Pathologies at the nexus of blood coagulation and inflammation: thrombin in hemostasis, cancer, and beyond

Abstract

Thrombin is the protease involved in blood coagulation. Its deregulation can lead to hemostatic abnormalities, which range from subtle subclinical to serious life-threatening coagulopathies, i.e., during septicemia. Additionally, thrombin plays important roles in many (patho)physiological conditions that reach far beyond its well-established role in stemming blood loss and thrombosis, including embryonic development and angiogenesis but also extending to inflammatory processes, complement activation, and even tumor biology. In this review, we will address thrombin’s broad roles in diverse (patho)physiological processes in an integrative way. We will also discuss thrombin as an emerging major target for novel therapies.

Cross Talk Pathways Between Coagulation and Inflammation

“…This allows it to complex with small amounts of circulating factor VIIa, 7 enhancing the latter's catalytic activity and triggering coagulation by activating coagulation factors IX and X. With sufficient TF exposure and sustained injury, the amount of thrombin generated can be amplified to exceed a threshold beyond several negative regulatory influences to promote platelet activation, fibrin clot formation, and a myriad of proinflammatory events, 8 the latter primarily mediated via activation of PAR cell signaling pathways (see below). This includes, for example, recruitment and activation of monocytes, neutrophils, and platelets, induction of leukocyte adhesion molecules by endothelial cells, release of proinflammatory cytokines, and activation of complement.…”

“…8 Thrombin exerts its hemostatic and thrombotic effects through the coagulation-inflammation axis, where it cleaves fibrinogen to generate an insoluble fibrin clot; amplifies its own production through pro-cofactor activation; and activates various cell types via proteolytic cleavage of PARs (reviewed in Coughlin 32 ). PARs are expressed in many cell types, including platelets, endothelial, immune, and epithelial cells, astrocytes, and neurons.…”

Coagulation and non‐coagulation effects of thrombin

“…Given the abundant cellular expression of PARs, it is hardly surprising that thrombin is involved in many physiologic processes, such as embryogenic development, angiogenesis, wound healing, and inflammation, as well as in pathophysiologic processes, such as atherosclerosis, sepsis, cancer, and neuropathology [23]. Depending on the conditions of PAR activation, thrombin can have opposing effects on a cell; for instance, it contributes to both anti-inflammatory and proinflammatory processes, regulates both endothelial integrity and endothelial permeability, and can induce both vasodilatation and vasoconstriction [7,19,23].…”

“…Depending on the conditions of PAR activation, thrombin can have opposing effects on a cell; for instance, it contributes to both anti-inflammatory and proinflammatory processes, regulates both endothelial integrity and endothelial permeability, and can induce both vasodilatation and vasoconstriction [7,19,23].…”

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“…It is an important part of haemostasis; the cessation of blood loss from a damage vessel, whereby a damaged blood vessel wall is covered by a platelet and fibrin containing clot to stop bleeding and begin repair of haemorrhage or obstructive clotting [9]. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss [10]. Thrombin is an enzyme that presides over the conversion of fibrinogen to fibrin [11].…”