Prekallikrein Inhibition Associated Anticoagulant
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1 Prekallikrein Inhibition Associated with the Lupus Anticoagulant A Mechanism of Thrombosis MICHAEL J. SANFELIPPO, M.S. AND CHRISTOPHER J. DRAYNA, M.D. Sanfelippo, Michael J., and Drayna, Christopher J.: Prekallikrein inhibition associated with the lupus anticoagulant. A mechanism of thrombosis. Am J Clin Pathol 77: , The lupus anticoagulant was identified in three patients. Laboratory studies gave evidence of inhibitory activity directed against phospholipid and prekallikrein. Inhibition of prekallikrein has not been reported previously. When exposed to kaolin, all three patients' plasmas failed to develop the level of fibrinolytic activity achieved by similarly treated normal plasma. The data suggest that compromised fibrinolytic capacity may be a contributing factor in the development of thrombosis in patients with the lupus anticoagulant. (Key words: Lupus anticoagulant; Prekallikrein; Thrombosis.) THE LUPUS ANTICOAGULANT is a spontaneously occurring inhibitor of blood coagulation which appears in the plasma of patients with autoimmune diseases including systemic lupus erythematosus (SLE) and drug reactions. This inhibitor is thought to be an immunoglobulin of the IgG or IgM class. The inhibitory activity of this protein is heterogeneous. In most cases it appears to be directed against phospholipid. However, it has also been reported to inhibit fibrin polymerization, 9 activated factor X, 2 factors IX and XI, 7 and factors XI and XII. 8 Laboratory tests such as the partial thromboplastin time and, less frequently, the prothrombin time are prolonged when phospholipid inhibition occurs. Hemorrhagic complications anticipated from these test results are rarely encountered unless an additional hemostatic defect is present. Paradoxically, thrombosis appears to occur with greater frequency than does hemorrhage when the lupus anticoagulant is present. The occurrence of thrombosis in the presence of the lupus anticoagulant was fist rec- Received April 21, 1981; received revised manuscript and accepted for publication July 1, Supported in part by Grant No from the Scientific Advancement and Education Fund of Columbia Hospital. Address reprint requests to Mr. Sanfelippo: Department of Laboratory Medicine, Columbia Hospital, 2025 E. Newport Avenue, Milwaukee, Wisconsin Departments of Laboratory Medicine and Medicine, Columbia Hospital, Milwaukee, Wisconsin ognized in The prevalence of this complication has been reviewed recently. 10 ' 12 Several explanations have been offered for the increased incidence of thrombosis in patients with the lupus anticoagulant, but not until recently have specific changes in procoagulant proteins or physiologic control mechanisms been demonstrated. Angels-Cano and co-workers' reported an increase in von Willebrand Factor activity (VIII R:WF) and a decrease in plasminogen activator release both proteins of endothelial cell origin. We recently observed lupus anticoagulant activity in three patients with autoimmune disease. One had mixed connective tissue, another systemic lupus erythematosus, and the third procainamide-induced lupus erythematosus. A previously unreported inhibition of prekallikrein (Fletcher Factor) was observed in all three cases. Prekallikrein is a cofactor participating in the activation of plasminogen by factor XII (contact activation). It has also been shown to activate factor XII, generate kinin, and function as a chemotactic factor. 17 Subsequent studies demonstrated an impairment- of contact activation of the fibrinolytic system in all three patients. Methods Prothrombin time and partial thromboplastin time tests were performed with Thromboplastin C and AC- TIN (Dade Diagnostic, Inc., Miami, Florida), respectively. The thrombin time was performed with bovine thrombin diluted to yield a clotting time with normal plasma of seconds. Patient times were compared to those of fresh normal controls. Assays for coagulation factors VIII, IX, XI, XII were performed by the activated partial thromboplastin time method using commercial deficient plasmas (Dade Di /82/0300/0275 $00.75 American Society of Clinical Pathologists 275
2 276 SANFELIPPO AND DRAYNA A.J.C.P. March 1982 Table 1. Initial Laboratory Studies on Three Patient Prothrombin Partial (PTT) Thromboplastin PTT Patient Plasma + Plasma Thrombin Control ±10 sec agnostics, Miami, Florida) as the substrates. Specimens were assayed against a commercial reference pool (Cutter Biological, Berkeley, California). High molecular weight kininogen (HM WK) and prekallikrein were also assayed by the activated partial thromboplastin time method with appropriate deficient substrate plasmas (George King Bio-Medical, Overland Park, Kansas). A lyophilized normal plasma pool was used as the reference plasma for these assays. The prekallikrein assay of the last patient (Patient 3) was modified by using a partial thromboplastin reagent with silica activator (General Diagnostics, Morris Plains, New Jersey) and reducing the activation time to 1 minute to improve the sensitivity of the assay. 16 Inhibition of tissue factor was determined by the method of Schleider and colleagues. 14 Plasma from a healthy volunteer was used as a control in the two patients with normal prothrombin times. Plasma from a patient receiving Coumadin (prothrombin time: 20 seconds) was used as a control for Patient 3 who had a prolonged prothrombin time of 18 seconds. Antithrombin III was assayed by the method of Bick and co-workers. 3 Plasminogen was assayed by the method of Pochren and associates 13 using the Dade Protopath system (Dade Diagnostics, Inc., Miami, Florida). Kaolin-induced fibrinolytic activity was determined by the method of Ogston and colleagues" with the following modification. The lysis time was determined by monitoring the light transmission through the formed clot with a Chrono-Log model 201 aggregometer (Chrono-Log Corp., Havertown, Pa.) and a Heathkit model 1R-13M chart recorder (Heath Company, Benton Harbor, Michigan). The rate of inhibition of prekallikrein was determined in one of the three patients (Patient 1). plasma was incubated at 37 C with an equal volume of the patient (inhibitor) plasma. Aliquots were withdrawn at 30 seconds, 10 minutes, and 20 minutes, and assayed for prekallikrein. A control consisting of normal plasma and an equal volume of prekallikrein deficient plasma was similarly tested. The per cent prekallikrein inhibited was determined by dividing the difference between the prekallikrein level in the control and test by the control and multiplying by 100. A whole, native blood activated partial thromboplastin time, the "HAREM" test, was performed as described by Blakely 4 with the exception that the test was run at 37 C. Case 1 Case Histories An 18-year-old white female nursing student was admitted to the hospital in October 1978 with signs and symptoms of deep vein thrombophlebitis of the left lower extremity. Two years previously she had been involved in a motor vehicle accident and sustained a fracture and extensive contusions to that leg, but there was no recent injury. She otherwise felt well. Doppler study suggested venous obstruction at the level of the midcalf. Coagulation parameters were drawn prior to beginning anticoagulant therapy, and are summarized in Table 1. A positive antinuclear antibody (ANA) of 1:640 with a speckled pattern was found. Because of the presence of a circulating anticoagulant, conservative therapy was employed with elevations, heat, and antiinflammatory medication and her symptoms resolved. In December 1978 she developed low-grade fever, malaise, abdominal discomfort, and inflammation of her second and third metacarpalphalangeal joints. Anti-extractable nuclear antigen (Anti-ENA) was weakly reactive at a titer of 1:16. Antibodies to ribonuclear protein (RNP) and Smith (SM) antigens were negative. The skin biopsy detected IgM weakly present in the basement membrane as well as in the blood vessels. A tentative diagnosis of systemic lupus erythematosus was made. She was then begun on naproxen, 250 mg t.i.d., and hydroxychloroquine sulfate, 200 mg b.i.d., and her symptoms resolved. Case 2 A 30-year-old white woman hospitalized for pyelonephritis developed left groin discomfort and left thigh
3 Vol. 77 No. 3 PREKALLIKREIN INHIBITION 277 Patients with the Lupus Anticoagulant Tissue Factor Inhibition (Ratio Patient / Control time) <1.2 Antithrombin III (%) Plasminogen (CTA Units) HAREM Test Platelet Count X 107mm 3 Adequate (peripheral smear estimate) swelling shortly after admission. A complete obstruction at the level of the distal femoral vein was demonstrated by venogram. Admission laboratory studies revealed a hematocrit of 27.5%, leukocyte count of 2,700/mm 3, and a platelet count of 163,000/mm 3. The sedimentation rate was 120 mm/hour and reticulocyte count of 0.6%. The ANA was positive with a speckled and rimmed pattern to a titer of 1:1600. The RNP was positive with a titer of 1:16 by counter immunoelectrophoresis. C3, C4, and total hemolytic complement levels were normal. Cryoglobulin was negative and the creatine was 0.7 mg/dl. There was no laboratory evidence of hemolysis. Urine cultures grew 100,000 colonies of Escherichia coli. Seven years earlier, the patient presented with polyarthritis involving her hands, knees, wrists, and toes associated with Raynaud's phenomenon and dysphagia. At that time she had a high titered positive ANA and a positive anti-ena. A diagnosis of mixed connective tissue disease was made. Prior to starting her on anticoagulants for presumed deep vein thrombophlebitis of the left femoral vein a prothrombin time, partial thromboplastin time and HAREM test were drawn. The results are summarized in Table 1. The diagnosis of circulating anticoagulant was established and she was cautiously begun on heparin. She was treated for seven days and converted to warfarin therapy without complications. Prednisone, 7.5 mg q.d., was added and her fever and groin discomfort resolved. She remained on steroids for three months and had no further thrombotic events. She discontinued her medication and has been doing well for some time. Case 3 An 81-year-old white man was admitted into the hospital because of venous stasis ulcer of the left lower extremity. Past medical history included two myocardial infarctions, congestive heart failure, and essential hypertension. He had been receiving digoxin and furosemide daily, and procainamide, q.6.h. for ventricular arrhythmias. A recent history of rectal bleeding, epistaxis, and hematuria was elicited. At the time of admission, pancytopenia was noted with a leukocyte count of 3,900/mm 3 with a normal differential, a hematocrit of 27% with normal erythrocyte indices, and platelet count of 86,000. Antinuclear antibody was positive in a titer of 1:320 with a homogenous pattern. A direct Coomb's test was positive. VDRL was positive, but the treponemia pallidum hemagglutination inhibition test performed by the Wisconsin State Laboratory of Hygiene was negative. A bone marrow aspiration disclosed marked hyperplasia of both the myeloid and erythroid series with a normal M:E ratio. Coagulation studies are summarized in Table 1. A diagnosis of procainamide-induced systemic lupus erythematosus with circulating lupus anticoagulant was established. Procainamide was discontinued and the patient was treated with transfusions of packed erythrocytes and fresh frozen plasma with cessation of his bleeding. Five weeks later the platelet count was 62,000. His bleeding episodes ceased and he was discharged. Results Two of the three patients, Patients 1 and 2, were brought to our attention because of prolonged HAREM test results obtained prior to institution of heparin therapy for thrombophlebitis. The third patient was referred Table 2. Correction of Abnormal PTT with Various Reagents, Patient 1 Specimen plasma Patient plasma Patient plasma + normal plasma Patient plasma + aged serum Patient plasma + absorbed plasma Patient plasma + VIII deficient plasma Patient plasma + IX deficient plasma Patient plasma + XI deficient plasma Patient plasma + XII deficient plasma Patient plasma + HMWK deficient plasma Patient plasma + prekallikrein deficient plasma Partial Thromboplastin
4 278 Patient 1 Patient 2 Patient 3 VIII (%) SANFELIPPO AND DRAYNA Table 3. Factor Assays on Patients with the Lupus Anticoagulant IX (%) XI (%) XII (%) Fitzgerald Factor (%) Low Dilution 2% (1:10) 10% (1:5) 1% (1:10) % A.J.C.P. March 1982 Prekallikrein High Dilution 160% (1:40) 29% (1:10) 80% (1:80) % from another hospital for evaluation of prolonged partial thromboplastin time. All three patient plasmas had prolonged partial thromboplastin times which failed to normalize when mixed with an equal volume of normal plasma. In addition, each of these inhibited tissue factor. These laboratory findings are consistent with the presence of the lupus anticoagulant. The results of the initial coagulation studies on the three patients are shown in Table 1. Mixing experiments were done on the plasma from Case 1 to determine if there was inhibition of any procoagulants. The results of these tests are given in Table 2. Prekallikrein deficient plasma was the only deficient plasma tested which failed to affect some degree of shortening of the prolonged partial thromboplastin time of the plasma from Patient 1. This suggested that either the patient had an underlying deficiency of prekallikrein or that the inhibitor was also acting on prekallikrein. Assays of other coagulation factors exhibited none of the inhibition seen in the assay of prekallikrein (Table 3). Moderate reductions in levels of factors XII and XI were observed in the plasmas of Patients 2 and 3, respectively. However, no evidence of inhibition was seen in these assays, i.e., increasing activity with increase in plasma dilution. Unfortunately, insufficient HMWK deficient plasma was available to permit assay of this factor in Patients 2 and 3. The results of the factor assays are presented in Table 3. The rate of inhibition of prekallikrein by the plasma of Patient 1 was found to be rapid. Incubation of patient plasma with normal plasma for 30 seconds resulted in Table 4. Contact Activation of Fibrinolysis by Kaolin in Three Patients with the Lupus Anticoagulant Plasma Patient 1 Patient 2 Patient 3 Congenital XII deficient Congenital prekallikrein deficient range Lysis (minutes) >120 > a loss of 89% of the prekallikrein activity in the normal plasma. After 10 minutes of incubation, 96% of the activity had been lost. There was no additional loss of prekallikrein activity at 20 minutes. The contact activation of fibrinolysis by kaolin was impaired in all three patient plasmas. These results are summarized in Table 4. Discussion Inhibition of specific coagulation factors by the lupus anticoagulant has been well-documented. 2,7,8 However, to the best of our knowledge, there have been no previous reports of prekallikrein inhibition associated with the lupus anticoagulant. The observation of prekallikrein inhibition associated with the lupus anticoagulant suggests a mechanism in the development of thrombosis in SLE patients. Prekallikrein is now recognized to be the plasminogen proactivator required in the factor XII dependent pathway of plasminogen activation. 5 Inhibition of prekallikrein may therefore compromise the activation of the fibrinolytic system by this pathway. This hypothesis was supported by the observation of diminished contact activation of fibrinolysis in all three patients. There are other mechanisms which may play a significant role in the development of thrombosis in the SLE patient. Bowie and co-workers 6 have demonstrated an accelerated generation of procoagulant activity in a modified thromboplastin generation time test. Peck and colleagues 12 have suggested chronic disseminated intravascular coagulation, vasculitis, and prolonged immobility of the patient as significant causes of thrombosis. More recently, Angles-Cano and associates 1 demonstrated changes in proteins of endothelial cell origin; specifically elevations in von Willebrand factor activity (VIII R:WF) and decreased plasminogen activator release. These changes were postulated to be related to vascular endothelial damage secondary to immune complex deposition. Some or all of these mechanisms may contribute significantly to the development of thrombosis in the SLE patient. However, the presence of the lupus anticoagulant appears to be particularly significant in the development of thrombosis. A review of several series of
5 Vol. 77 No. 3 PREKALLIKREIN INHIBITION 279 SLE patients indicates that the incidence of thrombosis in SLE patients with the anticoagulant is almost twice that of SLE patients without the anticoagulant. In the earliest series reported by Bowie and co-workers, 6 thrombosis occurred only in those patients with the inhibitor. Mueh and associates 10 reported one or more thrombotic episode in 8 of 35 patients (23%) with SLE and the anticoagulant. Peck, 12 however, reported the occurrence of thrombosis in 14 of 1 (10%) SLE patients, but the number of patients with the anticoagulant in his series was not stated. However, the anticoagulant has been estimated to occur in approximately 6% of patients with SLE. 15 In the Angles-Cano series' 12 of 28 cases of SLE patients had the lupus anticoagulant. Thrombosis occurred in three of these 12 patients (25%). Thrombosis also occurred in two of 14 patients (14%) without the anticoagulant. Interestingly, two of their patients without thrombosis had acquired von Willebrand syndrome. The reason for the increased incidence of thrombosis in the presence of the lupus anticoagulant may be the inhibition of prekallikrein with subsequent compromise of the fibrinolytic system. In view of the increased incidence of thrombosis in SLE patients with the anticoagulant, it would be useful to screen SLE patients for the anticoagulant. This can be achieved with three simple laboratory procedures, the prothrombin time, partial thromboplastin time, and the tissue thromboplastin inhibition test. References 1. Angles-Cano E, Sultan Y, Clauvel J: Predisposing factors to thrombosis in systemic lupus erythematosus. J Lab Clin Med 94: , Bernhardt B, Valletta M: Lupus anticoagulant in myelofibrosis. Am J Med Sci 272: , Bick RL, Koracs I, Fekete LF: A new two-stage assay for antithrombin III: clinical and laboratory evaluation. Thromb Res 8: , Blakely J A: A rapid bedside method for the control of heparin therapy. Can Med Assoc J 99: , Bouma BN, Griffin JH: Deficiency of factor XH-dependent plasminogen proactivator in prekallikrein-deficient plasma. J Lab Clin Med 91: , Bowie EJW, Thompon JH, Pascuzzi CA; et al: Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med 62: , Castro O, Farber LR, Clyne LP: Circulating anticoagulants against factors IX and XI in systemic lupus erythematosus. Ann Int Med 77: , Cronbert S, Nilsson IM: Circulating anticoagulant against factors XI and XII together with massive spontaneous platelet aggregation. Scand J Haematatol 10: , Galanakis DK, Ginzler EM, Fikrig SM: Monoclonal IgG anticoagulants delaying fibrin aggregation in two patients with systemic lupus erythematosus (SLE). Blood 52: , Mueh JR, Herbst KD, Rapaport.SI: Thrombosis in patients with the lupus anticoagulant. Ann Int Med 92: , Ogston D, Bennett NB, Ogston CM, et al: The assay of a plasma component necessary for the generation of a plasminogen ac-. tivator in the presence of hagemari factor (Hageman Factor Co-Factor). Br J Haematol 20: , Peck B, Hoffman GS, Franck WA: Thrombophlebitis in systemic lupus erythematosus. JAMA 204: , Pochron SP, Mitchell GA; Albareda I, et al: Afluorescentsubstrate assay for plasminogen. Thromb Res 13: , Schleider MA, Nachman RL, Jaffe EA, et al: A clinical study of the lupus anticoagulant. Blood 48: , Shapiro SS, Hultin M: Acquired inhibitors to the blood coagulation factors. Semin Thromb Hemostas 1: , Sibley C, Evatt BL: Improving the sensitivity of the Fletcher Factor Assay. Am J Clin Pathol 71: , Weiss AS, Galiin JI, Kaplan AP: Fletcher factor deficiency. J Clin Invest 53: , 1974
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