Inherited platelet function disorders are rare and cause lifelong bleeding tendencies. Diagnosis is confirmed by platelet aggregation tests. Platelet transfusion is usually necessary to control serious bleeding.
Diagnosis of platelet function disorders usually requires the assistance of physicians expert in coagulation disorders. A wide variety of these disorders can occur, with or without thombocytopenia.
Normal hemostasis requires:
Platelet adhesion
Platelet activation
Platelet adhesion occurs when platelets bind to exposed vascular subendothelium, a process that requires von Willebrand factor (VWF) and the platelet glycoprotein Ib/IX complex (1).
Platelet activation promotes platelet aggregation and fibrinogen binding and requires the platelet glycoprotein IIb/IIIa complex. Activation occurs when platelets release adenosine diphosphate (ADP) from platelet dense storage granules and convert arachidonic acid to thromboxane A2 via a cyclooxygenase-mediated reaction. The released ADP acts on the P2Y12 receptor on other platelets, thereby activating them and recruiting them to the site of injury. Additionally, ADP (and thromboxane A2) then promotes changes in the platelet glycoprotein IIb/IIIa complex, which in turn increases fibrinogen binding, thereby allowing platelets to aggregate.
Inherited platelet function disorders are suspected in patients with lifelong bleeding disorders who have normal platelet counts and coagulation study results, and sometimes a history of bleeding in other family members. Diagnosis usually is based on platelet aggregation and secretion tests; however, the results of these tests can be highly variable, and interpretation of results is often inconclusive (see table ). Platelet aggregation tests assess the ability of platelets to clump in response to the addition of various activators (eg, collagen, epinephrine, ADP, ristocetin).
Platelet secretion tests measure the release of dense storage granule content after stimulation by these various platelet activators.
Platelet aggregometry studies are unreliable when platelet counts are < 100,000/mcL (< 100 × 109/L).
Genetic panels are now available to characterize which of the hundreds of mutations might be involved.
Results of Aggregation Tests in Inherited Platelet Function Disorders
Disorder | Collagen, Epinephrine, and Low-Dose ADP | High-Dose ADP | Ristocetin |
|---|---|---|---|
Disorders of platelet adhesion (eg, Bernard-Soulier syndrome, von Willebrand disease) | Normal | Normal | Impaired |
Disorders of amplification of platelet activation | Impaired | Normal | Normal |
Thrombasthenia (eg, loss of the glycoprotein IIb/IIIa receptor) | Absent | Absent | Normal or impaired |
ADP = adenosine diphosphate. | |||
Disorders of platelet adhesion
Bernard-Soulier syndrome is a rare autosomal recessive disorder. It causes thrombocytopenia and impairs platelet adhesion via a defect in the glycoprotein Ib/IX complex that binds endothelial VWF. Bleeding may be severe. Platelets are unusually large. They do not aggregate with ristocetin but aggregate normally with ADP, collagen, and epinephrine.
Large platelets associated with functional abnormalities also occur in the May-Hegglin anomaly, a thrombocytopenic disorder with abnormal white blood cell inclusions, and in the Chédiak-Higashi syndrome.
Platelet transfusion is necessary to control serious bleeding in all of these disorders.
Von Willebrand disease is due to a deficiency or defect in VWF, which is needed to permit platelet adhesion. It is often treated with desmopressin or VWF replacement with virally inactivated intermediate-purity factor VIII concentrate or recombinant VWF products. For minor procedures such as dental work, the use of tranexamic acid will often suffice to prevent or treat bleeding.
Disorders of platelet activation
Disorders of amplification of platelet activation are the most common inherited platelet function disorders and produce mild bleeding. They may result from decreased ADP in the platelet dense granules (storage pool deficiency), from an inability to generate thromboxane A2 from arachidonic acid, or from an inability of platelets to aggregate with each other in response to thromboxane A2.
Platelet aggregation studies show impaired responses to collagen, epinephrine, and low-dose ADP, with preserved aggregation in response to ristocetin and high-dose ADP. The same pattern can result from use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin, the effect of which can persist for several days. Therefore, platelet aggregation tests should not be done in patients who have taken these medications in the previous 10 days.
Thrombasthenia
Thrombasthenia (Glanzmann disease) is a rare autosomal recessive disorder causing a defect in the platelet glycoprotein IIb/IIIa receptor; platelets cannot aggregate. Patients may have severe mucosal bleeding (eg, nosebleeds that stop only after nasal packing and transfusions of platelet concentrates). The diagnosis is confirmed by the finding that platelets fail to aggregate after exposure to epinephrine, collagen, or even high levels of ADP but do aggregate transiently after exposure to ristocetin. Platelet transfusion is usually necessary to control serious bleeding.
Reference
1. Hayward CPM, Tasneem S. When it's not Glanzmann thrombasthenia or Bernard-Soulier syndrome: diagnosing other qualitative platelet disorders. Hematology Am Soc Hematol Educ Program. 2025;2025(1):137-146. doi:10.1182/hematology.2025000699
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