Antithrombotic effects due to pharmacological modulation of thrombin-activatable fibrinolysis inhibitor in rats

Hiteshkumar Soni, Ajay Sharma, Shvetank Bhatt, Mukul R. Jain, Pankaj R. Patel

Research output: Contribution to journalArticle

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Abstract

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a basic carboxypeptidase zymogen that can be activated by thrombin. Activated TAFI (TAFIa) cleaves carboxyl-terminal lysine residues from partially degraded fibrin, rendering it resistant to fibrinolysis by endogenous tissue plasminogen activator (tPA). Carboxypeptidase inhibitor (CPI) isolated from potato inhibits TAFIa and reduces clot lysis time in rabbit and mouse plasma. In the present study, we report the effect of CPI on tPA-mediated clot lysis using rat plasma in vitro. CPI at 400, 600 and 800 ng/ml caused a dose-dependent enhancement of tPA-induced clot lysis. In vivo effect of CPI was also investigated using ferric chloride-induced arterial thrombosis model in rat. The results showed that i.v. administration of CPI significantly prolonged the 'time to occlusion' at the dose of 2 and 4 mg/kg. At 2 mg/kg i.v. dose in rat, CPI showed no effect on prothrombin time and activated partial thromboplastin time, indicating noninterference of CPI with other clotting factors in mediating its thrombolytic effect through TAFI inhibition. Furthermore, 2 mg/kg i.v. dose of CPI did not produce significant increase in bleeding time when tested in rat tail-transection bleeding model. These results provide evidence for a role of TAFI in arterial thrombosis in rats and suggest that TAFI inhibition could be explored as an attractive target for the development of new antithrombotic drugs.

Original languageEnglish (US)
Pages (from-to)304-309
Number of pages6
JournalPharmacology
Volume82
Issue number4
DOIs
StatePublished - Nov 1 2008

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Carboxypeptidase B2
Carboxypeptidases
Pharmacology
Tissue Plasminogen Activator
Thrombosis
Fibrin Clot Lysis Time
Enzyme Precursors
Bleeding Time
Blood Coagulation Factors
Partial Thromboplastin Time
Prothrombin Time
Fibrinolysis
Solanum tuberosum
Fibrin
Thrombin
Lysine
Tail
Hemorrhage

All Science Journal Classification (ASJC) codes

  • Pharmacology

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Antithrombotic effects due to pharmacological modulation of thrombin-activatable fibrinolysis inhibitor in rats. / Soni, Hiteshkumar; Sharma, Ajay; Bhatt, Shvetank; Jain, Mukul R.; Patel, Pankaj R.

In: Pharmacology, Vol. 82, No. 4, 01.11.2008, p. 304-309.

Research output: Contribution to journalArticle

Soni, Hiteshkumar ; Sharma, Ajay ; Bhatt, Shvetank ; Jain, Mukul R. ; Patel, Pankaj R. / Antithrombotic effects due to pharmacological modulation of thrombin-activatable fibrinolysis inhibitor in rats. In: Pharmacology. 2008 ; Vol. 82, No. 4. pp. 304-309.
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