Posts Tagged: fibrin

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Platelet participation in neutrophil extracellular trap formation (NETosis). Activated platelets interact with neutrophils via platelet P-selectin and neutrophil PSGL-1 (P-selectin glycoprotein ligand-1), with interactions stabilized by a series of secondary adhesion interactions, including the ones mediated by platelet GP (glycoprotein) Ib and leukocyte Mac-1 (αMβ2). This interaction can contribute to trigger the release of NETs, consisting of chromatin containing citrullinated histones complexed with antimicrobial proteases, such as elastase and myeloperoxidase, in a process called NETosis. NETs serve to enhance the clearance of pathogens. They also contribute to clot formation by forming a mesh with platelets and fibrin and accumulating coagulation factors, such as tissue factor (TF). [Powerpoint File]

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Role for platelets in inflammation and response to pathogens. At sites of damaged or inflamed endothelium, platelet adhesion occurs through various interactions, such as with exposed subendothelium, P-selectin expression on activated endothelium, and release of ultralarge vWF (von Willebrand factor). Adherent platelets, in turn, recruit white blood cells (WBCs), which can subsequently transmigrate across the endothelium. Heterotypic cell interactions between platelets and WBCs or red blood cells (RBCs) can occur and are associated with increases in systemic inflammation. Activated platelets can trigger the release of neutrophil extracellular traps (NETs), which contribute to microbial clearance and clot formation. Platelets also interact with viral and bacterial pathogens to contribute to their clearance and respond to gut microbiota that can modulate platelet function. [Powerpoint File]

Systems Analysis of Thrombus Formation

Systems Analysis of Thrombus Formation

Scott L. Diamond

Systems biology of thrombosis. The computer simulation of clotting requires a multiscale and integrated description of platelet signaling and adhesion, coagulation kinetics, and hemodyamics. Platelet signaling is driven by soluble activators (ADP, thromboxane A2 [TXA2], thrombin), soluble inhibitors (NO, prostacyclin [PGI2] and insoluble activators (collagen) to drive intracellular calcium mobilization. Calcium mobilization occurs rapidly through IP3-mediated release and store-operated calcium entry (STIM1-Orai1). Dense platelet deposits in clots result in significant ADP and thromboxane and thrombin-driven signaling, often targeted by inhibition of P2Y12, cyclooxygenase (COX)-1, and PAR1, respectively. During coagulation, the generation of thrombin (FIIa) is primarily driven by TF/FVIIa (extrinsic tenase) via subsequent engagement of the FIXa/VIIIa (intrinsic tenase) and FXaVa (prothrombinase). Thrombin has significant regulatory control on its own production through activation of FVIIIa, FVa, FXIa, as well as regulation of fibrin through activation of FXIIIa that crosslinks fibrin. Local hemodynamics (inset; reprinted from Taylor et al3 with permission of the publisher. Copyright ©2013, Elsevier.) can be determined by computational fluid dynamics to define locations with at-risk plaque burden, stenosis, and high wall shear stress. Full systems biology models of platelet activation and coagulation in a patient-specific flow field are directed at simulation of acute coronary syndromes (bottom). AC indicates adenylate cyclase; AP, antiplasmin; APC, activated protein C; ATIII, antithrombin III; catG, cathepsin G; CTI, corn trypsin inhibitor; DTS, dense tubular system; EC, endothelial cell; FDP, fibrin degradation product; GC, guanylate cyclase; GPVI, glycoprotein VI; HMWK, high molecular weight kininogen; HNE, human neutrophil elastase; IP, prostacyclin receptor; MG, macroglobulin; NO, nitric oxide; P2Y purinergic receptor type 2; PAI, plasminogen activator inhibitor; PAR, protease activated receptor; PC, protein C; PLC, phospholipase; PMCA, plasma membrane calcium ATPase; PN2, proteonexin 2; PS, protein S; TM, thrombomodulin; TP, thromboxane receptor; tPA, tissue-type plasminogen activator; and uPA, urokinase plasminogen activator. [Powerpoint File]