Dysfunction in the coagulation system and schizophrenia

Abstract

Although different hypotheses have been formulated to explain schizophrenia pathogenesis, the links between them are weak. The observation that five psychotic patients on chronic warfarin therapy for deep-vein thrombosis showed long-term remission of psychotic symptoms made us suspect that abnormalities in the coagulation pathway, specifically low tissue plasminogen activator (tPA) activity, could be one of the missing links. Our hypothesis is supported by a high prevalence of conditions affecting tPA activity in drug-naive schizophrenia, such as antiphospholipid antibodies, elevated cytokine levels, hyperinsulinemia and hyperhomocysteinemia. We recently screened a group of schizophrenia patients and controls for conditions affecting tPA activity. Free-protein S deficiency was highly prevalent among patients, but not found in controls. Free-protein S and functional protein C are natural anticoagulants that form complexes that inhibit tPA inhibitors. All participants had normal protein C levels, suggesting that protein S could have a role in schizophrenia, independent of protein C. Chronic patients and those studied during acute episodes had between three and six conditions affecting tPA and/or protein S activity, while patients in remission had up to two, which led us to postulate that multiple conditions affecting tPA and/or protein S activity could contribute to the full expression of schizophrenia phenotype. This paper describes the physiological roles of tPA and protein S, reviewing how their activity influences pathogenesis and comorbidity of schizophrenia. Next, it analyzes how activity of tPA and protein S is influenced by biochemical abnormalities found in schizophrenia. Last, it suggests future directions for research, such as studies on animal models and on therapeutic approaches for schizophrenia aiming at increasing tPA and protein S activity.

Antipsychotic treatment is associated with inflammatory and metabolic biomarkers alterations among first‐episode psychosis patients: A 7‐month follow‐up study

“…This is characterized by an elevation of IL‐6, and acute phase proteins (ie, ferritin and PAI‐1). Several previous studies have also noted elevated IL‐6 (Di Nicola et al, ; Stojanovic et al, ; Upthegrove et al, ), as well as increased levels of ferritin and PAI‐1 (Hoirisch‐Clapauch, Amaral, Mezzasalma, Panizzutti, & Nardi, ; Schwarz et al, ) in FEP or chronic patients. Reduced leptin level may be taken as reduced nutritional status of patients, reflecting somewhat reduced amount of fat tissue in antipsychotic‐naïve FEP patients.…”

Acquired Factor XII Deficiency in a Patient with Schizophrenia

“…Additionally, biological mechanisms of hypercoagulability and hypofibrinolysis can develop hypercoagulable state which is known as an important factor in developing thromboembolism in some schizophrenia patients [10]. Previous studies have shown associations between tPA activity, C and S proteins level, and thromboembolism risk in schizophrenia patients [3]. There is no evidence of a direct relationship between schizophrenia and coagulation factors.…”

“…On the other hand, schizophrenia is known as a complex neurodevelopmental disorder that various molecular pathways are involved in its pathogenesis. Recently, it has been demonstrated the link between hemostatic process and pathogenesis of schizophrenia [3]. Additionally, a protein-protein interaction study revealed the relationship between coagulation factor genes (III, VII and X) and antipsychotic-associated genes [4].…”

ATP-Nlrp3 Inflammasome-Complement Cascade Axis in Sterile Brain Inflammation in Psychiatric Patients and its Impact on Stem Cell Trafficking

“…Based on this we will provide supporting evidence that the occurrence of psychiatric disorders is linked to the presence of sterile inflammation induced primarily in the brain tissue or as result of systemic inflammation process in other organs that may affect the central nervous system [5][6][7]. It is well known that patients suffering from mental disorders often exhibit inflammation-related abnormalities in the peripheral blood, including elevated levels of circulating pro-inflammatory cytokines and chemokines, increased numbers of circulating monocytes and neutrophils, as well as enhanced reactivity of microglia, astrocytes, and brain endothelial cells to various pro-inflammatory signals [5][6][7][8][9][10][11][12][13][14].…”