Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow

Jevgenia Zilberman-Rudenko, Asako Itakura, Chantal P. Wiesenekker, Ralf Vetter, Coen Maas, David Gailani, Erik Tucker, Andras Gruber, Christoph Gerdes, Owen McCarty

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

OBJECTIVE—: Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor–coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was aimed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. APPROACH AND RESULTS—: Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization, and fibrin formation on immobilized collagen and tissue factor under shear flow, ex vivo. Downstream of the thrombus formed on immobilized collagen or collagen and 10 pmol/L tissue factor, platelet CD62P expression, microaggregate formation, and progressive platelet consumption were significantly reduced in the presence of FXI function-blocking antibodies or a thrombin inhibitor in a shear rate– and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. CONCLUSIONS—: This study demonstrates that the FXI–thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlight FXI as a novel therapeutic target for inhibiting distal thrombus formation without affecting proximal platelet adhesion.

Original languageEnglish (US)
JournalArteriosclerosis, Thrombosis, and Vascular Biology
DOIs
StateAccepted/In press - Jan 14 2016

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Factor XI
Platelet Activation
Thrombosis
Blood Platelets
Thrombin
Collagen
Thromboplastin
Blocking Antibodies
Fibrin
Platelet Aggregation
Primates
Pharmacology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow. / Zilberman-Rudenko, Jevgenia; Itakura, Asako; Wiesenekker, Chantal P.; Vetter, Ralf; Maas, Coen; Gailani, David; Tucker, Erik; Gruber, Andras; Gerdes, Christoph; McCarty, Owen.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, 14.01.2016.

Research output: Contribution to journalArticle

Zilberman-Rudenko, Jevgenia ; Itakura, Asako ; Wiesenekker, Chantal P. ; Vetter, Ralf ; Maas, Coen ; Gailani, David ; Tucker, Erik ; Gruber, Andras ; Gerdes, Christoph ; McCarty, Owen. / Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2016.
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abstract = "OBJECTIVE—: Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor–coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was aimed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. APPROACH AND RESULTS—: Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization, and fibrin formation on immobilized collagen and tissue factor under shear flow, ex vivo. Downstream of the thrombus formed on immobilized collagen or collagen and 10 pmol/L tissue factor, platelet CD62P expression, microaggregate formation, and progressive platelet consumption were significantly reduced in the presence of FXI function-blocking antibodies or a thrombin inhibitor in a shear rate– and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. CONCLUSIONS—: This study demonstrates that the FXI–thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlight FXI as a novel therapeutic target for inhibiting distal thrombus formation without affecting proximal platelet adhesion.",
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AU - Vetter, Ralf

AU - Maas, Coen

AU - Gailani, David

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AB - OBJECTIVE—: Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor–coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was aimed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. APPROACH AND RESULTS—: Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization, and fibrin formation on immobilized collagen and tissue factor under shear flow, ex vivo. Downstream of the thrombus formed on immobilized collagen or collagen and 10 pmol/L tissue factor, platelet CD62P expression, microaggregate formation, and progressive platelet consumption were significantly reduced in the presence of FXI function-blocking antibodies or a thrombin inhibitor in a shear rate– and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. CONCLUSIONS—: This study demonstrates that the FXI–thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlight FXI as a novel therapeutic target for inhibiting distal thrombus formation without affecting proximal platelet adhesion.

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