Original Communications| Volume 130, ISSUE 5, P809-818, November 2001

Inhibition of factor Xa suppresses the expression of tissue factor in human monocytes and lipopolysaccharide-induced endotoxemia in rats


      Background. Activated factor X (FXa) is involved in hemostasis, thrombogenesis, inflammation, and cellular immune response. Tissue factor (TF) is an initiator of blood coagulation. We investigated whether FXa induces TF expression in human peripheral monocytes and whether treatment with FXa inhibitor reduces TF expression in an experimental model of rat endotoxemia. Methods. Human peripheral mononuclear cells were used to determine TF expression induced by FXa. Experimental rat endotoxemia was induced by intravenous bolus injection of lipopolysaccharide (LPS). A specific FXa inhibitor, DX-9065a, was administered subcutaneously immediately after LPS injection. Results. FXa induced TF expression in monocytes without intervention of thrombin and the expression was suppressed by FXa inhibitor. In the experimental model of rat endotoxemia, TF and TF mRNA expression levels in the liver were reduced by DX-9065a. Moreover, administration of DX-9065a suppressed the rise in plasma concentrations of thrombin-antithrombin III complex (TAT) and monocyte chemoattractant protein-1 (MCP-1). Conclusions. Our results indicated that FXa can induce TF expression in human peripheral monocytes and that inhibition of FXa reduces TF expression in the liver of rat endotoxemia. These results suggest that FXa is an important factor for TF expression in sepsis. (Surgery 2001;130:809-18.)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Davie EW
        • Fujikawa K
        • Kisiel W
        The coagulation cascade: initiation, maintenance, and regulation.
        Biochemistry. 1991; 30: 10363-10370
        • Nicholson AC
        • Nachman RL
        • Altieri DC
        • Summers BD
        • Ruf W
        • Edgington TS
        • et al.
        Effector cell protease receptor-1 is a vascular receptor for coagulation factor Xa.
        J Biol Chem. 1996; 271: 28407-28413
        • Bono F
        • Herault JP
        • Avril C
        • Schaeffer P
        • Lormeau JC
        • Herbert JM
        Human umbilical vein endothelial cells express high affinity receptors for factor Xa.
        J Cell Physiol. 1997; 172: 36-43
        • Ko FN
        • Yang YC
        • Huang SC
        • Ou JT
        Coagulation factor Xa stimulates platelet-derived growth factor release and mitogenesis in cultured vascular smooth muscle cells of rat.
        J Clin Invest. 1996; 98: 1493-1501
        • Cirino G
        • Cicala C
        • Bucci M
        • Sorrentino L
        • Ambrosini G
        • De Dominicis G
        • et al.
        Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo.
        J Clin Invest. 1997; 99: 2446-2451
        • Herault JP
        • Bono F
        • Avril C
        • Schaeffer P
        • Herbert JM
        Activation of human vascular endothelial cells by factor Xa: effect of specific inhibitors.
        Biochem Pharmacol. 1999; 57: 603-610
        • Senden NH
        • Jeunhomme TM
        • Heemskerk JW
        • Wagenvoord R
        • Van't Veer C
        • Hemker HC
        • et al.
        Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells.
        J Immunol. 1998; 161: 4318-4324
        • Papapetropoulos A
        • Piccardoni P
        • Cirino G
        • Bucci M
        • Sorrentino R
        • Cicala C
        • et al.
        Hypotension and inflammatory cytokine gene expression triggered by factor Xa-nitric oxide signaling.
        Proc Natl Acad Sci U S A. 1998; 95: 4738-4742
        • Nemerson Y
        Tissue factor and hemostasis.
        Blood. 1988; 71: 1-8
        • Todoroki H
        • Higure A
        • Okamoto K
        • Okazaki K
        • Nagafuchi Y
        • Takeda S
        • et al.
        Possible role of platelet-activating factor in the in vivo expression of tissue factor in neutrophils.
        J Surg Res. 1998; 80: 149-155
        • Hall AJ
        • Vos HL
        • Bertina RM
        Lipopolysaccharide induction of tissue factor in THP-1 cells involves Jun protein phosphorylation and nuclear factor κB nuclear translocation.
        J Biol Chem. 1999; 274: 376-383
        • Drake TA
        • Morrissey JH
        • Edgington TS
        Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis.
        Am J Pathol. 1989; 134: 1087-1097
        • Gregory SA
        • Morrissey JH
        • Edgington TS
        Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin.
        Mol Cell Biol. 1989; 9: 2752-2755
        • Warr TA
        • Rao LV
        • Rapaport SI
        Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity.
        Blood. 1990; 75: 1481-1489
        • Taylor Jr, FB
        • Chang A
        • Ruf W
        • Morrissey JH
        • Hinshaw L
        • Catlett R
        • et al.
        Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody.
        Circ Shock. 1991; 33: 127-134
        • Dackiw AP
        • McGilvray ID
        • Woodside M
        • Nathens AB
        • Marshall JC
        • Rotstein OD
        Prevention of endotoxin-induced mortality by antitissue factor immunization.
        Arch Surg. 1996; 131: 1273-1278
        • Higure A
        • Okamoto K
        • Hirata K
        • Todoroki H
        • Nagafuchi Y
        • Takeda S
        • et al.
        Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis.
        Thromb Haemost. 1996; 75: 791-795
        • Todoroki H
        • Nakamura S
        • Higure A
        • Okamoto K
        • Takeda S
        • Nagata N
        • et al.
        Neutrophils express tissue factor in a monkey model of sepsis.
        Surgery. 2000; 127: 209-216
        • Yamazaki M
        • Asakura H
        • Aoshima K
        • Saito M
        • Jokaji H
        • Uotani C
        • et al.
        Effects of DX- 9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats.
        Thromb Haemost. 1994; 72: 393-396
        • Morishima Y
        • Tanabe K
        • Terada Y
        • Hara T
        • Kunitada S
        Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor: comparison with a direct thrombin inhibitor and antithrombin III-dependent anticoagulants.
        Thromb Haemost. 1997; 78: 1366-1371
        • Prasa D
        • Svendsen L
        • Stürzebecher J
        Inhibition of thrombin generation in plasma by inhibitors of factor Xa.
        Thromb Haemost. 1997; 78: 1215-1220
        • Rogers KL
        • Chi L
        • Rapundalo ST
        • Kramer JB
        • Gallagher KP
        Effects of a factor Xa inhibitor, DX-9065a, in a novel rabbit model of venous thrombosis.
        Basic Res Cardiol. 1999; 94: 15-22
        • Tanabe K
        • Terada Y
        • Shibutani T
        • Kunitada S
        • Kondo T
        A specific inhibitor of factor Xa, DX-9065a, exerts effective protection against experimental tumor induced disseminated intravascular coagulation in rats.
        Thromb Res. 1999; 96: 135-143
        • Yamaguchi Y
        • Okabe K
        • Liang J
        • Matsumura F
        • Ohshiro H
        • Ishihara K
        • et al.
        A synthetic selective inhibitor of factor Xa, DX-9065a, reduces monocyte chemoattractant protein-1 expression after ischemia-reperfusion injury in rat liver.
        Dig Dis Sci. 1999; 44: 2568-2576
        • Kaiser B
        • Jeske W
        • Walenga JM
        • Fareed J
        Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood.
        Blood Coagul Fibrinolysis. 1999; 10: 495-501
        • Bartha K
        • Brisson C
        • Archipoff G
        • de la Salle C
        • Lanza F
        • Cazenave JP
        • et al.
        Thrombin regulates tissue factor and thrombomodulin mRNA levels and activities in human saphenous vein endothelial cells by distinct mechanisms.
        J Biol Chem. 1993; 268: 421-429
        • Anrather D
        • Millan MT
        • Palmetshofer A
        • Robson SC
        • Geczy C
        • Ritchie AJ
        • et al.
        Thrombin activates nuclear factor-κB and potentiates endothelial cell activation by TNF.
        J Immunol. 1997; 159: 5620-5628
        • Amirkhosravi A
        • Alexander M
        • May K
        • Francis DA
        • Warnes G
        • Biggerstaff J
        • et al.
        The importance of platelets in the expression of monocyte tissue factor antigen measured by a new whole blood flow cytometric assay.
        Thromb Haemost. 1996; 75: 87-95
        • Surprenant YM
        • Zuckerman SH
        A novel microtiter plate assay for the quantitation of procoagulant activity on adherent monocytes, macrophage and endothelial cells.
        Thromb Res. 1989; 53: 339-346
        • Pötgens AJ
        • Lubsen NH
        • van Altena G
        • Schoenmakers JG
        • Ruiter DJ
        • de Waal RM
        Measurement of tissue factor messenger RNA levels in human endothelial cells by a quantitative RT-PCR assay.
        Thromb Haemost. 1994; 71: 208-213
        • Kobayashi Y
        • Yoshimura N
        • Nakamura K
        • Yamagishi H
        • Oka T
        Expression of tissue factor in hepatic ischemic-reperfusion injury of the rat.
        Transplantation. 1998; 66: 708-716
        • Nishimura H
        • Tsuji H
        • Masuda H
        • Nakagawa K
        • Nakahara Y
        • Kitamura H
        • et al.
        Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells.
        Thromb Haemost. 1997; 77: 1189-1195
        • Schecter AD
        • Rollins BJ
        • Zhang YJ
        • Charo IF
        • Fallon JT
        • Rossikhina M
        • et al.
        Tissue factor is induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells.
        J Biol Chem. 1997; 272: 28568-28573
        • Sueishi K
        • Nanno S
        • Tanaka K
        Permeability enhancing and chemotactic activities of lower molecular weight degradation products of human fibrinogen.
        Thromb Haemost. 1981; 45: 90-94
        • Senior RM
        • Skogen WF
        • Griffin GL
        • Wilner GD
        Effects of fibrinogen derivatives upon the inflammatory response. Studies with human fibrinopeptide B.
        J Clin Invest. 1986; 77: 1014-1019
        • Yamashita T
        • Tsuji T
        • Matsuoka A
        • Giddings JC
        • Yamamoto J
        The antithrombotic effect of synthetic low molecular weight human factor Xa inhibitor, DX-9065a, on He-Ne laser-induced thrombosis in rat mesenteric microvessels.
        Thromb Res. 1997; 85: 45-51
        • Fan J
        • Kapus A
        • Li YH
        • Rizoli S
        • Marshall JC
        • Rotstein OD
        Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role of tumor necrosis factor.
        Am J Respir Cell Mol Biol. 2000; 22: 412-421
        • Giesen PL
        • Rauch U
        • Bohrmann B
        • Kling D
        • Roque M
        • Fallon JT
        • et al.
        Blood-borne tissue factor: another view of thrombosis.
        Proc Natl Acad Sci U S A. 1999; 96: 2311-2315
        • Rauch U
        • Bonderman D
        • Bohrmann B
        • Badimon JJ
        • Himber J
        • Riederer MA
        • et al.
        Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor.
        Blood. 2000; 96: 170-175