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The lupus anticoagulant and its role in thrombosis
The Lupus Anticoagulant Thrombosis
and its Role in
G. Tobelem, R. Cariou, A. Camez The lupus anticoagulant is usually found in the plasma of patients with systemic lupus SUMMARY. erythematosus. Lupus anticoagulants are antibodies to phosphoiipids and probably to phosphodiesterlinked phosphate groups. A high frequency of thrombotic events in patients with lupus anticoagulant has been reported. Nevertheless the pathogenesis of thrombosis in these patients remains unknown. Endothelium which plays a key role in the antithrombogenic-thrombogenic balance could be a target for the lupus anticoagulant and alterations of some endothelial-cell functions could be responsible for the thrombotic events. The effects of the lupus anticoagulant on the phospholipids of the protein C-thrombomodulin complex may be important although evidence of such a reaction in vivo is awaited,
Lupus anticoagulant is a common clotting abnormality found in patients with systemic lupus erythematosus.’ It is frequently associated with a false positive syphilis test, anticardiolipin and antinuclear antibodies.* The diagnosis of lupus anticoagulant is considered when the activated partial thromboplastin time is prolonged, all other clotting factor activities being normal. It is confirmed by demonstrating that the patient’s plasma prolongs the activated partial thromboplastin time of normal plasma. In addition to systemic lupus erythematosus, other diseases can be associated with a lupus anticoagulant including autoimmune diseases, neoplastic diseases, lymphoproliferative disorders and drug-induced disorders. Sometimes no recognisable underlying disease is found. Lupus anticoagulants are auto-antibodies to phospholipids and probably to phosphodiester-linked phosphate groups. Phosphatidylserine may be the main target.3 The association of lupus anticoagulant with other auto-antibodies (anticardiolipin, antinuclear, antivimentin . . .) led to the hypothesis that all these antibodies were directed against a common antigenic structure, the phosphodiester group. Each G. Tobelem, R. Cariou, A. Camez, Department of Angiohematology, HBpital Lariboisitre, 2 rue Ambroise Part, 75010 Paris, France. I-24
Blood Reviews ( 1987) I, 2 Longman Group UK Ltd
IQ1987
antibody could prefer a particular geometry of the epitope.4 The antiphospholipid specificity of the lupus anticoagulants provides an explanation of their effects on in vitro coagulation. In effect, they are responsible for an in vitro hypocoagulability but they are not associated with an in vivo hemorrhagic tendency. This suggests that the lupus anticoagulants are able to neutralize the exogeneous phospholipids added in vitro to stimulate the clotting system while they are not active in vivo in blocking the binding of clotting factors to the platelet-membrane phospholipids. Furthermore, a high frequency of thrombotic events in patients with lupus anticoagulant, whatever the underlying disease, has been reported for several years by many groups. It is now well established that the lupus anticoagulant is a risk factor of thrombosis.* Recent works have attempted to find the mechanisms of this phenomenon.
Thrombosis in Patients with Lupus Anticoagulant Prevalence of Thrombotic Events Lechner and Pabinger-Fashing, l reviewing 259 published cases with lupus anticoagulant found that 32.8% had at least one thrombotic event. Similarly in
22 THE LUPUS ANTICOAGULANT AND ITS ROLE IN THROMBOSIS two French series of 40 cases,5’6 a percentage of 38% was noted. These reviews, however, probably overestimate the frequency. In agreement with Lechner and Pabinger-Fashing,’ the prevalence of lupus anticoagulant in patients with at least one venous thrombosis or pulmonary embolism was less than 2% in the last 500 patients with venous thrombosis we investigated. Interestingly in a series of 62 young survivors of myocardial infarction, 13 patients (21%) had raised anticardiolipin antibody levels.’
caters of high risk. It is interesting to point out that the underlying disease associated with the lupus anticoagulant was not important as a risk factor in the occurrence of the thrombotic events. Nevertheless, more data are required to confirm the delineation of high and low risk groups. For instance the level of the lupus anticoagulant antibody with time could be relevant to the risk of thrombosis. Better knowledge of the target of the lupus anticoagulant and of the mechanism of thrombosis are probably necessary before the risks can be properly assessed.
Site of Thrombosis Deep vein thrombosis of the legs is the commonest thrombotic event.’ Most thrombosis are recurrent and appear spontaneous. They are very often complicated by pulmonary embolism. Arterial thrombosis (cerebrovascular accidents or peripheral arteries) are reported in 25% of the cases. Pulmonary hypertension has also been observed. Myocardial infarction is not considered common in patients with lupus anticoagulant but the work of Hamsten et al,’ already mentioned, could have modified this point of view. Recurrent Abortions Another striking clinical manifestation of lupus anticoagulant is thrombosis of the placental vessels leading to recurrent abortions. In 1975 Nilsson et ala first reported the case of a woman with antinuclear antibodies and lupus anticoagulant who had three pregnancies which terminated in intrauterine death. In the fourth pregnancy caesarean section was performed and the placenta showed abundant infarcts, necrosis and fibrin deposits. The striking coincidence of early abortion, late intrauterine death and venous thrombosis in female patients with lupus anticoagulant has since been reported by several groups.g These observations indeed led to elucidation of the mechanism of thrombosis associated with lupus anticoagulant and these arose from the detection of immunoglobulins interfering with prostacyclin production in a patient with arterial thrombosis, intrauterine death and lupus anticoagulant. l O The implications of these findings will be discussed later. Finally, Lockshin et al’ l reported that the level of antibody to cardiolipin was the most sensitive means of predicting fetal distress or death in patients with systemic lupus erythematosus. Dejinition of the Thrombosis Risk Lechner and Pabinger-Fashing’ tried to define subgroups with high and low risk of thrombosis. The available data did not allow a clearcut classification of these subgroups but useful indicators for the risk of thrombosis were proposed. Age above 10 years, a normal prothrombin level, a platelet count above 50000/~1, high level of anticardiolipin antibody and lupus anticoagulant of IgG class would represent indi-
Pathogenesis of Thrombosis Lupus Anticoagulant
in Patients
with
The known effects of the lupus anticoagulant on platelets and plasma coagulation do not provide any insight as to the risk of thrombosis. Further studies have focused on events at the endothelium level. The endothelial cells secrete prostacyclini2 and tissue plasminogen activator.13 The endothelium provides thrombomodulin that accelerates the rate of thrombin-dependent protein C conversion, allows neutralisation of bound thrombin by antithrombin and directly inhibits procoagulant activity of thrombin.14 On the other hand the endothelial cells secrete tissue plasminogen activator inhibitor’ 5 and Willebrand factor.16 Finally tissue factor activity is localised to the surface of endothelium. l 7 Eflect of Lupus Anticoagulant on Prostacyclin Production A reduction of prostacyclin production has been shown to be produced by IgG from a patient with an history of multiples thrombosis and abortionslo and this has been confirmed by others’** lg although details are lacking in the latter studies. We have not been able to find any inhibition of prostacyclin production by human endothelial cells in the presence of purified IgG containing lupus anticoagulant activity from 15 patients. Cines et aL2* who have demonstrated that antibodies to endothelial cell antigens were present in the sera of systemic lupus erythematosus patients, failed also to demonstrate any inhibition. Indeed they found an increased production of prostacyclin following exposure to the IgG fraction from two patients. Immunological injury of endothelial cells mediated by endothelium antibodies induced increases significantly the secretion of prostacyclin.21 An enhanced prostacyclin production has been found in diseases with a thrombotic risk and this may be a possible consequence of vascular insults.22 From a clinical point of view, the sites of thrombosis in patients with the lupus anticoagulant are mainly deep veins and prostacyclin is unlikely to play a role in deep vein thrombosis development. Nevertheless, since aspirin improved fetal survival in pregnancies with lupus anticoagulant, it could mean that in such situations the
BLOOD
prostacyclin-thromboxane involved.9
A,
balance
could
be
Fibrinolysis Abnormalities of fibrinolysis have been reported in patients with lupus anticoagulant in in vivo studies. Angles Cano et al23 using the venous occlusion test reported a reduced or absent fibrinolytic response in 24 of 28 patients with systemic lupus. Among these patients, 12 had a lupus anticoagulant and 5 had thrombotic episodes. IgG from three of four patients with lupus anticoagulant inhibited fibrinolytic activity when studied by Todd’s technique.24 Decreased tissue plasminogen activity, increased tissue plasminogen activator inhibition and increased plasmin inhibitor have been reported in respectively 63, 85 and 29% of 55 tested patients with systemic lupu~.~~ These abnormalities are probably related to the damage of vascular endothelium in systemic lupus.
Thrombomodulin
REVIEWS
23
a cofactor which accelerates the rate of the inactivation of factors Va and VIIIa by activated protein C. A part of the plasma protein S (about 60% of the total protein S) is bound by the C, binding protein. Only the free protein S is able to interact with activated protein C. It has been reported that an increased level of C, binding protein in lupus could be responsible for an increased binding potency of protein S and consequently of a decreased circulating free protein S.29
Other Endothelial
Cell Functions
The thrombogenic properties of the endothelium could be enhanced in systemic lupus as a result of vascular injuries. That has been postulated as the explanation for the increased level of plasma factor VIII / von Willebrand factor.23 More interesting is the possibility that lupus anticoagulant or other immunologic process (auto-antibodies, monocytes, interleukin 1, etc) could increase the tissue factor procoagulant activity of endothelial cells.
Protein C Protein S Complex
Protein C, a vitamin K-dependent protein, is a potent inactivator of factors Va and VIIIa, and probably increases fibrinolytic activity.26 Thrombomodulin present at the endothelial surface accelerates the rate of protein C activation. Patients with decreased level of protein C have a high risk of thrombosis. In vivo, protein C activation is difficult to assess. Until recently, there were no reports of impaired thrombomodulin-dependent activation of protein C. We investigated the effect of IgG fractions from three patients with the lupus anticoagulant on the rate of protein C activation by cultured human endothelial cells from umbilical cord veins.27 All the three patients had recurrent thrombotic episodes. Our results have shown that antibodies in the IgG fraction that contain the lupus anticoagulant can inhibit the interactions among thrombin, protein C and thrombomodulin on the surface of endothelial cells and decrease significantly the rate of protein C activation. The lupus anticoagulant antibodies could block the phospholipids associated with thrombomodulin activity at the vessel level. It has been reported that active phospholipids must be preserved for full thrombomodulin activity to be achieved. Recently another groupZ8 described an IgM lupus anticoagulant that neutralised the enhancing effect of phospholipids on purified endothelial thrombomodulin activity. These observations suggest that patients with lupus anticoagulant can be at risk of thrombosis due to a lowered amount of activated protein C produced by the thrombin-thrombomodulin complex. This could be also of particular relevance in the placenta, where thrombosis may be responsible for recurrent abortion. These very interesting data and exciting hypothesis need, however, to be extended and confirmed in studies of larger series of patients. Protein S. another vitamin K-dependent protein, is
Treatment Since there is no increase in bleeding tendency in cases with a lupus anticoagulant while the patients are at a high risk of thrombosis, anticoagulant therapy is indicated. Depending on whether treatment is for a thrombotic event or for prophylaxis either heparin or oral anticoagulants may be required, the effect of therapy on lupus anticoagulant being monitored by using dilution tests. Treatment with steroids or immunosuppressive agents has a role. In pregnancy fetal death has been prevented by maternal-antibody suppression with prednisone therapy and by using aspirin as an antiplatelet agent.9
References 1. Lechner K, Pabinger-Fashing I 1985 Lupus anticoagulant and thrombosis. A study of 25 cases and review of the literature. Haemostasis 15:254262 2. Harris E N, Gharavi A E, Boey M L, Pate1 B M, Mackorth Young C G, Loizou S, Hughes G V R 1983 Anticardiolipin antibodies: detection by radio-immunoassay and association with thrombosis in systemic lupus erythematosus. The Lancet 2: 1212-1214 3. Thiagarjan P, Shapira S S, De Marco L 1980 Monoclonal immunoglobulin M coagulation inhibitor with phospholipid specificity. Journal of Clinical Investigation 66: 3977405 4. Schwartz R S, Stollar B D 1985 Origi& of anti-DNA autoantibodies. Journal of Clinical Investigation 75: 321-327 5. Bletry 0, Mathieu A, Piette J C, Meyer 0, Conard J, Wechsler B, Godeau P 1983 Fonnes hematologiques du lupus erythemateux dimemine avec et sans facteurs antinucltaires. La Revue de M&de&e Interne 4: 4146 6. Camez A, Tobelem G, Bellucci S, Dupuy E, Soria C, Rotschild C, Caen J 1986 Evolution des manifestations associ&es a l’anticoagulant circulant antiprothrombinase. La Presse MMicale 15: 515-5 18 7. Hamsten A, Bjorkholm M, Norberg R, Defaire U, Holm G 1986 Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cardiovascular events. The Lancet 1: 113-l 15 8. Nilsson I M, Astedt B, Hedner U, Berezin D 1975 Intrauterine death and circulating anticoagulant (antithromboplastin). Acta Medica Scandinavia 197: 1533159
24
THE LUPUS ANTICOAGULANT
AND ITS ROLE IN THROMBOSIS
9. Lubbe W F, Butler W S, Palmer S J, L&gins G C 1983 Fetal survival after prednisone suppression of maternal lupus anticoagulant. The Lancet I:-1 361-1363 10. Carreras L 0. Machin S J. Deman R. Defrevn G. Vermvlen J. Spitz B, Van Asschc A 1981 Arterial thrombosis,‘intrauterine. death and lupus anticoagulant: detection of immunoglobulin interfering with prostacyclin formation. The Lancet 1: 244-246 11. Lockshin M D, Druzin M L, Goei S, Qamar T, Magid M S, Jovanovic L, Ferenc M 1985 Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. The New England Journal of Medicine 313: 152-l 56 12. Wecksler B B, Marcus A J, Jaffee E A 1977 Synthesis of prostaglandin I, (prostacyclin) by cultured human and bovine endothelial cells. Proceedings of the National Academy of Sciences of USA 14: 3922-3926 13. Shepro D, Schleef R, Hechtman H B 1980 Plasminogen activator activity by cultured bovine aortic endothelial cells. Life Sciences 26: 415422 14. Esmon C T, Owen W G, Esmon N L 1982 Isolation of a membrane bound cofactor for thrombin catalized activation of protein C. Journal of Biological Chemistry 257: 859-864 15. Dosne A M, Dupuy E, Boderin E 1978 Production of fibrinolytic inhibitor by cultured endothelial cells derived from human umbilical vein. Thrombosis Research 1Z: 377-387 16. Jaffe E A, Hoyer L W, Nachman R L 1973 Synthesis of antihemophilic factor antigen by cultured human endothelial cells. Journal of Clinical Investigation 52: 2757-2764 17. Maynard J R, Heckman C A, Pitlick F A, Nemerson Y 1975 Association of tissue factor activity with the surface of cultured cells. Journal of Clinical Investigation 55: 814-824 18. Elias M, Eldor A 1984 Thromboembolism in patients with the lupus type circulating anticoagulant. Archives of Internal Medicine 144: 51&515 19. De Castellarnau C, Vila L, Sancho M J, Bouell M, Fontcuberta J, Ruttlant M L 1983. Lupus anticoagulant, recurrent abortion and prostacyclin production by cultured smooth muscle cells. The Lancet 1: 1137-1138
20. Cines D B, Lyss A P, Reebee M, Bina M, Deharatus J 1984 Presence of complement fixing antiendothelial cell antibodies in SLE. Joumalbf Clinical Investigation 73: 61 l-625 21. Goldsmith J C, Connick J J 1984 Immunologic iniurv to vascular endothelial cells. Effect on release oiprostacyclin. Blood 63: 984-989 22. Fitzgerald G A, Smith B, Perdersen A K, Brash A R 1984 Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. The New England Journal of Medicine 310: 1065-1068 23. Angles Cano E, Sultan Y, Clauvel J P 1979 Predisposing factors to thrombosis in SLE possible relation to endothelial cell damage. Journal of Laboratory and Clinical Medicine 94: 312-323 24. Ounoughen M, Bachoudi N, Angles Cano E, Borin 1, Lessana Lebowitch M, Sultan Y, Clauvel J P 1983 Evidence for an inhibitor of plasminogen activator release from endothelial cells in patients with systemic lupus erythematosus. Thrombosis and Haemostasis 50: 194 25. Glas-Greenwalt P, Shashikant K, Allen C, Pollek V E 1984 Fibrinolysis in health and disease: severe abnormalities in SLE. Journal of Laboratory and Clinical Medicine 104: 962-976 26. Esmon C T, Esmon N L, Harris K W 1982 Complex formation between thrombin and thrombomodulin inhibits both thrombin catalyzed fibrin formation and factor V activation. Journal of Biological Chemistry 257: 79447947 27. Cariou R, Tobelem G, Soria C, Caen J 1986 Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. The New England Journal of Medicine 314: 119>1194 28. Freyssinet J M, Wiesel M L, Gauchy J, Boneu B, Cazenave J P 1986 An IgM lupus anticoagulant that neutralizes the enhancing effect of phospholipid on purified endothelial thrombomodulin activity. A mechanism for thrombosis. Thrombosis and Haemostasis 55: 309-313 29. Comp P C, Doray D, Patton D, Esmon C T 1986 An abnormal plasma distribution of protein S occurs in functional protein S deficiency Blood 67: 504508
and its Role in
G. Tobelem, R. Cariou, A. Camez The lupus anticoagulant is usually found in the plasma of patients with systemic lupus SUMMARY. erythematosus. Lupus anticoagulants are antibodies to phosphoiipids and probably to phosphodiesterlinked phosphate groups. A high frequency of thrombotic events in patients with lupus anticoagulant has been reported. Nevertheless the pathogenesis of thrombosis in these patients remains unknown. Endothelium which plays a key role in the antithrombogenic-thrombogenic balance could be a target for the lupus anticoagulant and alterations of some endothelial-cell functions could be responsible for the thrombotic events. The effects of the lupus anticoagulant on the phospholipids of the protein C-thrombomodulin complex may be important although evidence of such a reaction in vivo is awaited,
Lupus anticoagulant is a common clotting abnormality found in patients with systemic lupus erythematosus.’ It is frequently associated with a false positive syphilis test, anticardiolipin and antinuclear antibodies.* The diagnosis of lupus anticoagulant is considered when the activated partial thromboplastin time is prolonged, all other clotting factor activities being normal. It is confirmed by demonstrating that the patient’s plasma prolongs the activated partial thromboplastin time of normal plasma. In addition to systemic lupus erythematosus, other diseases can be associated with a lupus anticoagulant including autoimmune diseases, neoplastic diseases, lymphoproliferative disorders and drug-induced disorders. Sometimes no recognisable underlying disease is found. Lupus anticoagulants are auto-antibodies to phospholipids and probably to phosphodiester-linked phosphate groups. Phosphatidylserine may be the main target.3 The association of lupus anticoagulant with other auto-antibodies (anticardiolipin, antinuclear, antivimentin . . .) led to the hypothesis that all these antibodies were directed against a common antigenic structure, the phosphodiester group. Each G. Tobelem, R. Cariou, A. Camez, Department of Angiohematology, HBpital Lariboisitre, 2 rue Ambroise Part, 75010 Paris, France. I-24
Blood Reviews ( 1987) I, 2 Longman Group UK Ltd
IQ1987
antibody could prefer a particular geometry of the epitope.4 The antiphospholipid specificity of the lupus anticoagulants provides an explanation of their effects on in vitro coagulation. In effect, they are responsible for an in vitro hypocoagulability but they are not associated with an in vivo hemorrhagic tendency. This suggests that the lupus anticoagulants are able to neutralize the exogeneous phospholipids added in vitro to stimulate the clotting system while they are not active in vivo in blocking the binding of clotting factors to the platelet-membrane phospholipids. Furthermore, a high frequency of thrombotic events in patients with lupus anticoagulant, whatever the underlying disease, has been reported for several years by many groups. It is now well established that the lupus anticoagulant is a risk factor of thrombosis.* Recent works have attempted to find the mechanisms of this phenomenon.
Thrombosis in Patients with Lupus Anticoagulant Prevalence of Thrombotic Events Lechner and Pabinger-Fashing, l reviewing 259 published cases with lupus anticoagulant found that 32.8% had at least one thrombotic event. Similarly in
22 THE LUPUS ANTICOAGULANT AND ITS ROLE IN THROMBOSIS two French series of 40 cases,5’6 a percentage of 38% was noted. These reviews, however, probably overestimate the frequency. In agreement with Lechner and Pabinger-Fashing,’ the prevalence of lupus anticoagulant in patients with at least one venous thrombosis or pulmonary embolism was less than 2% in the last 500 patients with venous thrombosis we investigated. Interestingly in a series of 62 young survivors of myocardial infarction, 13 patients (21%) had raised anticardiolipin antibody levels.’
caters of high risk. It is interesting to point out that the underlying disease associated with the lupus anticoagulant was not important as a risk factor in the occurrence of the thrombotic events. Nevertheless, more data are required to confirm the delineation of high and low risk groups. For instance the level of the lupus anticoagulant antibody with time could be relevant to the risk of thrombosis. Better knowledge of the target of the lupus anticoagulant and of the mechanism of thrombosis are probably necessary before the risks can be properly assessed.
Site of Thrombosis Deep vein thrombosis of the legs is the commonest thrombotic event.’ Most thrombosis are recurrent and appear spontaneous. They are very often complicated by pulmonary embolism. Arterial thrombosis (cerebrovascular accidents or peripheral arteries) are reported in 25% of the cases. Pulmonary hypertension has also been observed. Myocardial infarction is not considered common in patients with lupus anticoagulant but the work of Hamsten et al,’ already mentioned, could have modified this point of view. Recurrent Abortions Another striking clinical manifestation of lupus anticoagulant is thrombosis of the placental vessels leading to recurrent abortions. In 1975 Nilsson et ala first reported the case of a woman with antinuclear antibodies and lupus anticoagulant who had three pregnancies which terminated in intrauterine death. In the fourth pregnancy caesarean section was performed and the placenta showed abundant infarcts, necrosis and fibrin deposits. The striking coincidence of early abortion, late intrauterine death and venous thrombosis in female patients with lupus anticoagulant has since been reported by several groups.g These observations indeed led to elucidation of the mechanism of thrombosis associated with lupus anticoagulant and these arose from the detection of immunoglobulins interfering with prostacyclin production in a patient with arterial thrombosis, intrauterine death and lupus anticoagulant. l O The implications of these findings will be discussed later. Finally, Lockshin et al’ l reported that the level of antibody to cardiolipin was the most sensitive means of predicting fetal distress or death in patients with systemic lupus erythematosus. Dejinition of the Thrombosis Risk Lechner and Pabinger-Fashing’ tried to define subgroups with high and low risk of thrombosis. The available data did not allow a clearcut classification of these subgroups but useful indicators for the risk of thrombosis were proposed. Age above 10 years, a normal prothrombin level, a platelet count above 50000/~1, high level of anticardiolipin antibody and lupus anticoagulant of IgG class would represent indi-
Pathogenesis of Thrombosis Lupus Anticoagulant
in Patients
with
The known effects of the lupus anticoagulant on platelets and plasma coagulation do not provide any insight as to the risk of thrombosis. Further studies have focused on events at the endothelium level. The endothelial cells secrete prostacyclini2 and tissue plasminogen activator.13 The endothelium provides thrombomodulin that accelerates the rate of thrombin-dependent protein C conversion, allows neutralisation of bound thrombin by antithrombin and directly inhibits procoagulant activity of thrombin.14 On the other hand the endothelial cells secrete tissue plasminogen activator inhibitor’ 5 and Willebrand factor.16 Finally tissue factor activity is localised to the surface of endothelium. l 7 Eflect of Lupus Anticoagulant on Prostacyclin Production A reduction of prostacyclin production has been shown to be produced by IgG from a patient with an history of multiples thrombosis and abortionslo and this has been confirmed by others’** lg although details are lacking in the latter studies. We have not been able to find any inhibition of prostacyclin production by human endothelial cells in the presence of purified IgG containing lupus anticoagulant activity from 15 patients. Cines et aL2* who have demonstrated that antibodies to endothelial cell antigens were present in the sera of systemic lupus erythematosus patients, failed also to demonstrate any inhibition. Indeed they found an increased production of prostacyclin following exposure to the IgG fraction from two patients. Immunological injury of endothelial cells mediated by endothelium antibodies induced increases significantly the secretion of prostacyclin.21 An enhanced prostacyclin production has been found in diseases with a thrombotic risk and this may be a possible consequence of vascular insults.22 From a clinical point of view, the sites of thrombosis in patients with the lupus anticoagulant are mainly deep veins and prostacyclin is unlikely to play a role in deep vein thrombosis development. Nevertheless, since aspirin improved fetal survival in pregnancies with lupus anticoagulant, it could mean that in such situations the
BLOOD
prostacyclin-thromboxane involved.9
A,
balance
could
be
Fibrinolysis Abnormalities of fibrinolysis have been reported in patients with lupus anticoagulant in in vivo studies. Angles Cano et al23 using the venous occlusion test reported a reduced or absent fibrinolytic response in 24 of 28 patients with systemic lupus. Among these patients, 12 had a lupus anticoagulant and 5 had thrombotic episodes. IgG from three of four patients with lupus anticoagulant inhibited fibrinolytic activity when studied by Todd’s technique.24 Decreased tissue plasminogen activity, increased tissue plasminogen activator inhibition and increased plasmin inhibitor have been reported in respectively 63, 85 and 29% of 55 tested patients with systemic lupu~.~~ These abnormalities are probably related to the damage of vascular endothelium in systemic lupus.
Thrombomodulin
REVIEWS
23
a cofactor which accelerates the rate of the inactivation of factors Va and VIIIa by activated protein C. A part of the plasma protein S (about 60% of the total protein S) is bound by the C, binding protein. Only the free protein S is able to interact with activated protein C. It has been reported that an increased level of C, binding protein in lupus could be responsible for an increased binding potency of protein S and consequently of a decreased circulating free protein S.29
Other Endothelial
Cell Functions
The thrombogenic properties of the endothelium could be enhanced in systemic lupus as a result of vascular injuries. That has been postulated as the explanation for the increased level of plasma factor VIII / von Willebrand factor.23 More interesting is the possibility that lupus anticoagulant or other immunologic process (auto-antibodies, monocytes, interleukin 1, etc) could increase the tissue factor procoagulant activity of endothelial cells.
Protein C Protein S Complex
Protein C, a vitamin K-dependent protein, is a potent inactivator of factors Va and VIIIa, and probably increases fibrinolytic activity.26 Thrombomodulin present at the endothelial surface accelerates the rate of protein C activation. Patients with decreased level of protein C have a high risk of thrombosis. In vivo, protein C activation is difficult to assess. Until recently, there were no reports of impaired thrombomodulin-dependent activation of protein C. We investigated the effect of IgG fractions from three patients with the lupus anticoagulant on the rate of protein C activation by cultured human endothelial cells from umbilical cord veins.27 All the three patients had recurrent thrombotic episodes. Our results have shown that antibodies in the IgG fraction that contain the lupus anticoagulant can inhibit the interactions among thrombin, protein C and thrombomodulin on the surface of endothelial cells and decrease significantly the rate of protein C activation. The lupus anticoagulant antibodies could block the phospholipids associated with thrombomodulin activity at the vessel level. It has been reported that active phospholipids must be preserved for full thrombomodulin activity to be achieved. Recently another groupZ8 described an IgM lupus anticoagulant that neutralised the enhancing effect of phospholipids on purified endothelial thrombomodulin activity. These observations suggest that patients with lupus anticoagulant can be at risk of thrombosis due to a lowered amount of activated protein C produced by the thrombin-thrombomodulin complex. This could be also of particular relevance in the placenta, where thrombosis may be responsible for recurrent abortion. These very interesting data and exciting hypothesis need, however, to be extended and confirmed in studies of larger series of patients. Protein S. another vitamin K-dependent protein, is
Treatment Since there is no increase in bleeding tendency in cases with a lupus anticoagulant while the patients are at a high risk of thrombosis, anticoagulant therapy is indicated. Depending on whether treatment is for a thrombotic event or for prophylaxis either heparin or oral anticoagulants may be required, the effect of therapy on lupus anticoagulant being monitored by using dilution tests. Treatment with steroids or immunosuppressive agents has a role. In pregnancy fetal death has been prevented by maternal-antibody suppression with prednisone therapy and by using aspirin as an antiplatelet agent.9
References 1. Lechner K, Pabinger-Fashing I 1985 Lupus anticoagulant and thrombosis. A study of 25 cases and review of the literature. Haemostasis 15:254262 2. Harris E N, Gharavi A E, Boey M L, Pate1 B M, Mackorth Young C G, Loizou S, Hughes G V R 1983 Anticardiolipin antibodies: detection by radio-immunoassay and association with thrombosis in systemic lupus erythematosus. The Lancet 2: 1212-1214 3. Thiagarjan P, Shapira S S, De Marco L 1980 Monoclonal immunoglobulin M coagulation inhibitor with phospholipid specificity. Journal of Clinical Investigation 66: 3977405 4. Schwartz R S, Stollar B D 1985 Origi& of anti-DNA autoantibodies. Journal of Clinical Investigation 75: 321-327 5. Bletry 0, Mathieu A, Piette J C, Meyer 0, Conard J, Wechsler B, Godeau P 1983 Fonnes hematologiques du lupus erythemateux dimemine avec et sans facteurs antinucltaires. La Revue de M&de&e Interne 4: 4146 6. Camez A, Tobelem G, Bellucci S, Dupuy E, Soria C, Rotschild C, Caen J 1986 Evolution des manifestations associ&es a l’anticoagulant circulant antiprothrombinase. La Presse MMicale 15: 515-5 18 7. Hamsten A, Bjorkholm M, Norberg R, Defaire U, Holm G 1986 Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cardiovascular events. The Lancet 1: 113-l 15 8. Nilsson I M, Astedt B, Hedner U, Berezin D 1975 Intrauterine death and circulating anticoagulant (antithromboplastin). Acta Medica Scandinavia 197: 1533159
24
THE LUPUS ANTICOAGULANT
AND ITS ROLE IN THROMBOSIS
9. Lubbe W F, Butler W S, Palmer S J, L&gins G C 1983 Fetal survival after prednisone suppression of maternal lupus anticoagulant. The Lancet I:-1 361-1363 10. Carreras L 0. Machin S J. Deman R. Defrevn G. Vermvlen J. Spitz B, Van Asschc A 1981 Arterial thrombosis,‘intrauterine. death and lupus anticoagulant: detection of immunoglobulin interfering with prostacyclin formation. The Lancet 1: 244-246 11. Lockshin M D, Druzin M L, Goei S, Qamar T, Magid M S, Jovanovic L, Ferenc M 1985 Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. The New England Journal of Medicine 313: 152-l 56 12. Wecksler B B, Marcus A J, Jaffee E A 1977 Synthesis of prostaglandin I, (prostacyclin) by cultured human and bovine endothelial cells. Proceedings of the National Academy of Sciences of USA 14: 3922-3926 13. Shepro D, Schleef R, Hechtman H B 1980 Plasminogen activator activity by cultured bovine aortic endothelial cells. Life Sciences 26: 415422 14. Esmon C T, Owen W G, Esmon N L 1982 Isolation of a membrane bound cofactor for thrombin catalized activation of protein C. Journal of Biological Chemistry 257: 859-864 15. Dosne A M, Dupuy E, Boderin E 1978 Production of fibrinolytic inhibitor by cultured endothelial cells derived from human umbilical vein. Thrombosis Research 1Z: 377-387 16. Jaffe E A, Hoyer L W, Nachman R L 1973 Synthesis of antihemophilic factor antigen by cultured human endothelial cells. Journal of Clinical Investigation 52: 2757-2764 17. Maynard J R, Heckman C A, Pitlick F A, Nemerson Y 1975 Association of tissue factor activity with the surface of cultured cells. Journal of Clinical Investigation 55: 814-824 18. Elias M, Eldor A 1984 Thromboembolism in patients with the lupus type circulating anticoagulant. Archives of Internal Medicine 144: 51&515 19. De Castellarnau C, Vila L, Sancho M J, Bouell M, Fontcuberta J, Ruttlant M L 1983. Lupus anticoagulant, recurrent abortion and prostacyclin production by cultured smooth muscle cells. The Lancet 1: 1137-1138
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