The products of four genes (GPIBA, GPIBB, GP9 and GP5) assemble within maturing MK in the marrow to form the GPIb-IX-V complex. Mutations within GPIBA, GPIBB and GP9 in BSS prevent formation or trafficking of the complex through endoplasmic reticulum (ER) and the Golgi apparatus [6]. In rare variant forms, platelets express nonfunctional GPIbα; in platelet-type von Willebrand selleck disease (VWD), specific GPIBA mutations lead to upregulated GPIbα function and a clinical condition resembling type 2B VWD where macrothrombocytopenia (and sometimes circulating platelet aggregates) due to activating mutations in exon 28 of the VWF gene may also affect

megakaryopoiesis [7]. The platelet-collagen interaction under flow is a multistep process involving α2β1 and GPVI which signals through the FcRγ-chain [2,6]. Like α2β1, GPVI density is under learn more the control of SNPs and epigenetic factors; however, a loss in the collagen response due to mutations in GP6 occurs in rare families. Members of the seven transmembrane domain family of G-protein-linked receptors mediate platelet responses to soluble agonists. Rare patients with a decreased and reversible platelet aggregation to ADP have mutant alleles at the P2YR12 locus while a defective platelet aggregation to TXA2 is caused by mutations in TA2R. Significantly, these patients mimic the

platelet function modifications achieved in anti-thrombotic

therapy by clopidogrel (and prasugrel) and aspirin respectively. Decreased platelet aggregation to adrenaline is often seen in routine screening although its contribution to excessive bleeding is unclear. Abnormalities of signal transduction pathways into which surface receptors are locked mostly concern patients with mild bleeding while congenital deficiencies of metabolic pathways also lead to platelet function abnormalities [2,6,8–10]. IPDs of secretion (storage pool disease, SPD) cause selective defects 上海皓元 in aggregation. SPD affecting dense granules, storage sites for serotonin, ADP and ATP, may be quite common and the granule deficiency severe or partial. When associated with abnormalities of other lysosome-related organelles they give clearly defined phenotypes [e.g. Hermansky–Pudlak (HPS) and Chediak–Higashi (CHS) syndromes] where melanosomal defects cause a lack of pigmentation of the skin and hair. Defects in at least 8 genes (HPS-1 through HPS-8) in HPS cause distinct subtypes with the encoded proteins interacting in complexes (BLOCS); the genetic defects disrupt these thereby affecting organelle biosynthesis and protein trafficking. In CHS, bleeding is associated with severe immunologic defects and progressive neurological dysfunction, a lymphoproliferative syndrome and an accelerated phase is seen in ∼90% of patients.