![]() ![]() One example of disease-specific tailoring of DIC is the significantly more intense coagulant response in early trauma. Whilst the DIC process could consume these different pathway components proportionately, the triggering pathology can influence the rate of thrombin generation and direct its function. Equally, thrombin is also pivotal in affecting opposing aspects of fibrinolysis, i.e., promoting through stimulating endothelial cell release of tissue plasminogen activator (tPA) to generate plasmin, and conversely, inhibiting through plasminogen activator inhibitor 1 (PAI-1) induction and thrombin-activatable fibrinolysis inhibitor (TAFI) activity. Conversely, thrombin also has anticoagulant properties through thrombomodulin (TM)-dependent protein C (PC) activation, and these mechanisms are well reviewed elsewhere. Thrombin is typically associated with procoagulant properties in cleaving fibrinogen into fibrin and also activating platelets, on which tenase (FIXa/VIIIa) and prothrombinase (FXa/Va) complexes assemble to propagate coagulation. Understanding the diverse and opposing thrombin-orchestrated effects is important in judging and refining management approaches when the fine homeostatic balance of normal thrombin generation is lost in DIC. The multifaceted role of thrombin generation in vivo This statement from collective experts in the field summarizes our understanding of the pathogenic concepts involved and shape our clinical considerations and management.ġ. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction". This concept has been taken into consideration by the International Society of Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee, which defines DIC as "an acquired syndrome characterized by intravascular activation of coagulation with loss of localization arising from different causes. 1), which can then disseminate systemically. In DIC, an excess of thrombin is generated and continued by inciting factors to overwhelm the homeostatically controlled hemostatic process ( Fig. These physiological processes are pathologically altered to varying degrees in patients developing disseminated intravascular coagulation (DIC). This results in the formation of a firm stable clot involving tight coordination between pro- and anticoagulant pathways as well as pro- and antifibrinolytic systems to maintain circulatory flow without perturbation from the growing thrombus. Normal hemostasis is a well-orchestrated process whereby adequate amounts of thrombin are generated at the site of vascular injury. Its usefulness and limitations are discussed alongside the advances and unanswered questions in DIC pathogenesis. ![]() ![]() To provide a practical diagnostic tool for acute DIC, a composite scoring system using rapidly available coagulation tests is recommended by the International Society on Thrombosis and Haemostasis. Their measurements as well as that of other DAMPs and molecular markers of thrombin generation are not yet applicable in the routine diagnostic laboratory. Clinically, high circulating levels of histones and histone–DNA complexes are associated with multiorgan failure, DIC, and adverse patient outcomes. Extracellular histones are increasingly recognized as significantly pathogenic in critical illnesses through direct cell toxicity, the promotion of thrombin generation, and the induction of neutrophil extracellular trap (NET) formation. In addition to the release of tissue plasminogen activator (tPA) and soluble thrombomodulin (sTM) following cellular activation and damage, respectively, there is the release of damage-associated molecular patterns (DAMPs) such as extracellular histones and cell-free DNA. This leads to consumption of both pro- and anticoagulant factors as well as endothelial dysfunction and disrupted homeostasis at the blood vessel wall interface. The etiology could be infectious or noninfectious, with the main pathophysiological mechanisms involving cross-activation among coagulation, innate immunity, and inflammatory responses. Typically, this is in response to a progressing disease state that is associated with significant cellular injury. Systemically sustained thrombin generation in vivo is the hallmark of disseminated intravascular coagulation (DIC).
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