Molecular Pathogenesis of Inherited Platelet Dysfunction

Abstract

Inherited platelet function disorders (IPFD) are characterized by normal platelet count and morphology but impaired function due to pathogenic variants in genes encoding membrane receptors, granule constituents, or intracellular signaling proteins. Glanzmann's thrombasthenia, the most representative IPFD, results from ITGA2B or ITGB3 mutations that disrupt the ?IIb?3 integrin complex, producing severe mucocutaneous bleeding. Advances in molecular genetics have expanded the IPFDs landscape to include defects in other platelet receptors (Glycoprotein (GP)-VI, P2Y(12), and thromboxane A(2)[TxA(2)]-R), signaling mediators (RASGRP2, FERMT3, G-protein regulators, PLC, and TxA(2) pathway enzymes), and granule biogenesis disorders such as Hermansky-Pudlak and Chediak-Higashi syndromes. High-throughput sequencing technologies, including long-read approaches, have greatly improved diagnostic yield and clarified genotype-phenotype correlations. Clinically, bleeding severity varies from mild to life-threatening, and management relies on antifibrinolytics, desmopressin, or platelet transfusion; recombinant activated factor VII and hematopoietic stem cell transplantation are reserved for selected cases. Emerging strategies such as gene therapy and bispecific antibodies that link platelets and coagulation factors represent promising advances toward targeted and preventive treatment. A better knowledge of the clinical features and understanding molecular pathogenesis of IPFDs not only enhances diagnostic precision and therapeutic options but also provides key insights into platelet biology, intracellular signaling, and the broader mechanisms of human hemostasis.