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At a glance

A genetic disorder characterized by giant platelets, mild-to-moderate thrombocytopenia, abnormal platelet function, and bleeding disproportionate to the reduced number of platelets.

Synonyms

Giant Platelet Syndrome; Familial Macrothrombocytopenia; (Congenital) Hemorrhagiparous Thrombocytic Dystrophy; Platelet Glycoprotein IIb/IIIa Deficiency; Glycoprotein Complex IIb-IIIa Deficiency; Platelet Fibrinogen Receptor Deficiency.

History

First described in 1948 by the French hematologists Jean Bernard and Jean-Pierre Soulier, who described a young Caucasian man (from consanguineous parents) suffering from a lifelong bleeding history.

Incidence

Probably less than 1:1,000,000 in the general population. Around 100 cases have been described. Due to misdiagnosis and underreporting, the real prevalence is most likely higher.

Genetic inheritance

Usually autosomal recessive (parental consanguinity is a known risk-factor), but one type of BSS (Bolzano variant) shows autosomal dominant inheritance. The genes encoding for GPIBA, GPIBB, GP5, and GP9 genes have been mapped to chromosomes 17q21, 22q11.2, 3q29, and 3q21, respectively. Mutations in these genes (except GP5) cause abnormal or deficient expression of platelet glycoprotein (GP) GPIb-IX-V complex. This results in decreased platelet adhesion to von Willebrand factor (vWF). Heterozygous family members may have approximately half the normal levels of platelet GP Ib-IX-V, however, they suffer, if at all, from only mild bleeding diathesis.

Pathophysiology

BSS is characterized by impaired platelet adhesion to the subendothelial vessel wall matrix due to a defect or absence in the GPIb-IX-V complex, which acts as the platelet membrane receptor for von Willebrand-Factor (vWF) and is required for normal primary hemostasis. GPIbα contains the vWF binding site, but also has binding sites for thrombin, factor VIIa, XI, and XII. Furthermore, the giant platelets show altered binding of factors V and XI and do not develop regular coagulation activity upon contact with collagen. Normal platelet adhesion triggers a change in the platelet conformation from a discoid to a more spherical shape with pseudopods. Bleeding seems to mainly result from the defective platelet binding to vWF and the loss of vWF-dependent platelet-to-platelet interactions in the thrombus formation. The binding of vWF to GPIbα also triggers intracellular signaling with activation of GPIIb-IIIa leading to binding of fibrinogen or vWF and facilitating platelet aggregation and clot contraction. The interaction of the cytoplasmic domain of GPIb-IX-V with multiple intracellular binding partners is involved in the control of the size and shape of the platelets.

Diagnosis

Based on the clinical picture of bleeding tendency that is often noted already during childhood. However, BSS has often been misdiagnosed as idiopathic thrombocytopenic purpura when based on clinical findings alone. In BSS, the platelet count is usually moderately decreased and the blood smear reveals enlarged (giant) platelets (macrothrombocytopenia) with quite variable morphology. These giant platelets can have a diameter of up to 10 µm (normal 2-3 µm) with dense granulomeres, giving ...

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