Venous thromboembolism and clozapine: an association unresolved

Orthostatic hypotension and tachycardia are the most common cardiovascular side effects of clozapine [1]. Several other rare cardiovascular side effects such as paradoxic hypertension [2], [3] and bradycardia [4], [5] can be viewed in the literature regarding clozapine’s safety. Myocarditis, cardiomyopathy [6], [7] and thromboembolic complications including pulmonary emboli [8], [9], [10], [11], [12], [13] have also been reported as rare but sometimes fatal adverse events associated with clozapine use. Although attention has been drawn in case reports to thromboembolic complications associated with clozapine, there is also evidence that the risk and occurrence of first-time idiopathic thromboembolism with atypical antipsychotics, including clozapine, might be less than those associated with conventional antipsychotics [14]. The issue of the association of venous thromboembolism and clozapine, an issue still under debate and unresolved, will be discussed here in the light of the following case.

A 24 year old male, with a diagnosis of paranoid schizophrenia according to DSM IV criteria, was admitted to hospital due to the exacerbation of his positive psychotic symptoms. In view of his intolerance and poor response to previous typical and atypical antipsychotic trials, his treatment was switched to clozapine. The clozapine dose was slowly titrated up to 250 mg/day. In the second week of clozapine treatment, the patient reported nausea and vomited several times. Despite a thorough investigation of the upper GIS tract no GIS pathology could be identified. The patient was followed up with adequate IV hydration for 3 days. A few days after the initiation of his GIS complaints, a subfebrile fever of 99.7°F was observed to increase up to 100.4°F twice. His general state worsened and the patient was immobilized for 4 days due to lassitude. In addition to lassitude, he reported a cramp like pain on his left calve. A physical examination revealed that his left calve muscle was tender and firm with associated swelling, and the doppler sonography finding was thrombosis of the left popliteal vein. The thrombosis was diagnosed on the 13th day of clozapine treatment. Thereafter, clozapine was discontinued and a switch to trifluoperazine was decided. He was anticoagulated initially with heparin and later with warfarin, and anticoagulation was monitored with international normalized ratio (INR). The patient was a smoker, yet there was no well defined family history of thromboembolic events, other than the presence of a grandfather who had died of a stroke in his 80’s. The day after the patient’s anticoagulation with low moleculer weight heparin, the following hemostaseological parameters were examined and found to be in normal range: activity of prothrombin time-100% (70–120%), prothrombin time- 12.6 sec (11–15 sec), INR- 1 (0.75–1.5), activated partial thromboplastin time (a PTT)- 29.4 sec (29–47 sec), fibrinogen- 640 (144–430), activity of antithrombin III- 91 (80–120), free protein S- 98 (70–130%). However, activated protein C resistance was short (87.9 sec, normal range 120–300 sec), and two separate mutations of heterozygotic character, factor V Leiden and factor II (prothrombin), were detected. Other risk factors for thrombosis (homocysteinemiea, collagen tissue disease) were also examined; homocysteine level (11.53) was within normal range (5–15 umol/L) and anticardiolipin and antiphospholipid IgM and IgG measurements as well as antinuclear antibody findings were all negative.

The risk factors associated with venous thromboembolism can be classified as acquired and inherited [15]. The frequency of thromboembolism associated with clozapine treatment is reported to be 1 in 2000–6000 in different countries [11], [16]. Venous thromboembolism has been suggested to be associated with clozapine use, especially in the early 3 months of treatment [11], yet significant risk factors have not been clearly identified [9], [10], [11], [12], [13]. A few studies conducted [14], [16] have not supported the increased risk of thromboembolic events in atypical antipsychotic users. We suggest that this case history further supports the contention that clozapine should not be directly associated with thromboembolic events without definite exclusion of certain risk factors. Smoking, dehydration (due to unexplained GIS symptoms described), immobilization and, most important of all, factor V Leiden and prothrombin mutations detected appear to be sufficient risk factors leading to this complication in our patient. The presence of additional genetic risk factors, or nongenetic factors, such as oral contraceptive use, pregnancy, surgery, smoking, dehydration or trauma, enhance the thrombotic potential in heterozygous patients [15]. To our knowledge, there is one more report of a thromboembolic event in which the patient using clozapine was a carrier of factor V Leiden mutation [12]. In none of the other cases reported were these important parameters evaluated. It is possible that antipsychotic drug use may enhance the onset of thrombosis when such genetic factors are present. Strong evidence is still lacking that clozapine, if not all antipsychotics, is associated with thromboembolic events without any major risk factors involved.