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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 2  |  Page : 227-231
Bleeding and Thrombosis in a Patient with Secondary Antiphospholipid Syndrome


1 Departments of Nephrology, Internal Medicine, Charles Nicolle Hospital, Tunis, Tunisia
2 Department of Hematology, Charles Nicolle Hospital, Tunis, Tunisia

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   Abstract 

Antiphospholipid antibodies have been associated with occurrence of arterial and venous thrombotic events and fetal loss, which together constitute the antiphospholipid syndrome (APS). However, bleeding is rare in this syndrome. We report a case of systemic lupus erythematosus (SLE) with APS complicated simultaneously by thrombotic and hemorrhagic events. A 34-year-old woman was a known case of diffuse proliferative lupus nephritis associated with APS, on treatment with corticosteroids, cyclophosphamide and anticoagulants. She presented in February 2004 with severe anemia, menorrhagia, gingival bleeding and acute loss of vision in the left eye. Investigations revealed a hematoma in the psoas muscle with thrombosis of the inferior vena cava and occlusion of the retinal vein. Blood tests revealed a strongly positive lupus anticoagulant, factor XI deficiency (35%) and decrease of free protein S (44%). Factor XI inhibitor, anti-prothrombin, and anti-protein S antibodies were absent. The patient was treated with corticosteroids and six pulses of cyclophosphamide, which resulted in a rapid disappearance of bleeding, reduction of hematoma and normalization of hematological abnormalities. She was maintained on corticosteroids, azathioprine and anticoagulant agents were introduced. After a follow-up of 28 months, there was no recurrence of bleeding, the thrombosis had resolved, and there was a decrease in the levels of circulating anticoagulant as well as anticardiolipin antibodies.

Keywords: Antiphospholipid syndrome, Lupus, Bleeding, Thrombosis

How to cite this article:
Kaaroud H, Beji S, Guermazi S, Moussa FB, Hamida FB, Ezzine S, Abdallah TB, El Younsi F, Kheder A. Bleeding and Thrombosis in a Patient with Secondary Antiphospholipid Syndrome. Saudi J Kidney Dis Transpl 2008;19:227-31

How to cite this URL:
Kaaroud H, Beji S, Guermazi S, Moussa FB, Hamida FB, Ezzine S, Abdallah TB, El Younsi F, Kheder A. Bleeding and Thrombosis in a Patient with Secondary Antiphospholipid Syndrome. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2019 Nov 12];19:227-31. Available from: http://www.sjkdt.org/text.asp?2008/19/2/227/39035

   Introduction Top


Antiphospholipid (APL) antibodies, namely lupus anticoagulant and anti-cardiolipin, represent a group of autoantibodies directed against phospholipids and phospholipid≠binding proteins. They have been associated with the occurrence of arterial and venous thrombotic events and fetal loss, which toge≠ther constitute the antiphospholipid syndrome (APS). Paradoxically, in this syndrome, bleeding is rare. APS was originally recog≠nized in patients with systemic lupus erythematosus (SLE) and has been described subsequently in patients with other rheuma≠tologic diseases or, without any underlying disease.

We herewith report a case of SLE with APS complicated simultaneously by throm≠botic and hemorrhagic events.


   Case Report Top


A 34-year-old woman was referred in February 2004 to our unit for management of severe anemia, menorrhagia, gingival bleeding and acute loss of vision in the left eye. She was a known case of SLE on regular follow-up in our center from 1992. The patient satisfied six of the ARA criteria laid down for the diagnosis of SLE. They included: arthritis, photosensitivity, class IV glomerulonephritis, thrombocytopenia, positive ANA and positive anti-DNA anti≠bodies. [1] She also tested positive for IgG anti-cardiolipin antibodies.

The patient was initially treated in 1992 with intravenous methylprednisolone 15 mg/kg/day for three days followed by oral corticosteroids 1 mg/kg/day with progressive tapering, which resulted in complete remi≠ssion of the nephropathy.

In 1997, a relapse of lupus nephritis occurred with the nephrotic syndrome and renal failure (serum creatinine: 120 Ķmol/L). A second renal biopsy showed active diffuse proliferative glomerulonephritis and the patient was treated with oral corticosteroids in a dose of 1 mg/kg/day with progressive tapering in addition to six monthly pulses of cyclophosphamide (CyP). An incomplete remission of the nephrotic syndrome was achieved while renal function returned to normal. However, the ANA and anti≠cardiolipin antibodies persisted. She was maintained on corticosteroids at a dose of 5 mg/day along with antiplatelet agents.

In 2001, the patient presented with phlebitis, which was treated and maintained on anticoagulant drugs. In 2004, she developed gingival and genital bleeding followed by acute monocular blindness, all of which persisted even one week after stopping the anticoagulants. Clinical examination at this time revealed the following: pallor, asymmetric edema of the lower limbs, BP of 150/70 mm Hg, pulse rate of 120/min, +++ proteinuria and ++ hematuria on urina≠lysis, an abdominal mass located in the right flank and a normal gynecologic examination. X-ray of the chest was normal and abdo≠minal ultrasound revealed a compressive hematoma of the psoas muscle with throm≠bosis of the inferior cava vein. Ophthalmo≠logic examination revealed occlusion of the retinal vein and gastric endoscopy was normal.

Laboratory tests showed a 24-hours proteinuria of 2.3 gm, serum protein of 38 g/L, serum albumin of 24.6 g/L, serum creatinine of 129 Ķmol/L, hemoglobin (Hb) of 4.6 g/dl, total leukocyte count of 10700/ mm 3 , platelet count of 100,000/mm 3 and erythrocyte sedimentation rate of 180 mm/ hour. The liver enzymes were normal.

The coagulation profile revealed pro≠thrombin time (PT) of 50%, cephalin kaolin time (CKT) of 65 secs (normal: 30-35 secs), activated thromboplastin time of 180 secs (normal: 35-45 secs), thrombin time of 23 secs (normal: 20-25 secs), a strongly positive lupus anticoagulant and factor XI level of 35% (normal: 65-130%) without factor XI inhibitor using coagulometric method. All other activating coagulation factors (II, V,VII, IX, X, XII, XIII) and physiological coagulation inhibitors (antithrombin III, protein S and C) were within normal limits.

Immunologic tests revealed presence of ANA: 1/100, anti-DNA antibodies, IgG anti-cardiolipin antibodies, C3: 48.4 mg/dl (91-157), C4: 54.2 mg/dl (14-44) and CH50: <10 IU/ml (25-60). The patient tested negative for anti-beta 2 glycoprotein I and anti-prothrombin, both tests performed by the ELISA method.

The patient was treated with intravenous methylprednisolone 1 g/day for three days followed by oral corticosteroids at a dose of 1 mg/kg/day with progressive tapering. In addition, four sessions of plasma exchange and six monthly pulses of CyP were given. A rapid improvement was noticed within two weeks with disappearance of bleeding, reduction of the hematoma and normalization of the hematological abnormalities with Hb of 13 g/dl, platelet count of 239,000/m 3 , PT of 94 %, CKT of 30 secs, PTT of 45 secs, factor XI of 92 % and protein S of 121 %.

The patient was maintained on cortico≠steroids 10 mg/day in association with azathioprine 2 mg/kg/day and anticoagulant agents were introduced. After a follow-up of 28 months, there was no recurrence of bleeding, there was disappearance of throm≠bosis of the inferior vena cava, persistence of monocular blindness, proteinuria was 1 g/24 hours, serum protein levels were 62 g/L with albumin levels of 31 g/L, serum creatinine was 73 Ķmol/L, the ANA tested negative and there was a reduction in levels of circulating anticoagulant and anti≠cardiolipin antibodies.


   Discussion Top


The APS is present in about 30% of patients with SLE. [2] This syndrome is associated with both arterial and venous thrombosis, fetal loss and moderate throm≠bocytopenia. [3] The prevalence of thrombosis in APS is not well established. In retros≠pective series, the rate of thrombotic recurrences was 19-29 events per 100 patients per year. Factors that may increase the risk of recurrent thrombosis are INR < 2.6, high blood pressure, smoking, lipid disorders and presence of signs of activity of SLE with high rate of APL antibodies. [4]

Our patient had APS secondary to SLE with recurrent venous thrombotic compli≠cations (phlebitis, vena caval and retinal thrombosis). Many mechanisms have been proposed to explain the prothrombotic tendency in APS. It is mainly due to inter≠action of APL antibodies with prohrombin, annexine V, plasmin and activation of adhe≠sion molecules on endothelial cells. [5] Bleeding is a rare complication of APS. It has been reported especially after surgery, anti≠coagulant treatment with INR > 4,5 and in children after viral infection. [6],[7]

Although APL antibodies often inhibit coagulation in vitro and prolong the PTT, there are few case reports of bleeding asso≠ciated with the presence of these antibodies alone without any other hemostatic abnor≠malities. In fact, we generally find an acquired hypoprothrombinemia defined as lupus-anticoagulant-hypoprothrombinemia syndrome, in these patients. [8] This deficiency in prothrombin factor is thought to be related to the presence of an autoantibody directed against prothrombin. [9] Some authors have demonstrated that this acquired hypo≠prothrombinemia stems from the rapid clearance of prothrombin antigen-antibody complexes from the circulation. Such patients have not only prolonged PTT but of PT due to severe prothrombin deficiency. [10] In our patient, the factor II levels were normal and anti-prothrombin antibody was absent.

The bleeding seen in our case could be explained by factor XI deficiency, low PT and PTT. In fact, hemorrhage has been rarely reported in heterozygous factor XI defi≠ciency, often after surgery and trauma, independently of its levels. [11] We suggest the presence of an auto antibody directed against factor XI despite absence of factor XI inhibitor since normalization of this factor was obtained after corticosteroid and immunosuppressive treatment. The absence of factor XI inhibitor can be due to possible difficulties to identify some inhibitors of coagulation factors in vitro. The prothrombin time and the dilute thromboplastin time were prolonged in our patient because of presence of high titer of lupus anticoagulant antibody.

The different bleeding complications reported are subdural hematoma, ovarian hemorrhage, pericapsular renal bleeding, menorrhagia, intestinal hemorrhage, spinal hematoma, epistaxis and hemarthrosis. [12] These hemorrhagic complications are usually isolated without thrombosis. Our patient developed simultaneously both thrombotic and hemorrhagic complications.

Since we believe that the disease is anti≠body mediated, immunosuppressive therapy should be effective in controlling this situa≠tion. In fact, in our patient treatment with corticosteroids, CyP and plasma exchange was effective with resolution of bleeding and correction of hematological abnormalities.

Plasma exchange is used to treat either thrombotic or hemorrhagic events by removing antibodies. [9] Anticoagulants were introduced in our patient after resolution of bleeding to treat thrombotic events with disappearance of vena caval thrombosis although retinal thrombosis persisted.


   Conclusion Top


The presence of APS suggests not only an increased risk for thrombosis but also clinical hemorrhage. The occurrence of these two complications simultaneously is a thera≠peutic problem. Management of hemorrhage with corticosteroids, immunosuppressive agents and plasma exchange is essential before initiating anticoagulation.

 
   References Top

1.Paradi A, Rebora A. ARA and EADV criteria for classification of systemic lupus erythe≠matosus in patients with cutaneous lupus erythematosus. Dermatology 1997;194(3): 217-20.  Back to cited text no. 1    
2.Stewart CJ. Lupus nephritis. J Am Soc Nephrol 1999;10:413-24.  Back to cited text no. 2    
3.Hughes GR. The anticardiolipin syndrome. Clin Exp Rheumatol 1985;3(4):285-6.  Back to cited text no. 3    
4.Krnic-Barrue S, O'Connor CR, Looney SW, Pieragengeli SS, Harris EN. A retrospective review of 61 pateints with antiphospholipid syndrome: Analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997;157(18):2101-8.  Back to cited text no. 4    
5.Esmon NL, Smirnov MD, Esmon CT. Lupus anticoagulants and thrombosis: The role of phospholipids. Haematologica 1997;82(4):474-7.  Back to cited text no. 5    
6.Castellino G, Cuadrado MJ, Godfrey T, Khamashta MA, Hughes GR. Characteristics of patients with antiphospholipid syndrome with major bleeding after oral anti≠coagulant treatment. Ann Rheum Dis 2001;60(5):527-30.  Back to cited text no. 6    
7.Ordi J, Vilardel M, Oristrell J, et al. Bleeding in patients with lupus anticoagulant. Lancet 1984;2(8407):868-9.  Back to cited text no. 7    
8.Peacock NW, Levine SP. Case report: the lupus anticoagulant hypoprothrombinaemia syndrome. Am J Med Sci 1994;307(5):346-9.  Back to cited text no. 8    
9.Bajaj SP, Rapaport SI, Fierer DS, Herbst KD, Schwartz DB. A mechanism for hypothrombinaemia of the acquired hypothrombinaemia-lupus anticoagulant syndrome. Blood 1983;61(4):684-92.  Back to cited text no. 9    
10.Small P. Severe haemorrhage in a patient with circulating anticoagulant, acquired hypothrombinaemia and systemic lupus erythemtosus. Arthritis Rheum 1988;31 (9):1210-1.  Back to cited text no. 10    
11.Franchini M, De Gironcoli M, Lippi G, Manzato F, April G, Gandi G. Prophylactic use of desmopressin in surgery in 6 patients with symptomatic heterozygous factor IX deficiency. Hematologica 2000;85(1):106-7.  Back to cited text no. 11    
12.Castellino G, Cuadrado MJ, Godfrey T, Khamashta MA, Hughes GR. Characteristics of patients with antiphospholipid syndrome with major bleeding after oral anticoagulant treatment. Ann Rheum Dis 2001;60(5): 527-30.  Back to cited text no. 12    

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Correspondence Address:
Hayet Kaaroud
Service de Nťphrologie et de Mťdecine Interne HŰpital Charles Nicolle, Tunis, Boulevard 9 Avril 1938, 1006 BS Tunis
Tunisia
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PMID: 18310872

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    Abstract
    Introduction
    Case Report
    Discussion
    Conclusion
    References
 

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