title: Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow.
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.
  
  
  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 platelet consumption without affecting proximal platelet adhesion.
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.). zilberma@ohsu.edu.
authors.forename: Jevgenia
authors.initials: J
authors.lastname: Zilberman-Rudenko
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: Asako
authors.initials: A
authors.lastname: Itakura
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: Chantal P
authors.initials: CP
authors.lastname: Wiesenekker
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: Ralf
authors.initials: R
authors.lastname: Vetter
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: David
authors.initials: D
authors.lastname: Gailani
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Gerdes
authors.affiliation: From the Biomedical Engineering, School of Medicine (J.Z.-R., A.I., C.P.W., E.I.T., A.G., O.J.T.M.) and Division of Hematology (A.G., O.J.T.M.), Oregon Health & Science University, Portland; Pathology and Medicine, School of Medicine, Vanderbilt University, Nashville, TN (D.G.); Aronora Inc., Portland, OR (E.I.T., A.G.); Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands (C.P.W., C.M.); and Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany (A.I., R.V., C.G.).
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D003094:Collagen / Q000097:blood; D004195:Disease Models, Animal; D005172:Factor XI / Q000378:metabolism*; D015945:Factor XIa / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D008297:Male; D040542:Mechanotransduction, Cellular; D019007:P-Selectin / Q000097:blood; D048530:Papio anubis; D015539:Platelet Activation; D010974:Platelet Aggregation; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors
chemical_list: D019007:P-Selectin; C546937:SELP protein, human; D005337:Fibrin; D003094:Collagen; D005172:Factor XI; D013925:Thromboplastin; D015945:Factor XIa; D013917:Thrombin
keywords: blood coagulation; blood platelets; factor XI; hemodynamics; platelet activation