© 1990 S. Karger AG, Basel 0250-8095/90/0103-0254S2.75/0
Am J Nephrol 1990;10:254-258
Systemic and Renal Fibrinolytic Activity in a Patient with Anticardiolipin Syndrome and Renal Thrombotic Microangiopathy Laurent Becquemont, Eric Thervet, Eric Rondeau, Roger Lacave, Béatrice Mougenot, Jean-Daniel Sraer Service de Néphrologie, Hôpital Tenon, Paris, France
Key Words. Fibrinolysis • Thrombosis • Renal failure Abstract. A 24-year-old white woman with a past history of recurrent venous thromboses of the lower extremities was admitted for hypertension and renal failure. She had a chronic cutaneous ulcer on the anterior side of the left leg and oral ulcers of the palatum. Laboratory tests demonstrated rapidly progressive renal failure and the presence of an anticardiolipin antibody (ELISA). Thrombosis of the inferior vena cava was shown by phlebocavographv. Renal biopsy revealed typical thrombotic microangiopathy. Tissue-type plasminogen activator (tPA) was visualized by immunofluorescence in endothelial cells of renal arterioles and glomeruli. Normal plasma levels of tPA, urokinase and plasminogen activator inhibitor 1 were found by ELISA, and tPA antigen levels rose after desmopressin acetate infusion. Thus, in this case, the diffuse thrombotic process was not related to defective circulating or renal fibrino lytic systems and could be promoted by the procoagulant effect of antiphospholipid antibodies.
Anticardiolipin syndrome has been recently identi fied in patients who have either lupus or more frequently lupus-like illness without substantial levels of antibodies to nuclear antigens [1-3]. These patients usually present with a constellation of features such as transient isch emic episodes, cerebrovascular accidents, recurrent spontaneous abortion, thrombocytopenia, venous and arterial thromboses and a lupus anticoagulant. They have circulating autoantibodies to anionic phospholip ids. which can be detected by various methods: serologic test for syphilis (VDRL test), phospholipid-dependent coagulation time (activated partial thromboplastin time) and an anticardiolipin antibody assay (radioimmunoas say or enzyme-linked immunosorbent assay) [4. 5]. Re cently. it has been reported that these patients may also present with renal thrombotic microangiopathy, in the absence of disseminated lupus erythematosus [6]. This suggested that renal vascular or glomerular thromboses, which occur more frequently in patients with lupus nephritis when circulating lupus anticoagulant is present
[7]. are not always a manifestation of renal vasculitis [8] but can be related to a thrombogenic effect of antiphos pholipid antibodies. The pathogenesis of vascular thrombosis which char acterizes the anticardiolipin syndrome is not well estab lished: increased platelet adhesiveness [1, 9], decreased prostacyclin synthesis [10, 11] and decreased fibrinolytic activity [12] have been suggested. On the other hand, in patients with thrombotic microangiopathy but without antiphospholipid antibodies, an increase in plasminogen activator inhibitor 1 (PAI1) with a decreased plasma fibrinolytic activity has been demonstrated [13], We report here a new case of the rare association of anticardiolipin syndrome with renal thrombotic mi croangiopathy and present a study of the fibrinolytic sys tem both in the plasma and in the kidney. Case Report The patient was a 24-year-old white female who complained of right flank pain irradiating to the right shoulder. Fever, nausea, vomiting and brown leukorrhea occurred. A diagnosis of salpingitis
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 11:34:51 PM
Introduction
Anticardiolipin Syndrome and Renal Thrombotic Microangiopathy
Before DDAVP ELT PAI1, ng/ml (20-100 ng/ml) (PA, ng/ml (5-25 ng/ml) uPA, ng/ml ( < 10 ng/ml)
>3 h 25 16 3
After DDAVP 40 min 28 50 3
ELT = Euglobulin lysis time; uPA = urokinase-type plasminogen activator. Normal ranges of antigen levels (90th percentile) deter mined by ELISA are indicated in parentheses.
associated with perihepatitis was considered, but both celioscopy and laparoscopy were normal. Serum creatinine level was 170 pmol/1. She was admitted to our department. During the year before admission, she had a cutaneous ulcer on the anterior side of her left leg. She had a past history of recurrent thromboses of the lower extremities. No drugs were given, in partic ular no oral contraceptive. No fetal loss occurred. There was no history of arthritis, malar rash, discoid rash, photosensitivity or serositis. Physical examination revealed a slight impairment of the general condition. Body weight was 55 kg, height 163 cm. tempera ture 38.8 °C, blood pressure 200/120 mm Hg, pulse rate 100 beats/ min. Tenderness and guarding was found in the upper right abdo men. Liver size was normal. There was no splenomegaly. ENT examination revealed oral ulcers of the palatum and a white coating on the tonsils. A skin biopsy of the cutaneous ulcer was performed. Cardiovascular, pulmonary and neurological examinations were normal. We found no lymphadenopathy or joint pain. On the sec ond day, a seizure occurred during a malignant hypertensive epi sode. The fundus oculi showed bilateral papillar edema. Laboratory data revealed the following: hemoglobin 12 g/dl with no schizocytes on a stained smear, hematocrit 35.8%, white blood cells 1 l,600/mmJ with 83% polymorphonuclear cells. 16% lympho cytes. Serum sodium was 140 mEq/1, serum potassium 4.5 mEq/l, total protein 7.1 g/dl and serum albumin 3.1 g/dl. Liver enzymes were normal. Serum urea nitrogen was 6 mmol/l, serum creatinine 195 pmol/1. Renal function, however, was rapidly impaired. Twen ty-four-hour urine protein was 4 g with 57% albumin and 43% glob ulin on electrophoresis. Urine analysis showed microhematuria with mild leukocyturia (Addis count 10,000 erythrocytes and 10,000 leukocytes/min, no cast). There was no urinary tract infection. There was no bacterial, viral or parasite disease. At admission, the hemo stasis test showed intravascular coagulation. The platelet count was 60,000/mm3, prothrombin time 45% and partial thromboplastin time 77 s. Clotting factors were all decreased. The test for fibrin split products in blood and urine was positive. Fibrinogen was 560 mg/ dl. All these signs quickly disappeared except thrombocytopenia and abnormal partial thromboplastin time. Antithrombin III, C protein and S protein were normal. Tissue-type plasminogen activator (tPA) antigen, PAI1 and urokinase plasma levels and euglobulin lysis time were measured before and after an intravenous administration of desmopressin acetate (DDAVP) in a dose of 0.4 pg/kg body weight, diluted in a saline solution, as described [14], The results are shown
in table 1. Euglobulin lysis time shortened (> 3 h before infusion and 40 min after). A high tPA plasma level and a normal PAI1 and urokinase plasma level before DDAVP were found. After DDAVP, there was an increase in the fibrinolytic activity caused by an increase in tPA plasma level, urokinase and PAI1 plasma levels being hardly modified. Immunologic tests revealed a significantly positive Dixon test. The presence of lupus anticoagulant was detected by a prolonged activated partial thromboplastin time and confirmed by a tissue thromboplastin inhibition test. An anticardiolipin antibody was detected by standardized ELISA (IgG only, dilution 1/100). Total hemolytic complement and C3 and C4 fractions were normal. Test for antinuclear antibodies by indirect immunofluorescence on rat liver and for antibodies to double-stranded DNA by Farr’s test were negative, as were tests for anti-Ro and anti-Sm antibodies. The patient was not HLA B5 positive. Chest X-ray was normal. Abdom inal computed tomography scan showed hypodensities in the left lobe of the liver. Phlebographia revealed thrombosis of the inferior vena cava under the renal veins. The association with an important collateral circulation suggested a chronic process. Polyvalent human immunoglobulins, 0.4 g/kg/day for 5 days were given. A dramatic increase in platelet count occurred. The first renal biopsy was performed. Strict control of blood pressure was obtained by an association of P-blockers (propranolol 20 mg/day i.v., then acebutolol 400 mg/day orally) with a converting enzyme inhibitor (captopril 100 mg/day orally). Three fresh frozen plasma units were transfused per day. Aspirin 100 mg/day and dipyrida mole (Persantine* ) 450 mg/day were given. Diuresis was main tained over 1 liter/day by furosemide (Lasilix* ) 1 g/day i.v. Because of rapid impairment of renal function, dialysis was begun on day 8, for a total of 12 sessions, 3 times a week. After 2 weeks, the patient felt well and was symptom free. Renal function then improved and stabilized after 2 months. When the patient was dismissed, serum urea nitrogen was 11 mmol/l. serum creatinine 240 pmol/1 and cre atinine clearance 19ml/min. A second renal biopsy was per formed.
Histopathological Findings Skin Biopsy
A specific aspect of chronic inflammatory tissue was found. There was no sign of chronic infection. First Renal Biopsy
Light microscopy examination of renal biopsy showed 10 glomeruli, of which 3 were sclerosed and 3 ischemic (fig. 1). The other glomeruli had widespread thickening of the capillary walls and numerous thrombi in the capillary lumens. The mesangium was slightly enlarged with fibrillar appearance and mild segmental hypercellularity. As in the glomeruli, fibrin thrombi were seen in some arterioles. Swelling of the endothelium was present in others. The interstitium was edematous with scattered lymphoplasmacytic cells. It was fibrous with atrophy in an area. By immunofluorescence, fibrin-
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Table 1. Plasma fibrinolytic components
255
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256
Fig. 1. First renal biopsy. Note fibrinous thrombi occluding cap illary lumens and thickening of the capillary walls. Hematoxylin eosin. X 312. Fig. 2. Second renal biopsy. Focal glomerulosclerosis, interstitial fibrosis and tubular atrophy. Arterioles are normal. PAS. X 125. Fig. 3. Immunofluorescence pattern with monoclonal anti-tPA antibody (EA 12 D), 5 |xg/ml. tPA is located at the endothelial sur face of arterioles and in the flocculus.
fibrinogen was detected in intracapillary and arteriolar thrombi. It was seen along the capillary walls of one glo merulus and in the mesangium in another. There was no immunoglobulin or complement deposit.
The two renal biopsies were stained by anti-tPA anti body. The expression of tPA along the endothelium sur face cells was not modified during and after the microan giopathic process (fig. 3).
Second Renal Biopsy
Comments Our patient has an anticardiolipin syndrome with renal thrombotic microangiopathy, and we present here evidence that the diffuse thrombotic process which char acterizes this syndrome is not related to an impaired fibrinolytic activity of both peripheral blood and kidney tissue. Chronic leg ulcer, oral palatine ulcers, cerebral vascular ischemic accident and thrombosis of the vena cava presented by our patient have been reported to occur in this syndrome [1, 15, 16], Usually, as in this
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 11:34:51 PM
Light microscopy sections disclosed up to 40 glomer uli (fig. 2); 25% of them were obsolescent. Half of the remaining glomeruli were ischemic. Hypertrophy of the mesangial matrix and mild mesangial cellular prolifera tion were observed in the others. Scattered areas of inter stitial fibrosis and tubular atrophy were present. Interlo bular arteries and arterioles were normal except for some arterioles the lumen of which was occluded by fibrohyalin material. An immunofluorescence study with an tifibrinogen antiserum was negative. No deposit of im munoglobulin or complement was observed.
Anticardiolipin Syndrome and Renal Thrombotic Microangiopathy
257
case, patients have no evidence of overt disseminated lupus erythematosus and no circulating antinuclear anti body [1,2]. Renal thromboses in anticardiolipin syndrome are usually associated with lupus nephritis [7, 17], Kant et al. [7] have shown that in patients suffering from lupus erythematosus and who have proliferative glomerulone phritis, arteriolar and glomerular thromboses occur more frequently when lupus anticoagulant is present. However recently Kincaid-Smith et al. [6] reported on 12 women with a circulating lupus anticoagulant and biopsy-proven renal thrombotic microangiopathy. As in our patient, no histological evidence of lupus glomerulo nephritis or vasculitis was found. This suggests that arte riolar and glomerular thromboses, previously related to lupus vasculitis [8], could in fact represent a conse quence of antiphospholipid antibodies. These antibodies act against phospholipids on plate let and vascular endothelium membranes and frequently induce autoimmune thrombopenia [18], as in our pa tient, or hemolytic anemia [1], They also interfere with phospholipid-dependent coagulation time, such as par tial activated thromboplastin time. However, hemor rhage is rarely observed, and paradoxically these anti bodies promote thrombosis in vivo [ 1]. The pathogenesis of thrombosis in this syndrome is not clearly established. A decrease in prostacyclin generation by endothelial cells has been reported in patients with lupus anticoagulant [10, 11]. These antibodies have been shown to induce platelet aggregation or release of procoagulant activity [ 19]. A defect of protein C activation has been reported [20], and a decreased plasma fibrinolytic activity has been suggested [12]. Sultan et al. [14] showed that, in lupus patients, fibrinolytic activity was decreased [21] and less responsive to DDAVP. Interestingly, in throm botic thrombocytopenic purpura, it has been reported that plasma fibrinolytic activity is decreased and that the circulating PAI1 level is increased [13]. We have pre viously observed renal PAI1 deposits in the severe forms of thrombotic microangiopathy [22], All these data sug gested that, in some cases, thromboses could be related to a decrease in fibrinolytic activity in the kidney and/or in the whole circulation. Conversely in our patient, studies of the fibrinolytic components in the kidney by immunofluorescence do not support a role for a defect of tPA or an increase in PAI 1, since tPA was found in endothelium as previously reported in normal kidneys [23] and PAI1 deposits were not demonstrated. Circulating fibrinolytic components appeared also normal, and response to DDAVP occurred
as reported by others. Finally fibrin deposits were no longer observed on the second renal biopsy, demonstrat ing that local fibrinolysis occurred. In conclusion, our observation further demonstrates that renal vascular and glomerular thromboses can be observed in patients with lupus anticoagulant but with out lupus nephritis. Intrarenal and circulating compo nents of the fibrinolytic system were not altered, suggest ing that a procoagulant activity, possibly induced or enhanced by antiphospholipid antibodies, could be the main factor leading to vascular thrombosis.
Acknowledgments We thank Miss Mina Mallet for the typing of the manuscript. This work was supported by grants from the Association ClaudeBernard and the Faculté de Médecine Saint-Antoine, Paris.
1 Harris EN, Gharavi AE. Hughes GRV: Antiphospholipid anti bodies. Clin Rheum Dis 1985:11:591-609. 2 Asherson RA, Harris EN: Anticardiolipin antibodies - Clinical associations. Postgrad Med J 1986;62:1081-1087. 3 Hughes GRV. Harris NN, Gharavi AE: The anticardiolipin syn drome. J Rheumatol 1986:13:486-489. 4 Colaço CB, Male DK: Antiphospholipid antibodies in syphilis and a thrombotic subset of SLE: Distinct profiles of epitopes specificity. Clin Exp Immunol 1985:59:449-456. 5 Meyer O, Piette JC, Bourgeois P. et al: Antiphospholipid anti bodies: A disease marker in 25 patients with antinuclear anti body negative systemic lupus erythematosus (SLE). Comparison with a group of 91 patients with antinuclear antibody positive SLE. J Rheumatol 1987:14:502-506. 6 Kincaid-Smith P, Fairley KF. Kloss M: Lupus anticoagulant associated with renal thrombotic microangiopathy and pregnan cy-related renal failure. Q J Med 1988:69:795-815. 7 Kant KS, Poliak VE. Weiss MA. et al: Glomerular thrombosis in systemic lupus erythematosus: Prevalence and significance. Medicine 1981:60:71-86. 8 Bhathena DB. Sobel BJ, Migdal SD: Non inflammatory renal microangiopathy of systemic lupus erythematosus (‘lupus vascu litis’). Am J Nephrol 1981; 1:144-159. 9 Elias M, Eldor A: Thromboembolism in patients with the lupustype circulating anticoagulant. Arch Intern Med 1984; 144:510— 515. 10 Carreras LO. Defreyn G. Machin SJ. et al: Arterial thrombosis, intrauterine death and ‘lupus’ anticoagulant: Detection of im munoglobulin interferin with prostacyclin formation. Lancet 1981 ;i:244—246. 11 Boev ML, Colaço CB. Gharavi AE. et al: Thrombosis in systemic lupus erythematosus: Striking association with the presence of circulating lupus anticoagulant. Br Med J 1983:287:1021— 1023.
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References
12 Byron MA, Allington MJ, Chapel HM, et al: Indications of vas cular endothelial cell dysfunction in systemic lupus erythemato sus. Ann Rheum Dis 1987:46:741-745. 13 Glas-Greenwalt P. Hall JM, Panke TW, et al: Fibrinolysis in health and disease: Abnormal levels of plasminogen activator, plasminogen activator inhibitor and protein C in thrombotic thrombocytopenic purpura. J Lab Clin Med 1986; 108:415— 422. 14 Sultan Y, Harris A. Strauch G, et al: A dynamic test to investi gate potential tissue plasminogen activator activity. Comparison of deamino-8-D-arginine vasopressin in venous occlusion in nor mal subjects and patients. J Lab Clin Med 1988:111:645-653. 15 Levine SR, Welch KMA: Cerebrovascular ischemia associated with lupus anticoagulant. Stroke 1987; 18:257—263. 16 Asherson RA, Derksen HWM, Harris EN, et al: Large vessel occlusion and gangrene in systemic lupus erythematosus and ‘lupus-like’ disease. A report of six cases. J Rheumatol 1986; 13: 740-747. 17 Glueck HI, Kant KS, Weiss MA. et al: Thrombosis in systemic lupus erythematosus. Relation to the presence of circulating anticoagulants. Arch Intern Med 1985;145:1389-1395. 18 Harris EN, Chan JKH. Asherson RA, et al: Thrombosis, recur rent fetal loss and thrombocytopenia: Predictive value of anticardiolipin antibody test. Arch Intern Med 1986; 146:2153— 2156. 19 Clark WF, Tevaarwerk GJM, Reid BD: Human platelet-immune complex interaction in plasma. J Lab Clin Med 1982; 100:917— 931.
Becquemont/Thervet/Rondeau/Lacave/Mougenot/Sraer
20 Freyssinet JM, Wiesel ML, Gauchy J, et al: An IgM lupus anti coagulant that neutralized the enhancing effect of phospholipid on purified endothelial thrombomodulin activity - A mecha nism for thrombosis. Thromb Haemost 1986:55:309-313. 21 Angles Cano E. Sultan Y, Clauvel JP: Predisposing factors to thrombosis in systemic lupus erythematosus: Possible relation to endothelial cell damage. J Lab Clin Med 1979;94:312-323. 22 Mougcnot B, Rondeau E, Kruithof EKO. et al: Presence of type I plasminogen activator inhibitor (PAI1) in renal fibrin deposits in human pathological conditions (abstract). Kidney Int 1988; 33:330. 23 Angles Cano E, Rondeau E, Delarue F, et al: Identification and cellular localization of plasminogen activators from human glo meruli. Thromb Haemost 1985;54:688-692.
Received; July 25, 1989 Accepted: January 10, 1990 E. Rondeau, MD Service de Néphrologie
Hôpital Tenon 4, rue de la Chine F-75020 Paris (France)
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258
Am J Nephrol 1990;10:254-258
Systemic and Renal Fibrinolytic Activity in a Patient with Anticardiolipin Syndrome and Renal Thrombotic Microangiopathy Laurent Becquemont, Eric Thervet, Eric Rondeau, Roger Lacave, Béatrice Mougenot, Jean-Daniel Sraer Service de Néphrologie, Hôpital Tenon, Paris, France
Key Words. Fibrinolysis • Thrombosis • Renal failure Abstract. A 24-year-old white woman with a past history of recurrent venous thromboses of the lower extremities was admitted for hypertension and renal failure. She had a chronic cutaneous ulcer on the anterior side of the left leg and oral ulcers of the palatum. Laboratory tests demonstrated rapidly progressive renal failure and the presence of an anticardiolipin antibody (ELISA). Thrombosis of the inferior vena cava was shown by phlebocavographv. Renal biopsy revealed typical thrombotic microangiopathy. Tissue-type plasminogen activator (tPA) was visualized by immunofluorescence in endothelial cells of renal arterioles and glomeruli. Normal plasma levels of tPA, urokinase and plasminogen activator inhibitor 1 were found by ELISA, and tPA antigen levels rose after desmopressin acetate infusion. Thus, in this case, the diffuse thrombotic process was not related to defective circulating or renal fibrino lytic systems and could be promoted by the procoagulant effect of antiphospholipid antibodies.
Anticardiolipin syndrome has been recently identi fied in patients who have either lupus or more frequently lupus-like illness without substantial levels of antibodies to nuclear antigens [1-3]. These patients usually present with a constellation of features such as transient isch emic episodes, cerebrovascular accidents, recurrent spontaneous abortion, thrombocytopenia, venous and arterial thromboses and a lupus anticoagulant. They have circulating autoantibodies to anionic phospholip ids. which can be detected by various methods: serologic test for syphilis (VDRL test), phospholipid-dependent coagulation time (activated partial thromboplastin time) and an anticardiolipin antibody assay (radioimmunoas say or enzyme-linked immunosorbent assay) [4. 5]. Re cently. it has been reported that these patients may also present with renal thrombotic microangiopathy, in the absence of disseminated lupus erythematosus [6]. This suggested that renal vascular or glomerular thromboses, which occur more frequently in patients with lupus nephritis when circulating lupus anticoagulant is present
[7]. are not always a manifestation of renal vasculitis [8] but can be related to a thrombogenic effect of antiphos pholipid antibodies. The pathogenesis of vascular thrombosis which char acterizes the anticardiolipin syndrome is not well estab lished: increased platelet adhesiveness [1, 9], decreased prostacyclin synthesis [10, 11] and decreased fibrinolytic activity [12] have been suggested. On the other hand, in patients with thrombotic microangiopathy but without antiphospholipid antibodies, an increase in plasminogen activator inhibitor 1 (PAI1) with a decreased plasma fibrinolytic activity has been demonstrated [13], We report here a new case of the rare association of anticardiolipin syndrome with renal thrombotic mi croangiopathy and present a study of the fibrinolytic sys tem both in the plasma and in the kidney. Case Report The patient was a 24-year-old white female who complained of right flank pain irradiating to the right shoulder. Fever, nausea, vomiting and brown leukorrhea occurred. A diagnosis of salpingitis
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 11:34:51 PM
Introduction
Anticardiolipin Syndrome and Renal Thrombotic Microangiopathy
Before DDAVP ELT PAI1, ng/ml (20-100 ng/ml) (PA, ng/ml (5-25 ng/ml) uPA, ng/ml ( < 10 ng/ml)
>3 h 25 16 3
After DDAVP 40 min 28 50 3
ELT = Euglobulin lysis time; uPA = urokinase-type plasminogen activator. Normal ranges of antigen levels (90th percentile) deter mined by ELISA are indicated in parentheses.
associated with perihepatitis was considered, but both celioscopy and laparoscopy were normal. Serum creatinine level was 170 pmol/1. She was admitted to our department. During the year before admission, she had a cutaneous ulcer on the anterior side of her left leg. She had a past history of recurrent thromboses of the lower extremities. No drugs were given, in partic ular no oral contraceptive. No fetal loss occurred. There was no history of arthritis, malar rash, discoid rash, photosensitivity or serositis. Physical examination revealed a slight impairment of the general condition. Body weight was 55 kg, height 163 cm. tempera ture 38.8 °C, blood pressure 200/120 mm Hg, pulse rate 100 beats/ min. Tenderness and guarding was found in the upper right abdo men. Liver size was normal. There was no splenomegaly. ENT examination revealed oral ulcers of the palatum and a white coating on the tonsils. A skin biopsy of the cutaneous ulcer was performed. Cardiovascular, pulmonary and neurological examinations were normal. We found no lymphadenopathy or joint pain. On the sec ond day, a seizure occurred during a malignant hypertensive epi sode. The fundus oculi showed bilateral papillar edema. Laboratory data revealed the following: hemoglobin 12 g/dl with no schizocytes on a stained smear, hematocrit 35.8%, white blood cells 1 l,600/mmJ with 83% polymorphonuclear cells. 16% lympho cytes. Serum sodium was 140 mEq/1, serum potassium 4.5 mEq/l, total protein 7.1 g/dl and serum albumin 3.1 g/dl. Liver enzymes were normal. Serum urea nitrogen was 6 mmol/l, serum creatinine 195 pmol/1. Renal function, however, was rapidly impaired. Twen ty-four-hour urine protein was 4 g with 57% albumin and 43% glob ulin on electrophoresis. Urine analysis showed microhematuria with mild leukocyturia (Addis count 10,000 erythrocytes and 10,000 leukocytes/min, no cast). There was no urinary tract infection. There was no bacterial, viral or parasite disease. At admission, the hemo stasis test showed intravascular coagulation. The platelet count was 60,000/mm3, prothrombin time 45% and partial thromboplastin time 77 s. Clotting factors were all decreased. The test for fibrin split products in blood and urine was positive. Fibrinogen was 560 mg/ dl. All these signs quickly disappeared except thrombocytopenia and abnormal partial thromboplastin time. Antithrombin III, C protein and S protein were normal. Tissue-type plasminogen activator (tPA) antigen, PAI1 and urokinase plasma levels and euglobulin lysis time were measured before and after an intravenous administration of desmopressin acetate (DDAVP) in a dose of 0.4 pg/kg body weight, diluted in a saline solution, as described [14], The results are shown
in table 1. Euglobulin lysis time shortened (> 3 h before infusion and 40 min after). A high tPA plasma level and a normal PAI1 and urokinase plasma level before DDAVP were found. After DDAVP, there was an increase in the fibrinolytic activity caused by an increase in tPA plasma level, urokinase and PAI1 plasma levels being hardly modified. Immunologic tests revealed a significantly positive Dixon test. The presence of lupus anticoagulant was detected by a prolonged activated partial thromboplastin time and confirmed by a tissue thromboplastin inhibition test. An anticardiolipin antibody was detected by standardized ELISA (IgG only, dilution 1/100). Total hemolytic complement and C3 and C4 fractions were normal. Test for antinuclear antibodies by indirect immunofluorescence on rat liver and for antibodies to double-stranded DNA by Farr’s test were negative, as were tests for anti-Ro and anti-Sm antibodies. The patient was not HLA B5 positive. Chest X-ray was normal. Abdom inal computed tomography scan showed hypodensities in the left lobe of the liver. Phlebographia revealed thrombosis of the inferior vena cava under the renal veins. The association with an important collateral circulation suggested a chronic process. Polyvalent human immunoglobulins, 0.4 g/kg/day for 5 days were given. A dramatic increase in platelet count occurred. The first renal biopsy was performed. Strict control of blood pressure was obtained by an association of P-blockers (propranolol 20 mg/day i.v., then acebutolol 400 mg/day orally) with a converting enzyme inhibitor (captopril 100 mg/day orally). Three fresh frozen plasma units were transfused per day. Aspirin 100 mg/day and dipyrida mole (Persantine* ) 450 mg/day were given. Diuresis was main tained over 1 liter/day by furosemide (Lasilix* ) 1 g/day i.v. Because of rapid impairment of renal function, dialysis was begun on day 8, for a total of 12 sessions, 3 times a week. After 2 weeks, the patient felt well and was symptom free. Renal function then improved and stabilized after 2 months. When the patient was dismissed, serum urea nitrogen was 11 mmol/l. serum creatinine 240 pmol/1 and cre atinine clearance 19ml/min. A second renal biopsy was per formed.
Histopathological Findings Skin Biopsy
A specific aspect of chronic inflammatory tissue was found. There was no sign of chronic infection. First Renal Biopsy
Light microscopy examination of renal biopsy showed 10 glomeruli, of which 3 were sclerosed and 3 ischemic (fig. 1). The other glomeruli had widespread thickening of the capillary walls and numerous thrombi in the capillary lumens. The mesangium was slightly enlarged with fibrillar appearance and mild segmental hypercellularity. As in the glomeruli, fibrin thrombi were seen in some arterioles. Swelling of the endothelium was present in others. The interstitium was edematous with scattered lymphoplasmacytic cells. It was fibrous with atrophy in an area. By immunofluorescence, fibrin-
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Table 1. Plasma fibrinolytic components
255
Becquemont/Thervet/Rondeau/Lacave/Mougenot/Sraer
256
Fig. 1. First renal biopsy. Note fibrinous thrombi occluding cap illary lumens and thickening of the capillary walls. Hematoxylin eosin. X 312. Fig. 2. Second renal biopsy. Focal glomerulosclerosis, interstitial fibrosis and tubular atrophy. Arterioles are normal. PAS. X 125. Fig. 3. Immunofluorescence pattern with monoclonal anti-tPA antibody (EA 12 D), 5 |xg/ml. tPA is located at the endothelial sur face of arterioles and in the flocculus.
fibrinogen was detected in intracapillary and arteriolar thrombi. It was seen along the capillary walls of one glo merulus and in the mesangium in another. There was no immunoglobulin or complement deposit.
The two renal biopsies were stained by anti-tPA anti body. The expression of tPA along the endothelium sur face cells was not modified during and after the microan giopathic process (fig. 3).
Second Renal Biopsy
Comments Our patient has an anticardiolipin syndrome with renal thrombotic microangiopathy, and we present here evidence that the diffuse thrombotic process which char acterizes this syndrome is not related to an impaired fibrinolytic activity of both peripheral blood and kidney tissue. Chronic leg ulcer, oral palatine ulcers, cerebral vascular ischemic accident and thrombosis of the vena cava presented by our patient have been reported to occur in this syndrome [1, 15, 16], Usually, as in this
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 11:34:51 PM
Light microscopy sections disclosed up to 40 glomer uli (fig. 2); 25% of them were obsolescent. Half of the remaining glomeruli were ischemic. Hypertrophy of the mesangial matrix and mild mesangial cellular prolifera tion were observed in the others. Scattered areas of inter stitial fibrosis and tubular atrophy were present. Interlo bular arteries and arterioles were normal except for some arterioles the lumen of which was occluded by fibrohyalin material. An immunofluorescence study with an tifibrinogen antiserum was negative. No deposit of im munoglobulin or complement was observed.
Anticardiolipin Syndrome and Renal Thrombotic Microangiopathy
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case, patients have no evidence of overt disseminated lupus erythematosus and no circulating antinuclear anti body [1,2]. Renal thromboses in anticardiolipin syndrome are usually associated with lupus nephritis [7, 17], Kant et al. [7] have shown that in patients suffering from lupus erythematosus and who have proliferative glomerulone phritis, arteriolar and glomerular thromboses occur more frequently when lupus anticoagulant is present. However recently Kincaid-Smith et al. [6] reported on 12 women with a circulating lupus anticoagulant and biopsy-proven renal thrombotic microangiopathy. As in our patient, no histological evidence of lupus glomerulo nephritis or vasculitis was found. This suggests that arte riolar and glomerular thromboses, previously related to lupus vasculitis [8], could in fact represent a conse quence of antiphospholipid antibodies. These antibodies act against phospholipids on plate let and vascular endothelium membranes and frequently induce autoimmune thrombopenia [18], as in our pa tient, or hemolytic anemia [1], They also interfere with phospholipid-dependent coagulation time, such as par tial activated thromboplastin time. However, hemor rhage is rarely observed, and paradoxically these anti bodies promote thrombosis in vivo [ 1]. The pathogenesis of thrombosis in this syndrome is not clearly established. A decrease in prostacyclin generation by endothelial cells has been reported in patients with lupus anticoagulant [10, 11]. These antibodies have been shown to induce platelet aggregation or release of procoagulant activity [ 19]. A defect of protein C activation has been reported [20], and a decreased plasma fibrinolytic activity has been suggested [12]. Sultan et al. [14] showed that, in lupus patients, fibrinolytic activity was decreased [21] and less responsive to DDAVP. Interestingly, in throm botic thrombocytopenic purpura, it has been reported that plasma fibrinolytic activity is decreased and that the circulating PAI1 level is increased [13]. We have pre viously observed renal PAI1 deposits in the severe forms of thrombotic microangiopathy [22], All these data sug gested that, in some cases, thromboses could be related to a decrease in fibrinolytic activity in the kidney and/or in the whole circulation. Conversely in our patient, studies of the fibrinolytic components in the kidney by immunofluorescence do not support a role for a defect of tPA or an increase in PAI 1, since tPA was found in endothelium as previously reported in normal kidneys [23] and PAI1 deposits were not demonstrated. Circulating fibrinolytic components appeared also normal, and response to DDAVP occurred
as reported by others. Finally fibrin deposits were no longer observed on the second renal biopsy, demonstrat ing that local fibrinolysis occurred. In conclusion, our observation further demonstrates that renal vascular and glomerular thromboses can be observed in patients with lupus anticoagulant but with out lupus nephritis. Intrarenal and circulating compo nents of the fibrinolytic system were not altered, suggest ing that a procoagulant activity, possibly induced or enhanced by antiphospholipid antibodies, could be the main factor leading to vascular thrombosis.
Acknowledgments We thank Miss Mina Mallet for the typing of the manuscript. This work was supported by grants from the Association ClaudeBernard and the Faculté de Médecine Saint-Antoine, Paris.
1 Harris EN, Gharavi AE. Hughes GRV: Antiphospholipid anti bodies. Clin Rheum Dis 1985:11:591-609. 2 Asherson RA, Harris EN: Anticardiolipin antibodies - Clinical associations. Postgrad Med J 1986;62:1081-1087. 3 Hughes GRV. Harris NN, Gharavi AE: The anticardiolipin syn drome. J Rheumatol 1986:13:486-489. 4 Colaço CB, Male DK: Antiphospholipid antibodies in syphilis and a thrombotic subset of SLE: Distinct profiles of epitopes specificity. Clin Exp Immunol 1985:59:449-456. 5 Meyer O, Piette JC, Bourgeois P. et al: Antiphospholipid anti bodies: A disease marker in 25 patients with antinuclear anti body negative systemic lupus erythematosus (SLE). Comparison with a group of 91 patients with antinuclear antibody positive SLE. J Rheumatol 1987:14:502-506. 6 Kincaid-Smith P, Fairley KF. Kloss M: Lupus anticoagulant associated with renal thrombotic microangiopathy and pregnan cy-related renal failure. Q J Med 1988:69:795-815. 7 Kant KS, Poliak VE. Weiss MA. et al: Glomerular thrombosis in systemic lupus erythematosus: Prevalence and significance. Medicine 1981:60:71-86. 8 Bhathena DB. Sobel BJ, Migdal SD: Non inflammatory renal microangiopathy of systemic lupus erythematosus (‘lupus vascu litis’). Am J Nephrol 1981; 1:144-159. 9 Elias M, Eldor A: Thromboembolism in patients with the lupustype circulating anticoagulant. Arch Intern Med 1984; 144:510— 515. 10 Carreras LO. Defreyn G. Machin SJ. et al: Arterial thrombosis, intrauterine death and ‘lupus’ anticoagulant: Detection of im munoglobulin interferin with prostacyclin formation. Lancet 1981 ;i:244—246. 11 Boev ML, Colaço CB. Gharavi AE. et al: Thrombosis in systemic lupus erythematosus: Striking association with the presence of circulating lupus anticoagulant. Br Med J 1983:287:1021— 1023.
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Becquemont/Thervet/Rondeau/Lacave/Mougenot/Sraer
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Received; July 25, 1989 Accepted: January 10, 1990 E. Rondeau, MD Service de Néphrologie
Hôpital Tenon 4, rue de la Chine F-75020 Paris (France)
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