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This chapter describes the classification, pathophysiology, clinical evaluation, and management of quantitative and qualitative inherited platelet disorders. Whereas some platelet disorders only result in bleeding, others are part of a broader clinical syndrome. Even with signs of bleeding, there is a large variability among patients. Bleeding is principally evident by excessive hemorrhage at mucocutaneous sites, ecchymoses, petechiae, epistaxis, gingival hemorrhage, and menorrhagia. The hereditary platelet disorders can be classified according to the underlying genetic mutation and the role the corresponding protein has in megakaryocyte and platelet production (Figs. 119–1 and 119–2). Furthermore, recommendations on how and when to use genomic analyses and deep sequencing in the diagnosis of possibly novel pathways that result in inherited platelet disorders are provided.1,2

Acronyms and Abbreviations

ADP, adenosine diphosphate; BLOC, biogenesis of lysosome-related organelles complex; BSS, Bernard-Soulier syndrome; βTG, β-thromboglobulin; cAMP, cyclic adenosine monophosphate; CAMT, Congenital amegakaryocytic thrombocytopenia;CRP, collagen-related peptide;FBC, Full blood count;GFI1b, growth factor independent 1B; GP, glycoprotein; GPS, gray platelet syndrome; GT, Glanzmann thrombasthenia; HLA, human leukocyte antigen; HPS, Hermansky-Pudlak syndrome; HTS, High-throughput sequencing; Ig, immunoglobulin; IP3, inositol 1,4,5-triphosphate;IPD, Inherited Platelet Disorders; ITG, Integrin; LAD, leukocyte adhesion deficiency; LRO, lysosome-related organelles; MK, Megakaryocyte; PAR, protease-activated receptor; PI, phosphoinositide;PF4, platelet factor 4; PKC, protein kinase C; PLA2alpha, phospholipase A2alphaPLC, phospholipase C; PT, Paris-Trousseau ;PT-VWD, Platelet-Type Von Willebrand Disease; rFVIIa, recombinant factor VIIa; SDS-PAGE, sodium dodecylsulfate polyacrylamide gel electrophoresis; TAR, Thrombocytopenia absent radius; THPO, receptor of thrombopoietin;TPO-RAS, thrombopoietin-receptor agonists;TGF, transforming growth factor; TXA2, thromboxane A2; VUS, Variant of Unknown Significance; VWD, von Willebrand disease; VWF, von Willebrand factor; WAS, Wiskott-Aldrich syndrome.

Figure 119–1.

The molecular regulation of megakaryopoiesis with platelet formation and some important platelet function pathways. Each of the known inherited platelet disorder genes are indicated and categorized according to their effect on megakaryocyte (MK) and platelet biology. Asterisks indicate inherited platelet disorders typically associated with phenotypes outside of the hematopoietic system. HSC, hematopoietic stem cell.

Figure 119–2.

Platelet signal transduction pathways. von Willebrand Factor (VWF) binds the glycoprotein (GP) Ib/IX/V receptor to mediate platelet adhesion. Fibrinogen binding to the integrin receptor α2Bβ3 is critical for platelet aggregation. CalDAG-GEFI stimulates GTP loading of Rap1 in response to an increase in intracellular Ca2+ that is released from dense (δ) granules after initial platelet activation and the activated Rap1 further leads to integrin αIIbβ3 activation to sustain platelet activation. Kindlin-3 is a protein with homology to talin that also binds to the cytoplasmic domain of the β3 subunit of integrin αIIbβ3. As CalDAG-GEFI, Kindlin-3 is also implicated in the inside-out activation of integrin αIIbβ3. Collagen triggers platelet activation via the GPVI receptor, which in turn phosphorylates and activates many downstream signaling proteins, including phospholipase C(PLC)γ that triggers calcium release from δ granules. The G protein–coupled receptor P2RY12 mediates adenosine diphosphate (ADP) interactions with platelets and is coupled ...

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