Platelet Biology and Receptor Pathways

Abstract

The main function of platelets is to participate in primary hemostasis through four distinct steps: adhesion, activation, secretion, and aggregation. Unraveling the molecular mechanisms underlying these steps has led to a better understanding of the pathophysiology of bleeding disorders, on one hand, and of thrombotic diseases, such as acute coronary syndromes, on the other. Platelets are cytoplasmic fragments of megakaryocytes formed in the bone marrow. They lack nuclei but contain organelles and structures, such as mitochondria, microtubules, and granules. Platelet granules contain different bioactive chemical mediators, many of which have a fundamental role in hemostasis and/or tissue healing. The platelet cytoplasm contains an open canalicular system that increases the effective surface area for the intake of stimulatory agonists and the release of effector substances. The submembrane region contains microfilaments of actin and myosin that mediate morphologic alterations characteristic of shape change. Resting platelets remain in the circulation for an average of approximately 10 days before being removed by macrophages of the reticuloendothelial system. A wide variety of transmembrane receptors cover the platelet membrane, including many integrins, leucine-rich repeat receptors, G protein-coupled receptors, proteins belonging to the immunoglobulin superfamily, C-type lectin receptors, tyrosine kinase receptors, and a variety of other types. In this article, we will review platelet biology under physiological and pathological conditions, with particular emphasis on the function of their membrane receptors.

The Two Faces of Thrombosis: Coagulation Cascade and Platelet Aggregation. Are Platelets the Main Therapeutic Target?

“…Once activated, platelets adhere to the site of injury and aggregate to form the haemostatic plug. The stability of the platelet aggregate is guaranteed by large amounts of fibrin [5].…”

“…Platelets are anucleate small cell-fragments derived from megakaryocytes and free circulating in the blood in a resting phenotype [5]. Upon stimulation, platelets rapidly change their structure for a substantial rearrangement of their cytoskeleton characterized by lamellipodia and pseudopodia, thus switching to an activated phenotype with pro-aggregation properties [23].…”

“…Several receptors may be indentified on the platelet surface, able to respond to a several stimuli (serotonin, shear stress, ADP, thrombin and others). The final event of the activator-receptor ligand is shape change, receptor clustering, granule secretion, synthesis of thromboxane, exposure of glycoprotein IIb/IIIa and then aggregation [5].…”

“…On platelet membrane there are two types of purinergic receptors: the P2Y group, that is a guanosine triphosphate coupled protein receptor and the P2X1 that is an ion channel receptor mediating extracellular calcium influx leading to change in platelet shape [5,27].…”

“…Moreover, serotonin induces vasoconstriction of the damaged vessels and promotes thrombus formation [37][38][39]. 2) CD40 ligand, a transmembrane glycoprotein stored in the granules of resting platelets and rapidly expressed on cell surface upon activation that induces release of fragment (CD40L) free circulating in the blood, thus serving as marker for in vivo platelet activation [5,24,40].…”