Division of Rheumatology and Immunology, University of Miami School of Medicine, Miami, Florida, USA
SIR, Antiphospholipid syndrome (APS) can demonstrate a range of clinical presentations from recurrent miscarriages to thrombosis [1]. It primarily affects women and is more common in patients with a history of autoimmune disease. Criteria for APS classification have been published [2]. These include vascular thrombosis, pregnancy morbidity, and the presence of anticardiolipin antibodies (ACA) of the IgG or IgM type and/or lupus anticoagulant (LAC).
APS is an uncommon disorder in children. Here we describe the youngest individual yet reported with native antibodies and cerebral vascular thrombosis due to APS. An 8-month-old previously healthy female infant presented with left-sided body weakness. One week before admission, she had a fever, upper respiratory tract infection symptoms and a generalized tonicclonic seizure. Decreased mobility of the left side of the infant's body was noted. A CT scan without contrast revealed subtle non-enhancing lesions in the right and left basal ganglia and the right internal capsule.
On the day of admission to our hospital, the infant had six generalized tonicclonic seizures. Physical examination was unremarkable except for left-sided diminished muscle tone and weakness. Left-sided deep tendon reflexes were +3 and left-sided Babinski sign was present. In addition, there was bilateral ankle clonus (+3 on the left, +2 on the right).
Laboratory testing revealed thrombocytosis (857000/mm3) and a haemoglobin concentration of 9.8 g/dl. Further studies, including white blood count, blood urea nitrogen, creatinine, electrolytes, urinalysis, liver enzymes, erythrocyte sedimentation rate, C-reactive protein and electrocardiogram, were normal. Haemoglobin electrophoresis demonstrated sickle cell trait.
ACA IgG antibody was positive at 73 GPL (IgG phospholipid units)/ml (normally <10/ml). Testing for LAC was negative. An antinuclear antibody (ANA) titre of 1:40 with a speckled pattern was detected, but more specific autoantibodies were absent. Prothrombin time, activated partial thromboplastin time, protein C, protein S, antithrombin III, activated protein C resistance and homocysteine concentration were within normal limits.
Magnetic resonance imaging of the brain was consistent with infarction of the right lateral basal ganglia, internal capsule and periventricular regions. The echocardiogram was negative for mural thrombus or valvular abnormalities, and a carotid Doppler ultrasound scan was normal as well. Electroencephalogram showed no clear epileptiform potentials.
The patient was diagnosed with APS as there were no clinical features or autoantibodies suggestive of any other autoimmune or connective tissue disease, except for a low titre of ANA. There was no evidence of maternal antibodies. Therapy was initiated with subcutaneous low-molecular weight heparin. The patient's seizures were controlled on phenobarbital and, following physical therapy, she recovered most of her motor function. No further events have occurred in 2 yr of follow-up.
Thromboembolic phenomena in the presence of ACA or a lupus anticoagulant are the hallmark features of the APS. Strokes are rare but can occur in children and adolescents. Baca et al. [3] reported 10 patients with a mean age of 5.8 yr with a cerebrovascular accident (CVA). Seven of these patients tested positive for ACA and/or LAC. They were subsequently treated with daily aspirin and no recurrences were reported. In another study [4], 13 children aged 316 yr with cerebral ischaemic events were matched with 13 control patients. Ten of the children with ischaemic events had ACA/LAC but none of the control patients did.
Laboratory features of APS include false-positive tests for syphilis, positive tests for ACA and LAC, and the presence of the more recently identified ß2-glycoprotein I (ß2-GPI). Solid-phase ELISA may identify ACA as IgG, IgM or IgA. LAC is a laboratory phenomenon that can be observed through prolongation of the partial thromboplastin time, the kaolin clotting time or the dilute Russel viper venom test; the absence of correction by a 1:1 mix; and partial correction of the prolongation by addition of a phospholipid preparation.
Recent evidence has revealed that the ligand for pathological ACA is not the phospholipid itself but one of a number of proteins that may function as natural anticoagulants. The most common and best characterized of these is ß2-GPI [5]. The fifth domain of ß2-GPI has a high positive charge, allowing the molecule to bind to highly negatively charged particles, such as phospholipids. Upon binding phospholipid, ß2-GPI undergoes a conformational change, exposing an epitope in the fourth domain. ACAs bind to this domain [6]. The exact mechanism of thrombophilia remains unclear.
What constitutes appropriate management for patients with antiphospholipid antibodies but without the clinical syndrome remains unclear. A reasonable approach may include modification of known thrombotic risk factors, such as smoking, oestrogen supplementation, obesity, hypertension and hypercholesterolaemia. Prophylactic aspirin or hydroxychloroquine have also been proposed.
In patients with established APS, anticoagulation with warfarin is recommended. One retrospective study concluded that patients treated with warfarin fared better than patients treated with aspirin if the international normalized ratio (INR) was kept above 2.5 [7]. A retrospective analysis of 147 patients concluded that anticoagulation with warfarin to an INR above 3 is more effective than lower levels of anticoagulation in preventing recurrent thrombotic events [8].
Infants and children with APS have a lower incidence of thrombosis than adults. Furthermore, children with systemic lupus erythematosus (SLE) have a lower rate of thrombosis compared with adults [9]. There is a paucity of data regarding the treatment of APS in infants and children. A recent review recommended high-intensity anticoagulation for 6 months followed by low-intensity anticoagulation indefinitely [10]. A problem that must be considered in treatment is the likelihood of inadvertent trauma in infants and children that may lead to more complications.
It is interesting that this patient was found to have sickle cell trait. One previous study found a significant association between ACA and sickle cell disease and trait compared with normal controls [11]. There was no association between ACA levels and complications from sickle cell disease. Patients with sickle cell trait were all healthy.
Again, to our knowledge, this is the youngest reported patient with a CVA secondary to native ACA and without maternally derived antibodies. This is also the first report of symptomatic APS associated with sickle cell trait.
Notes
Correspondence to: C. J. Lozada, 1150 NW 14th Street, Suite 310, Miami, FL 33136, USA.
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