Elsevier

Schizophrenia Research

Volume 159, Issue 1, October 2014, Pages 118-123
Schizophrenia Research

Markers of low activity of tissue plasminogen activator/plasmin are prevalent in schizophrenia patients

https://doi.org/10.1016/j.schres.2014.08.011Get rights and content

Abstract

Introduction

Clot buster tissue plasminogen activator (tPA) and its end-product plasmin play a well-defined role in neurochemistry. They mediate a number of events that culminate in tolerance against excitotoxicity, hippocampal neurogenesis, synaptic remodeling, neuronal plasticity, cognitive and emotional processing. Abnormalities in these processes have been implicated in schizophrenia pathogenesis.

Methods

Laboratory markers of low activity of tPA/plasmin were analyzed in 70 schizophrenia adults (DSM-IV), and 98 age-matched controls, consecutively selected at university hospitals.

Results

All but two patients had positive markers (1–6, mean 2.1). Twenty-nine patients and 11 controls had hyperinsulinemia (44% vs. 11%) and 20 patients and 11 controls had hypertriglyceridemia (29% vs. 11%). Both insulin and triglycerides stimulate production of plasminogen activator inhibitor (PAI)-1, a major tPA inhibitor. Nineteen patients and six controls had hyperhomocysteinemia (27% vs. 6%), a condition that impairs tPA catalytic activity. Fifteen patients (22%) but no controls had free-protein S deficiency, a condition that reduces PAI-1 inhibition. Twenty-one patients (30%) but no controls had 1–3 antiphospholipid antibodies in medium or/high levels. Such antibodies are able to inhibit tPA/plasmin activity. Both PAI-1 polymorphism 4G/5G and heterozygous prothrombin G20210A were more prevalent in patients (60% vs. 48% and 2% vs. 1%, respectively), but difference lacked significance. PAI-1 polymorphism was synergistic with hyperinsulinemia. Protein C deficiency was not detected in patients or controls.

Conclusion

We have found a high prevalence of markers of low tPA/plasmin activity in a sample of schizophrenia patients. Our findings should be validated in large studies, preferably in medication-naïve patients.

Introduction

We have previously reported that five patients with schizophrenia or schizoaffective disorders on warfarin therapy for long-term prevention of recurrent venous thromboembolism attained psychotic symptom remission and remain free of psychotropic medication for 2–11 years. On neuroimaging studies, none of these patients had brain ischemia (Hoirisch-Clapauch and Nardi, 2013a).

The only elements of the coagulation pathway that play a major role in the neurochemistry are clot buster tissue-plasminogen activator (tPA) and its end-product plasmin. tPA catalyzes important neuronal processes, such as cleavage of brain-derived neurotrophic factor precursor to anti-apoptotic mBDNF, proteolysis of vascular endothelial growth factor, N-methyl-D-aspartate (NMDA) receptor activation and regulation of dopamine release. As a result, tPA is involved in synaptic remodeling, neuronal plasticity, cognitive and emotional processing, in tolerance to excitotoxicity and hippocampal neurogenesis (reviewed in Hoirisch-Clapauch and Nardi, 2013b).

Assuming that psychotic symptom remission could have resulted from warfarin-induced normalization of tPA/plasmin activity, we decided to screen a group of schizophrenia patients for markers of low activity of these serine proteases, including metabolic markers (hyperhomocysteinemia, hyperinsulinemia and hypertriglyceridemia) and non-metabolic markers (lupus anticoagulant, anticardiolipin antibodies, anti-β2 glycoprotein 1 antibodies, low levels of functional protein C, low levels of free-protein S, 4G/5G polymorphism of the PAI-1 gene and prothrombin G20210A mutation). Two thrombophilias that do not affect the activity of tPA/plasmin, antithrombin III deficiency and factor V Leiden were also assessed. Results were compared to matched controls without any psychiatric disorder.

Section snippets

Study design

From January to December 2013, unrelated adults diagnosed with schizophrenia according to DSM-IV (American Psychiatric Association, 1994), and age-matched controls without a psychiatric diagnosis were consecutively recruited for the study. Patients and controls were respectively selected among in- and outpatients regularly seen at a psychiatric clinic and from the staff of a general hospital, in Rio de Janeiro, Brazil. Exclusion criteria consisted of pregnancy or the puerperium, use of

Results

Seventy-six patients were invited. Two declined and 74 were enrolled, but four failed to complete all aspects of the protocol. One hundred controls were invited and enrolled, but only 98 completed the study. Of the 70 patients studied, 68 had 1–6 markers of low tPA/plasmin activity (mean 2.1). Chronic patients and those studied during acute episodes exhibited the highest number of markers (3–6 markers per patient, mean 3.1). The two patients without markers were cocaine abusers at the time of

Discussion

Considering that most patients studied were not drug-naïve, it is possible that some of our findings were influenced by antipsychotic medication. Nonetheless, some authors have reported a high prevalence of markers of low tPA activity, such as antiphospholipid antibodies, hyperinsulinemia or hyperhomocysteinemia in medication-naïve schizophrenia patients (Delluc et al., 2014, Kale et al., 2010, Ryan et al., 2003). Additionally, it has been demonstrated that schizophrenia patients exhibit high

Limitations

One limitation of our study is that we did not take into account confounders such as high blood pressure, body-mass index, smoking, coffee-drinking, alcohol intake and drug abuse, recent acute psychotic episode, or schizophrenia duration. Additionally, it is imperative that our findings be validated in medication-naïve, first-episode patients.

Conclusions

We have found a high prevalence of markers of reduced tPA/plasmin activity in a sample of schizophrenia patients, compared to controls. Our findings should be validated in large studies, preferably in medication-naïve patients. Randomized controlled interventions are required to examine if interventions aimed at correcting tPA/plasmin activity may improve the course of schizophrenia.

Role of the funding source

This study was supported by grants from FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, E-26/110.643/2012), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, 456615/2013-0) and the National Institute for Translational Medicine (INCT-TM, CNPq).

Contributors

Both authors have equally contributed to the manuscript.

Conflict of interest

Dr. Hoirisch-Clapauch and Dr. Nardi report no biomedical financial interests or potential conflicts of interest.

Acknowledgment

The authors would like to thank the staff at IPUB for their help in data collection and staff at DASA laboratory for their technical support.

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