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Thromb Haemost 2018; 118(03): 502-513
DOI: 10.1055/s-0038-1627453
Cellular Haemostasis and Platelets
Schattauer GmbH Stuttgart

Suppressive Role of Tissue Factor Pathway Inhibitor-α in Platelet-Dependent Fibrin Formation under Flow Is Restricted to Low Procoagulant Strength

Stella Thomassen   *
,
Tom G. Mastenbroek   *
,
Frauke Swieringa
,
Kristien Winckers
,
Marion A.H. Feijge
,
Roy Schrijver
,
Judith M.E.M. Cosemans
,
Susan A. Maroney
,
Alan E. Mast
,
Tilman M. Hackeng
,
Johan W.M. Heemskerk

Funding S.T., J.M.E.M.C., T.M.H. and J.W.M.H. were funded by the Center for Translational Molecular Medicine (INCOAG). T.G.M. and J.M.E.M.C. were funded by Dutch Heart Foundation (2015T79). J.M.E.M.C. was funded by the Netherlands Organization for Scientific Research (NWO Vidi 91716421). A.E.M. was funded by the National Heart, Lung, and Blood Institute grant HL068835. F.S. was funded by Alexander von Humboldt Foundation.
Further Information

Publication History

27 July 2017

21 December 2017

Publication Date:
16 February 2018 (online)

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Abstract

Tissue factor pathway inhibitor-alpha (TFPI-α) is a Kunitz-type serine protease inhibitor, which suppresses coagulation by inhibiting the tissue factor (TF)/factor VIIa complex as well as factor Xa. In static plasma-phospholipid systems, TFPI-α thus suppresses both factor Xa and thrombin generation. In this article, we used a microfluidics approach to investigate how TFPI-α regulates fibrin clot formation in platelet thrombi at low wall shear rate. We therefore hypothesized that the anticoagulant effect of TFPI-α in plasma is a function of the local procoagulant strength—defined as the magnitude of thrombin generation under flow, due to local activities of TF/factor VIIa and factor Xa. To test this hypothesis, we modulated local coagulation by microspot coating of flow channels with 0 to 100 pM TF/collagen, or by using blood from patients with haemophilia A or B. For blood or plasma from healthy subjects, blocking of TFPI-α enhanced fibrin formation, extending from a platelet thrombus, under flow only at <2 pM coated TF. This enhancement was paralleled by an increased thrombin generation. For mouse plasma, genetic deficiency in TFPI enhanced fibrin formation under flow also at 0 pM TF microspots. On the other hand, using blood from haemophilia A or B patients, TFPI-α antagonism markedly enhanced fibrin formation at microspots with up to 100 pM coated TF. We conclude that, under flow, TFPI-α is capable to antagonize fibrin formation in a manner dependent on and restricted by local TF/factor VIIa and factor Xa activities.

Keywords

fibrin clot formation - haemophilia - mouse - platelets - TFPI - thrombin generation

* Stella Thomassen and Tom G. Mastenbroek contributed equally.


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