- Email: [email protected]
Coronary Bypass Surgery in Patients with Circulating Lupus Anticoagulant
Coronary Bypass Surgery in Patients with Circulating Lupus Anticoagulant James P. Kelly, M.D., Leonard Thomas, M.D., Peter V. Moulder, M.D., and Watts R. Webb, M.D. ABSTRACT Clinical and laboratory experience with circulating lupus anticoagulant in 3 patients undergoing coronary artery bypass procedures is reported. This circulatory anticoagulant inhibits activation of prothrombin by the prothrombin activator complex (factor Xa, factor V, and phospholipid). The presence of lupus anticoagulant was initially detected because of a prolonged activated partial thromboplastin time and a normal or mildly prolonged prothrombin time. The 3 patients underwent uncomplicated coronary artery bypass grafting and experienced no abnormal bleeding postoperatively. The lupus anticoagulant is a rare cause of bleeding after open-heart surgery. It appears to be a problem only when an additional coagulation defect is present.
inspection of a stained blood film. The presence of a circulating anticoagulant was suspected when a prolonged PTT was found in the absence of known clinical coagulopathy, and was confirmed by the failure of a 1:1 mixture of patient plasma and control plasma to correct the activated PTT to within 2 seconds of the control value. Dilute tissue thromboplastin assay, also known as the tissue thromboplastin inhibition test (TTI), was performed according to the method of Schleider and colleagues [9]. A ratio of patient to control clotting time (at a final thromboplastin (Simplastin; General Diagnostics, Morris Plains, NJ) concentration of 1:1,000) of 1.3 or greater was considered positive for the presence of LA. Case Reports
1. A 49-year-old man had a history of myocardial infarction with positive stress test results and chest pain. Cardiac catheterization showed severe triplevessel disease with moderate left ventricular dysfunction. The PTT was 68.9 seconds (normal range, 26 to 40 seconds), and the PT was normal. Platelet function and number were normal. Hematology workup revealed a circulating LA. The patient underwent an uncomplicated quadruplevessel coronary artery bypass procedure. Postoperatively, the PTT was prolonged at 42 seconds and the PT was 14 seconds. The fibrinogen level was 152 mg/dl (normal range, 177 to 375 mg/dl), and the bleeding time was greater than 20 seconds. He was given ten units of platelets, four units of fresh frozen plasma, and five units of packed red blood cells in the perioperative period. The total mediastinal drainage was 475 ml. The patient was discharged on postoperataive day 7. PATIENT 2. A 44-year-old man had a history of postinfarction angina. Cardiac catheterization demonstrated severe triple-vessel disease with good left ventricular function. Preoperative history and coagulation studies showed a PTT of 50.5 seconds and a normal PT. Hematology workup demonstrated a circulating LA. The patient underwent an uncomplicated quadruplevessel coronary bypass procedure. He received four units of fresh frozen plasma and two units of packed red blood cells in the perioperative period. Mediastinal drainage was 168 ml. The patient was discharged on postoperative day 8. PATIENT 3. A 58-year-old man had unstable angina. Cardiac catheterization showed severe triple-vessel disease with moderate left ventricular dysfunction. The preoperative PT was 14.7 seconds, and the PTT was 68.4 seconds. Platelet function and number were normal. Hematology workup showed a circulating LA. The fibrinogen level was 172 mg/dl.
PATIENT
Circulatory anticoagulants, including those directed against coagulation factors XII, XI, IX, and VII, have been reported in patients with systemic lupus erythematosus [l-51. However, the most common clotting abnormality is the so-called lupus anticoagulant (LA), which appears to block the activation of prothrombin by the prothrombin activator complex of factor Xa, factor V, and phospholipid [6, 71. The presence of LA is characterized by a prolonged activated partial thromboplastin time (PTT) and a mildly prolonged prothrombin time (PT). Prior to undergoing open-heart surgical procedures, our patients are screened with a routine coagulation profile that includes determination of PTT, PT, platelet count, and bleeding time. Three patients scheduled for coronary bypass grafting had unexplained elevations of PTT or PT or both, and were found to have LA. The cases of these patients are described, and the literature on open-heart surgical procedures in patients with LA is reviewed.
Material and Methods Prqthrombin time, activated PIT, thrombin time, and template bleeding time measurements were performed according to established methods [8]. Platelet counts were determined using an Ortho ELT-8 Automated Complete Blood Cell Analyzer and confirmed by visual
From the Departments of Medicine and Surgery, Tulane University School of Medicine, New Orleans, LA. Accepted for publication Jan 28, 1985. Address reprint requests to Dr. Kelly, Associate Professor of Cardiothoracic Surgery, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112.
261
262 The Annals of Thoracic Surgery Vol 40 No 3 September 1985
The patient underwent uncomplicated triple-vessel coronary bypass grafting. He received five units of cryoprecipitate and five units of blood in the perioperative period. The total mediastinal drainage was 350 ml. The patient was discharged on postoperative day 8.
Results Three patients are presented who underwent evaluation for prolonged PT or PTT or both prior to undergoing coronary revascularization. One of these patients had previously been found to have an abnormal activated PTT because of extensive testing undertaken before an operation on his lumbar spine. None of the patients had a clinical history of abnormal bleeding. All patients had abnormal PTTs, which were confirmed by our special hematology section. The results of antinuclear antibody tests were negative in 2 patients. The other patient had positive serological test results for syphilis. Results of both the mixing test for circulating anticoagulant and of the TTI were positive in each patient, thus establishing the diagnosis of circulating LA (Table 1).In all 3 patients, bleeding times were normal and platelet counts were in the low normal range. One patient had minor hepatic dysfunction as manifested by slight elevation of alkaline phosphatase and serum glutamic-oxaloacetictransaminase levels. The patient subsequently underwent removal of his gallbladder for cholelithiasis.
Comment Lupus anticoagulant is an antibody that has been demonstrated by several investigators [lo, 111. It is thought to be located in the immunoglobulin G or M fraction [ll, 121. The mode of action of this circulatory anticoagulant is believed to be inhibition of reaction of the formed prothrombin activator complex (factor Xa, factor V, and
Table 1. Preoperative Coagulation Studies in Patients with Circulating Lupus Anticoagulant Study
Patient 1
Patient 2
Patient 3
NORMAL PLASMA MIXING TEST
Activated partial thromboplastin time (sec) Patient plasma 68.9 50.5 37.6 37.2 PNP Mixture of patient plasma 60.1 41.1 and PNP (1:1)
68.4
35.1 50.4
~
TTI AT
1:1,000 DILUTION
Activated clotting time (sec) 108.4 Patient plasma 68.9 PNP 1.5 Patient plasmalPNP ratio I"P test.
109.8 62.4 1.8
90.9 55.6 1.6
= pooled normal plasma; TTI = tissue thromboplastin inhibitor
phospholipid) with prothrombin [ll, 121. The LA appears to be directed at the phospholipid portion of the prothrombin activator complex [2, 131. A high level of LA in the plasma can lead to prolongation of activated PTT and PT. Studies have confirmed that the activated PTT is a much more sensitive test than PT for detecting LA [12].Mixing plasma with a high titer of the LA with an equal volume of normal plasma will lead to prolongation of both the PT and the activated PTT. This finding was observed in all 3 of our patients (see Table 1). The effect of LA on the PT and activated PTT is not affected by the length of intubation or the temperature [7], as is the case when anticoagulants are directed against a specific coagulation factor. Since the description of LA in 1952 [14], more than 100 cases of circulating LA have been reported. In patients with systemic lupus erythematosus, the incidence of LA appears to be 5% [15]. Circulating LA has been reported in patients with other autoimmune diseases. In a 1976 study of LA, one-third of the patients had abnormalities of the coagulation mechanism without findings to suggest an autoimmune disease [16]. From these findings, it seems that LA may be more common than was previously recognized. Our experience suggests that patients with circulating LA, even though untreated, do not have excessive bleeding after cardiopulmonary bypass procedures. Conley and Hartmann [14] mentioned 2 patients with this condition who had coronary bypass grafting and aortic valve replacement with no bleeding complications. Only 1 patient with circulating LA has been reported to have bled excessively at operation, and this patient was uremic. Other studies have confirmed minimal bleeding in general surgical procedures [16, 171. Several clinical series suggest that circulatory LA is associated with a bleeding disorder only when a second coagulation defect is present [6, 7, 181. The experience just described demonstrates the absence of clinical bleeding problems even in the presence of further anticoagulation with heparin. This phenomenon may be explained by evidence suggesting that while the LA binds to extrinsic phospolipid (i.e,, Simplastin) in vitro, it does not bind to platelet phospholipid in vivo [17]. The 3 patients in the current report represent 0.3% of all adult patients who had open-heart surgical procedures at our institution during a four-year period. We used a standard heparinization regimen of 3 mg per kilogram of body weight in all of the patients, and we reversed the heparin with protamine sulfate (Table 2). Patients were given fresh frozen plasma or cryoprecipitate perioperatively because of apparent qualitative clotting abnormalities at the discretion of the individual surgeon. Patients did not bleed excessively as judged by mediastinal bleeding and total transfusion requirements. Clotting studies performed before discharge showed the activated PTT to be prolonged in all patients, and all left the hospital with a hematocrit of greater than 32%. Patients with LA may have an associated deficiency of factor I1 (prothrombin) activity [9]. Although the etiol-
263 Kelly et al: Coronary Bypass in Patients with LA
Table 2. Results of Heparinization during Cardiopulmonary Bypass in Patients with Circulating Lupus Anticoagulant ~~~
Activated Clotting Time (sec) Time of Study
Patient 1
Patient 2
Patient 3
Before operation After heparinization (3 m g w After protamine reversal
164 >1,000
145 >1,000
157 557
159
152
163
ogy of factor I1 deficiency i s unknown, if t h e PT i s normal, t h e patient m a y be a s s u m e d to have a level of factor I1 that is adequate for hemostasis [7]. Thrombocytopenia h a s also been reported i n patients w i t h LA, a n d platelet counts a n d bleeding times s h o u l d be examined i n patients w i t h this defect [6, 71. Several articles i n t h e literature h a v e reported a n increased incidence of thrombosis i n patients w i t h LA [17, 19, 201. While a n u m b e r of mechanisms for this have been postulated, Elias and Eldor [17] h a v e shown a plasma inhibitor of prostacyclin production i n 4 of 7 patients. It is of interest t h a t t h e y employed heparin anticoagulation i n 3 patients who h a d venous thrombosis and LA, and t h e n a prolonged oral anticoagulation regim e n . There w a s no recurrence of thrombosis. Treatment of this circulating anticoagulant w i t h steroids over a period of several weeks [7] h a s led t o a decrease i n lupus activity. Because of t h e possible side effects from long-term steroid use, the frequent need to operate urgently, and t h e minimal bleeding i n patients with LA who undergo cardiopulmonary bypass, we do n o t advocate prolonged steroid therapy, Instead, we suggest proceeding w i t h cardiopulmonary bypass a s soon as o t h e r bleeding abnormalities h a v e been ruled out.
References 1. Castro 0, Farber LR: Circulating anticoagulants against factor IX and XI in systemic lupus erythematosus. Ann Intern Med 77543, 1972 2. Krieger H, Leddy JP, Breckinridge RT: Studies on a circulating anticoagulant in systemic lupus erythematosus: evidence for inhibition of the function of activated plasma thromboplastin antecedent (factor XIa). Blood 46:189, 1975
3. Cronberg S, Nilson IM: Circulating anticoagulants against factor XI and XI1 together with massive spontaneous platelet aggregation. Scand J Haematol 10:309, 1973 4. Gobbi F, Stefanini M: Circulating anti-AHG anticoagulant in a patient with lupus erythematosus desseminatus. Acta Haematol (Basel) 28:155, 1962 5. Robboy SJ, Lewis EJ, Schurr PH, et al: Circulating anticoagulants to factor VIII. Am J Med 49:742, 1970 6. Margolius A, Jackson DP, Ratnoff OD: Circulating anticoagulants: a study of 40 cases and a review of the literature. Medicine 40:145, 1961 7. Feinstein DI, Rappaport SI: Acquired inhibitors of blood coagulation. In Spaet TH (ed): Progress in Hemostasis and Thrombosis. New York, Grune & Stratton, 1972, vol 1, p 75 8. Triplett DA, Harna CS (eds): Procedures for the Coagulation Laboratory. Chicago, American Society of Clinical Pathology, 1981 9. Schleider MA, Nachman RL, et al: A clinical study of the lupus anticoagulant. Blood 48:499, 1976 10. Laurel1 A, Nilsson IM: Hypergammaglobulinemia, circulating anticoagulants, and biologic false positive Wasserman reaction. J Lab Clin Med 49:694, 1957 11. Yin ET, Gaston LW: Purification and kinetic studies on a circulating anticoagulant in suspected cases of lupus erythematosus. Thromb Diath Haemorrh 14:88, 1965 12. Gonyea L, Herdman R, Bridges RA: The coagulation abnormalities in systemic lupus erythematosus. Thromb Diath Haemorrh 20:457, 1968 13. Velkamp JJ, Kerkhoven P, Leoliger EA: Circulating anticoagulants in disseminated lupus erythematosus: proposed mode of action. Haemostasis 2:253, 1973 4. Conley CL, Hartmann RC: a hemorrhagic disorder caused by a circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 31:621, 1952 5. Regan MG, Lackner H, Karpatkm S: Platelet function and coagulation profile in lupus erythematosus. Ann Intern Med 81:462, 1974 6. Boxer M, Ellman L, Corvabbe A: The lupus anticoagulant. Arthritis Rheum 19:1244, 1976 17. Elias M, Eldor A: Thromboembolism in patients with the "lupus"-type circulating anticoagulant. Arch Intern Med 144:510, 1984 18. Lee SL, Sanders M: A disorder of blood coagulation in systemic lupus erythematosus. J Clin Invest 34:1814, 1955 19. Much JR, Herbst KD, Rappaport SI: Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 94:156, 1980 20. Carrares LO, Machin SJ, Demon R, et al: Arterial thrombosis, intrauterine death and lupus anticoagulant: detection of immunoglobulin interfering with prostacyclin. Lancet 1:244, 1981
inspection of a stained blood film. The presence of a circulating anticoagulant was suspected when a prolonged PTT was found in the absence of known clinical coagulopathy, and was confirmed by the failure of a 1:1 mixture of patient plasma and control plasma to correct the activated PTT to within 2 seconds of the control value. Dilute tissue thromboplastin assay, also known as the tissue thromboplastin inhibition test (TTI), was performed according to the method of Schleider and colleagues [9]. A ratio of patient to control clotting time (at a final thromboplastin (Simplastin; General Diagnostics, Morris Plains, NJ) concentration of 1:1,000) of 1.3 or greater was considered positive for the presence of LA. Case Reports
1. A 49-year-old man had a history of myocardial infarction with positive stress test results and chest pain. Cardiac catheterization showed severe triplevessel disease with moderate left ventricular dysfunction. The PTT was 68.9 seconds (normal range, 26 to 40 seconds), and the PT was normal. Platelet function and number were normal. Hematology workup revealed a circulating LA. The patient underwent an uncomplicated quadruplevessel coronary artery bypass procedure. Postoperatively, the PTT was prolonged at 42 seconds and the PT was 14 seconds. The fibrinogen level was 152 mg/dl (normal range, 177 to 375 mg/dl), and the bleeding time was greater than 20 seconds. He was given ten units of platelets, four units of fresh frozen plasma, and five units of packed red blood cells in the perioperative period. The total mediastinal drainage was 475 ml. The patient was discharged on postoperataive day 7. PATIENT 2. A 44-year-old man had a history of postinfarction angina. Cardiac catheterization demonstrated severe triple-vessel disease with good left ventricular function. Preoperative history and coagulation studies showed a PTT of 50.5 seconds and a normal PT. Hematology workup demonstrated a circulating LA. The patient underwent an uncomplicated quadruplevessel coronary bypass procedure. He received four units of fresh frozen plasma and two units of packed red blood cells in the perioperative period. Mediastinal drainage was 168 ml. The patient was discharged on postoperative day 8. PATIENT 3. A 58-year-old man had unstable angina. Cardiac catheterization showed severe triple-vessel disease with moderate left ventricular dysfunction. The preoperative PT was 14.7 seconds, and the PTT was 68.4 seconds. Platelet function and number were normal. Hematology workup showed a circulating LA. The fibrinogen level was 172 mg/dl.
PATIENT
Circulatory anticoagulants, including those directed against coagulation factors XII, XI, IX, and VII, have been reported in patients with systemic lupus erythematosus [l-51. However, the most common clotting abnormality is the so-called lupus anticoagulant (LA), which appears to block the activation of prothrombin by the prothrombin activator complex of factor Xa, factor V, and phospholipid [6, 71. The presence of LA is characterized by a prolonged activated partial thromboplastin time (PTT) and a mildly prolonged prothrombin time (PT). Prior to undergoing open-heart surgical procedures, our patients are screened with a routine coagulation profile that includes determination of PTT, PT, platelet count, and bleeding time. Three patients scheduled for coronary bypass grafting had unexplained elevations of PTT or PT or both, and were found to have LA. The cases of these patients are described, and the literature on open-heart surgical procedures in patients with LA is reviewed.
Material and Methods Prqthrombin time, activated PIT, thrombin time, and template bleeding time measurements were performed according to established methods [8]. Platelet counts were determined using an Ortho ELT-8 Automated Complete Blood Cell Analyzer and confirmed by visual
From the Departments of Medicine and Surgery, Tulane University School of Medicine, New Orleans, LA. Accepted for publication Jan 28, 1985. Address reprint requests to Dr. Kelly, Associate Professor of Cardiothoracic Surgery, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112.
261
262 The Annals of Thoracic Surgery Vol 40 No 3 September 1985
The patient underwent uncomplicated triple-vessel coronary bypass grafting. He received five units of cryoprecipitate and five units of blood in the perioperative period. The total mediastinal drainage was 350 ml. The patient was discharged on postoperative day 8.
Results Three patients are presented who underwent evaluation for prolonged PT or PTT or both prior to undergoing coronary revascularization. One of these patients had previously been found to have an abnormal activated PTT because of extensive testing undertaken before an operation on his lumbar spine. None of the patients had a clinical history of abnormal bleeding. All patients had abnormal PTTs, which were confirmed by our special hematology section. The results of antinuclear antibody tests were negative in 2 patients. The other patient had positive serological test results for syphilis. Results of both the mixing test for circulating anticoagulant and of the TTI were positive in each patient, thus establishing the diagnosis of circulating LA (Table 1).In all 3 patients, bleeding times were normal and platelet counts were in the low normal range. One patient had minor hepatic dysfunction as manifested by slight elevation of alkaline phosphatase and serum glutamic-oxaloacetictransaminase levels. The patient subsequently underwent removal of his gallbladder for cholelithiasis.
Comment Lupus anticoagulant is an antibody that has been demonstrated by several investigators [lo, 111. It is thought to be located in the immunoglobulin G or M fraction [ll, 121. The mode of action of this circulatory anticoagulant is believed to be inhibition of reaction of the formed prothrombin activator complex (factor Xa, factor V, and
Table 1. Preoperative Coagulation Studies in Patients with Circulating Lupus Anticoagulant Study
Patient 1
Patient 2
Patient 3
NORMAL PLASMA MIXING TEST
Activated partial thromboplastin time (sec) Patient plasma 68.9 50.5 37.6 37.2 PNP Mixture of patient plasma 60.1 41.1 and PNP (1:1)
68.4
35.1 50.4
~
TTI AT
1:1,000 DILUTION
Activated clotting time (sec) 108.4 Patient plasma 68.9 PNP 1.5 Patient plasmalPNP ratio I"P test.
109.8 62.4 1.8
90.9 55.6 1.6
= pooled normal plasma; TTI = tissue thromboplastin inhibitor
phospholipid) with prothrombin [ll, 121. The LA appears to be directed at the phospholipid portion of the prothrombin activator complex [2, 131. A high level of LA in the plasma can lead to prolongation of activated PTT and PT. Studies have confirmed that the activated PTT is a much more sensitive test than PT for detecting LA [12].Mixing plasma with a high titer of the LA with an equal volume of normal plasma will lead to prolongation of both the PT and the activated PTT. This finding was observed in all 3 of our patients (see Table 1). The effect of LA on the PT and activated PTT is not affected by the length of intubation or the temperature [7], as is the case when anticoagulants are directed against a specific coagulation factor. Since the description of LA in 1952 [14], more than 100 cases of circulating LA have been reported. In patients with systemic lupus erythematosus, the incidence of LA appears to be 5% [15]. Circulating LA has been reported in patients with other autoimmune diseases. In a 1976 study of LA, one-third of the patients had abnormalities of the coagulation mechanism without findings to suggest an autoimmune disease [16]. From these findings, it seems that LA may be more common than was previously recognized. Our experience suggests that patients with circulating LA, even though untreated, do not have excessive bleeding after cardiopulmonary bypass procedures. Conley and Hartmann [14] mentioned 2 patients with this condition who had coronary bypass grafting and aortic valve replacement with no bleeding complications. Only 1 patient with circulating LA has been reported to have bled excessively at operation, and this patient was uremic. Other studies have confirmed minimal bleeding in general surgical procedures [16, 171. Several clinical series suggest that circulatory LA is associated with a bleeding disorder only when a second coagulation defect is present [6, 7, 181. The experience just described demonstrates the absence of clinical bleeding problems even in the presence of further anticoagulation with heparin. This phenomenon may be explained by evidence suggesting that while the LA binds to extrinsic phospolipid (i.e,, Simplastin) in vitro, it does not bind to platelet phospholipid in vivo [17]. The 3 patients in the current report represent 0.3% of all adult patients who had open-heart surgical procedures at our institution during a four-year period. We used a standard heparinization regimen of 3 mg per kilogram of body weight in all of the patients, and we reversed the heparin with protamine sulfate (Table 2). Patients were given fresh frozen plasma or cryoprecipitate perioperatively because of apparent qualitative clotting abnormalities at the discretion of the individual surgeon. Patients did not bleed excessively as judged by mediastinal bleeding and total transfusion requirements. Clotting studies performed before discharge showed the activated PTT to be prolonged in all patients, and all left the hospital with a hematocrit of greater than 32%. Patients with LA may have an associated deficiency of factor I1 (prothrombin) activity [9]. Although the etiol-
263 Kelly et al: Coronary Bypass in Patients with LA
Table 2. Results of Heparinization during Cardiopulmonary Bypass in Patients with Circulating Lupus Anticoagulant ~~~
Activated Clotting Time (sec) Time of Study
Patient 1
Patient 2
Patient 3
Before operation After heparinization (3 m g w After protamine reversal
164 >1,000
145 >1,000
157 557
159
152
163
ogy of factor I1 deficiency i s unknown, if t h e PT i s normal, t h e patient m a y be a s s u m e d to have a level of factor I1 that is adequate for hemostasis [7]. Thrombocytopenia h a s also been reported i n patients w i t h LA, a n d platelet counts a n d bleeding times s h o u l d be examined i n patients w i t h this defect [6, 71. Several articles i n t h e literature h a v e reported a n increased incidence of thrombosis i n patients w i t h LA [17, 19, 201. While a n u m b e r of mechanisms for this have been postulated, Elias and Eldor [17] h a v e shown a plasma inhibitor of prostacyclin production i n 4 of 7 patients. It is of interest t h a t t h e y employed heparin anticoagulation i n 3 patients who h a d venous thrombosis and LA, and t h e n a prolonged oral anticoagulation regim e n . There w a s no recurrence of thrombosis. Treatment of this circulating anticoagulant w i t h steroids over a period of several weeks [7] h a s led t o a decrease i n lupus activity. Because of t h e possible side effects from long-term steroid use, the frequent need to operate urgently, and t h e minimal bleeding i n patients with LA who undergo cardiopulmonary bypass, we do n o t advocate prolonged steroid therapy, Instead, we suggest proceeding w i t h cardiopulmonary bypass a s soon as o t h e r bleeding abnormalities h a v e been ruled out.
References 1. Castro 0, Farber LR: Circulating anticoagulants against factor IX and XI in systemic lupus erythematosus. Ann Intern Med 77543, 1972 2. Krieger H, Leddy JP, Breckinridge RT: Studies on a circulating anticoagulant in systemic lupus erythematosus: evidence for inhibition of the function of activated plasma thromboplastin antecedent (factor XIa). Blood 46:189, 1975
3. Cronberg S, Nilson IM: Circulating anticoagulants against factor XI and XI1 together with massive spontaneous platelet aggregation. Scand J Haematol 10:309, 1973 4. Gobbi F, Stefanini M: Circulating anti-AHG anticoagulant in a patient with lupus erythematosus desseminatus. Acta Haematol (Basel) 28:155, 1962 5. Robboy SJ, Lewis EJ, Schurr PH, et al: Circulating anticoagulants to factor VIII. Am J Med 49:742, 1970 6. Margolius A, Jackson DP, Ratnoff OD: Circulating anticoagulants: a study of 40 cases and a review of the literature. Medicine 40:145, 1961 7. Feinstein DI, Rappaport SI: Acquired inhibitors of blood coagulation. In Spaet TH (ed): Progress in Hemostasis and Thrombosis. New York, Grune & Stratton, 1972, vol 1, p 75 8. Triplett DA, Harna CS (eds): Procedures for the Coagulation Laboratory. Chicago, American Society of Clinical Pathology, 1981 9. Schleider MA, Nachman RL, et al: A clinical study of the lupus anticoagulant. Blood 48:499, 1976 10. Laurel1 A, Nilsson IM: Hypergammaglobulinemia, circulating anticoagulants, and biologic false positive Wasserman reaction. J Lab Clin Med 49:694, 1957 11. Yin ET, Gaston LW: Purification and kinetic studies on a circulating anticoagulant in suspected cases of lupus erythematosus. Thromb Diath Haemorrh 14:88, 1965 12. Gonyea L, Herdman R, Bridges RA: The coagulation abnormalities in systemic lupus erythematosus. Thromb Diath Haemorrh 20:457, 1968 13. Velkamp JJ, Kerkhoven P, Leoliger EA: Circulating anticoagulants in disseminated lupus erythematosus: proposed mode of action. Haemostasis 2:253, 1973 4. Conley CL, Hartmann RC: a hemorrhagic disorder caused by a circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 31:621, 1952 5. Regan MG, Lackner H, Karpatkm S: Platelet function and coagulation profile in lupus erythematosus. Ann Intern Med 81:462, 1974 6. Boxer M, Ellman L, Corvabbe A: The lupus anticoagulant. Arthritis Rheum 19:1244, 1976 17. Elias M, Eldor A: Thromboembolism in patients with the "lupus"-type circulating anticoagulant. Arch Intern Med 144:510, 1984 18. Lee SL, Sanders M: A disorder of blood coagulation in systemic lupus erythematosus. J Clin Invest 34:1814, 1955 19. Much JR, Herbst KD, Rappaport SI: Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 94:156, 1980 20. Carrares LO, Machin SJ, Demon R, et al: Arterial thrombosis, intrauterine death and lupus anticoagulant: detection of immunoglobulin interfering with prostacyclin. Lancet 1:244, 1981