Thrombomodulin as a Physiological Modulator of Intravascular Injury

Abstract

Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelialand blood cell-derived damage-associated molecular patterns (DAMPs), and DAMPmediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects.

Management of Disseminated Intravascular Coagulation in Acute Leukemias

“…The recombinant, soluble form of TM (comprising the extracellular domain of TM) is thought to primarily affect thromboinflammation through the neutralization of several damage-associated molecular patterns, including histones and HMGB1, as well as activated complement factors. 43 Reversal of laboratory indices of DIC during treatment with recTM was observed, as well as a reduction in hemorrhagic death. 44 However, DIC in sepsis is different from leukemias in the levels of protein C, and it may be difficult to predict the risk of bleeding related to recTM infusion and generation of activated protein C, in the latter patients.…”

Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs

“… 8 , 9 Endothelial cells express key molecules that regulate the balance between hemostasis and thrombosis such as thrombomodulin and von Willebrand factor (VWF). 9 , 10 , 11 , 12 In COVID-19 patients, elevated plasma levels of soluble VWF, thrombomodulin, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and P-selectin have been shown, suggesting endothelial cell activation and dysfunction. 13 , 14 , 15 , 16 Several researchers predicted that vascular endothelial cells in COVID-19 increased adhesion molecule expression for platelet and leukocyte migration and pro-inflammatory cytokine and chemokine production.…”

“… 26 , 27 , 28 , 29 , 30 Furthermore, endothelial transmembrane molecules such as thrombomodulin and ICAM-1 are generally cleaved by enzymes and released into the blood in diseased conditions, suggesting that a transcriptional profile of endothelial cells would not reflect their dysfunctional phenotype during COVID-19. 11 , 12 , 31 Also, it remains unclear whether endothelial cell dysfunction and damage in COVID-19 are induced by direct SARS-CoV-2 infection or indirectly through pathologic conditions such as hypoxia and pro-inflammatory cytokine milieu. Some studies have shown ACE2 expression on endothelial cells with limited evidence for the direct infection by SARS-CoV-2.…”

Post-stroke Delivery of Valproic Acid Promotes Functional Recovery and Differentially Modifies Responses of Peri-Infarct Microglia

“…It is part of the anticoagulant protein C system, in which thrombomodulin binds with thrombin and promotes the cleavage of protein C and thrombin activatable fibrinolysis inhibitor, thereby inhibiting coagulation (Wenzel et al, 2014). Additionally, it interferes with inflammation, stabilizes barrier function, and promotes angiogenesis under pathological conditions (Watanabe-Kusunoki et al, 2020). Clec10a is a member of the C-type lectin receptor family and is expressed by myeloid APC, such as dendritic cells and macrophages (Ilarregui et al, 2019).…”