associated with factor deficiencies (including those secondary to vitamin K deficiency). However, his bleeding time is found to be prolonged; as thrombocytopenia and coagulation factor deficiencies have been excluded, this leaves a disorder of platelet function are the only remaining possibility. Platelet function disorders can be acquired or inherited in origin; uremia and antiplatelet drug therapy are the most common causes of the former, but can be excluded based on his history. Important inherited causes include von Willebrand disease (VWD), Bernard Soulier syndrome (BSS), grey platelet syndrome, and Glanzmann's Thrombasthenia (GT). However, VWD is excluded by the negative von Willebrand screen; grey platelet syndrome is also unlikely, as this is associated with thrombocytopenia, and abnormal, large, agranular platelets in the peripheral smear. Note that BSS is also usually associated with giant platelets in the peripheral smear; it is definitively excluded by the presence of normal platelet agglutination with ristocetin (indicating normal function of the glycoprotein Ib receptors). Thus, GT is the only major possibility remaining, and indeed is highly likely, given the lack of platelet agglutination with ADP, collagen, adrenaline, and sodium arachidonate (all of which directly or indirectly activate the glycoprotein IIb/IIIa receptor). Confirmation is provided by the flow cytometry report showing glycoproteins IIb and IIIa to be only 5.7% of normal levels. Note also the presence of increased levels of platelet-associated immunoglobulin G, along with high titres of serum IgG2; this suggests at the presence of antiplatelet antibodies to the missing/abnormal receptor, even though (rather surprisingly) there is no history of transfusion. As GT is transmitted in an autosomal recessive fashion, his family members should be screened for the disease. Platelet transfusion is only indicated in the presence of acute bleeding; hematopoietic stem cell transplantation is a last resort in individuals who have recurrent episodes of severe bleeding. There is no role for Vitamin K supplementation in his management.


Discussion

Glanzmann's thrombasthenia (GT) is the most common inherited disorder of platelet function; it is caused by qualitative or quantitative deficiencies of fibrinogen receptor αIIbβ3 (known as Glycoprotein IIb/IIIa), resulting in defective platelet aggregation and subsequent bleeding. The disease is inherited in an autosomal recessive manner, and is most often observed in populations with increased consanguinity; there is a slight female preponderance. Note that glycoprotein IIb/IIIa (GpIIb/IIIa) is a receptor found on platelets; it is activated following platelet stimulation by ADP, epinephrine, collagen or thrombin. Activated GpIIb/IIIa has the ability to bind fibrinogen, von Willebrand factor, fibronectin and vitronectin. Once thus bound, the complex bridges two platelets, and initiates fibrinogen-dependent platelet-platelet interaction, giving rise to primary and secondary platelet aggregation. In GT, defective function of the GPIIb/IIIa receptor results in impaired platelet aggregation, and prolonged bleeding in spite of normal platelet morphology, sizes, and counts. Interesting, the disease shows a variable bleeding tendency; some persons experience minimal bruising, while others have frequent, potentially fatal hemorrhages; the degree of bleeding does not necessarily correlate with platelet GpIIb/IIIa levels. Affected individuals often present with mucocutaneous bleeding at birth or early infancy; however, some escape attention until a much later age. Menorrhagia, epistaxis, gingival bleeding, and postoperative bleeding are the most common manifestations; gastrointestinal bleeding and hematuria are less frequent, while postpartum hemorrhage has also been known to occur. Examination may reveal petechiae and ecchymoses, although spontaneous bruising is uncommon. Basic hematological studies are usually only significant for a prolonged bleeding time; note that platelet counts, sizes and morphology are within normal parameters. Platelet aggregation tests are a key diagnostic tool, demonstrating impaired aggregation with agonists such as ADP, thrombin, collagen, and epinephrine, but normal results with ristocetin. This is because the ristocetin test assesses the ability of von Willebrand factor to bind with the GpIb receptor (which is unaffected in GT); all the other agonists directly and/or indirectly activate the GpIIb/IIIa receptor. Flow cytometry and monoclonal antibody testing allow for confirmation of the diagnosis, and are also of use in screening potential carriers (i.e. close family members). The management of these patients revolves around treatment of bleeding episodes, and prevention of future bleeds. Antifibrinolytics such as tranexamic acid, and topical agents such as gelfoam, fibrin sealants and polyethylene glycol polymers may help in controlling minor mucosal bleeding. More severe episodes can be treated via platelet transfusion; to prevent alloimmunization, leucodepleted blood products produced by mechanical filtration, or platelets matched via human leucocyte antigen (HLA) should be used. Desmopressin (DDAVP) is known to improve hemostasis, and is currently used in many clinical settings, despite the absence of research evidence; note that it does not normalize the bleeding time. Administration of recombinant human activated factor VII (rFVIIa) has been shown to be of high efficacy in patients with antibodies to GPIIb/IIIa and/or HLA (and who thus cannot be transfused). Hematopoietic stem cell transplantation (HSCT) is a final option in individuals who experience severe recurrent hemorrhages; it is curative. Measures to prevent bleeds include avoidance of intramuscular injections, antiplatelet drugs, and anticoagulants which decrease platelet function and/or coagulation; patients should also be educated on the importance of regular dental care.


Take home messages

  1. Glanzmann's Thrombasthenia (GT) is an inherited disorder of platelet function.
  2. The presence of a prolonged bleeding time is a key clue towards the diagnosis of GT.
  3. Flow cytometry and monoclonal antibody testing allow confirmation of the presence of GT.
  4. In patients who require platelet transfusion, leucodepleted or HLA matched platelets should be used to minimize alloimunization.

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