Pulmonary thromboembolism associated with the use of new antipsychotics in a paediatric patient.

Abstract

Atypical antipsychotics can be associated with deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) in adults.1 However, we found no references in children. We report a 14-year-old male with Down syndrome receiving antipsychotics who suffered a DVT followed by a PTE. He had no history of thromboembolic risk beyond being slightly overweight: he had no history of cancer disease, had not been immobilised, travelled long distance, nor undergone recent surgery. He had no family history of thrombosis. Three weeks earlier he suffered bronchopneumonia associated with asthenia, fatigue, fever and intermittent cough. Suddenly, his left leg became swollen and red from the groin to the ankle. He was mildly tachypnoeic with subcostal retraction. Pulmonary angiography confirmed PTE in the lobar and segmental branches of the lower lobes in both pulmonary arteries. He had been diagnosed with oppositional defiant disorder, and at age 14, became increasingly aggressive. After he attacked his mother he was started on risperidone (2 mg daily), withdrawn after 3 months due to poor tolerance and replaced with aripiprazole (5 mg daily). Finally, paliperidone (3 mg daily for 8 months increased to 6 mg daily for the 5 months prior to admission) was added to aripiprazole. Upon admission to the paediatric intensive care unit, cardiorespiratory stability was maintained. His left leg was red and swollen. Echocardiography identified mild tricuspid regurgitation with a wide pulmonary artery trunk, without impact on the ejection fraction or diastolic filling. Vascular ultrasound of the lower limbs identified significant left venous thrombosis, including the common distal iliac, internal and external, common femoral, saphenous arch and the proximal third of the external femoral veins. A thrombophilia study was negative. Paliperidone and aripiprazole were replaced by tiapride and anticoagulant treatment with sodium heparin in continuous infusion (activated partial thromboplastin time between 45 and 70 s) for 9 days, when it was replaced by oral warfarin. Swelling and mobility of the affected limb progressively improved and a partial recanalization of the thrombus was evident on ultrasound. Echocardiograms and serum levels of brain natriuretic peptide (BNP) peptide and ultrasensitive troponin were normal; pulmonary tomography 20 days after admission showed improvement. The child was discharged at 27 days. Typical antipsychotics may be a risk factor for DVT and PTE.2 The risk is higher with atypical antipsychotics3 and with the most sedative of the typical antipsychotics.4 Clozapine has been the most implicated; aripiprazole and quetiapine do not seem to be associated.4 A recent review concluded the risk is greater at the beginning of treatment (first 12 months, maximum within the first three) and that it is directly proportional to dose increases and polytherapy,5 both applicable to our patient. Increased risk was also associated with parenteral administration.5 The underlying mechanisms are not well understood. Sedation, metabolic syndrome and hyperprolactinaemia are possible related factors.6 Increased platelet aggregation has also been suggested for typical antipsychotics7 through hyperprolactinaemia although aripiprazole (with partial dopamine agonism) and clozapine (weak antagonism) hardly have this side effect.8 In another study, clozapine, risperidone and haloperidol, structurally different, significantly interfered with platelet aggregation; however, with a similar molecule olanzapine, this did not occur.6 A strong affinity between serotonin 5-HT2A receptors and atypical antipsychotics can induce platelet aggregation.9 We consider paliperidone as the main predisposing factor for DVT in our patient, especially given its recent introduction. Despite the lack of data on aripiprazole and the low dose used, its association with paliperidone may have contributed to the event. Finally, we would like to warn about the risks of over-medication and polypharmacy, especially in children and young people. First-line pharmacological treatment of behavioural disorders is common and potentially dangerous. Grateful thanks to all the staff of the paediatric intensive care unit for their undivided dedication to the care of children and their families; Dr Adela Meseguer for her continuous support; and James Peters for his assistance in language translation.