Clozapine-Induced Recurrent Pulmonary Thromboembolism

To the Editor: Clozapine is an atypical antipsychotic, effective in the treatment of resistant schizophrenia.¹ Its widespread use has been limited by its adverse drug profile, which includes agranulocytosis, sedation, weight gain, diabetes mellitus, seizures, and myocarditis.^2–4 Pulmonary thromboembolism is a rarely reported adverse effect with clozapine therapy.^5,6 In a study of the 67,072 patients registered in the Clozaril National Registry between 1991 and 1993, the absolute risk of death from pulmonary embolism was increased by a factor of 5.2 among current clozapine users, as compared with past users of clozapine.⁵ We report on a patient with chronic schizophrenia on clozapine 50 mg/day, who developed recurrent episodes of pulmonary thromboembolism, which did not recur after discontinuation and symptomatic treatment.

Case Study

A 34-year-old single man diagnosed with paranoid schizophrenia for 16 years, was put on clozapine, considering his treatment resistance; there was significant reduction in psychotic symptoms and improvement in socio-occupational functioning. He was maintaining well on clozapine 50 mg/day for the past 7 years. He presented with a history of breathing difficulty and was admitted under cardiology for evaluation. Previous medical records revealed an episode of dyspnea on exertion and chest pain 4 years earlier, that was diagnosed as acute pulmonary thromboembolism, pulmonary infarction, severe pulmonary arterial hypertension, right ventricular dysfunction, and left-sided proximal left lower limb deep vein thrombosis. Thrombolysis was done with streptokinase, and he was advised coumarin prophylaxis, which he had discontinued on his own after 1 year. However, clozapine 50 mg/day was continued thereafter for 4 years by his treating psychiatrist. On examination, he had tachycardia, BP: 140/90 mmHg, RR: 20/min., raised JVP with prominent “a wave,” loud P2, widely split A2P2, end diastolic murmur in the pulmonary area, and occasional crepitations in both lung fields. Investigations, including complete hemogram, renal and liver function tests, and serum electrolytes, were within normal limits. His prothrombin time was 16.8 (control: 13.5) seconds, and INR was 1.08. An electrocardiogram revealed sinus tachycardia and T-wave inversion in V1–V4, whereas echocardiogram showed severe tricuspid regurgitation with pulmonary arterial hypertension, dilated right atrium and ventricle, mild right-ventricular dysfunction, with good left-ventricular function. Venous Doppler of lower limbs showed chronic thrombosis with partial recanalization of left superficial femoral and popliteal veins in the left lower limb and no deep vein thrombosis in the right lower limb. An emergency CT angiogram showed intraluminal filling defects in both right and left pulmonary artery main bronchus, extending into both the descending branches, suggestive of thrombi and dilated pulmonary artery with the dilated right ventricle suggestive of pulmonary thromboembolism. He was thrombolyzed with tenecteplase (TNK) and started on tablet warfarin 5 mg, tablet digoxin 0.25 mg, half tablet of furosemide 40 mg, and spironolactone 50 mg per day. Considering a possibility of recurrent pulmonary thromboembolism due to clozapine, he was referred to us for further management. Clozapine was discontinued, and he was started on haloperidol 5 mg/day, which was gradually increased to 10 mg/day, along with trihexiphenidyl 4 mg/day. On these medications, he was maintaining well at follow-up after 3 months, without recurrence of thromboembolism or psychotic symptoms.

Discussion

In our case study, recurrent venous thromboembolism occurred while the patient was on clozapine therapy, which did not recur after discontinuation. No other factors could be identified after investigations. The association between clozapine and venous thromboembolism has been highlighted in several case reports.^7–11 In a large study,⁵ pulmonary embolus was found to be the second most common cause of death among current clozapine users. In most cases, symptoms occurred within the first 3 months of clozapine treatment,⁶ although the time varied from 12 days to several years.^8–10 In another report, current exposure to conventional antipsychotic drugs was found to be associated with a significantly increased risk of first-time, idiopathic venous thromboembolism, as compared with non-use.¹² The risk was higher (24.1 times) for low-potency drugs, such as chlorpromazine, in contrast to 3.3 times for high-potency drugs, such as haloperidol. Hagg et al.⁶ reviewed 12 cases of thromboembolism that occurred during clozapine treatment and suggested that men might be more prone to developing this reaction than women.

Mechanisms for venous thrombogenesis include damage to the vessel wall, stasis, or slowing of blood flow, and abnormalities of coagulation. The mechanism underlying the association of thromboembolism with clozapine is not known, but it has been suggested that clozapine may exacerbate several indirect risk factors, such as obesity, sedation, and resultant immobility.¹³ Recently, it has been proposed that as clozapine possesses affinity for 5HT_2a receptors that is 10 times greater than for D₂ receptors, it is possible that 5HT_2a-induced platelet aggregation may be affected, leading to thromboembolism.¹⁴ Considering the high mortality associated with pulmonary thromboembolism, it is imperative to maintain a high index of suspicion for this relatively uncommon but fatal adverse event associated with clozapine, specifically when such events are occurring repetitively.