Chapter 120: Hereditary Qualitative Platelet Disorders

SUMMARY

Abnormalities of platelet function manifest themselves primarily as excessive hemorrhage at mucocutaneous sites, with ecchymoses, petechiae, epistaxis, gingival hemorrhage, and menorrhagia most common. Both quantitative and qualitative platelet abnormalities can produce these symptoms, so it is necessary to exclude thrombocytopenia (Chap. 117) by performing a platelet count. Chapter 121 discusses acquired qualitative platelet abnormalities and this chapter discusses the hereditary qualitative platelet abnormalities.

The hereditary qualitative platelet disorders can be classified according to the major locus of the defect (see Table 120–1 and Fig. 120–1). Thus, abnormalities of platelet glycoproteins, platelet granules, and signal transduction and secretion can all result in hemorrhagic diatheses and prolonged bleeding times. Glanzmann thrombasthenia results from abnormalities in one of two integrin subunits, either α_IIb (glycoprotein [GP] IIb) or β₃ (GPIIIa), resulting in loss or dysfunction of the α_IIb β₃ (GPIIb/IIIa) receptor. This results in a profound defect in platelet aggregation and secondary defects in platelet adhesion, secretion, and platelet coagulant activity. Heterozygous gain of function mutations in α_IIbβ₃ can result in a syndrome of macrothrombocytopenia. Loss of the platelet GPIb–IX–V complex because of abnormalities in GPIbα, GPIbβ, or GPIX results in the Bernard-Soulier syndrome, which is characterized by giant platelets and modest thrombocytopenia. The major defect is in platelet adhesion because of a decrease in platelet interactions with von Willebrand factor, but abnormalities in α_IIbβ₃ activation and thrombin-induced aggregation are also present. A gain of function defect in GPIbα (platelet-type [pseudo-] von Willebrand disease) can produce a hemorrhagic disorder via depletion of high-molecular-weight von Willebrand multimers. Inherited defects in platelet dense or α granules, agonist receptors, or proteins and mechanisms involved in signal transduction and secretion also lead to platelet dysfunction and produce hemorrhagic symptoms.

Abnormalities of platelet coagulant activity, that is, the ability of platelets to facilitate thrombin generation (Chap. 112), can lead to a hemorrhagic diathesis. Impaired platelet function may occur in association with mutations in transcription factors RUNX1, GATA-1, FLI-1, and GFI1B, and these patients have thrombocytopenia as well.

Acronyms and Abbreviations

ADP, adenosine diphosphate; BSS, Bernard-Soulier syndrome; βTG, β-thromboglobulin; BLOC, biogenesis of lysosome-related organelles complex; cAMP, cyclic adenosine monophosphate; EDTA, ethylenediaminetetraacetic acid; GFI1b, growth factor independent 1B; GPS, gray platelet syndrome; GT, Glanzmann thrombasthenia; HLA, human leukocyte antigen; HPS, Hermansky-Pudlak syndrome; Ig, immunoglobulin; LAD, leukocyte adhesion deficiency; MIDAS, metal ion-dependent adhesion site; PAR, protease-activated receptor; PF4, platelet factor 4; PKC; protein kinase C; PLC, phospholipase C; rFVIIa, recombinant factor VIIa; TGF, transforming growth factor; TXA₂, thromboxane A₂; VWD, von Willebrand disease; VWF, von Willebrand factor.