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Abstract
Sepsis is associated with thrombocytopenia and microvascular thrombosis. Studies have described platelets implication in this pathology but their kinetics of activation and behavior remain poorly known. We show in a mouse model of peritonitis, the appearance of platelet-rich thrombi in organ microvessels and organ damage. Complementary methods are necessary to characterize platelet activation during sepsis as circulating soluble markers and platelet-monocyte aggregates revealed early platelet activation, while surface activation markers were detected at later stage. A microfluidic based ex-vivo thrombosis assay demonstrated that platelets from septic mice have a prothrombotic behavior at shear rate encountered in microvessels. Interestingly, we found that even though phosphoinositide-3-kinase β−deficient platelet mice formed less thrombi in liver microcirculation, peritoneal sepsis activates a platelet alternative pathway to compensate the otherwise mandatory role of this lipid-kinase to form stable thrombi at high shear rate. Platelets are rapidly activated during sepsis. Thrombocytopenia can be attributed in part to platelet-rich thrombi formation in capillaries and platelet-leukocytes interactions. Platelets from septic mice have a prothrombotic phenotype at a shear rate encountered in arterioles. Further studies are necessary to unravel molecular mechanisms leading to this prothrombotic state of platelets in order to guide the development of future treatments of polymicrobial sepsis.
Highlights
Sepsis is a major cause of mortality and critical illness in the world[1,2] and is considered as a major public health concern whose incidence is increasing[3]
Platelets are thought to play a major role in sepsis with thrombocytopenia being recognized as an independent risk factor for mortality of patients admitted to the intensive care units with severe sepsis or septic shock[7]
New targets for antithrombotic therapy have been proposed such as Class IA phosphoinositide 3-kinase (PI3K) β isoform that participates in the regulation of a range of functional platelet responses, including sustained activation of αIIbβ[3] integrin
Summary
Sepsis is a major cause of mortality and critical illness in the world[1,2] and is considered as a major public health concern whose incidence is increasing[3]. Platelets are anucleated circulating cells playing an essential role in hemostasis and thrombosis They are highly reactive to extracellular stimuli through activation of a variety of specific membrane receptors for soluble agonists or adhesive proteins allowing platelet adhesion, activation, secretion and aggregation to form a plug, which, together with activation of the coagulation system, safeguards vessel integrity and prevent hemorrhage[8]. Drugs inhibiting platelet activation, such as acetylsalicylic acid (ASA) or P2Y12 inhibitors, may have a benefit in reducing thrombo-inflammation, arterial microthrombi and in turn multiple organ failure in critically ill septic patients. It has been shown that in vivo, isoform-selective PI3Kβ inhibitors prevent occlusive thrombus formation but do not prolong the bleeding time[21,22] Such inhibitor could be of interest in the treatment of septic patients. We studied platelet prothrombotic properties at high shear rate encountered in microvessels and evaluated the impact of platelet PI3Kβ inhibition
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