Further Evidence for an Anti-Thrombotic Role for Tumor Necrosis Factor alpha.

Experiments in mice have suggested that TNFα can reduce thrombosis in vivo. Cambien et al., (2003) found that administration of TNFα decreased platelet aggregation, expression of P-selectin and binding of fibrinogen. This correlated with an increased bleeding time which was not seen in mice lacking inducible nitric oxide synthase or TNF receptor 1 and 2. That TNFα may act to reduce thrombus formation in humans has been suggested by isolated case reports where patients, following treatment with infliximab (Remicade, Centocor) to lower TNFα levels, developed a pro-thrombotic state. Complications include pulmonary thrombo-embolism, Budd-Chiari syndrome, deep venous thrombosis, retinal vein thrombosis and cerebral thrombophlebitis. These reports hint at a role for TNFα as an anti-thrombotic agent in humans but are confounded by the murine component of infliximab which may potentially trigger severe infusion reactions and could hence conceivably account for the thrombosis. We report two patients who developed pulmonary emboli following treatment with the alternative anti-TNFα therapies: etancercept (Enbrel, Wyeth) and adalimumab (Humira, Abbott). Both males were in their early sixties with long-established seropositive erosive rheumatoid arthritis and developed pulmonary embolus 4 months after introduction of etanercept 25 mg twice weekly (patient 1) and 6 months after commencing adalimumab 40mg fortnightly (patient 2). They presented to our regional hospital with signs and symptoms suggestive of pulmonary embolus secondary to deep vein thrombosis. Investigations including appropriate imaging studies and blood tests confirmed the diagnosis and the men were commenced on warfarin. Hypercoaguablility screening, including activated partial thromboplastin time, dilute Russell viper venom time, silica clotting time, antithrombin, protein C & S, cardiolipin IgG & IgM and factor II were all normal. Neither patient had antinuclear antibodies though both were positive for rheumatoid factor. Patient 2 alone was heterozygous for the Factor V Leiden mutation but had no previous personal or family history of thrombosis. Both patients continued on their respective anti-TNFα therapies and Patient 1 had a further serious thrombotic episode 6 weeks after completing a 6-month course of warfarin, indicating persistent thrombotic tendency on treatment. A causal link between thrombosis and anti-TNFα treatment is suggested by the absence of predisposing sources and the timing of the emboli which occurred shortly after introduction of therapy in patients with long disease histories and no prior evidence of hypercoagulability. Unlike infliximab, etanercept and adalimumab do not contain murine components. Etanercept is a soluble TNFα receptor whilst adalimumab is a fully humanized monoclonal antibody, thus ruling out immune reactions to foreign components as a cause of thrombosis. A review of the collected reports of adverse effects of medication maintained by the UK Medicines and Healthcare Regulatory Agency indicates that by June 2006 pulmonary embolus has been reported 16, 8 and 6 times in patients receiving infliximab, etanercept and adalimumab respectively. This data and our case reports suggest that TNFα acts to inhibit thrombosis in humans in vivo and raises the question of whether patients treated with agents designed to lower TNFα levels should be offered prophylaxis to reduce risk of thrombosis.