Hoirisch-Clapauch Silvia, Nardi Antonio E
Department of Hematology, Hospital Federal dos Servidores do Estado, Ministry of Health, Rio de Janeiro, Brazil.
Institute of Psychiatry, Federal University of Rio de Janeiro, National Institute for Translational Medicine, INCT-TM, CNPq, Brazil.
Schizophr Res. 2014 Oct;159(1):118-23. doi: 10.1016/j.schres.2014.08.011. Epub 2014 Sep 7.
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.
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.
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.
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.
溶栓药物组织型纤溶酶原激活剂（tPA）及其终产物纤溶酶在神经化学中发挥着明确的作用。它们介导一系列最终导致对兴奋性毒性产生耐受性、海马神经发生、突触重塑、神经元可塑性、认知和情感加工的事件。这些过程的异常与精神分裂症的发病机制有关。
在大学医院连续选取70名成年精神分裂症患者（DSM-IV）和98名年龄匹配的对照，分析tPA/纤溶酶低活性的实验室指标。
除两名患者外，所有患者的标志物均为阳性（1 - 6，平均2.1）。29名患者和11名对照患有高胰岛素血症（44%对11%），20名患者和11名对照患有高甘油三酯血症（29%对11%）。胰岛素和甘油三酯均刺激纤溶酶原激活物抑制剂（PAI）-1的产生，PAI-1是主要的tPA抑制剂。19名患者和6名对照患有高同型半胱氨酸血症（27%对6%），这种情况会损害tPA的催化活性。15名患者（22%）存在游离蛋白S缺乏，但对照中无此情况，游离蛋白S缺乏会降低对PAI-1的抑制作用。21名患者（30%）存在中高水平的1 - 3抗磷脂抗体，而对照中无此情况。此类抗体能够抑制tPA/纤溶酶活性。PAI-1基因多态性4G/5G和杂合型凝血酶原G20210A在患者中更为普遍（分别为60%对48%和2%对1%），但差异无统计学意义。PAI-1基因多态性与高胰岛素血症具有协同作用。患者和对照中均未检测到蛋白C缺乏。
我们在一组精神分裂症患者样本中发现tPA/纤溶酶低活性标志物的高患病率。我们的研究结果应在大型研究中进行验证，最好是在未用药的患者中验证。
