Antithrombotic effect of recombinant human soluble thrombomodulin on endotoxin-induced disseminated intravascular coagulation in rats

Gonda, Y; Hirata, Shigeto; Saitoh, Ken-ichi; Aoki, Yoshikazu; Mohri, Mitsunobu; Gomi, K; Sugihara, T.T.; Kiyota, Takao; Yamamoto, Shuji; Ishida, T.; Maruyama, Ikuro

doi:10.1016/0049-3848(93)90201-x

Cited by 50 publications

(28 citation statements)

References 26 publications

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“…Thus, recombinant forms of TM are protective in animal models of tissue factor-or endotoxin-induced disseminated intravascular coagulation or lung injury [206][207][208] and transgenic mice lacking the Nterminal lectin-like domain of TM, although appearing normal under baseline conditions, had reduced survival after endotoxin challenge, accumulated more neutrophils in their lungs, responded with larger infarcts after myocardial ischemia/reperfusion, and developed worse arthrogenicinduced arthritis than wild-type mice. However, deletion of the lectin-like domain did not alter in vivo APC formation, indicating that the pro-inflammatory effect of the mutant TM was not due to suppression of APC.…”

Section: Thrombomodulin and Inflammationmentioning

confidence: 94%

The Multifunctional Protein C System

España¹,

Medina²,

Navarro³

et al. 2005

CMCCHA

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The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.

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Section: Thrombomodulin and Inflammationmentioning

confidence: 94%

The Multifunctional Protein C System

España¹,

Medina²,

Navarro³

et al. 2005

CMCCHA

View full text Add to dashboard Cite

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“…Functions of TM beyond the blood coagulation system are being established. It has been shown that TM possesses anti-inflammatory activity [38]. TM is also believed to inhibit tumor growth progression [39].…”

Section: Discussionmentioning

confidence: 99%

Recombinant Thrombomodulin Inhibits Thrombin-Induced Vascular Endothelial Growth Factor Production in Neuronal Cells

Sarker

Yamahata²,

Nakata³

et al. 1999

Pathophysiol Haemos Thromb

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Thrombin is a serine protease which is generated from its precursor prothrombin by the activation of the blood coagulation cascade. Thrombin converts fibrinogen to fibrin, activates platelets and several coagulation factors, and plays a central role in thrombosis and hemostasis by regulating platelet aggregation and blood coagulation. Here, we show that thrombn enhanced vascular endothelial growth factor (VEGF) production in a dose- and time-dependent manner in the supernatant of cultured PC-12 cells, as determined by enzyme-linked immunosorbent assay (ELISA). Thrombin receptor agonist peptide (SFLLRNPNDKYEPF, TRAP) exerted an effect similar to thrombin on VEGF production. Thrombin-induced VEGF production was significantly attenuated by recombinant human thrombomodulin (rTM) and its minimal functional domain E456. Furthermore, the antioxidant N-acetyl-L-cysteine (NAC) markedly inhibited thrombin-induced VEGF production. Thus, rTM and NAC apparently inhibited the effect of thrombin on VEGF production in neuronal cells.

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“…[117][118][119] Although these forms of TM may be effective as anticoagulants, their clinical use for sepsis or inflammatory disorders is likely to be complicated by bleeding, similar to APC. Might the lectinlike domain of TM be efficacious as a therapeutic agent in sepsis, thereby sparing the bleeding side effect?…”

Section: Therapeutic Prospectsmentioning

confidence: 99%

Thrombomodulin-Protein C-EPCR System

Wouwer

Collen

Conway

2004

ATVB

316

151

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Abstract-Late in the 18th century, William Hewson recognized that the formation of a clot is characteristic of many febrile, inflammatory diseases (Owen C. A History of Blood Coagulation. Rochester, Minnesota: Mayo Foundation;. Since that time, there has been steady progress in our understanding of coagulation and inflammation, but it is only in the past few decades that the molecular mechanisms linking these 2 biologic systems have started to be delineated. Most of these can be traced to the vasculature, where the systems most intimately interact. Thrombomodulin (TM), a cell surface-expressed glycoprotein, predominantly synthesized by vascular endothelial cells, is a critical cofactor for thrombin-mediated activation of protein C (PC), an event further amplified by the endothelial cell protein C receptor (EPCR). Activated PC (APC), in turn, is best known for its natural anticoagulant properties. Recent evidence has revealed that TM, APC, and EPCR have activities that impact not only on coagulation but also on inflammation, fibrinolysis, and cell proliferation. This review highlights recent insights into the diverse functions of this complex multimolecular system and how its components are integrated to maintain homeostasis under hypercoagulable and/or proinflammatory stress conditions. Overall, the described advances underscore the usefulness of elucidating the relevant molecular pathways that link both systems for the development of novel therapeutic and diagnostic targets for a wide range of inflammatory diseases.

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Antithrombotic effect of recombinant human soluble thrombomodulin on endotoxin-induced disseminated intravascular coagulation in rats

Cited by 50 publications

References 26 publications

The Multifunctional Protein C System

The Multifunctional Protein C System

Recombinant Thrombomodulin Inhibits Thrombin-Induced Vascular Endothelial Growth Factor Production in Neuronal Cells

Thrombomodulin-Protein C-EPCR System

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