WKY Chan, KW Lee, S Ho

Abstract

Antiphospholipid antibodies are well known to be present in the serum of patients with systemic lupus erythematosus (SLE). It is important to identify these antibodies not only because they have unique clinical features but also important in the clinical management. We report a pediatric patient who has systemic lupus erythematosus and recurrent leg ulcers. Her problems illustrate that adequate control of lupus activity does not prevent the child from complications of thrombosis. Use of anticoagulants like aspirin or warfarin is necessary. Regular echocardiogram is also indicated since there is progressive involvement of valvular lesions and the need of antibiotic prophylaxis for infective endocarditis should be considered. Early identification of the antibodies and use of appropriate anticoagulant therapy could avoid major thrombotic events.

Introduction

The association between a circulating anticoagulant and thrombosis was well known in patients with systemic lupus erythematosus. Conley & Hartman¹ in 1952 first described an inhibitor identified in the plasma of SLE patients. That inhibitor directed against the phospholipid portion of prothrombin activator complex and they called it the lupus anticoagulant. In 1983, Hughes et al² described a clinical syndrome with wide spread arterial and venous thrombosis associated with antiphospholipid antibodies. In the past fifteen years, the features of antiphospholipid antibody syndrome have been increasingly recognized in children. The association between recurrent arterial or venous thrombosis, recurrent fetal loss, recurrent strokes, thrombocytopenia, livedo reticularis and cardiac valve lesions characterize antiphospholipid antibody syndrome (APS). Since thrombosis can occur anywhere in the body, symptoms may be heterogeneous depending on the type of organs and vessels involved. The syndrome can be a primary disease or associated with other connective tissue disease especially systemic lupus erythematosus.

We describe a girl who presented to us 5 years ago. Her clinical course illustrates the importance of identifying these antibodies in the management of her problems.

Case report

A 13 years old girl presented to us for recurrent right ankle pain and leg ulcer for one month. There was frequent epistaxis, weight loss and decreased appetite. Physical examination at that time revealed butterfly rash over both cheeks, right ankle arthritis and a leg ulcer measured 2 cm in diameter over the lateral malleolus of right ankle. She developed fever after admission and sepsis work up was negative.

Investigations at that time revealed hemoglobin: 10.9 g/dl, platelet: 73 X 10⁹/L, white cell count: 4 X 10⁹/L, prothrombin time: 13.5 second, activated partial thrombin time (aPTT): 70.6 second, INR: normal, ANF titre 1:160 (nucleolar pattern), anti-dsDNA titre: 303 (increased), C3 : 33 mg/dl (60-130), C4 : 5 mg/dl (13-60), anti-Ro positive, lupus anticoagulant positive, anticardiolipin antibody IgG: 76 GPL unit/ml ( normal < 15 ), anticardiolipin antibody 1gM: 14 GPL unit/ml (normal < 15), IgG: 26.6 g/L , IgA: 3.33 g/L, 1gM: 1.12 g/L, urea and creatinine were normal, serum albumin 46 g/L, serum globulin 41 g/L, proteinuria was 15 mg/m²/hr and calculated creatinine clearance from 24 hours urine was 165 ml/min/1.73m². Ophthalmological examination was normal. Radiological examination of both ankles did not show any bony lesions. Lung function test was normal. First echocardiogram was normal. Renal biopsy showed focal mesangioproliferative glomerulonephritis. Immunofluorescence staining of the kidney tissue showed capillary and mesangial granular deposit for IgG, IgA, IgM, C3 and C1q. The renal histology was compatible with WHO class II lupus glomerulonephritis.

She was diagnosed to have systemic lupus erythematosus and oral prednisone 1.5mg/Kg/day was commenced. Her fever and constitutional symptoms subsided and platelet count was back to normal within 2 weeks of daily steroid. Her leg ulcers required debridement and it healed ten months later. During follow up, the child was noticed to have marked livedo reticularis and she complained of recurrent tenderness along the superficial veins of both feet despite she was kept on alternate day steroid and lupus activity was under control.

Twenty-two months after first presentation, she complained of bilateral thrombophlebitis over dorsum of both feet and bilateral small necrotic lesions over dorsum of both feet, near the distal end of the fourth metatarsals. Investigations at that time showed antids-DNA titre of 40 only, C3: 69 mg/dL (normal), platelet: 95 X 10⁹/L, anticardiolipin IgG: 6 GPL unit/mi (normal). Prothrombin time: 11.5 second, control plasma: 13 seconds, I.N.R. <1, aPTT: 52.5 seconds, control plasma: 32 seconds, Kaolin clotting time: 235 seconds, control plasma: 66 seconds. 'Mixing test' and dilute tissue thromboplastin inhibition test indicated the presence of lupus anticoagulant. Platelet neutralization procedure was positive. Laboratory investigations confirmed the presence of lupus anticoagulant in the serum of the child.

In view of the recurrent superficial thrombophlebitis and recurrent venous ulcers, aspirin was started. The necrotic lesion over the left foot became an ulcer measured 1.5cm in diameter. Debridement and secondary suture was performed. The right-sided lesion healed spontaneously. Echocardiogram performed at that time showed mild to moderate eccentric mitral regurgitation, normal mitral valve anatomy and clinically there was no murmur detected.

The child was maintained on daily aspirin 100-200 mg daily in addition to steroid which controlled her lupus activity. Thrombophlebitis or venous ulcer did not recur in the last three years. Her latest Doppler study of deep veins of both lower limbs did not show any evidence of thrombosis.

Discussion

Antiphospholipid antibody (aPL) is not a single antibody. It is a family of autoantibodies that crossreact with various phospholipids. The serum of a patient may have mixtures of various types of aPL with different immunochemical characteristics and biological properties. These antibodies can be identified by their cross reactivity to syphilis antigen and give a false positive VDRL, or by their activity detected by ELISA, or detected as lupus anticoagulant (LAC). The simplest but least sensitive and least specific test is the VDRL. The second method, using ELISA to measure the antibody that binds to phospholipids coated onto a tube or plate, is very sensitive but not highly specific. With this technique, we can further subclass the antibody into anticardiolipin (aCL) IgG, IgM. The functional tests that identify lupus anticoagulant are more specific but less sensitive than the ELISA is. Among the three tests, consensus conferences have established international standards for the ELISA and are seeking to establish standards for the lupus anticoagulant. A patient can have any single test, any combination of two, or all three tests positive.^4,9

Apart from systemic lupus erythematosus, aPL is also known to occur in conditions like acute infections, acute rheumatic fever and other connective tissue disease like juvenile chronic arthritis. Antiphospholipid antibodies detected in these conditions do not confer an equivalent risk of thrombosis.³ This mean that our current assay of aPL detect a heterogeneous group of antibodies and only a particular subset is associated with thrombotic events.⁵

Thrombosis is the main complication of APS. Pathohistologically, the affected vessel is occluded by a bland thrombus without inflammation. Thus thrombosis is not a secondary event to vasculitis.⁵ New data showed that a large proportion of "antiphospholipid" antibodies do not in fact recognize phospholipids. The antigenic target of antibodies detected in conventional anticardiolipin and LAC assay are phospholipid binding proteins, most notably β₂ Glycoprotein I (β₂GPI) and prothrombin.⁶ Specificity for β₂GPI seems to be one of the features that distinguishes aCL associated with APS from aCL associated with infection and malignancies. Patients with LAC also have a high incidence of antibodies against prothrombin which might be the antigenic target of lupus anticoagulant.⁶

Unlike the plethora of studies in adults, majority of data available in children are case reports. The spectrum of clinical manifestations can be categorized into venous occlusive disease, arterial occlusive disease, catastrophic occlusive disease and other associated problems.

Deep vein thrombosis in the lower limbs, pulmonary thromboemboism, cerebral venous sinus thrombosis, Addison's disease, retinal vein thrombosis have been described. Arterial thrombosis presented as recurrent strokes, transient ischemic attacks, renal artery thrombosis, myocardial infarction, mesenteric artery thrombosis, avascular necrosis of femoral epiphysis have been reported. Other associated features like livedo reticularis, thrombotic skin lesions, cardiac valve lesions, thrombocytopenia, hemolytic anemia and non-vascular neurological events like chorea are well known features.^2-3,5

Cutaneous manifestations like livedo reticularis is a prominent feature in some patients. Some patients with Sneddon's syndrome (a triad of livedo reticularis, ischemic cerebrovascular disease and hypertension) also found to have positive aPL. Recurrent skin ulcers, nail-splinter hemorrhage and skin nodules have also been described as dermatological manisfestations.^2,5

Valvular lesions, particularly affecting the mitral valves in SLE patients, appear to be correlated with the presence of antiphospholipid antibodies. Khamashta ,et al⁷ reported that 22.7% of their 132 SLE patients have valvular lesions and antiphospholipid antibodies were present in 50 patients. The prevalence of valvular vegetations and mitral regurgitation was significantly higher in SLE patients with antiphospholipid antibodies than in those without.⁸

Concerning our patient, she showed cutaneous manifestations of APS. Her serological markers included anticardiolipin antibodies are normalized with steroid therapy. However her leg ulcers recurred and LAC was still detected in her serum. Biopsy of her leg ulcer was not performed in initial presentation and probably it can enable us to differentiate a thrombotic phenomenon from a vaculitic ulcer and therapy can be initiated earlier.

It is not surprising that her initial echocardiogram was normal. The damage may not be evident in the initial presentation. It is therefore important to repeat cardiac assessment and antibiotic prophylaxis against bacterial endocarditis is necessary. ⁸ To handle the recurrent ulcers, antiplatelet agent seems adequate in our patient. Smoking, use of estrogen containing oral contraceptive pills and prolonged immobilization are risk factors for thrombosis. She should avoid these as far as possible.

There is no consensus in the use of anticoagulant therapy particular in children. Nevertheless it is generally agreed on the need to treat patients who experience an aPL-related thrombosis to prevent recurrence. Khamashta, et al¹⁰ suggests the use of long-term anticoagulant therapy in which the international normalized ratio is maintained at or above 3. With this high INR, risk of bleeding is definite especially in children whom play and sport are unavoidable. Most authors suggest aspirin for very small vessel disease or for minor non-threatening venous occlusion. Warfarin is considered for arterial and major venous occlusions. However the duration of treatment is controversial. Simple serological positivity without symptoms may not warrant the use of anticoagulants.⁹

The prevalence of aPL and the associated thrombotic events in Chinese patients are not well known. Recognition of these antibodies is not only important to paediatricians who look after children with SLE, it is also important to neurologist, cardiologist and hematologist.

References

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