clozapine and Thromboembolism

Clinical studies suggest that the second generation antipsychotics (APs) clozapine and olanzapine and to a lesser extent the typical antipsychotics may be associated with a procoagulant and proinflammatory state that promotes venous thromboembolism. We evaluated here several blood factors associated with coagulation and inflammation in AP-treated schizophrenia patients and their first-degree relatives.. Procoagulant factors (fibrinogen and plasminogen activator inhibitor [PAI-1]), the anticoagulant factor antithrombin III [AT-III], and inflammation-related factors (C-reactive protein [CRP] and leptin) were assessed in patients chronically treated with clozapine (n=29), olanzapine (n=29), typical APs (n=30) and first degree relatives of clozapine (n=23) and olanzapine subjects (n=11).. The typical AP group had the highest CRP level (p=0.013) in spite of having the lowest body mass index (BMI). Patients as a single group had higher CRP levels than relatives (p=0.003). The typical AP group also had the highest AT-III levels (p=0.021). Fibrinogen levels did not differ between the groups (p=0.13). Olanzapine patients displayed the highest PAI-1 and leptin levels among the drug-treated subjects, but values were similar to those observed in their relatives, and were significantly correlated with the BMI.. A homogeneous negative profile of high inflammation and procoagulant factors along with low levels of anticoagulants was not detected in any group. While preliminary, our results suggest that the observed abnormalities were not related to a direct drug effect, but to elevated BMI (high PAI-1 and leptin in olanzapine-treated patients). We speculate that the high CRP in the typical AP group might be related to poor lifestyle habits, but this must we confirmed in future studies.

Topics: Adult; Antipsychotic Agents; Antithrombin III; Benzodiazepines; Body Mass Index; C-Reactive Protein; Clozapine; Dose-Response Relationship, Drug; Female; Fibrinogen; Humans; Inflammation Mediators; Leptin; Life Style; Male; Middle Aged; Olanzapine; Plasminogen Activator Inhibitor 1; Risk Factors; Schizophrenia; Thromboembolism; Thrombophilia

1. Several studies suggest an association between venous thromboembolism and the use of antipsychotic drugs, especially clozapine, but the biological mechanisms are unknown. It has been suggested that antipsychotic drugs enhance aggregation of platelets and thereby increase the risk of venous thrombosis. The purpose of the present study was to examine the effects of clozapine and its main metabolite, N-desmethyl clozapine, as well as olanzapine, risperidone and haloperidol, on platelet adhesion and aggregation and on plasma coagulation in vitro. 2. Blood was collected from healthy subjects free of medication. Platelet adhesion to different protein surfaces and aggregation were measured in microplates. The coagulation methods of activated partial thromboplastin time (APTT) and prothrombin time were performed in platelet-poor plasma. 3. Clozapine was the only compound that increased platelet adhesion and aggregation and shortened APTT. The effect appeared at therapeutic concentrations and was significant but weak. 4. This weak effect of clozapine on haemostasis may explain, in part, the association of this compound and venous thromboembolism.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Coagulation; Blood Platelets; Clozapine; Dose-Response Relationship, Drug; Female; Haloperidol; Humans; In Vitro Techniques; Male; Middle Aged; Olanzapine; Partial Thromboplastin Time; Platelet Adhesiveness; Platelet Aggregation; Prothrombin Time; Risperidone; Thromboembolism; Venous Thrombosis

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Pulmonary Embolism; Schizophrenia; Thromboembolism; Venous Thrombosis

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Clozapine; Humans; Pulmonary Embolism; Thromboembolism; United States; Venous Thrombosis

Topics: Adrenergic Uptake Inhibitors; Amitriptyline; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Chlorpromazine; Clozapine; Humans; Imipramine; Incidence; Thromboembolism; Venous Thrombosis

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Risk Factors; Thromboembolism; Venous Thrombosis

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Pulmonary Embolism; Risk Factors; Schizophrenia; Thromboembolism; United States; United States Food and Drug Administration; Venous Thrombosis