Procoagulant platelets: are they necrotic?

Abstract

Apoptosis and necrosis represent distinct cell death processes that regulate mammalian development, physiology and disease. Apoptosis characteristically leads to the silent destruction and removal of cells in the absence of an inflammatory response. In contrast, necrotic cell death can induce physiologic inflammatory responses linked to tissue defense and repair. Although anucleate, platelets undergo programmed cell death, with apoptosis playing an important role in clearing effete platelets from the circulation. While it has long been recognized that procoagulant platelets exhibit characteristic features of dying cells, recent studies have demonstrated that platelet procoagulant function can occur independent of apoptosis. A growing body of evidence suggest that the biochemical, morphologic and functional changes underlying agonist-induced platelet procoagulant function are broadly consistent with cell necrosis, raising the possibility that distinct death pathways regulate platelet function and survival. In this article, we will discuss the mechanisms underlying apoptotic and necrotic cell death pathways and examine the evidence linking these pathways to the platelet procoagulant response. We will also discuss the potential contribution of these pathways to the platelet storage lesion and propose a simplified nomenclature to describe procoagulant platelets. IntroductionUntil the early 1970s it was thought that all cells die as a result of necrosis (Table 1); a form of cell death that is prominent when tissues undergo extensive damage from trauma or disease. This concept changed dramatically in 1972 after the landmark observations of Kerr and colleagues, 9 who described a new form of cell death, termed apoptosis (Table 1). Since then, the genetic and biochemical processes responsible for apoptotic cell death have been extensively investigated. It is now well defined that apoptosis is a key process underlying human development, normal physiology and a range of common human diseases. 10 In contrast, the concepts underlying necrosis have become less clear-cut. While it has long been assumed that necrosis is predominantly a pathologic process resulting from tissue injury, there is growing evidence that cells can orchestrate their own demise through programmed cell necrosis in a manner that initiates physiologic inflammatory and repair responses. [2][3][4][6][7][8] Although anucleate, platelets have the capacity to undergo programmed cell death (Table 1). This has been most clearly demonstrated with platelet apoptosis; a process that is important for clearance of effete platelets from the circulation. 1,11 Many of the features of apoptosis (membrane fragmentation, cytoskeletal disruption, microvesiculation, caspase activation and phosphatidylserine [PS] exposure) are observed during prolonged platelet storage ex vivo and during the conversion of activated platelets to a procoagulant state, raising the possibility that apoptosis may also regulate platelet function. However, recent studies have demonstrated that the m...

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

“…While this model is not designed to mimic the precise sequence of pathogenetic events linked to specific thromboinflammatory diseases, it nonetheless provides important insights into the molecular processes by which dying endothelial cells promote leukocyte trafficking in vivo. The disruption of membrane phospholipid asymmetry in endothelial cells leading to PS exposure is a characteristic feature of dying cells regardless of the cause 44,45 , as in the antiphospholipid syndrome 46 , in response to immunomodulatory and chemotherapeutic regimens containing agents such as thalidomide 47 and arsenic 48 , and after ischaemia reperfusion [49][50][51] . Therefore, our observations related to PS-positive endothelial cells after needle injury may have relevance to disease processes.…”

Protein kinase A determines platelet life span and survival by regulating apoptosis

“…Simultaneously, PKA activity, as indicated by phosphorylation of PKA substrate GPIbβ at Ser166 (20) and total PKA activity in the platelets, was obviously reduced in the aged platelets ( Figure 1, A and B). Platelets were demonstrated as undergoing apoptosis under blood-banking conditions (6,8,21). We detected apoptotic events in stored platelets (Suppatients with ITP, diabetes, and sepsis.…”

“…Activation of PKA protects stored platelets from apoptosis, clearance, and loss of function. Apoptosis results in storage lesion, leading to dysfunction and rapid clearance of transfused platelets (6,8,21). We therefore investigated the role of PKA in regulating platelet apoptosis during storage with PKA activator forskolin and inhibitor H89.…”

Analysis of procoagulant phosphatidylserine‐exposing platelets by imaging flow cytometry

“…As a result, following platelet stimulation, discrete subpopulations are formed 1. Procoagulant platelets are one such subpopulation,2, 3 the nomenclature of which varies in the literature from collagen/convulxin and thrombin‐activated (COAT/COATED) platelets,4, 5, 6 to necrotic platelets,7 SCIPs (sustained calcium‐induced platelet morphology),8 superactivated,9 and zombie platelets 10. The procoagulant surface of activated platelets results from loss of normal membrane phospholipid bilayer asymmetry in resting platelets; upon stimulation, the anionic aminophospholipid phosphatidylserine (PS) is translocated from the inner membrane leaflet, where it is normally sequestered, to the outer leaflet 1, 2.…”