Hereditary Intrinsic Platelet Disorders
Hereditary intrinsic platelet disorders are rare and cause lifelong bleeding tendencies. Diagnosis is confirmed by platelet aggregation tests. Platelet transfusion is usually necessary to control serious bleeding.
(See also Overview of Platelet Disorders.)
Normal hemostasis requires platelet adhesion and activation.
Platelet adhesion (ie, of platelets to exposed vascular subendothelium) requires von Willebrand factor (VWF) and the platelet glycoprotein Ib/IX complex.
Platelet activation promotes platelet aggregation and fibrinogen binding and requires the platelet glycoprotein IIb/IIIa complex. Activation involves release of adenosine diphosphate (ADP) from platelet storage granules and conversion of 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.
Hereditary intrinsic platelet disorders can involve defects in any of these substrates and steps. These disorders are suspected in patients with lifelong bleeding disorders who have normal platelet counts and coagulation study results. Diagnosis usually is based on platelet aggregation tests; however, the results of platelet aggregation tests can be highly variable, and interpretation of results is often inconclusive (see Table: Results of Aggregation Tests in Hereditary Disorders of Platelet Function). Platelet aggregation tests assess the ability of platelets to clump in response to the addition of various activators (eg, collagen, epinephrine, ADP, ristocetin). Platelet aggregometry studies are unreliable when platelet counts are < 100,000/μL.
Results of Aggregation Tests in Hereditary Disorders of Platelet Function
Bernard-Soulier syndrome is a rare autosomal recessive disorder. It 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 WBCs, and in the Chédiak-Higashi syndrome.
Platelet transfusion is necessary to control serious bleeding.
von Willebrand disease is due to a deficiency or defect in the von Willebrand factor (VWF) that is needed to permit platelet adhesion. It is often treated with desmopressin or VWF replacement with pasteurized intermediate-purity factor VIII concentrate or the newer recombinant VWF products.
Disorders of amplification of platelet activation are the most common hereditary intrinsic platelet disorders and produce mild bleeding. They may result from decreased ADP in the platelet granules (storage pool deficiency), from an inability to generate thromboxane A2 from arachidonic acid, or from an inability of platelets to aggregate in response to thromboxane A2.
Platelet aggregation tests reveal impaired aggregation after exposure to collagen, epinephrine, and low levels of ADP and normal aggregation after exposure to high levels of ADP. The same pattern can result from use of NSAIDs or aspirin, the effect of which can persist for several days. Therefore, platelet aggregation tests should not be done in patients who have recently taken these drugs.
Thrombasthenia (Glanzmann disease) is a rare autosomal recessive disorder causing a defect in the platelet glycoprotein IIb/IIIa complex; 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 necessary to control serious bleeding.