Rheumatology 2001; 40: 585-587
© 2001 British Society for Rheumatology
Paediatric Rheumatology |
Diffuse muscular haemorrhage as presenting sign of juvenile systemic lupus erythematosus and lupus anticoagulant hypoprothrombinaemia syndrome
Paediatric Rheumatology/Series Editor: P. Woo
Department of Pediatrics and
1 Coagulation–Hematology Laboratory, Sapir Medical Center, Kfar Saba, Israel
Abstract
Lupus anticoagulants are closely related to systemic lupus erythemathosus (SLE) and to thrombotic events. We describe a 12 year-old girl with a bilateral intramuscular haemorrhage of the gastrocnemius muscles as her main initial presentation of juvenile SLE. Laboratory work-up revealed lupus anticoagulant-hypoprothrombinaemia syndrome (LAHS) with very low levels of factor II due to autoantibodies. She showed a good initial clinical and laboratory response to prednisone therapy, however steroid dependency developed. To the best of our knowledge, this is the first case reported of juvenile SLE presenting with LAHS.
KEY WORDS: Systemic lupus erythematosus, Lupus anticoagulant–hypoprothrombinaemia syndrome, Paediatric, Haemorrhage.
Lupus anticoagulants (LA) are closely associated with systemic lupus erythematosus (SLE) and have recently been accepted by the American College of Rheumatology as a criterion for SLE [1]. Usually, antibodies to phospholipid proteins (APLA) cause hypercoagulability, resulting in thrombotic events; however, sporadic cases of bleeding diatheses have been described in the presence of APLA associated with antibodies to coagulation factors. In particular, anti-factor II (FII) antibodies have been reported as a rare cause of bleeding in lupus patients [2–4].
Case report
A 12-yr-old, previously healthy Yemenite–Jewish girl developed painful swelling of her right leg, extending from the popliteal fossa to the ankle. Ten days later she was immobilized by similar but more severe symptoms appearing in her left leg. Additionally, gingival bleeding was noted, as well as the appearance of spontaneous bruising on her arms and legs. The family history revealed two paternal aunts with SLE.
On admission she was bedridden, suffering extreme pain. Paleness, multiple ecchymoses on the extremities, and hepatomegaly were detected. Swelling, redness, warmth and extreme tenderness were noted in both legs, more on the left, from the distal thighs and through the calves. There was no evidence of arthritis. Also noted was oozing of blood from venipuncture sites.
Laboratory investigations revealed a very high erythrocyte sedimentation rate, anaemia and markedly prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) (Table 1
). Evaluation of clotting factors revealed FII less than 5% (normal range 50–110%) and low levels of factors IX (17%) and XI (29%). We found a neutralizing antiprothrombin antibody in 50:50 mixing studies, a phenomenon that has been described only rarely [5]. The addition of 50% healthy plasma to the patient's plasma did not restore the clotting time. Further studies showed Coombs’ positive anaemia, markedly reduced complement levels, the presence of antinuclear antibodies (ANA) (Table 1) and negativity for anti-double-stranded DNA antibodies. Investigations of related factors of hypercoagulability, including protein C, protein S, anti-thrombin III, activated protein C resistance (APCR) and the FII mutation had negative results. An extensive infectious disease workup ruled out adenovirus, hepatitis A, B and C, cytomegalovirus, Epstein–Barr virus, coxsackievirus and other enteroviruses.
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Sonographic studies of both calves ruled out vein thrombosis and Baker's cyst but detected increased echogenicity in the gastrocnemius muscles, consisting of thickening and discontinuity of the muscle fibres. Magnetic resonance imaging of both calves demonstrated a resolving haemorrhage in the right gastrocnemius and a more recent diffuse haemorrhage in the contralateral muscle (Fig. 1
).
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Because our adolescent girl demonstrated Coombs' positive anaemia, positive ANA, low complement levels, LA with evidence of an anti-prothrombin antibody, and a strong positive family history, we proposed a diagnosis of suspected juvenile SLE.
The patient was treated with oral prednisone (2 mg/kg per day in two divided doses) and physical therapy; a significant improvement was observed within 10 days and clotting function tests normalized. After 1 month of treatment the patient was completely asymptomatic, and a tapering-off schedule of prednisone was implemented. Three months later, while the patient was on low-dose prednisone (<0.5 mg/kg per day), mild bruising reappeared accompanied by a slightly prolonged PT and decreased FII levels (Table 1
). Clinical and laboratory signs resolved after increasing the prednisone dose and the addition of hydroxychloroquine (HCQ).
During the follow-up period of 1-yr, the patient remained asymptomatic, off prednisone and on HCQ. The FII level remained between 40 and 50%.
Discussion
Rare case reports of bleeding diatheses associated with LA prompted studies to further the understanding of their mode of action. Hypoprothrombinaemia was found in conjunction with circulating anticoagulants in patients with a tendency to bleed. The condition was termed lupus anticoagulant–hypoprothrombinaemia syndrome (LAHS). Further investigation revealed antiprothrombin antibodies, usually non-neutralizing, that reacted with epitopes on the carboxy-terminal portion of the FII molecule.
Paediatric cases of LAHS have been documented [2–4, 6, 7]. Such cases can be divided into two major categories: those with an underlying systemic disease (usually SLE) and those with transient LAHS, which is often related to a preceding viral disease, particularly adenovirus [8]. In most of these patients the clinical and laboratory manifestations resolved spontaneously. The majority of reported cases of LAHS, however, were in children with SLE and not among the postviral disease group [4]. The SLE patients needed increased corticosteroid doses to ameliorate the clinical haemorrhage symptoms and to normalize clotting abnormalities [2–6]. Azathioprine and intravenous immunoglobulins have been used occasionally as steroid-sparing agents [3, 4, 9].
Prompt and close follow-up is needed in these patients in order to keep the delicate balance between bleeding and clotting. The low concentration of FII probably protects the patients from the thrombotic events associated with APLA. When the level of FII is increased, indicating lower levels of anti-prothrombin antibodies, the risk of thrombosis due to the presence of APLA is increased [10]. We elected to add HCQ as additive anti-inflammatory and possibly thromboembolic prophylaxis.
In summary, our patient presented a case of paediatric LAHS as the first manifestation of juvenile SLE. Close follow-up is indicated in order to maintain the delicate balance between the haemorrhagic and thrombophilic tendencies, along with periodic screening for additional manifestations of SLE.
Notes
Correspondence to: Y. Uziel, Pediatric Rheumatology, Sapir Medical Center, 44281 Kfar Saba, Israel. 
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