[17] Meizothrombin: Active intermediate formed during prothrombinase-catalyzed activation of prothrombin

Doyle, Margaret F.; Haley, Paul E.

doi:10.1016/0076-6879(93)22020-g

Cited by 25 publications

(21 citation statements)

References 15 publications

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Section: Resultsmentioning

confidence: 99%

“…However, the product is rapidly and near quantitatively autolyzed, leading to the removal of the propiece and the formation of a proteinase species resembling thrombin (41). Consequently, most studies have relied on mIIa stabilized by covalent modification of the active site or by the use of tight binding inhibitors to preclude autolysis (41). However, ligation of the active site by reversible or irreversible inhibitors is established to drive zymogen-like forms of thrombin to proteinase-like states (13,16).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Meizothrombin Is an Unexpectedly Zymogen-like Variant of Thrombin

Bradford

Krishnaswamy

2012

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Meizothrombin Is an Unexpectedly Zymogen-like Variant of Thrombin

Bradford

Krishnaswamy

2012

Journal of Biological Chemistry

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“…Cleavage of prothrombin to prothrombin fragments 1 and 2 and alpha thrombin is only one pathway of thrombin activation. Alternatively, prothrombin can be cleaved to form the intermediate form meizothrombin, which may have a better potential to activate protein C than thrombin [25,26] . This route of thrombin activation is not mirrored by prothrombin fragments 1 and 2, and whether heparin and inogatran have different effects on the alternative ways of activation is not known.…”

Section: Discussionmentioning

confidence: 99%

The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease

Linder

Oldgren²,

Egberg³

et al. 1999

European Heart Journal

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Aim This study evaluated a novel specific thrombin inhibitor, inogatran, in comparison with unfractionated heparin, with regard to markers for coagulation activity in patients with unstable coronary artery disease. Methods and ResultsIn the Thrombin Inhibition In Myocardial ischaemia (TRIM) study patients were randomized to one of three different doses of inogatran or to unfractionated heparin, given intravenously over 72 h. In a subpopulation of 320 patients, markers for coagulation activity were measured at baseline, during and after the study infusion.Prothrombin fragment 1+2, indicating thrombin generation, decreased in the low, medium and high dose inogatran groups and in the heparin group during the first 6 h of treatment by 12%, 15%, 21% and 26%, respectively. From 6 h to 72 h after the start of infusion the levels changed by 7%, 6%, 4% and +34%, respectively. The increase in the heparin group continued after the infusion was stopped. Thrombin-antithrombin complex, also indicating thrombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during the first 6 h of treatment. During the same period soluble fibrin, an intermediate in fibrin formation, increased both in the low and medium inogatran group by 9%, while a decrease by 4% and 18%, respectively, was seen in the high dose inogatran group and in the heparin group. Fibrin dissolution, as measured by fibrin D-dimer, decreased during the first 24 h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24 h after discontinuation of infusion, fibrin D-dimer increased by 6%, 23%, 25% and 44%, respectively.After 72 h, at the end of infusion, patients treated with inogatran, to a larger extent than those given heparin, had suffered from death, myocardial infarction or refractory angina pectoris. After 7 days this trend was less marked. ConclusionThe more pronounced decrease in thrombin generation and fibrin turnover during the first 6 h of infusion, and the later increase in thrombin generation and fibrin turnover, in the heparin group, as compared to the inogatran groups, may be related to the lower clinical event rate during infusion with heparin compared with inogatran and the recurrence of ischaemic events, early after cessation of heparin infusion. (Eur Heart J 1999; 20: 506-518)

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“…81,87 These 2 products continue to self-associate in a noncovalent manner (K d ϳ 10 Ϫ8 M). 87 In contrast, factor Xa-membrane cleaves prothrombin first at Arg271 to give rise to prethrombin 2; subsequent cleavage of this intermediate at Arg320 gives rise to ␣-thrombin, with fragment 1•2 as the other product of the reaction. It is not clear whether the enhancement in k cat for the enzymatic reaction is a consequence of alterations in the factor Xa active site, prothrombin as a substrate, or alterations in both enzyme and substrate when bound to factor Va.…”

Section: Function Cofactor For Factor Xa In Prothrombinasementioning

confidence: 99%