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Tissue Factor Pathway and the Antiphospholipid Syndrome
doi:10.1006/jaut.2000.0397, available online at http://www.idealibrary.com on
Journal of Autoimmunity (2000) 15, 217–220
Tissue Factor Pathway and the Antiphospholipid Syndrome Robert A. S. Roubey Division of Rheumatology and Immunology, The University of North Carolina, Chapel Hill, NC, USA
Key words: tissue factor, tissue factor pathway inhibitor, monocytes, endothelial cells
Expression of tissue factor activity on cells in contact with flowing blood is the trigger for physiological coagulation as well as many types of thrombosis. A number of older observations and considerable recent data suggest that increased tissue factor activity is an important cause of hypercoagulability in the antiphospholipid syndrome. Potential mechanisms contributing to upregulation of the tissue factor pathway include increased expression of tissue factor due to increased transcription, increased functional activity of tissue factor molecules due to de-encryption and decreased activity of tissue factor pathway inhibitor. Autoantibodies and/or immune complexes appear to play a major role in enhanced tissue factor activity, although increased levels of inflammatory cytokines may also contribute. Anti-2-glycoprotein I autoantibodies have been specifically implicated in the antibody-mediated enhancement of tissue factor activity. © 2000 Academic Press
Introduction
cells or peripheral blood cells (at least not in a functionally active form). Structurally, TF is a member of the cytokine receptor superfamily. It is a high affinity receptor for coagulation factor VII/VIIa and functions as an essential co-factor for factor VIIa to efficiently cleave its substrates, factor IX and factor X, to their active forms (factors IXa and Xa). Tissue factor pathway inhibitor (TFPI) is a trivalent Kunitz-type protease inhibitor that regulates the initiation of coagulation via factor Xa-dependent feedback inhibition of TF/VIIa. TFPI inhibits both factors VIIa and Xa by forming a quaternary complex (TFPI, TF, VIIa, Xa) via an interaction that requires calcium ions and is enhanced by anionic phospholipid membrane. TFPI may also inhibit factor Xa directly in a phospholipid-independent manner. There are three intravascular pools of TFPI. About 10–50% of TFPI circulates in plasma at a concentration of 50–150 ng/ml, much of which is complexed to lipoproteins. Approximately 50–90% of TFPI is bound to vessel wall glycosaminoglycans and can be released into plasma by injection of heparin. A small amount of TFPI is stored in platelets and released upon platelet activation.
Numerous mechanisms have been proposed to explain hypercoagulability in the antiphospholipid syndrome (APS). At the present time, the most consistent and reproducible data support two major mechanisms: (1) inhibition of the protein C pathway and (2) upregulation of the tissue factor (TF; CD142) pathway. This review will focus on the latter. It should be kept in mind that multiple pathophysiological mechanisms probably play a role in APS. Inhibition of the protein C pathway, for example, may account for venous thrombosis, but is unlikely to explain arterial thrombosis. In contrast, increased TF activity may be associated with both arterial and venous thrombosis. If, as widely hypothesized, autoantibodies directly contribute to hypercoagulability in APS then it is likely that different autoantibodies or autoantibody subsets have different pathological activities and account for the heterogeneous clinical manifestations of the syndrome.
The TF Pathway Tissue factor is the physiological initiator of normal coagulation and a major initiator of clotting in thrombotic disease (Figure 1). It is a transmembrane protein constitutively expressed on the surfaces of various cell types outside the vasculature, but not on endothelial
Regulation of TF Activity on Cells in Contact with Blood Endothelial cells, blood monocytes and other cells in contact with blood, do not constitutively express functional TF. These cells synthesize and express TF following stimulation with lipopolysaccharide (LPS) and certain inflammatory cytokines. Inducible
Correspondence to: Robert A. S. Roubey, Division of Rheumatology and Immunology, University of North Carolina, CB #7280, Rm 3330 Thurston Building, Chapel Hill, NC27599-7280, USA. Fax: 919-9661739. E-mail: [email protected] 217 0896–8411/00/060217+04 $35.00/0
© 2000 Academic Press
218
R. A. S. Roubey
Figure 1. The TF Pathway. The transmembrane protein TF is a high affinity receptor and co-factor for the enzyme factor VIIa. Factor VIIa/TF cleaves factor X and factor IX to form factor Xa and IXa (IX and IXa are not shown in this figure). Factor Xa forms the prothrombinase complex with factor Va and cleaves prothrombin (factor II) to yield thrombin (factor IIa), as shown on the right side of the figure. TFPI inhibits factor VIIa/TF via factor Xa-dependent feedback, forming a quaternary complex, as shown on the left side of the figure.
expression of TF is controlled by transcription [1] and enhanced expression is not thought to be due to release of preformed TF molecules. Given that the physiological activation of the TF pathway in coagulation must be very rapid, however, it seems unlikely that transcription alone regulates TF activity. The amount of TF antigen expressed on a cell surface often does not correlate with procoagulant activity [2]. Recent data suggest that TF activity is normally ‘encrypted’ on the surface of TF-bearing cells, i.e. although TF antigen is detectable on the surfaces of unactivated cells, its full procoagulant activity is not. Stimulation of cells with calcium ionophore results in a rapid increase in TF activity without a concomitant increase in TF antigen expression. This phenomenon was initially attributed to changes in morphology and membrane lipid expression. More recently, however, attention has focused on changes in TF itself. Recent data suggest that TF encryption is due to the dimerization of TF molecules on the cell surface [3]. In this model, TF dimers are inactive and TF activity after stimulation is due to the rapid dissociation of dimers into active TF monomers. Expression of phosphatidylserine on the outer leaflet of the cell membrane also enhances TF activity.
The TF Pathway and Thrombosis Increased TF activity has been implicated in a number of thrombotic conditions and hypercoagulable states.
Increased expression of TF on vascular endothelial cells and monocytes has been reported in patients with cancer [4], Gram-negative bacterial sepsis [5, 6], atherosclerosis [7] and OKT3-induced coagulopathy in renal transplant patients [8]. The physiological importance of TFPI is evidenced by the fact that ‘knockout’ of the TFPI gene in mice is lethal [9]. A TFPI mutation associated with thrombosis has recently been described [10].
The TF Pathway in APS The possible role of the TF pathway in APS was first suggested by several studies demonstrating that sera from certain patients with systemic lupus erythematosus enhanced the procoagulant activity of cultured endothelial cells [11–14]. Most data indicated that the stimulating factor(s) were antibodies, although one study [13] suggested that antibodies enhanced the effects of suboptimal concentrations of TNF-. More recently, attention has focused on increased TF expression and procoagulant activity on circulating blood monocytes. In 1990 de Prost et al. reported that monocyte procoagulant activity was increased in patients with systemic lupus erythematosus, about half of whom had lupus anti-coagulants [15]. Serum from these patients increased TF activity on normal monocytes, although the serum factor responsible did not appear to be immunoglobulins. In retrospect, the experiments with purified IgG were performed
Tissue factor pathway and APS
under serum-free conditions and the absence of 2-glycoprotein I (2-GPI) may have been a key factor. Subsequently, a number of groups have found that serum, plasma, purified total IgG, and anti-2-GPI antibodies from APS patients enhance TF expression and procoagulant activity on normal monocytes [16–20]. In one study, Schved et al. [17] demonstrated that F(ab′)2 antibody fragments retained these procoagulant effects, suggesting that Fc receptors are not involved. Ex vivo monocytes from APS patients have recently been found to have increased expression of TF and of TF mRNA [21, 22]. Increased TF was associated with IgG anticardiolipin antibodies and a history of thrombosis. Experiments using patient-derived human monoclonal antibodies suggest that anti-2-GPI autoantibodies play an important role in enhance monocyte TF expression activity in APS [18, 19]. Recent data from our laboratory suggest another possible mechanism. We have recently detected autoantibodies directed against TFPI in APS patients and found an association of these antibodies with arterial thrombosis and stroke [23]. Studies are under way to determine the functional effects of these autoantibodies. Still another mechanism may be related to recent reports of cellular autoimmunity to 2-GPI. Visvanathan and McNeil [24] reported that 2-GPIspecific T cells are of the Th1 phenotype and produce interferon-, a cytokine known to stimulate monocyte TF expression [25].
Future Directions A consistent body of data support the hypothesis that enhanced tissue factor activity on blood monocytes and/or vascular endothelial cells contribute to hypercoagulability in APS. Important issues to be addressed by future research include determining the mechanisms by which autoantibodies and their antigens stimulate TF transcription and/or TF de-encryption, the effects of autoantibodies on TFPI function, and whether therapy designed to downregulation of TF activity is of value in APS.
219
6.
7.
8.
9. 10.
11.
12.
13.
14.
15.
References 1. Gregory S.A., Morrissey S.A., Edgington T.S. 1989. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol. Cell. Biol. 9: 2752–2755 2. Monroe D.M., Hoffman M., Roberts H.R. 1996. Transmission of a procoagulant signal from tissue factor-bearing cells to platelets. Blood Coag. Fibrinol. 7: 459–464 3. Bach R.R., Moldow C.F. 1997. Mechanisms of tissue factor activation on HL-60 cells. Blood 89: 3270–3276 4. Edwards R.L., Rickles F.R., Cronlund M. 1981. Abnormalities of blood coagulation in patients with cancer. Mononuclear cell tissue factor generation. J. Lab. Clin. Med. 98: 917–928 5. Colucci M., Balconi G., Lorenzet R., Pietra A., Locati D., Donati M.B., Semeraro N. 1983. Cultured human
16.
17.
18.
19.
endothelial cells generate tissue factor in response to endotoxin. J. Clin. Invest. 71: 1893–1896 Osterud B., Flaegstad T. 1983. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb. Haemost. 49: 5–7 Weis J.R., Pitas R.E., Wilson B.D., Rodgers G.M. 1991. Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor and reduces protein C activation. FASEB J. 5: 2459–2465 Pradier O., Surquin M., Stordeur P., De Pauw L., Kinnaert P., Vereerstraeten P., Capel P., Goldman M., Abramowicz D. 1996. Monocyte procoagulant activity induced by in vivo administration of the OKT3 monoclonal antibody. Blood 87: 3768–3774 Broze G.J.J. 1998. Tissue factor pathway inhibitor gene disruption. Blood. Coag. Fibrinol. 9(Suppl. 1): S89–S92 Kleesiek K., Schmidt M., Gotting C., Schwenz B., Lange S., Muller-Berghaus G., Brinkmann T., Prohaska W. 1999. The 536C→T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb. Haemost. 82: 1–5 Tannenbaum S.H., Finko R., Cines D.B. 1986. Antibody and immune complexes induce tissue factor production by human endothelial cells. J. Immunol. 137: 1532–1537 Rustin M.H., Bull H.A., Machin S.J., Isenberg D.A., Snaith M.L., Dowd P.M. 1988. Effects of the lupus anticoagulant in patients with systemic lupus erythematosus on endothelial cell prostacyclin release and procoagulant activity. J. Invest. Dermatol. 90: 744–748 Hasselaar P., Derksen R.H.W.M., Oosting J.D., Blokzijl L., De Groot P.G. 1989. Synergistic effect of low doses of tumor necrosis factor and sera from patients with systemic lupus erythematosus on the expression of procoagulant activity by cultured endothelial cells. Thromb. Haemost. 62: 654–660 Branch D.W., Rodgers G.M. 1993. Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: a possible mechanism of thrombosis. Am. J. Obstet. Gynecol. 168: 206–210 de Prost D., Ollivier V., Ternisien C., Chollet-Martin S. 1990. Increased monocyte procoagulant activity independent of the lupus anticoagulant in patients with systemic lupus erythematosus. Thromb. Haemost. 64: 216–221 Korberg A., Blank M., Kaufman S., Shoenfeld Y. 1994. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. J. Immunol. 153: 1328–1332 Schved J.-F., Gris J.-C., Ollivier V., Wautier J.-L., Tobelem G., Caen J. 1992. Procoagulant activity of endotoxin or tumor necrosis factor activated monocytes is enhanced by IgG from patients with lupus anticoagulant. Am. J. Hematol. 41: 92–96 Amengual O., Atsumi T., Khamashta M.A., Hughes G.R.V. 1998. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb. Haemost. 79: 276–281 Reverter J.C., Tassies D., Font J., Khamashta M.A., Ichikawa K., Cervera R., Escolar G., Hughes G.R., Ingelmo M., Ordinas A. 1998. Effects of human
220
monoclonal anticardiolipin antibodies on platelet function and on tissue factor expression on monocytes. Arthritis Rheum. 41: 1420–1427 20. Reverter J.C., Tassies D., Font J., Monteagudo J., Escolar G., Ingelmo M., Ordinas A. 1996. Hypercoagulable state in patients with antiphospholipid syndrome is related to high induced tissue factor expression on monocytes and to low free protein S. Arterioscler. Thromb. Vasc. Biol. 16: 1319–1326 21. Cuadrado M.J., Lo´ pez-Pedrera C., Khamashta M.A., Camps M.T., Tinahones F., Torres A., Hughes G.R.V., Velasco F. 1997. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum. 40: 834–841 22. Dobado-Berrios P.M., Lo´ pez-Pedrera C., Velasco F., Aguirre M.A., Torres A., Cuadrado M.J. 1999.
R. A. S. Roubey
Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. Thromb. Haemost. 82: 1578–1582 23. C q akir B., Arnett F.C., Roubey R.A.S. 1999. Autoantibodies to tissue factor pathway inhibitor in the antiphospholipid syndrome. Arthritis Rheum. 42: S281–S281 (Abstract) 24. Visvanathan S., McNeil H.P. 1999. Cellular immunity to 2-glycoprotein I in patients with the antiphospholipid syndrome. J. Immunol. 162: 6919–6925 25. Del Prete G., De Carli M., Lammel R.M., D’Elios M.M., Daniel K.C., Giusti B., Abbate R., Romagnani S. 1995. Th1 and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes. Blood 86: 250–257
Journal of Autoimmunity (2000) 15, 217–220
Tissue Factor Pathway and the Antiphospholipid Syndrome Robert A. S. Roubey Division of Rheumatology and Immunology, The University of North Carolina, Chapel Hill, NC, USA
Key words: tissue factor, tissue factor pathway inhibitor, monocytes, endothelial cells
Expression of tissue factor activity on cells in contact with flowing blood is the trigger for physiological coagulation as well as many types of thrombosis. A number of older observations and considerable recent data suggest that increased tissue factor activity is an important cause of hypercoagulability in the antiphospholipid syndrome. Potential mechanisms contributing to upregulation of the tissue factor pathway include increased expression of tissue factor due to increased transcription, increased functional activity of tissue factor molecules due to de-encryption and decreased activity of tissue factor pathway inhibitor. Autoantibodies and/or immune complexes appear to play a major role in enhanced tissue factor activity, although increased levels of inflammatory cytokines may also contribute. Anti-2-glycoprotein I autoantibodies have been specifically implicated in the antibody-mediated enhancement of tissue factor activity. © 2000 Academic Press
Introduction
cells or peripheral blood cells (at least not in a functionally active form). Structurally, TF is a member of the cytokine receptor superfamily. It is a high affinity receptor for coagulation factor VII/VIIa and functions as an essential co-factor for factor VIIa to efficiently cleave its substrates, factor IX and factor X, to their active forms (factors IXa and Xa). Tissue factor pathway inhibitor (TFPI) is a trivalent Kunitz-type protease inhibitor that regulates the initiation of coagulation via factor Xa-dependent feedback inhibition of TF/VIIa. TFPI inhibits both factors VIIa and Xa by forming a quaternary complex (TFPI, TF, VIIa, Xa) via an interaction that requires calcium ions and is enhanced by anionic phospholipid membrane. TFPI may also inhibit factor Xa directly in a phospholipid-independent manner. There are three intravascular pools of TFPI. About 10–50% of TFPI circulates in plasma at a concentration of 50–150 ng/ml, much of which is complexed to lipoproteins. Approximately 50–90% of TFPI is bound to vessel wall glycosaminoglycans and can be released into plasma by injection of heparin. A small amount of TFPI is stored in platelets and released upon platelet activation.
Numerous mechanisms have been proposed to explain hypercoagulability in the antiphospholipid syndrome (APS). At the present time, the most consistent and reproducible data support two major mechanisms: (1) inhibition of the protein C pathway and (2) upregulation of the tissue factor (TF; CD142) pathway. This review will focus on the latter. It should be kept in mind that multiple pathophysiological mechanisms probably play a role in APS. Inhibition of the protein C pathway, for example, may account for venous thrombosis, but is unlikely to explain arterial thrombosis. In contrast, increased TF activity may be associated with both arterial and venous thrombosis. If, as widely hypothesized, autoantibodies directly contribute to hypercoagulability in APS then it is likely that different autoantibodies or autoantibody subsets have different pathological activities and account for the heterogeneous clinical manifestations of the syndrome.
The TF Pathway Tissue factor is the physiological initiator of normal coagulation and a major initiator of clotting in thrombotic disease (Figure 1). It is a transmembrane protein constitutively expressed on the surfaces of various cell types outside the vasculature, but not on endothelial
Regulation of TF Activity on Cells in Contact with Blood Endothelial cells, blood monocytes and other cells in contact with blood, do not constitutively express functional TF. These cells synthesize and express TF following stimulation with lipopolysaccharide (LPS) and certain inflammatory cytokines. Inducible
Correspondence to: Robert A. S. Roubey, Division of Rheumatology and Immunology, University of North Carolina, CB #7280, Rm 3330 Thurston Building, Chapel Hill, NC27599-7280, USA. Fax: 919-9661739. E-mail: [email protected] 217 0896–8411/00/060217+04 $35.00/0
© 2000 Academic Press
218
R. A. S. Roubey
Figure 1. The TF Pathway. The transmembrane protein TF is a high affinity receptor and co-factor for the enzyme factor VIIa. Factor VIIa/TF cleaves factor X and factor IX to form factor Xa and IXa (IX and IXa are not shown in this figure). Factor Xa forms the prothrombinase complex with factor Va and cleaves prothrombin (factor II) to yield thrombin (factor IIa), as shown on the right side of the figure. TFPI inhibits factor VIIa/TF via factor Xa-dependent feedback, forming a quaternary complex, as shown on the left side of the figure.
expression of TF is controlled by transcription [1] and enhanced expression is not thought to be due to release of preformed TF molecules. Given that the physiological activation of the TF pathway in coagulation must be very rapid, however, it seems unlikely that transcription alone regulates TF activity. The amount of TF antigen expressed on a cell surface often does not correlate with procoagulant activity [2]. Recent data suggest that TF activity is normally ‘encrypted’ on the surface of TF-bearing cells, i.e. although TF antigen is detectable on the surfaces of unactivated cells, its full procoagulant activity is not. Stimulation of cells with calcium ionophore results in a rapid increase in TF activity without a concomitant increase in TF antigen expression. This phenomenon was initially attributed to changes in morphology and membrane lipid expression. More recently, however, attention has focused on changes in TF itself. Recent data suggest that TF encryption is due to the dimerization of TF molecules on the cell surface [3]. In this model, TF dimers are inactive and TF activity after stimulation is due to the rapid dissociation of dimers into active TF monomers. Expression of phosphatidylserine on the outer leaflet of the cell membrane also enhances TF activity.
The TF Pathway and Thrombosis Increased TF activity has been implicated in a number of thrombotic conditions and hypercoagulable states.
Increased expression of TF on vascular endothelial cells and monocytes has been reported in patients with cancer [4], Gram-negative bacterial sepsis [5, 6], atherosclerosis [7] and OKT3-induced coagulopathy in renal transplant patients [8]. The physiological importance of TFPI is evidenced by the fact that ‘knockout’ of the TFPI gene in mice is lethal [9]. A TFPI mutation associated with thrombosis has recently been described [10].
The TF Pathway in APS The possible role of the TF pathway in APS was first suggested by several studies demonstrating that sera from certain patients with systemic lupus erythematosus enhanced the procoagulant activity of cultured endothelial cells [11–14]. Most data indicated that the stimulating factor(s) were antibodies, although one study [13] suggested that antibodies enhanced the effects of suboptimal concentrations of TNF-. More recently, attention has focused on increased TF expression and procoagulant activity on circulating blood monocytes. In 1990 de Prost et al. reported that monocyte procoagulant activity was increased in patients with systemic lupus erythematosus, about half of whom had lupus anti-coagulants [15]. Serum from these patients increased TF activity on normal monocytes, although the serum factor responsible did not appear to be immunoglobulins. In retrospect, the experiments with purified IgG were performed
Tissue factor pathway and APS
under serum-free conditions and the absence of 2-glycoprotein I (2-GPI) may have been a key factor. Subsequently, a number of groups have found that serum, plasma, purified total IgG, and anti-2-GPI antibodies from APS patients enhance TF expression and procoagulant activity on normal monocytes [16–20]. In one study, Schved et al. [17] demonstrated that F(ab′)2 antibody fragments retained these procoagulant effects, suggesting that Fc receptors are not involved. Ex vivo monocytes from APS patients have recently been found to have increased expression of TF and of TF mRNA [21, 22]. Increased TF was associated with IgG anticardiolipin antibodies and a history of thrombosis. Experiments using patient-derived human monoclonal antibodies suggest that anti-2-GPI autoantibodies play an important role in enhance monocyte TF expression activity in APS [18, 19]. Recent data from our laboratory suggest another possible mechanism. We have recently detected autoantibodies directed against TFPI in APS patients and found an association of these antibodies with arterial thrombosis and stroke [23]. Studies are under way to determine the functional effects of these autoantibodies. Still another mechanism may be related to recent reports of cellular autoimmunity to 2-GPI. Visvanathan and McNeil [24] reported that 2-GPIspecific T cells are of the Th1 phenotype and produce interferon-, a cytokine known to stimulate monocyte TF expression [25].
Future Directions A consistent body of data support the hypothesis that enhanced tissue factor activity on blood monocytes and/or vascular endothelial cells contribute to hypercoagulability in APS. Important issues to be addressed by future research include determining the mechanisms by which autoantibodies and their antigens stimulate TF transcription and/or TF de-encryption, the effects of autoantibodies on TFPI function, and whether therapy designed to downregulation of TF activity is of value in APS.
219
6.
7.
8.
9. 10.
11.
12.
13.
14.
15.
References 1. Gregory S.A., Morrissey S.A., Edgington T.S. 1989. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol. Cell. Biol. 9: 2752–2755 2. Monroe D.M., Hoffman M., Roberts H.R. 1996. Transmission of a procoagulant signal from tissue factor-bearing cells to platelets. Blood Coag. Fibrinol. 7: 459–464 3. Bach R.R., Moldow C.F. 1997. Mechanisms of tissue factor activation on HL-60 cells. Blood 89: 3270–3276 4. Edwards R.L., Rickles F.R., Cronlund M. 1981. Abnormalities of blood coagulation in patients with cancer. Mononuclear cell tissue factor generation. J. Lab. Clin. Med. 98: 917–928 5. Colucci M., Balconi G., Lorenzet R., Pietra A., Locati D., Donati M.B., Semeraro N. 1983. Cultured human
16.
17.
18.
19.
endothelial cells generate tissue factor in response to endotoxin. J. Clin. Invest. 71: 1893–1896 Osterud B., Flaegstad T. 1983. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb. Haemost. 49: 5–7 Weis J.R., Pitas R.E., Wilson B.D., Rodgers G.M. 1991. Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor and reduces protein C activation. FASEB J. 5: 2459–2465 Pradier O., Surquin M., Stordeur P., De Pauw L., Kinnaert P., Vereerstraeten P., Capel P., Goldman M., Abramowicz D. 1996. Monocyte procoagulant activity induced by in vivo administration of the OKT3 monoclonal antibody. Blood 87: 3768–3774 Broze G.J.J. 1998. Tissue factor pathway inhibitor gene disruption. Blood. Coag. Fibrinol. 9(Suppl. 1): S89–S92 Kleesiek K., Schmidt M., Gotting C., Schwenz B., Lange S., Muller-Berghaus G., Brinkmann T., Prohaska W. 1999. The 536C→T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb. Haemost. 82: 1–5 Tannenbaum S.H., Finko R., Cines D.B. 1986. Antibody and immune complexes induce tissue factor production by human endothelial cells. J. Immunol. 137: 1532–1537 Rustin M.H., Bull H.A., Machin S.J., Isenberg D.A., Snaith M.L., Dowd P.M. 1988. Effects of the lupus anticoagulant in patients with systemic lupus erythematosus on endothelial cell prostacyclin release and procoagulant activity. J. Invest. Dermatol. 90: 744–748 Hasselaar P., Derksen R.H.W.M., Oosting J.D., Blokzijl L., De Groot P.G. 1989. Synergistic effect of low doses of tumor necrosis factor and sera from patients with systemic lupus erythematosus on the expression of procoagulant activity by cultured endothelial cells. Thromb. Haemost. 62: 654–660 Branch D.W., Rodgers G.M. 1993. Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: a possible mechanism of thrombosis. Am. J. Obstet. Gynecol. 168: 206–210 de Prost D., Ollivier V., Ternisien C., Chollet-Martin S. 1990. Increased monocyte procoagulant activity independent of the lupus anticoagulant in patients with systemic lupus erythematosus. Thromb. Haemost. 64: 216–221 Korberg A., Blank M., Kaufman S., Shoenfeld Y. 1994. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. J. Immunol. 153: 1328–1332 Schved J.-F., Gris J.-C., Ollivier V., Wautier J.-L., Tobelem G., Caen J. 1992. Procoagulant activity of endotoxin or tumor necrosis factor activated monocytes is enhanced by IgG from patients with lupus anticoagulant. Am. J. Hematol. 41: 92–96 Amengual O., Atsumi T., Khamashta M.A., Hughes G.R.V. 1998. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb. Haemost. 79: 276–281 Reverter J.C., Tassies D., Font J., Khamashta M.A., Ichikawa K., Cervera R., Escolar G., Hughes G.R., Ingelmo M., Ordinas A. 1998. Effects of human
220
monoclonal anticardiolipin antibodies on platelet function and on tissue factor expression on monocytes. Arthritis Rheum. 41: 1420–1427 20. Reverter J.C., Tassies D., Font J., Monteagudo J., Escolar G., Ingelmo M., Ordinas A. 1996. Hypercoagulable state in patients with antiphospholipid syndrome is related to high induced tissue factor expression on monocytes and to low free protein S. Arterioscler. Thromb. Vasc. Biol. 16: 1319–1326 21. Cuadrado M.J., Lo´ pez-Pedrera C., Khamashta M.A., Camps M.T., Tinahones F., Torres A., Hughes G.R.V., Velasco F. 1997. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum. 40: 834–841 22. Dobado-Berrios P.M., Lo´ pez-Pedrera C., Velasco F., Aguirre M.A., Torres A., Cuadrado M.J. 1999.
R. A. S. Roubey
Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. Thromb. Haemost. 82: 1578–1582 23. C q akir B., Arnett F.C., Roubey R.A.S. 1999. Autoantibodies to tissue factor pathway inhibitor in the antiphospholipid syndrome. Arthritis Rheum. 42: S281–S281 (Abstract) 24. Visvanathan S., McNeil H.P. 1999. Cellular immunity to 2-glycoprotein I in patients with the antiphospholipid syndrome. J. Immunol. 162: 6919–6925 25. Del Prete G., De Carli M., Lammel R.M., D’Elios M.M., Daniel K.C., Giusti B., Abbate R., Romagnani S. 1995. Th1 and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes. Blood 86: 250–257