BioAcyl Corp

Coagulopathy is a systemic pathological condition in which the blood’s ability to clot is impaired with varying degrees of fibrinolysis. The schematic illustrates the different sepsis-induced phenotypes around the Thrombomodulin (TM)-thrombin switch (1) [47, 48]. The TM-thrombin “switch” regulates coagulation and fibrinolysis in both directions depending on different activators and inhibitors at the thrombin-TM active sites (EFF-like domains) [47, 48]. During an early infection, patients appear to have a procoagulable phenotype which may form from activation of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) (2), which decreases plasmin levels (3) and increases fibrinogen to form a stronger a stronger clot. As infection progresses the phenotype may change to a more hypocoagulable state where fibrinogen is decreased, D-dimers increase (fibrinolysis), and in extreme cases progresses to a specific hypocoagulation dominated by hyperfibrinolysis with microvascular fibrin deposits (DIC). The phenotypic change from a hyper- to hypo-coagulable state to disseminated intravascular coagulopathy (DIC) appears to be associated with a transition from a TF-dominated inflammatory microenvironment, favoring EGF-like Domain 3–6), to a non-TF dominated environment, favoring EGF-like Domain 4–6, with high mortality. This hypothesis requires knowledge of cytokines, immune cells, tPA, PAI-1, α₂-antiplasmin, fibrinogen, TAFI levels and remains to be tested. Drugs to modulate the thrombin-TM “switch” following infection and sepsis are urgently required. TPA: tissue plasminogen activator; PAI-1: plasminogen activator inhibitor-1; WVF: Von Willebrand factor; S100A10: S100 calcium binding protein A10; FVIII: Factor VIII; EPCR: endothelial protein C receptor; FDP: FDP: fibrin degradation product