TAFIa, PAI-1 and α2-antiplasmin

complementary roles in regulating lysis of thrombi and plasma clots

N. J. Mutch, L. Thomas, N. R. Moore, K. M. Lisiak, N. A. Booth

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

PAI-1 and alpha(2)-antiplasmin (alpha(2)AP) are the principal direct inhibitors of fibrinolytic proteases. Thrombin activatable fibrinolysis inhibitor (TAFI), a plasma procarboxypeptidase activated by thrombin-thrombomodulin to form TAFIa, also regulates fibrinolysis by modulating fibrin. In this study, the relative contributions of PAI-1, alpha(2)AP and TAFIa to inhibition of lysis were assessed. In platelet-poor plasma clots, alpha(2)AP, TAFIa and PAI-1 all inhibited lysis, as shown by the addition of neutralizing antibodies to alpha(2)AP and PAI-1 +/- CPI, a potato carboxypeptidase inhibitor. alpha(2)AP played the largest role in regulating plasma clot lysis, but neutralization of inhibitors in combinations was more effective in shortening lysis times, with a maximal effect when all three inhibitors were neutralized. In platelet-rich clots, a larger contribution of PAI-1 was evident. Tissue plasminogen activator induced lysis of model thrombi, made from whole blood, was approximately doubled on incorporation of CPI, illustrating a substantial contribution of TAFIa to inhibition of thrombus lysis. Similar increases in thrombus lysis were observed on inclusion of neutralizing antibodies to PAI-1 and alpha(2)AP, with alpha(2)AP playing the dominant role. Maximal thrombus lysis occurred upon neutralization of all three inhibitors. These observations suggest that, despite the differences in concentrations and activities of inhibitors, and the different modes of action, the roles of the three are complementary in both plasma clot lysis and thrombus lysis.

Original languageEnglish
Pages (from-to)812-817
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume5
Issue number4
Early online date9 Feb 2007
DOIs
Publication statusPublished - Apr 2007

Keywords

  • antifibrinolytic agents
  • blood coagulation
  • blood platelets
  • carboxypeptidase U
  • fibrinolysis
  • humans
  • plasminogen activator inhibitor 1
  • platelet-rich plasma
  • recombinant fusion proteins
  • thrombosis
  • time factors
  • tissue plasminogen activator
  • alpha-2-antiplasmin

Cite this

TAFIa, PAI-1 and α2-antiplasmin : complementary roles in regulating lysis of thrombi and plasma clots. / Mutch, N. J.; Thomas, L.; Moore, N. R.; Lisiak, K. M.; Booth, N. A.

In: Journal of Thrombosis and Haemostasis, Vol. 5, No. 4, 04.2007, p. 812-817.

Research output: Contribution to journalArticle

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T2 - complementary roles in regulating lysis of thrombi and plasma clots

AU - Mutch, N. J.

AU - Thomas, L.

AU - Moore, N. R.

AU - Lisiak, K. M.

AU - Booth, N. A.

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N2 - PAI-1 and alpha(2)-antiplasmin (alpha(2)AP) are the principal direct inhibitors of fibrinolytic proteases. Thrombin activatable fibrinolysis inhibitor (TAFI), a plasma procarboxypeptidase activated by thrombin-thrombomodulin to form TAFIa, also regulates fibrinolysis by modulating fibrin. In this study, the relative contributions of PAI-1, alpha(2)AP and TAFIa to inhibition of lysis were assessed. In platelet-poor plasma clots, alpha(2)AP, TAFIa and PAI-1 all inhibited lysis, as shown by the addition of neutralizing antibodies to alpha(2)AP and PAI-1 +/- CPI, a potato carboxypeptidase inhibitor. alpha(2)AP played the largest role in regulating plasma clot lysis, but neutralization of inhibitors in combinations was more effective in shortening lysis times, with a maximal effect when all three inhibitors were neutralized. In platelet-rich clots, a larger contribution of PAI-1 was evident. Tissue plasminogen activator induced lysis of model thrombi, made from whole blood, was approximately doubled on incorporation of CPI, illustrating a substantial contribution of TAFIa to inhibition of thrombus lysis. Similar increases in thrombus lysis were observed on inclusion of neutralizing antibodies to PAI-1 and alpha(2)AP, with alpha(2)AP playing the dominant role. Maximal thrombus lysis occurred upon neutralization of all three inhibitors. These observations suggest that, despite the differences in concentrations and activities of inhibitors, and the different modes of action, the roles of the three are complementary in both plasma clot lysis and thrombus lysis.

AB - PAI-1 and alpha(2)-antiplasmin (alpha(2)AP) are the principal direct inhibitors of fibrinolytic proteases. Thrombin activatable fibrinolysis inhibitor (TAFI), a plasma procarboxypeptidase activated by thrombin-thrombomodulin to form TAFIa, also regulates fibrinolysis by modulating fibrin. In this study, the relative contributions of PAI-1, alpha(2)AP and TAFIa to inhibition of lysis were assessed. In platelet-poor plasma clots, alpha(2)AP, TAFIa and PAI-1 all inhibited lysis, as shown by the addition of neutralizing antibodies to alpha(2)AP and PAI-1 +/- CPI, a potato carboxypeptidase inhibitor. alpha(2)AP played the largest role in regulating plasma clot lysis, but neutralization of inhibitors in combinations was more effective in shortening lysis times, with a maximal effect when all three inhibitors were neutralized. In platelet-rich clots, a larger contribution of PAI-1 was evident. Tissue plasminogen activator induced lysis of model thrombi, made from whole blood, was approximately doubled on incorporation of CPI, illustrating a substantial contribution of TAFIa to inhibition of thrombus lysis. Similar increases in thrombus lysis were observed on inclusion of neutralizing antibodies to PAI-1 and alpha(2)AP, with alpha(2)AP playing the dominant role. Maximal thrombus lysis occurred upon neutralization of all three inhibitors. These observations suggest that, despite the differences in concentrations and activities of inhibitors, and the different modes of action, the roles of the three are complementary in both plasma clot lysis and thrombus lysis.

KW - antifibrinolytic agents

KW - blood coagulation

KW - blood platelets

KW - carboxypeptidase U

KW - fibrinolysis

KW - humans

KW - plasminogen activator inhibitor 1

KW - platelet-rich plasma

KW - recombinant fusion proteins

KW - thrombosis

KW - time factors

KW - tissue plasminogen activator

KW - alpha-2-antiplasmin

U2 - 10.1111/J.1538-7836.2007.02430.X

DO - 10.1111/J.1538-7836.2007.02430.X

M3 - Article

VL - 5

SP - 812

EP - 817

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 4

ER -