Inducible Carboxypeptidase Activity

Redlitz, Alexander; Nicolini, Fabio; Malycky, Janis L.; Topol, Eric J.; Plow, Edward F.

doi:10.1161/01.cir.93.7.1328

Cited by 95 publications

(63 citation statements)

References 9 publications

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“…An inducible carboxypeptidase activity has been demonstrated earlier in dogs with electrically induced coronary artery thrombosis and concomitant lysis with t-PA [165]. Some years later, other investigators [172,173] identified this carboxypeptidase activity as CPU, and they also showed that co-administration of t-PA and a CPU inhibitor; potato tuber carboxypeptidase inhibitor (PTCI), significantly improved t-PAinduced thrombolysis in a rabbit jugular vein thrombosis model.…”

Section: Thrombolysis and Carboxypeptidase U Inhibition -Paper IVmentioning

confidence: 97%

“…A comparison between groups that gave the same prolongation of APTT also revealed that melagatran at a dose of 0.3 mg/(kg×h) gave a significantly better flow than hirudin at a dose of 1.2 mg/(kg×h) or heparin at a dose of 50 IU/(kg×h), which supports the hypothesis that a low-molecular weight direct thrombin inhibitor is more effective in inhibiting clotassociated thrombin. However, during the preparation of Paper II, some new data were presented that suggested an additional mechanism that might explain why there seems to be a profibrinolytic effect of small direct thrombin inhibitors [165].…”

Section: Thrombolysis and Thrombin Inhibition -Paper IImentioning

confidence: 99%

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Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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Section: Thrombolysis and Carboxypeptidase U Inhibition -Paper IVmentioning

confidence: 97%

Section: Thrombolysis and Thrombin Inhibition -Paper IImentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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“…It has been suggested that TAFI may block exaggerated fibrinolysis in this manner. In fact, inhibition of TAFI activity by a carboxypeptidase inhibitor stimulated fibrinolysis in an animal model [66]. Notably, activity of TAFI was inhibited by 60 % in APL patients [67].…”

Section: Hyperfibrinolysismentioning

confidence: 98%

Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin

Ikezoe

2013

Int J Hematol

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Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhagerelated death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.

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“…1 Various animal models have demonstrated that TAFI regulates both venous and arterial fibrinolysis in vivo. [2][3][4][5] Furthermore, epidemiological studies have shown elevated TAFI levels to be a mild risk factor for the development of a first or recurrent venous thrombosis. [6][7][8] However, studies on the association between single nucleotide polymorphisms (SNP) that are associated with TAFI levels and the risk of venous thrombosis have given conflicting results.…”

Section: Introductionmentioning

confidence: 99%

Low thrombin activatable fibrinolysis inhibitor activity levels are associated with an increased risk of a first myocardial infarction in men

Meltzer¹,

Doggen²,

Groot³

et al. 2009

Haematologica

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BackgroundStudies on the relation between thrombin activatable fibrinolysis inhibitor (TAFI) and arterial thrombosis have produced conflicting results.TAFI regulates fibrinolysis, but other roles of this inhibitor, including anti-inflammatory properties, have also been demonstrated. Design and MethodsWe investigated the association between TAFI activity and the risk of myocardial infarction. Additionally, we studied the association of common single nucleotide polymorphisms in the TAFI gene with levels of the TAFI protein and risk of myocardial infarction.We included 554 men under 70 years old with a first myocardial infarction and 643 controls participating in the Study of Myocardial Infarctions Leiden (SMILE), a case-control study. ResultsWe found odds ratios (95% confidence intervals) of a first myocardial infarction of 2.4 (1.6-3.6), 3.2 (2.1-4.7) and 3.4 (2.3-5.1) for subjects whose TAFI levels were in the third, second and first quartiles (lowest TAFI levels), respectively, compared with the fourth quartile, after adjusting for arterial disease risk factors. The rare -438A and 1040T alleles were associated with lower, and the rare 505G allele with higher TAFI levels than the common alleles. Carriers of the -438A allele had an increased risk of myocardial infarction (odds ratio 1.6 (1.0-2.5) for AA; odds ratio 1.2 (0.9-1.5) for AG compared with GG). The other single nucleotide polymorphisms were not associated with myocardial infarction. ConclusionsLow TAFI activity levels are associated with increased risk of a first myocardial infarction in men. The results on the association between TAFI single nucleotide polymorphisms and myocardial infarction were inconsistent.Key words: TAFI, myocardial infarction, genetics, epidemiology.Citation: Meltzer ME, Doggen CJM, de Groot PG, Meijers JCM, Rosendaal FR, and Lisman T. Low thrombin activatable fibrinolysis inhibitor activity levels are associated with an increased risk of a first myocardial infarction in men. Haematologica 2009; 94:811-818. doi:10.3324/haematol.2008 This is an open-access paper. Low thrombin activatable fibrinolysis inhibitor activity levels are associated with an increased risk of a first myocardial infarction in men

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Inducible Carboxypeptidase Activity

Abstract: These data indicate that carboxypeptidase activity is induced in vivo and may influence thrombolysis.

Cited by 95 publications

References 9 publications

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin

Low thrombin activatable fibrinolysis inhibitor activity levels are associated with an increased risk of a first myocardial infarction in men

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