Year : 2008 | Volume
: 19 | Issue : 2 | Page : 227--231
Bleeding and Thrombosis in a Patient with Secondary Antiphospholipid Syndrome
Hayet Kaaroud1, Soumaya Beji1, Sami Guermazi2, Fatma Ben Moussa1, Fethi Ben Hamida1, Sami Ezzine1, Taieb Ben Abdallah1, Fethi El Younsi1, Adel Kheder1,
1 Departments of Nephrology, Internal Medicine, Charles Nicolle Hospital, Tunis, Tunisia
2 Department of Hematology, Charles Nicolle Hospital, Tunis, Tunisia
Service de Néphrologie et de Médecine Interne Hôpital Charles Nicolle, Tunis, Boulevard 9 Avril 1938, 1006 BS Tunis
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.
|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;19:227-231
|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 2020 Sep 20 ];19:227-231
Available from: http://www.sjkdt.org/text.asp?2008/19/2/227/39035
Antiphospholipid (APL) antibodies, namely lupus anticoagulant and anti-cardiolipin, represent a group of autoantibodies directed against phospholipids and phospholipidbinding proteins. They have been associated with the occurrence of arterial and venous thrombotic events and fetal loss, which together constitute the antiphospholipid syndrome (APS). Paradoxically, in this syndrome, bleeding is rare. APS was originally recognized in patients with systemic lupus erythematosus (SLE) and has been described subsequently in patients with other rheumatologic diseases or, without any underlying disease.
We herewith report a case of SLE with APS complicated simultaneously by thrombotic and hemorrhagic events.
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 antibodies.  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 remission of the nephropathy.
In 1997, a relapse of lupus nephritis occurred with the nephrotic syndrome and renal failure (serum creatinine: 120 µmol/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 anticardiolipin 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 urinalysis, an abdominal mass located in the right flank and a normal gynecologic examination. X-ray of the chest was normal and abdominal ultrasound revealed a compressive hematoma of the psoas muscle with thrombosis of the inferior cava vein. Ophthalmologic 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 µmol/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 prothrombin 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: 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 corticosteroids 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 thrombosis 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 µmol/L, the ANA tested negative and there was a reduction in levels of circulating anticoagulant and anticardiolipin antibodies.
The APS is present in about 30% of patients with SLE.  This syndrome is associated with both arterial and venous thrombosis, fetal loss and moderate thrombocytopenia.  The prevalence of thrombosis in APS is not well established. In retrospective 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 
Our patient had APS secondary to SLE with recurrent venous thrombotic complications (phlebitis, vena caval and retinal thrombosis). Many mechanisms have been proposed to explain the prothrombotic tendency in APS. It is mainly due to interaction of APL antibodies with prohrombin, annexine V, plasmin and activation of adhesion molecules on endothelial cells.  Bleeding is a rare complication of APS. It has been reported especially after surgery, anticoagulant treatment with INR > 4,5 and in children after viral infection. ,
Although APL antibodies often inhibit coagulation in vitro and prolong the PTT, there are few case reports of bleeding associated with the presence of these antibodies alone without any other hemostatic abnormalities. In fact, we generally find an acquired hypoprothrombinemia defined as lupus-anticoagulant-hypoprothrombinemia syndrome, in these patients.  This deficiency in prothrombin factor is thought to be related to the presence of an autoantibody directed against prothrombin.  Some authors have demonstrated that this acquired hypoprothrombinemia 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.  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 deficiency, often after surgery and trauma, independently of its levels.  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.  These hemorrhagic complications are usually isolated without thrombosis. Our patient developed simultaneously both thrombotic and hemorrhagic complications.
Since we believe that the disease is antibody mediated, immunosuppressive therapy should be effective in controlling this situation. 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.  Anticoagulants were introduced in our patient after resolution of bleeding to treat thrombotic events with disappearance of vena caval thrombosis although retinal thrombosis persisted.
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 therapeutic problem. Management of hemorrhage with corticosteroids, immunosuppressive agents and plasma exchange is essential before initiating anticoagulation.
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