Indian Pediatrics 2000;37: 197-200
Immune Thrombocytopenic Purpura with Multiple Auto-Antibodies: Evolution into Systemic Lupus Erythematosus
| Sudeshna Mitra, Neelam
Marwaha*, R.K. Marwaha, Amita Trehan,
From the Departments of Pediatrics, *Hematology and **Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India.
Reprint requests: Dr. R.K. Marwaha, Additional Professor, Incharge Division of Pediatric Hematology-Oncology, Advanced Pediatric Center, PGIMER, Chandigarh 160 012, India.
Manuscript Received: June 14, 1999;
Initial review completed: July 29, 1999;
Revision Accepted: August 26, 1999
SLE is an episodic disease presenting with intermittent symptoms and signs till there is complete evolution. It is characterized by multisystem involvement and the presence of several autoantibodies. Idiopathic thrombocyto-penic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are well known to predate a diagnosis of SLE(1,2), more commonly in childhood onset SLE (<14 years) than in adults(3). We report here a child who presented as autoimmune thrombocyto-penic purpura and multiple autoantibodies for 3 years, while she remained anti-nuclear antibody (ANA) nega-tive. At the end of this period, she evolved into full-blown SLE and succumbed to complica-tions of the disease.
A 9-year-old girl, presented in February 1995 with spontaneous oozing from a loose tooth which, on extraction, bled profusely. Blood was transfused and the local area sutured. Intermittent oozing continued for a week when she developed purpurae. There was no rash, arthralgia/arthritis or history of drug intake. Examination revealed purpurae and minimal bleeding from gums. A clinical possibility of von Willebrand's disease was entertained. Investigations showed a prolonged activated partial thromboplastin time with kaolin (APTT). This prompted a search for lupus anti-coagulant (LA) which was detected to be positive by the following tests: kaolin clotting time index was 25% (normal upto 15%), dilute russell viper venom time ratio was 1.2 (normal upto 1.1) and dilute tissue thromboplastin time ratio 1.5/1.7/2.1 (normal upto 1.1). Platelet count was 10´109/L, hemoglobin was 9.8 g/dl with normal total and differential leukocyte counts. A bone-marrow aspiration showed increased megakaryocytes. Antiplatelet anti-bodies were demonstrated by the indirect plate-let suspension immunofluorescence test. She was diagnosed to have autoimmune thrombo-cytopenic purpura(AITP) with LA and started on 2 mg/kg/d of oral prednisolone. Ten days later, the bleeds had stopped and the platelet count had normalized. However, LA persisted. Steroids were tapered off after 3 weeks. She remained asymptomatic for the next 14 months with platelet counts ranging from 45 to 150´109/L.
She was readmitted in April 1996 with acute onset progressive pallor following a febrile episode. She had mild icterus, severe pallor and hepatosplenomegaly. The reticulocyte count was elevated whilst the anemia was normocytic, normochromic. A diagnosis of autoimmune hemolytic anemia (AIHA) was confirmed with a positive direct Coombs' test (DCT). She was transfused blood and restarted on oral steroids. This resulted in significant improvement within a week. One month later, hepatosplenomegaly disappeared. Steroids were gradually tapered to 5 mg on alternate days. Platelet counts ranged between 131 to 243´109/L whilst hemoglobin stabilized around 12g/dl. She continued to have LA, antiplatelet antibodies and a positive DCT. In September 1997, she was detected to have high IgG anti-cardiolipin antibody (ACLA) level (229.0 mg/ml). ANA, LE cell phenomenon and anti-ds-DNA were repeatedly negative for 3 years. In June 1998, she developed severe pallor following menorrhagia, requiring packed red cell transfusions. Platelet count had dropped to 90´109/L. ANA continued to be negative. In September, she developed bilateral ankle arthritis with a vasculitic rash in the same region. At this stage, ANA showed rim pattern. LE cell phenomenon was negative. Platelet count was normal. She was put on prednisolone 50 mg daily. A month later, she had a right focal seizure with secondary generalizaton. She was found to be hypertensive with evidence of left ventricular failure (LVF). Fundoscopy showed bilateral papilledema. In view of her previous clinical course, a diagnosis of SLE with myocarditis and CNS vasculitis was made. Investigations revealed anemia, polymor-phonuclear leukocytosis, normal platelet count, a markedly prolonged APTT and azotemia. DCT was positive. Echocardiography showed ruptured septal leaflet of tricuspid valve, regurgitation of AV valves, pulmonary hypertension and reduced LV function. A X-ray of the chest showed severe pulmonary edema. A right parieto-occipital, non-hemorrhagic infarct was seen on CT head. Anti ds-DNA had turned positive. Inspite of aggressive manage-ment of acute LVF, treatment with anti-convulsants, pulse dexamethasone, low-molecular-weight heparin, low-dose aspirin and blood transfusions, she expired within a few days of hospitalization.
The clinical presentations of thrombo-cytopenia associated with SLE could be as: (i) chronic thrombocytopenia, (ii) an acute fall in platelets which may be life-threatening, or (iii) initially as autoimmune ITP followed by other manifestations of SLE several years later. The patient under discussion falls in the third category, which constitutes 3-16% of patients(4).
The most common form of anemia in SLE is anemia of chronic disease, which is normo-cytic normochromic. Coombs' test is mild and only occasionally severe enough to require steroids(5). The propositus, had a rare presenta-tion which fulfils the criteria of antiphospholipid syndrome (APS). She had thrombocytopenia, hemolytic anemia, evidence of arterial occlusion in the brain preterminally, a high level of IgG anticardiolipin antibodies(6) and lupus anti-coagulant. APS in this case was probably secon-dary to SLE although the disease manifested 3 years later.
Thombosis, rather than bleeding, is the usual presentation of LA(7), bleeding occurring only if there is a concomitant hemostatic defect. In our patient, thrombocytopenia was the likely cause of bleeding. In a study on 100 patients with LA(8), 4 had hemorrhage with severe thrombocytopenia. In AITP with antiphos-pholipid antibodies (APLA), thrombosis is commoner than bleeding even in the face of thrombocytopenia(7). This was another aspect of rarity in our case of SLE with APS.
Both primary and secondary APS have been described in children(7). In a study in adults, comparing primary and secondary APS, it was observed that the incidence of thrombo-cytopenia was equal in the two groups but hemolytic anemia was significantly more common in those secondary to SLE(9). A higher incidence of Coombs' positivity in SLE patients with LA compared to non_SLE patients with LA has been reported(10). In retrospect, therefore, this child was more likely to evolve into SLE rather that remain a case of primary APS.
She had multiple autoantibodies: those against phospholipids (LA and ACLA), plate-lets, RBCs and finally against nuclear antigens. A similar case with autommune disease and APLA, who fulfilled criteria of SLE, has been described(11). However presentation was with thrombosis and anti-dsDNA was positive early in the course. ANA have been demonstrated in the serum of some patients with AIHA and/or ITP(12) but it has been suggested that only high titres of ANA or presence of anti-DNA antibodies predicts the likelihood of developing SLE later(13).
The nature of antibodies which led to thrombocytopenia in our case is contro-versial. Antiphospholipid antibodies have been shown to bind to circulating platelets(14). Alter-natively, antibodies to platelet membrane glycoproteins Ib/IX and IIb/IIIa have been demonstrated in patients with APS and may be causative in immune destruction(15). In this child, antiplatelet antibodies were measured by the indirect platelet suspension immuno-fluorescence test which detects platelet associated surface IgG but does not differentiate between target specificity. Coombs' positivity can be logically extrapolated from reactivity of APLA with phospholipid in RBC membrane. In a prospective study on 500 patients of SLE(16), it was found that thrombocytopenia and hemolytic anemia were associated with ACLA. Patients with primary APS have been seen to evolve into SLE later(17). In contrast, patients of AITP and/or AIHA with ANA have been reported who have never developed SLE(12).
The patient had a rapid deteriorating course terminally with both cardiac and neurologic manifestations. Valvular vegetations, regurgita-tion, stenosis are present in cardiac disease of SLE. An association with ACLA is known(18). Similarly, neurologic manifestations of SLE have also been linked to APLA. However, cerebral ischemia is more common in primary APS rather than with underlying diseases(18).
Management of APS is fraught with controversies. Prolonged high dose warfarin is recommended in those with a history of thrombosis(17) which was not the case in our patient for the initial 3 years, Steroids administered for the relief of thrombocytopenia and severe AIHA, could have had a suppressive effect on a smouldering SLE. The propositus illustrates the need for meticulous clinical and serological monitoring in patients with apparent immune thrombocytopenic purpura who have atypical manifestations. Early detection of SLE could merit more aggressive immuno-suppressive therapy.
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