What's new in using platelet research? To unravel thrombopathies and other human disorders

Abstract

This review on platelet research focuses on defects of adhesion, cytoskeletal organisation, signal transduction and secretion. Platelet defects can be studied by different laboratory platelet functional assays and morphological studies. Easy bruising or a suspected platelet-based bleeding disorder is of course the most obvious reason to test the platelet function in a patient. However, nowadays platelet research also contributes to our understanding of human pathology in other disciplines such as neurology, nephrology, endocrinology and metabolic diseases. Apart from a discussion on classical thrombopathies, this review will also deal with the less commonly known relation between platelet research and disorders with a broader clinical phenotype. Classical thrombopathies involve disorders of platelet adhesion such as Glanzmann thrombastenia and Bernard-Soulier syndrome, defective G protein signalling diseases with impaired phospholipase C activation, and abnormal platelet granule secretion disorders such as gray platelet disorder and delta-storage pool disease. Other clinical symptoms besides a bleeding tendency have been described in MYH9-related disorders and Duchenne muscular dystrophy due to adhesion defects, and also in disorders of impaired Gs signalling, in Hermansky Pudlack disease and Chediak Higashi disease with abnormal secretion. Finally, platelet research can also be used to unravel novel mechanisms involved in many neurological disorders such as depression and autism with only a subclinical platelet defect.

Fig. 1

a Schematic model of the main components involved in platelet adhesion and the cytoskeleton proteins. Platelet adhesion and its subsequent activation by calcium release is mainly regulated by the platelet receptor αIIbβ3 after binding to fibrinogen or the RGD domain of vWF, the main vWF receptor GPIb/IX/V and the collagen receptor α2β1. Microtubules together with the cytoplasmic, actin-rich cytoskeleton are responsible for the platelet structure. Different actin binding proteins have been identified in platelets such as filamin A, myosin and dystrophin. b Schematic model of G protein signal transduction in platelets regulated by Gq for platelet activation by the ultimate step of calcium release. Gi and Gs further influence the platelet activation by respectively inhibiting and stimulating the intracellular cAMP formation. c Schematic model of platelet secretion. The second amplification step in platelet activation is the release of alpha and dense granules in platelets guarantying irreversible platelet activation

Fig. 2

Electron microscopy (original magnification ×22,500) of platelets showing the dense tubular system (DTS), microtubules (MT), open canalicular system (OCS), alpha granules (G), glycogen (Gly) and the dense bodies (DB)