Congenital platelet disorders and understanding of platelet function

Abstract

SummaryGenetic defects of platelets constitute rare diseases that include bleeding syndromes of autosomal dominant, recessive or X-linked inheritance. They affect platelet production, resulting in a low circulating platelet count and changes in platelet morphology, platelet function, or a combination of both with altered megakaryopoiesis and a defective platelet response. As a result, blood platelets fail to fulfil their haemostatic function. Most studied of the platelet function disorders are deficiencies of glycoprotein mediators of adhesion and aggregation while defects of primary receptors for stimuli include the P2Y 12 ADP receptor. Studies on inherited defects of (i) secretion from storage organelles (dense granules, a-granules), (ii) the platelet cytoskeleton and (iii) the generation of pro-coagulant activity have identified genes indirectly controlling the functional response. Signalling pathway defects leading to agonist-specific modifications of platelet aggregation are the current target of exome-sequencing strategies. We now review recent advances in the molecular characterization of platelet function defects.

Inherited macrothrombocytopenias on the rise

“…Instead, the data support a model (depicted in Figure 6 of Padrón-Barthe et al 1 ) where the precursors for primitive blood and yolk sac endothelium are already specified before gastrulation, 3,4 and colonize the yolk sac sequentially with the endothelial-fated lineage encircling the blood-fated cells. 10 The authors propose that part of the labeled yolk sac endothelium represents the hemogenic endothelium that contributes to blood through an endothelial to hematopoietic transition.…”

Megakaryocyte- and megakaryocyte precursor–related gene therapies

“…18,19 Correction of inherited platelet defects Defects of distinct platelet proteins are very rare (1:1 000 000 individuals); however, taken collectively, a molecular genetic defect in a gene that plays a role in normal platelet function occurs in 1:10 000 individuals usually manifesting itself in the form of uncontrolled bleeding. 35 A recent review by Nurden and Nurden elegantly illustrates several known genetic defects affecting platelet proteins that may be ideal candidates for gene therapy including surface molecules (TMEM16F, Scott syndrome), cytoplasmic (STIM1/ORAI, Stormorken syndrome) and structural proteins (WASP, WIPF1, Wiskott-Aldrich syndrome) as well as granule constituents (NBEAL2,GFI1B, gray platelet syndrome). 36 Disorders resulting from platelet defects are commonly referred to as "benign" because uncontrolled bleeding frequently responds favorably to treatment with platelet transfusions, use of antifibrinolytic agents, and recombinant factor VIIa (FVIIa).…”

Assessment of platelet function: Laboratory and point-of-care methods

“…ADP agonist is generally used to investigate congenital/acquired bleeding disorders by LTA [22] . In the presence of different platelet alteration, ADP induced platelet aggregation may result reduced (P2Y12 defects, storage pool deficiency of α and δ granules, and defects of α granules) or severely impaired (Glanzmann's thrombasthenia) [42,50] . ADP at high concentrations (i.e., ≥ 10 µmol/ L) is used to monitor thienopyridines effect: ticlopidine, clopidogrel, prasugrel and ticagrelor act through the P2Y12 ADP receptor causing selective inhibition of responses to ADP [44,45,[51][52][53][54][55] .…”