蛋白Z和蛋白Z依赖的蛋白酶抑制剂在血栓性疾病中的作用

蛋白Z是一种维生素K依赖性蛋白,作为蛋白Z依赖的蛋白酶抑制剂(ZPI)的辅因子,在磷脂和钙离子存在的条件下,能够抑制因子Xa,ZPI也能抑制因子Ⅺa.蛋白Z,ZPI与血栓性疾病中的关系已有初步研究.     

蛋白Z和蛋白Z依赖的蛋白酶抑制剂研究进展

蛋白Z是一种维生素K依赖性蛋白,作为蛋白Z依赖的蛋白酶抑制剂(ZPI)的辅因子,在磷脂和钙离子存在的条件下,能够抑制因子Xa,ZPI也能抑制因子Xla。蛋白Z和 ZPI与血栓性疾病如心脑血管疾病、静脉血栓形成及不明原因流产等疾病的关系已有初步研究。     

蛋白质Z、蛋白质Z依赖性蛋白酶抑制物与卒中

蛋白质Z(proteinz,PZ)是一种维生素K依赖性蛋白,作为蛋白质Z依赖性蛋白酶抑制物(protein Z-dependent protease inhibitor,ZPI)的辅助因子,在磷脂和钙离子存在的条件下,能抑制凝血因子Ⅹa,使ZPI活性提高近1 000倍,从而在m栓形成过程中发挥作用.ZPI可单独抑制凝血因子Ⅺa.ZPI的活性也在抑制凝血因子Ⅹa和Ⅺa的过程中被消耗.文章对Pz、ZPI的生物特性及与卒中的关联做了综述.     

骨髓增生异常综合征患者血小板变化与血浆纤溶抑制物和蛋白Z的关系

目的探讨初诊骨髓增生异常综合征（MDS）患者血小板变化与血浆凝血酶激活的纤溶抑制物（TAFI）和蛋白Z的关系。方法初诊原发性MDS患者78例,其中血小板减少59例,血小板正常19例。另取40例同期健康体检者为对照组。采用酶联免疫吸附法测定各组血浆TAFI和蛋白Z浓度。结果 MDS患者血小板减少、血小板正常及对照组血浆TAFI、蛋白Z浓度差异有统计学意义（P均〈0.01）。MDS患者血小板减少组血浆TAFI水平与血小板计数呈负相关（r=-0.868,P〈0.01）,血浆蛋白Z水平与血小板计数呈正相关（r=0.924,P〈0.01）。MDS患者血小板正常组及对照组血浆TAFI及蛋白Z水平与血小板计数无关。结论初诊MDS患者血小板计数减少时血浆TAFI和蛋白Z水平的变化是一种代偿性的改变,有利于减轻出血倾向。     

蛋白Z与出血及血栓性疾病

血液凝血 抗凝、纤溶系统的失衡是引起出血和血栓性疾病的主要机制。抗凝蛋白在凝血过程中发挥着重要的调节作用 ,其中蛋白C(PC)、蛋白S(PS)、抗凝血酶等的作用机制已基本明确 ,蛋白Z(PZ)是近年来新发现的维生素K(VK)依赖性糖蛋白 ,对PZ的研究使我们对凝血机制有了新的深入了解。PZ有多种生物学作用 ,主要是介导了凝血酶与内皮细胞表面磷脂的结合 ,发挥抗凝活性。一、PZ概况Prowse及Esnouf[1] 首次从牛血浆中提取出一种新的VK依赖性蛋白的糖蛋白 ,属于丝氨酸蛋白酶抑制物超家族成员。在无Ca2 + 、PZ及磷脂存在时 ,PZ不依赖性蛋…     

C反应蛋白与缺血性卒中

C反应蛋白（CRP）是一种急相蛋白，是机体潜在炎症的征兆，在机体天然免疫过程中发挥着重要作用。近年来的研究表明炎症与缺血性卒中有关。文章就CRP与缺血性卒中发病和预后之间的关系做了综述。     

C反应蛋白与缺血性卒中

C反应蛋白(CRP)是一种急相蛋白,是机体潜在炎症的征兆,在机体天然免疫过程中发挥着重要作用。近年来的研究表明炎症与缺血性卒中有关。文章就CRP与缺血性卒中发病和预后之间的关系做了综述。     

肌节Z盘:心肌细胞的信号转导中心

近年发现，除形成Z盘的骨架蛋白外，还有许多蛋白定位于Z盘，如结合或募集离子通道、Na-Ca交换体、蛋白激酶、蛋白磷酸酶、磷酸二酯酶、蛋白水解酶、组蛋白乙酰转移酶与组蛋白脱乙酰化酶等的蛋白分子，参与了多条信号转导通道的信号调节作用。Z盘还能感知心肌细胞的应力与应变，使结合其上的一些蛋白向核转位，调节基因表达。另外，T管穿行于Z盘之间，可使各类调节信号能快速发挥作用。因此，Z盘部位实质上成为心肌细胞中的信号转导中心。     

C-反应蛋白与缺血性卒中

C-反应蛋白(CliP)是一种炎性标志物,其主要通过凝血纤溶、炎症和补体系统等发挥作用。已有大量研究证实CRP与缺血性卒中的风险性相关,并且在急性缺血性卒中后的循环中有高水平的表达。它的水平增高是不稳定性动脉粥样硬化疾病发生的危险信号,也预示着脑梗死患者的预后不良。降低ClIP水平有望可减少缺血性卒中的复发,改善其预后。     

高迁移率族蛋白 B1与缺血性卒中

高迁移率族蛋白 B1(high mobility group protein box 1, HMGB1)是一种典型的非组蛋白,在细胞核内具有多种功能。近年来的研究表明,HMGB1可释放到细胞外发挥广泛的细胞学效应。缺血性卒中是发病率和致残率最高的疾病之一。越来越多的证据表明,HMGB1在缺血性卒中的发生和发展过程中起到多种重要作用。文章就 HMGB1在缺血性卒中中的作用进行了综述。     

Protein Z in ischaemic stroke

Many risk factors associated with ischaemic stroke are known, including high levels of fibrinogen or factor VII. Protein Z is a vitamin K-dependent coagulation factor, which was found to promote the assembly of thrombin with phospholipid vesicles that might promote coagulation. Indeed, a low protein Z level may be associated with a varying bleeding tendency. Therefore, we hypothesized that high protein Z levels could induce a hypercoagulable state and performed a case-control study to investigate a potential association between high protein Z plasma levels and ischaemic stroke. We measured protein Z in plasma samples from 157 patients with stroke of unknown aetiology and 192 control subjects. All patients had survived an ischaemic stroke or transient ischaemic attack (TIA) for at least 2 months. We found an increased relative risk of ischaemic stroke with increasing protein Z levels, with an odds ratio of 4.3 [95% confidence interval (CI): 1.7--11] for protein Z plasma levels > or = 160%. Excluding patients with a history of venous thromboembolism from the analysis, the same result was obtained (odds ratio 4.2; 95% CI: 1.6--11.2). Using a logistic regression model, this association also remained significant (P = 0.04) after adjustment for established risk factors. Our data indicated that a high plasma level of protein Z is an independent risk factor for ischaemic stroke.     

Low protein Z levels and risk of ischemic stroke: differences by diabetic status and gender

Protein Z was recently shown to act as an essential cofactor for protein Z-dependent protease inhibitor, a potent downregulator of coagulation Factor Xa. Thus, deficiency of protein Z is hypothesized to lead to a prothrombotic state, but two publications reported opposing results for the relationship of protein Z levels with ischemic stroke in young European subjects (mean age 33-40 years). We performed a study of stroke in a different ethnic population of greater mean age (57 years) to further clarify this issue. An ELISA was developed to measure protein Z antigen in 154 patients with ischemic stroke and in 206 controls in a largely Hispanic population. Low plasma protein Z values were significantly associated with ischemic stroke except in diabetic subjects and females. The mean protein Z value was significantly lower in stroke cases than in controls for nondiabetic subjects [1.78 +/- 0.77 (S.D.) versus 2.28 +/- 0.88 microg/ml, P < 0.0001] and for males (1.90 +/- 0.90 versus 2.42 +/- 0.99 microg/ml, P = 0.0004). Stroke risk was higher in subjects with protein Z levels at or below the fifteenth percentile of controls (相似文献   

Protein Z in healthy human individuals and in patients with a bleeding tendency

Protein Z is a vitamin-K-dependent plasma glycoprotein; its physiological function is not clear. Low protein Z levels were found in patients with otherwise unexplained bleeding disorders. It was therefore suggested that low protein Z levels might be associated with a bleeding diathesis. In the present study we measured protein Z levels in plasma samples of 48 patients with a suspected bleeding disorder and in plasma samples of 200 healthy adult individuals. We found protein Z to have a wide normal range in healthy men and women. Significantly lower protein Z levels were observed in women compared to men, whereas no correlation was found with age or other vitamin-K-dependent coagulation proteins. None of the 48 patients with a bleeding disorder had a protein Z level below the normal range. However, protein Z was significantly lower in the group of male patients with a bleeding history as compared to healthy men. In conclusion, our data indicate that low-normal protein Z levels are not associated with a bleeding tendency. However, it remains to be determined whether a low protein Z level is a weak cofactor associated with an increased bleeding tendency and whether decreased or absent protein Z (conditions not detected in our patients) might constitute a haemorrhagic diathesis.     

Frequency of protein Z deficiency in patients with ischaemic stroke

Prothrombotic phenotype has been described in protein-Z deficient mice, but the thrombotic risk associated with protein Z deficiency in human beings is unknown. We saw a protein Z plasma concentration deficiency of about 20% in 169 patients, from two hospitals, who had ischaemic stroke, whereas the frequency in 88 controls was about 5%. We saw no increase in the frequency of protein Z deficiency in 56 patients with venous thrombophilia. However, why protein Z deficiency was only observed in arterial thrombosis remains unknown.     

Protein Z: a new factor of thrombophilia?

INTRODUCTION: Sometimes, in front of a clinical setting of thrombophilia, the biological findings are helpless. Therefore we suggest to test a protein Z deficiency. EXEGESIS: Protein Z is a vitamin-K dependent protein forming a complex with the Z protein-dependent protease inhibitor for inhibiting the activated factor X; so protein Z acts as a "natural low molecular weight heparin". The prothrombotic phenotype associated with protein Z deficiency includes early fetal losses (before the 20th week of gestation), early and relapsing venous thrombosis in patients with factor V Leiden mutation and somehow ischaemic stroke in young people. CONCLUSION: The protein Z deficiency seems to be associated with a particular prothrombotic phenotype including early fetal losses as well as early and relapsing venous thromboses in patients carrying the factor V Leiden mutation. It is unclear whether or not it plays a role as a thrombophilic factor especially in the arterial vascular field.     

High frequency of protein Z deficiency in patients with unexplained early fetal loss

The protein Z-protein Z-dependent inhibitor complex is a factor Xa inhibitor. Protein Z deficiencies have recently been described in patients with ischemic stroke. As placenta infarction leads to poor pregnancy outcome, we studied protein Z plasma concentrations in nonthrombotic, nonthrombophilic consecutive patients with unexplained pregnancy wastage. A significant amount of protein Z deficiencies was only found in the early fetal loss group (< 1 mg/L; 44 of 200, P < 10(-4)) and mainly in the case of fetal demise between the beginning of the 10th and the end of the 15th week of gestation (odds ratio, 6.7 [3.1-14.8], P < 10(-3)). These deficiencies were not due to partial vitamin K1 deficiency, and at least some of them were constitutional ones. In women, protein Z deficiency may induce an enhanced risk of severe placental insufficiency soon after the connection of maternal and fetal circulations.     

ALOX5AP与卒中

ALOX5AP位于染色体13q12-13,编码5-脂氧合酶激活蛋白(FLAP)。FLAP在调节白细胞三烯的形成中起关键作用。研究表明,携带此基因的人群患卒中的风险增高2倍。因此,ALOX5AP在卒中的发病机制中起着重要作用。     

R255h amino acid substitution of protein Z identified in patients with factor V Leiden mutation

The clinical significance of diminished protein Z in plasma is controversial. Studies in mice demonstrated that deficiency of protein Z dramatically increases the prothrombotic tendency of factor V Leiden mutation. This finding was confirmed by initial results in humans, indicating that thromboembolism in factor V Leiden patients with lowered protein Z level occurs earlier than in patients with normal protein Z levels. Consequently, the aim of our present study was to find out whether genetic alterations of protein Z were demonstrated in patients with factor V Leiden mutation and early onset of thromboembolic disease. DNA-sequencing of the protein Z gene was performed in two patients with factor V Leiden mutation, early onset of thromboembolism, and lowered protein Z levels. In both patients, R255H substitution of the protein Z gene was identified. Subsequently, the R255H substitution was also found in 12 of 132 additional patients. Patients presenting with the R255H substitution in addition to factor V Leiden mutation showed thromboembolic events more frequently than factor V Leiden patients without R255H substitution of the protein Z gene. In conclusion, R255H substitution of the protein Z gene seems to influence clinical symptoms of thromboembolism in factor V Leiden patients.     

Protein C deficiency and anticardiolipin antibodies in a family with premature stroke

Anticardiolipin antibodies and, rarely, protein C deficiency have been described in patients with stroke. The familial coexistence of these two prothrombotic defects has not been previously reported. We describe a family with debilitating strokes occurring at an early age in whom both anticardiolipin antibodies and protein C deficiency were found. The propositus and her deceased mother both suffered a stroke at age 50 years. The propositus had both anticardiolipin antibodies and protein C deficiency. After a detailed study of the remainder of the family, the tendency to form anticardiolipin antibodies appeared to be inherited independently of the protein C deficiency. The simultaneous occurrence of these abnormalities in one family suggests that it may be useful to test for both anticardiolipin antibodies and inherited anticoagulant protein deficiencies in patients with unusual or unexplained stroke. The differential expression of both protein C deficiency and anticardiolipin antibody production in various members of the described family may allow insight into the relative contributions of these two prothrombotic abnormalities for the development of thrombotic complications, including stroke.