Mechanisms Underlying Dichotomous Procoagulant COAT Platelet Generation—A Conceptual Review Summarizing Current Knowledge

Abstract

Procoagulant platelets are a subtype of activated platelets that sustains thrombin generation in order to consolidate the clot and stop bleeding. This aspect of platelet activation is gaining more and more recognition and interest. In fact, next to aggregating platelets, procoagulant platelets are key regulators of thrombus formation. Imbalance of both subpopulations can lead to undesired thrombotic or bleeding events. COAT platelets derive from a common pro-aggregatory phenotype in cells capable of accumulating enough cytosolic calcium to trigger specific pathways that mediate the loss of their aggregating properties and the development of new adhesive and procoagulant characteristics. Complex cascades of signaling events are involved and this may explain why an inter-individual variability exists in procoagulant potential. Nowadays, we know the key agonists and mediators underlying the generation of a procoagulant platelet response. However, we still lack insight into the actual mechanisms controlling this dichotomous pattern (i.e., procoagulant versus aggregating phenotype). In this review, we describe the phenotypic characteristics of procoagulant COAT platelets, we detail the current knowledge on the mechanisms of the procoagulant response, and discuss possible drivers of this dichotomous diversification, in particular addressing the impact of the platelet environment during in vivo thrombus formation.

Identification of platelet subpopulations in cryopreserved platelet components using multi-colour imaging flow cytometry

“…The current literature proposes that the development of platelet subpopulations may be based on a spectrum of activation, depending on the strength of stimulation and the cytoplasmic calcium concentration 57 , 58 . It has also been suggested that procoagulant and apoptotic platelets may be interrelated 24 , 25 , 34 .…”

Discriminating young platelets on human leukocyte antigen-I expression highlights their extremely high reactivity potential

“…These data are in agreement with a previous report by Alberio’s group describing a high proportion of COAT platelets within the TO bright population [ 16 ]. To become procoagulant, a high and sustained intracytopasmic calcium rise is required to externalize PS and bind coagulations factors [ 3 , 17 ]. Because platelet aging has been reported to be linked to a decrease in cytoskeletal protein, mitochondrial number, and calcium dynamics [ 18 ], it could represent one of the mechanisms explaining the propensity of young platelets to become procoagulant.…”

“…Procoagulant or COAT (COllagen And Thrombin activated) platelets are activated platelets exposing negatively charged aminophospholipids and binding several α -granular proteins including factor V and von Willebrand factor (vWF), which cluster together to form a coat [ 2 ]. Approximately one-third of platelets become procoagulant after stimulation, but this predisposition is still under debate [ 3 ].…”

Platelets from patients with myeloproliferative neoplasms have increased numbers of mitochondria that are hypersensitive to depolarization by thrombin

“…Depolarization is associated with permeabilization of the mitochondrial membrane and causes a spike in cytoplasmic calcium which can, in turn, lead to depolarization of adjacent mitochondria 10 . When the density of mitochondria within the platelet is increased, this would be predicted to enable more efficient propagation of calcium flux to adjacent mitochondria 27 . Consistent with this hypothesis, thrombin hypersensitivity to depolarization was most marked in the cohort of patients with ET (versus PV) in whom mitochondrial mass showed the greatest increase.…”