14-06: Congenital Disorders of Platelet Function

GENERAL CONSIDERATIONS

Heritable qualitative platelet disorders are far less common than acquired platelet function disorders and lead to variably severe bleeding, often beginning in childhood. Occasionally, however, disorders of platelet function may go undetected until later in life when excessive bleeding occurs following a sufficient hemostatic challenge. Thus, the true incidence of hereditary qualitative platelet disorders is unknown.

Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive bleeding disorder due to reduced or abnormal platelet membrane expression of glycoprotein Ib/IX (vWF receptor).

Glanzmann thrombasthenia results from an abnormality in the platelet glycoprotein IIb/IIIa receptor on the platelet membrane. Glycoprotein IIb/IIIa is the fibrinogen receptor critical for linking platelets during initial platelet aggregation/platelet plug formation. Inheritance is autosomal recessive.

Under normal circumstances, activated platelets release the contents of platelet granules to reinforce the aggregatory response. Storage pool disease includes a spectrum of defects in release of alpha or dense (delta) platelet granules, or both (alpha-delta storage pool disease).

CLINICAL FINDINGS

A. Symptoms and Signs

Bleeding due to defective platelets is usually mucocutaneous, but it is not limited to mucocutaneous surfaces. The onset of bleeding with Glanzmann thrombasthenia is usually in infancy or childhood, but some forms are milder and present later in life. The degree of deficiency in IIb/IIIa may not correlate well with bleeding symptoms. Patients with storage pool disease are affected by variable bleeding, ranging from mild and trauma-related to spontaneous.

B. Laboratory Findings

In Bernard-Soulier syndrome, there are abnormally large platelets (approaching the size of red cells), moderate thrombocytopenia, and a prolonged bleeding time. Platelet aggregation studies show a marked defect in response to ristocetin, whereas aggregation in response to other agonists is normal; the addition of normal platelets corrects the abnormal aggregation. The diagnosis can be confirmed by platelet flow cytometry.

In Glanzmann thrombasthenia, platelet aggregation studies show marked impairment of aggregation in response to stimulation with various agonists, which reflects the critical role of the fibrinogen receptor in platelet plug formation.

Storage pool disease describes defects in the number, content, or function of platelet alpha or dense granules, or both. The gray platelet syndrome comprises abnormalities of platelet alpha granules, thrombocytopenia, and marrow fibrosis. The blood smear shows agranular platelets, and the diagnosis is confirmed with electron microscopy.

Albinism-associated storage pool disease involves defective dense granules in disorders of oculocutaneous albinism, such as the Hermansky-Pudlak and Chediak-Higashi syndromes. Electron microscopy confirms the diagnosis.

Non–albinism-associated storage pool disease results from quantitative or qualitative defects in dense granules and is seen in Ehlers-Danlos and Wiskott-Aldrich syndromes, among others.

The Quebec platelet ...