Thrombomodulin inhibits the activation of factor xiii by thrombin

Polgár, János; Léránt, István; Muszbek, László; Machovich, Raymund

doi:10.1016/0049-3848(86)90079-4

Cited by 23 publications

(11 citation statements)

References 11 publications

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“…In this regard, the present study reflects many similarities in the two systems. Thrombomodulin blocks the ability of thrombin to cleave its natural substrates, factor V (26), factor XIII (27), fibrinogen (26), and platelets (28). EPCR prevents inactivation of factor Va by APC.…”

Section: Discussionmentioning

confidence: 99%

The Endothelial Cell Protein C Receptor

Regan

Stearns-Kurosawa

Mollica

et al. 1996

Journal of Biological Chemistry

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A soluble form of the endothelial cell protein C receptor (EPCR) was analyzed for the ability to modulate the functional properties of protein C and activated protein C (APC). In a plasma clotting system initiated with factor Xa, EPCR blocked the anticoagulant activity of APC in a dose-dependent fashion. EPCR had no influence on clotting in the absence of APC. Consistent with the plasma results, EPCR slowed the proteolytic inactivation of factor Va by slowing both of the key proteolytic cleavages in the heavy chain of factor Va. EPCR did not prevent protein C activation by the soluble thrombinthrombomodulin complex, did not alter the inactivation of APC by ␣ 1 -antitrypsin or protein C inhibitor, and did not influence the kinetics of peptide paranitroanilide substrate cleavage significantly. We conclude that EPCR binds to an exosite on APC that selectively modulates the enzyme specificity in a manner reminiscent of the influence of thrombomodulin on thrombin.

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Section: Discussionmentioning

confidence: 99%

The Endothelial Cell Protein C Receptor

Regan

Stearns-Kurosawa

Mollica

et al. 1996

Journal of Biological Chemistry

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“…8 The complex catalytically generates activated protein C and enhances the rate of protein C activation by thrombin at least 1,000-fold. 9 In addition, complex formation blocks the procoagulant activity of thrombin, resulting in the loss of thrombin's activation of fibrinogen, 10 - 15 factor V, 10 platelets, 1116 endothelial cells, 17 and factor XIII 18 and inactivation of protein S. 19 - 20 Thrombin can still be inhibited by its physiological inhibitor, antithrombin Ill, while bound to thrombomodulin. When this occurs, the thrombin-antithrombin III complex dissociates rapidly, freeing thrombomodulin for continued protein C activation.…”

Section: Properties Of the Protein C Pathwaymentioning

confidence: 99%

The protein C anticoagulant pathway.

Esmon

1992

Arterioscler Thromb

296

154

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“…Second, a specific endothelial cell-surface thrombin receptor, thrombomodulin, complexes thrombin, thereby altering its substrate specificity (18). Thrombin complexed to thrombomodulin no longer functions as a coagulant by cleaving fibrinogen and activating FV and FVIII (19); it functions as an inhibitor of coagulation by activating the protein Clprotein S inhibitory system (20,21). Activated protein C downregulates thrombin generation by limited proteolysis of FVa and FVIIIa (22).…”

mentioning

confidence: 99%

α2-Macroglobulin Remains as Important as Antithrombin III for Thrombin Regulation in Cord Plasma in the Presence of Endothelial Cell Surfaces

Delorme

Berry³

et al. 1995

Pediatr Res

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---r =--9 ------------ __1 ----7 ---' ------71-7 -- ABSTRACTInfants and children rarely develop thrombotic complications compared with adults, suggesting that there are protective mechanisms in place for the young. Because endothelial cell surfaces regulate thrombin formation and inhibition, we compared thrombin regulation by human umbilical vein endothelial cell surfaces exposed to defibrinated cord and adult plasmas. After activation by either 10% activated partial thromboplastin reagent (strong activator) or coagulant phospholipids (weak activator) the following were measured: free thrombin, thrombin bound to antithrombin I11 (ATIII), heparin cofactor 11, a,-macroglobulin (a2M), and prothrombin concentration. Free thrombin activity was expressed as remaining activity, after subtraction of thrombin-a2M activity. After 10% activated partial thromboplastin reagent, 100% of prothrombin was consumed and significant amounts of thrombin generated by 2 min. Cord plasma generated significantly less thrombin than adult plasma, reflecting the lower initial plasma concentration of prothrombin. Correspondingly, concentrations of thrombin inhibitor complexes were significantly greater in adult plasma than in cord plasma. After coagulant phospholipids, 50% of prothrombin was consumed and negligible thrombin activity measured for both adult and cord plasma. Similar amounts of thrombin inhibitor complexes were formed. ATIII was the predominant inhibitor of thrombin in adult plasma, whereas a,M was as important as ATIII in cord plasma for both activators. When cord plasma concentrations of ATIII were increased to adult values, the proportion complexed to a2M decreased. We conclude that on human umbilical vein endothelial cells, the capacity to generate thrombin is decreased in adult and cord plasmas. Furthermore, a2M is at least as important an inhibitor as ATIII in cord plasma, even in the presence of Thromboembolic complications rarely occur in fetuses and newborns, suggesting that protective mechanisms are in place in the young. Biologically, the ability to regulate thrombin formation and activity are of central importance to the prevention and formation of large-vessel thrombi. Regulation of thrombin under physiologic circumstances involves both plasma coagulation and inhibitors, as well as interactions with

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Thrombomodulin inhibits the activation of factor xiii by thrombin

Cited by 23 publications

References 11 publications

The Endothelial Cell Protein C Receptor

The Endothelial Cell Protein C Receptor

The protein C anticoagulant pathway.

α2-Macroglobulin Remains as Important as Antithrombin III for Thrombin Regulation in Cord Plasma in the Presence of Endothelial Cell Surfaces

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