Showing papers on "Protein Z published in 2007"

Protein Z/Z-dependent protease inhibitor (PZ/ZPI) anticoagulant system and thrombosis

Abstract: A new anticoagulant system involving a serpin has been recently characterised. The protein Z/Z-dependent protease inhibitor (PZ/ZPI) system inhibits activated factors X, XI and IX by different mechanisms. By homology with other anticoagulant systems (antithrombin or the protein C/protein S), deficiency of the serpin (ZPI) or its cofactor (PZ) might imbalance the haemostatic system with thrombotic consequences. Evidence supports the in vivo anticoagulant role of this complex and the thrombotic consequences of its deficiency. Non-sense variations of the ZPI (W303X and R67X) have been associated with increased risk of venous thrombosis. Moreover, PZ deficient mice carrying the FV Leiden have a thrombotic phenotype. Finally, some reports suggest that PZ deficiency might increase the risk of thrombosis. However, other studies question the thrombotic relevance of both ZPI and PZ deficiencies. This system could play a redundant role in haemostasis that explains the conflicting results on its thrombotic potential, which might be exacerbated in combination with other prothrombotic factors.

Preeclampsia is associated with low concentrations of protein Z

Abstract: Objective. Protein Z, a vitamin K-dependent plasma protein, has an important role in the regulation of the coagulation cascade. Protein Z deficiency has been associated with unexplained pregnancy loss and adverse pregnancy outcome in patients with thrombophilia. This study was conducted to determine if preeclampsia (PE), small for gestational age (SGA), and fetal demise are associated with changes in maternal plasma concentrations of protein Z.Study design. This cross-sectional study included normal pregnant women (N = 71), patients with PE (N = 130), patients who delivered an SGA neonate (N = 58), and patients with fetal demise (N = 58). Maternal plasma protein Z concentrations were measured by a sensitive and specific immunoassay. Protein Z deficiency was defined as maternal plasma concentrations ≤5th percentile of the normal pregnancy group (≤1.59 µg/mL). Non-parametric statistics were used for analysis.Results. (1) Patients with PE had a lower median plasma concentration of protein Z than normal pregn...

Modifications of protein Z and interleukin-6 during the acute phase of coronary artery disease.

Abstract: Protein Z is a vitamin K-dependent plasma protein that acts as a cofactor for the inactivation of activated factor X by forming a complex with a specific plasma protein Zdependent protease inhibitor [1]. Over the past years, protein Z has been investigated in different prothrombotic conditions, ranging from ischaemic cerebrovascular disease through pregnancy complications to coronary artery disease, and a role for altered levels of this protein has been reported [2–4]. However, some uncertainties regarding the real role of this protein on the occurrence of such diseases still remain. In particular, the relationship between this protein and the inflammatory pathway has been scarcely investigated. Only two previous studies have analysed the interaction between protein Z and proinflammatory cytokines: in 1999 Undar et al. showed an inverse correlation between protein Z and interleukin6 in patients with haematological malignancies [5], while in 2002 Vasse et al., in an ‘in-vitro’ study, demonstrated that protein Z biosynthesis by hepatic cells was only weakly affected by some inflammatory cytokines [6]. Actually, the very broad range of protein Z levels shown within the normal population suggests that protein Z may act as an acute phase protein, possibly being regulated by inflammatory cytokines. However, no clear data regarding the interplay between inflammatory reactants and protein Z in patients with atherosclerotic diseases are present.

Low protein Z levels in patients with peripheral arterial disease

Abstract: Conflicting findings regarding the association between protein Z and atherosclerotic disease have been reported. The aim of this case-control study was to evaluate the role of protein Z in a peripheral localization of atherosclerosis. We studied protein Z levels in 120 patients (102 male, 18 female; median age: 75 years) admitted to the Unit of Vascular Surgery of the University of Florence with a clinical manifestation of peripheral arterial disease (PAD), and in 360 healthy subjects selected to be comparable to the patients group in terms of age and gender. Protein Z levels were found to be significantly (p<0.05) lower in PAD patients [1,594 (89-3,635) ng/ml] compared to the healthy control group [1,728 (300-3,736) ng/ml]. A logistic regression analysis showed, at univariate analysis, a significantly increased risk of PAD in patients with low levels of protein Z (<5th percentile of our control group: <601 ng/ml) (OR: 5.72, 95%CI 3.07-10.66; p<0.0001). After adjustment for age, gender and traditional cardiovascular risk factors the association was confirmed (OR: 5.83, 95%CI 2.83-12.01; p<0.0001). Moreover, a significant association between low protein Z levels and clinical severity of the disease, evaluated through Fontaine's stages, was reported after adjustment for age, gender, and traditional cardiovascular risk factors (general linear model, p for trend: 0.03). In conclusion, our data shows an association between low protein Z levels and the occurrence of PAD. These findings provide evidence for the role of protein Z in the pathogenesis of the atherosclerotic disease.

Prospective study of polymorphisms of the protein Z-dependent protease inhibitor and risk of venous thromboembolism.

Abstract: Prospective study of polymorphisms of the protein Z-dependent protease inhibitor and risk of venous thromboembolism -

Mutations R67X and W303X of the protein Z-dependent protease inhibitor gene and venous thromboembolic disease: a case–control study in Italian subjects

Abstract: The protein Z-dependent protease inhibitor (ZPI) is a single-chain glycoprotein, which appears to play a role in coagulation. In vitro studies indicate that this protein is a serpin and could act as inhibitor of coagulation [1, 2]. ZPI inhibits the activated factors X and XI by different molecular mechanisms and its inhibitory activity is enhanced by heparin. Low levels of either protein Z or ZPI have been shown to be associated with ischemic stroke [3, 4] and central retinal vein or artery occlusion [5]. No association was found between plasma levels of protein Z and ZPI and venous thrombosis [6, 7]. Nevertheless, it has been recently shown that, among 16 mutations/polymorphisms of ZPI gene, two nonsense mutations (R67X and W303X) were associated with venous thromboembolic disease (VTE) in New Zealand [8]. Considering both mutations, heterozygous subjects were 4.4% in VTE patients and 0.8% in normal controls. In that study, patients were included if they had their first thromboembolic event before the age of 60 years. Moreover, both patients and controls were European White subjects, of whom >90% of northern European ancestry, and the W303X mutation was more frequent than the R67X one. According to a different study, however, the W303X mutation was not present in any of 1018 Spanish patients with VTE, suggesting that this gene variant could be a founder mutation, restricted to specific population [9]. In that study, the R67X mutation was present in 0.9% of controls and 3% of VTE subjects. These conflicting data would indicate that the two nonsense ZPI gene mutations would play a thrombotic role only in specific ethnic groups, suggesting the relevance to test the frequency of these mutations in other populations. Therefore, aim of our study was to investigate the presence of the R67X and W303X mutations in thromboembolic Italian patients. Our study was conducted on DNA samples collected from 183 consecutive VTE patients (80 males, 103 females) with a first episode of venous thrombosis before 75 years old and 135 blood donors (64 males, 71 females) without a history of thromboembolism as normal controls. The R67X and W303X mutations were detected according to the bidirectional allelespecific PCR method published by Van de Water [8]. The R67X mutation was not present in any of the Italian VTE patients or control subjects. The W303X mutation was present in two Italian VTE patients (1.1%) and one control (0.74%). According to the v test, this difference was not statistically significant. The overall frequency of these ZPI gene mutations in control subjects was similar to that reported in the New Zealand study. However, with respect to the same study, the frequency of ZPI gene mutations in the Italian cohort of VTE patients was much lower. Among Italian VTE subjects, the two patients that D. Fabbro Istituto di Genetica, Policlinico Universitario di Udine, Udine, Italy

Plasma Protein Z and Protein C Inhibitors and Their Role in Hypercoagulability of Thalassemia

Abstract: A hypercoagulable state has been described in thalassemia patients, partly due to a deficiency of inhibitors, protein C (PC) in particular. Since a potential role of a new hemostatic factor named prot

Coagulation-related factors, thrombomodulin and protein Z, are not associated with risk for oral cancer.

Abstract: Background: The link between thrombosis and cancer has been well established. Levels of protein Z and thrombomodulin indirectly regulate thrombin productionl and therefore may affect cancer susceptibility. Patients and Methods: The functional polymorphisms -13A/G and -33G/A in protein Z and thrombomodulin genes (respectively) influence transcription. The two polymorphisms were investigated in 160 oral cancer patients and 168 controls of equivalent age, gender and ethnicity using restriction fragment length polymorphism typing. Results: The frequency of the -13G allele, which results in lower expression of protein Z gene, was not significantly elevated in patients compared to controls (8.1% and 6.3%, respectively; odds ratio 1.35, 95% confidence interval 0.72- 2.56). No carriers of the thrombomodulin low expression -33A allele were identified, underscoring the rarity of this allele in Caucasians. Conclusion: Inherited predisposition affecting protein Z or thrombomodulin levels does not modulate susceptibility to oral cancer. Any possible contribution of thrombin to oral oncogenesis may involve other factors. The link between thrombosis and cancer has been well established (1). Recently, some coagulation-related agents have been shown to influence the risk for oral squamous cell carcinoma (OSCC) and, therefore, the study of factors

Role of protein z in stroke.

Abstract: Protein Z (PZ) is a vitamin K-dependent plasma glycoprotein that acts as a cofactor for PZ-dependent protease inhibitor to inhibit coagulation factor X(a). Studies in mice suggest that that decreased blood PZ levels lead to reduced inhibition of blood coagulation, thereby predisposing to thrombosis; however, clinical studies in humans have yielded conflicting results. Among patients with stroke, some epidemiologic studies have reported that reduced PZ levels increase the risk of stroke, whereas others have reported no association between PZ levels and stroke, or that elevated PZ levels increase stroke risk. Polymorphisms involving the gene for PZ can influence the PZ concentration and some polymorphisms (eg, intron G79A AA allele) may be protective against stroke, particularly among younger individuals. Although the association between PZ levels and stroke appears to be stronger in younger patients and in patients who do not have conventional vascular risk factors, it remains unclear whether the link between PZ levels and stroke is confounded or causal or whether blood levels of PZ are altered as a consequence of the acute stroke event.

Protein Z and natural anticoagulants in children on peritoneal dialysis and hemodialysis

Abstract: Hemostatic alterations due to abnormalities in the coagulation and fibrinolytic system may occur in dialysis patients. Protein Z (PZ) is a vitamin K-dependent coagulation protein promoting assembly of thrombin with phospholipid vesicles. The aim of this study was to investigate PZ and natural anticoagulants in children on hemodialysis (HD) and peritoneal dialysis (PD). Protein Z, protein C (PC), protein S (PS), antithrombin III (AT III), and fibrinogen levels were studied in 24 PD, 13 HD patients and 23 controls. Plasma PZ levels in patients on HD were significantly higher than those on PD and control group (p = 0.04, p = 0.03). We observed elevated PC, PS and AT III activities in children on PD when compared to controls (p = 0.011, p = 0.003, p < 0.001). In HD patients, only PS activity was increased compared to controls (p = 0.016). PC and PS activities did not differ between PD and HD patients whereas AT III activity was higher in PD patients compared to HD patients (p < 0.001). Normal/high levels of PC, PS and AT III suggest that children on PD or HD treatment do not seem to have an increased risk of thrombogenesis due to reduction of these proteins. Increased PZ levels, however, might contribute to the hemostatic alterations in children on HD treatment along with other well known abnormalities.

Hybridization Probe Genotyping of the R67X Nonsense Polymorphism in the Protein Z-Dependent Protease Inhibitor Reveals a New R67Q Mutation

Abstract: The protein Z-dependent protease inhibitor (ZPI, gene symbol SERPINA10 , serine peptidase inhibitor, clade A, member 10) inhibits the hemostatic factors Xa and XIa, and in vitro studies indicate that it is an anticoagulant (1)(2). However, the exact role of ZPI in the coagulation system is still unknown. In a recent study, 1018 patients with an episode of venous thromboembolism and 1018 controls with no history of thromboembolic disease were screened for different ZPI polymorphisms(3). A multivariant analysis, which included the Factor V Leiden mutation and the prothombin 20210 G>A sequence alteration, showed that the R67X change is an independent risk factor for venous thrombosis. The calculated odds ratios were 3.32, 5.32, and 4.24 for ZPI-R67X, Factor V Leiden, and prothombin 20210 G>A, respectively(3). We designed an assay for rapid detection of the R67X mutation that involves real-time PCR and melting point analysis on a LightCycler 1.5 Instrument. Primers (5′-CAG CTT GCC AAG GAG AC-3′ and 5′-CTC TCT TGA TCT GGG TTT CAG T-3′; NM 016186 position 686–702 and …