Abstract
The physiological heterogeneity of platelets leads to diverse responses and the formation of discrete subpopulations upon platelet stimulation. Procoagulant platelets are an example of such subpopulations, a key characteristic of which is exposure either of the anionic aminophospholipid phosphatidylserine (PS) or of tissue factor on the activated platelet surface. This review focuses on the former, in which PS exposure on a subpopulation of platelets facilitates assembly of the intrinsic tenase and prothrombinase complexes, thereby accelerating thrombin generation on the activated platelet surface, contributing importantly to the hemostatic process. Mechanisms involved in platelet PS exposure, and accompanying events, induced by physiologically relevant agonists are considered then contrasted with PS exposure resulting from intrinsic pathway-mediated apoptosis in platelets. Pathologies of PS exposure, both inherited and acquired, are described. A consideration of platelet PS exposure as an antithrombotic target concludes the review.
Highlights
Blood vessel wall injury sets into play processes that lead to the formation of a hemostatic plug that stops the bleeding from the injury site
We focus on mechanisms involved in PS exposure induced by platelet activation to form a subpopulation of procoagulant platelets, contrasting it with PS exposure resulting from platelet apoptosis
In a recently described third pathway that is distinct from the aforementioned canonical pathways, binding of oxidized low-density lipoprotein to platelet membrane glycoprotein (GP)IV (CD36) and signaling through extracellular signal-regulated protein kinase (ERK)5 mitogenactivated protein (MAP) kinase leads to PS exposure
Summary
Blood vessel wall injury sets into play processes that lead to the formation of a hemostatic plug that stops the bleeding from the injury site. It has long been recognized that activated platelets contribute in a major way to fibrin formation; this is well-exemplified in the cell-based model of coagulation [2] This procoagulant property of platelets, earlier termed platelet factor 3 availability (PF3a) and assayed by measuring the ability of platelets to promote thrombin and fibrin formation [3], results from exposure of the anionic aminophospholipid phosphatidylserine (PS) on the surface of activated platelets [4]. A unique feature of procoagulant platelet formation is that only a subpopulation of activated platelets exposes PS This was recognized over 25 years ago by flow cytometry [19] using fluorescently labeled annexin A5 that binds PS with high affinity in a Ca2+-dependent manner. Scramblase activity has long been described in platelets [4], the protein involved in Ca2+dependent PS exposure was only identified a decade ago as TMEM16F (anoctamin 6) [47,48,49]. Evidence is accumulating that TMEM16F is itself a scramblase [e.g., Watanabe et al [50]; Le et al [51]]
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