Abstract
Clozapine is an atypical antipsychotic used for the treatment of schizophrenia. The prescribed target daily doses may reach 900 mg. Literature studies report a connection between clozapine usage and thrombosis development. Our in vitro study aimed to provide insight into molecular bases of this observation, investigating clozapine binding to fibrinogen, the main plasma protein involved in hemostasis. Fibrinogen/clozapine interaction was confirmed by protein fluorescence quenching, with an affinity constant of 1.7 × 105 M−1. Direct interactions did not affect the structure of fibrinogen, nor fibrinogen melting temperature. Clozapine binding affected fibrin formation by reducing coagulation speed and thickness of fibrin fibers suggesting that in the presence of clozapine, fibrinogen may acquire thrombogenic characteristics. Although no difference in fibrin gel porosity was detected, other factors present in the blood may act synergistically with altered fibrin formation to modify fibrin clot, thus increasing the risk for development of thrombosis in patients on clozapine treatment. ORAC and HORAC assays showed that clozapine reduced free radical-induced oxidation of fibrinogen. All observed effects of clozapine on fibrinogen are dose-dependent, with the effect on fibrin formation being more pronounced.
Highlights
Half a century after launch, the first "atypical" antipsychotic drug clozapine (Fig.1A) is still the only medication licensed for treatment-resistant schizophrenia
What is interesting is that the estimated affinity constant of fibrinogen for clozapine is an order of magnitude higher compared to human serum albumin (HSA)/clozapine complex [29]
It seems that preferential clozapine binding to fibrinogen over HSA will not significantly affect the distribution of the free drug in the circulation and its pharmacological properties
Summary
Half a century after launch, the first "atypical" antipsychotic drug clozapine (Fig. 1A) is still the only medication licensed for treatment-resistant schizophrenia. Prescribed in the target doses of 300 900 mg per day, clozapine is useful in the treatment of schizophrenia symptoms partially or fully resistant to treatment with other antipsychotic drugs, or accompanied by persistent suicidal or self-injurious behavior, by mechanisms that go beyond dopamine receptor (D2) blockade [1]. Known as coagulation factor I, the primary biological function of fibrinogen is in the process of hemostasis. This protein is involved in both primary hemostasis, by its interaction with blood platelets and secondary hemostasis, by fibrin clot formation [4]. Fibrinogen interacts with proteins, ions, and small ligands, which all affect its functional properties [4,5,6,7]
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