Low Protein Z Levels Research Articles

Protein Z measurement in acute myeloid leukemia patients

Background Protein Z (PZ) is a vitamin K-dependent plasma protein. The role of PZ in the pathogenesis of hemostatic disorders remains to be established. However, a significant association was found between low PZ levels and arterial vascular diseases, pregnancy complications and disseminated intravascular coagulation, stroke and antiphospholipid syndrome. On the other hand, it has been suggested that PZ deficiency is associated with hemorrhagic disorders, perhaps related to capillary fragility.Aim Measurement of the level of PZ in newly diagnosed acute myeloid leukemia (AML) patients and correlate it with bleeding tendency or thrombosis.Patients and methods This study was held on 90 participants divided into 60 adult (AML) patients and 30 healthy controls of matched age and sex from the Internal Medicine Department, Ain Shams University Hospital. Enzyme-linked immunosorbent assay kits are used for the estimation of PZ levels after taking informed consent.Results A low level of PZ was detected in AML patients compared with controls (P<0.001). A statistical correlation was observed between bleeding attacks and PZ level (P=0.008). The best cutoff value for PZ as a predictor for bleeding was more than 350 ng/l by the receiver operating characteristic curve.Conclusion Low PZ level is a cofactor of bleeding in AML patients.

Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults.

Protein Z (PZ) is a vitamin K-dependent plasma protein that exhibits both pro- and anticoagulant properties. Both low and high PZ levels have been linked to ischaemic stroke. Although PZ-lowering gene variants have been found to be less common in ischaemic stroke, the relationship remains unclear. We investigated PZ levels and PROZ variants in a multi-ethnic case-control study of unexplained stroke in participants aged 18 to 64. Plasma PZ was measured in cases (≥2 months post-stroke) and controls. PZ polymorphisms G79A (rs3024735) and A13G (2273971) were genotyped. A combined genetic score (0-4 minor alleles) was created assuming additive effects. A total of 715 individuals (1:1.4 cases:controls) was included. Analyses revealed evidence of a non-linear association. After adjusting for demographic and clinical covariates, PZ levels >2.5 µg/ml (90th %ile) were significantly associated with cryptogenic stroke (OR 2.41 [95 % CI 1.34, 4.34]) as compared with lower levels. Higher genetic score was related to progressively lower levels of PZ, and the presence of four minor alleles was associated with lower odds of stroke (adjusted OR 0.26 [95 % CI 0.07, 0.96]) versus 0 minor alleles. In this multi-ethnic study of young and middle-aged adults, there was evidence of a non-linear positive association between PZ level and unexplained stroke, with a directionally consistent association for genetic variants related to PZ levels and cryptogenic stroke. These findings support elevated PZ levels as a risk factor for cryptogenic stroke.

Protein Z Deficiency in Patients with Bleeding History. Is It a Coagulopathy?.

AbstractAbstract 2227 Introduction:Protein Z (PZ) is a vitamin K-dependent protein. In hemostasis PZ has two functions: together with Factor Xa it forms an inhibiting complex with the PZ- dependent protease-inhibitor and it enhances binding of Thrombin to phospholipid surfaces. Therefore, low PZ levels may induce thrombosis or bleeding.The latter has been questioned by Vasse 2008 and in 1995 Kemkes-Matthes reported in 58% of patients (pts) with a bleeding history PZ deficiency as the only abnormality. Aim of the study:To evaluate if low PZ levels are associated with a bleeding tendency, we reviewed data of pts referred to or laboratory. PZ determination is part of our diagnostic work up, including whole blood count, PT, PTT, VWF/FVIII-complex, FXIII and platelet function studies. Material and Methods:Over a 1 year period we investigated PZ level in 173 pts. PZ concentration was determined by ELISA (Asserachrom Protein Z; Diagnostica Stago), a sandwich immunoassay using a mouse monoclonal antibody against PZ, normal range 1600 – 3300 μg/l, mean 2600 μg/l published by Miletich. Our normal range obtained by 62 donors 990–2490, mean 1740μg/l (+/− 2SD). PZ <1000μg/l is considered to be abnormal. Results:In 75/173 (43%) pts with a bleeding history (e.g. postoperative hemorrhage, epistaxis, menorrhagia) no coagulation abnormality was detected. In 41/98 (42%) low PZ level was the only abnormality (mean PZ 642, range 195–994). 57/98 (58%) were diagnosed with vWD n=17; platelet function disorders n=10 or ASA/drugs causing platelet dysfunction n=20, others n=10. In 21/57 (37%) low PZ level was detected additionally (mean PZ 699μg/l; range 219–949) and in the remaining 36/57 (mean PZ 1689; range 1036–2842). Conclusion:Surprisingly, in 24% of pts with a bleeding history the only abnormality was PZ deficiency. Therefore, we consider PZ determination a useful parameter in patients with a bleeding history after ruling out more common disorders. Low PZ levels may cause a coagulopathy in some pts. Disclosures:No relevant conflicts of interest to declare.

Low Levels of Protein Z Are Associated With HELLP Syndrome and its Severity

Protein Z (PZ) was found to be associated with pregnancy complications. There are no data implying an association between hemolysis (H), elevated liver enzymes (EL), and low platelet counts (LP) (HELLP) syndrome and changes in plasma levels of PZ. The aim of this study is to investigate whether HELLP syndrome is associated with plasma concentrations of PZ. Protein Z levels in 29 women with HELLP syndrome were compared with 29 healthy, nulliparous and 25 normal pregnant women. The median PZ levels in patients with HELLP syndrome were found to be significantly lower than those of pregnant women. No significant difference was found between HELLP and healthy groups. Protein Z levels correlated with platelet counts, lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) levels in patients with HELLP syndrome. Median PZ level was higher in partial HELLP than in complete HELLP. We calculated 1330 ng/mL as a cutoff value for PZ level to discriminate HELLP syndrome from normal pregnancy. Low PZ levels are associated with the pathobiology of HELLP syndrome.

Low protein Z levels but not the protein Z gene G79A polymorphism are a risk factor for ischemic stroke

Background Protein Z (PZ) is a vitamin K-dependent plasma protein that plays a role in both pro-and anticoagulant pathways, but its exact physiological function remains unclear. The aim of this study was to determine the association between the G79A PZ gene polymorphism in intron F, PZ levels and the occurrence of ischemic stroke. Methods We performed a case–control study in 118 Caucasian patients with first ever ischemic stroke or TIA confirmed by CT, and 113 age-and sex-matched population controls. Venous blood samples for PZ levels were collected 7 to 14 days and 3 months after stroke onset. Estimates of relative risk (odds ratios) were adjusted for vascular risk factors. Results The adjusted relative risk of ischemic stroke associated with PZ levels in the lowest quartile versus the highest quartile was 3.0 (95% CI: 1.1–8.7) at 7–14 days, and 5.1 (95% CI: 1.2–21.9) at 3 months after the stroke. PZ levels in the convalescent sample were significantly lower than in the acute sample. In the convalescent sample, odds ratios increased with lower quartiles of protein Z level (test for trend p = 0.02). Thirty-nine patients (33%) and 32 (28%) controls were heterozygous for the G79A PZ gene polymorphism and 4 (3%) patients and 4 (4%) controls had the AA-genotype. The PZ levels were significantly lower in subjects with the AA-genotype and intermediate in heterozygote subjects. The odds ratio of ischemic stroke associated with A-allele carriers versus GG-homozygotes was 1.2 (95% CI: 0.7–2.1). Conclusion No association between the G79A PZ gene polymorphism and the occurrence of stroke was observed. However, low PZ levels are independently associated with an increased risk of ischemic stroke.

Protein Z levels and anti-protein Z antibodies in patients with arterial and venous thrombosis

Introduction The thrombotic risk associated with protein Z (PZ) deficiency is unclear. Anti-protein Z (anti-PZ) has been described as a risk factor in unexplained embryo demise. The aim of our study was to evaluate a possible PZ deficiency and presence of anti-PZ antibodies on thrombotic diseases. Material and methods We performed a case-control study on 114 patients with preexisting arterial or venous thrombosis (50 and 64, respectively). Thrombosis was studied based on etiology (creating factor risk subgroups) and on specific thrombotic disease. Results PZ levels of patients were significantly lower compared to controls (1709 + − 761.3 ng/mL vs. 2437 + − 964.7 ng/mL P = 0.001). The high arterial risk factor subgroup showed the lowest PZ level (1267.5 + − 609 ng/mL) whereas the rest of arterial and venous etiological subgroups presented similar PZ levels. Patients with peripheral artery disease had the lowest PZ level (1022 + − 966 ng/mL). The rest of arterial and venous thrombotic diseases presented similar PZ levels. A significant increased risk for arterial and venous thrombosis for the lowest (< 1685 ng/mL) quartile of PZ has been founded (OR:52, P = 0.001 and OR:18, P = 0.007, respectively). Anti-PZ antibodies were negative in the majority of patients, although mean anti-PZ IgG antibody levels in the arterial thrombosis group were significantly higher compared to venous thrombosis and control groups ( P = 0.05 and P = 0.005, respectively). Conclusions The results suggest that both arterial and venous thrombotic events are related to low PZ levels and that low PZ concentrations are associated with thrombosis in our study. In arterial thrombosis our findings strengthen previous studies that related low PZ levels to atherosclerotic disease. Anti-PZ antibodies do not seem to play a potent role in thrombosis.

Low protein Z levels in children with nephrotic syndrome

Acquired deficiency of anticoagulant proteins, due to loss in the urine, has been proposed as one of the major thrombogenic alterations in nephrotic syndrome (NS). Protein Z (PZ) is a single-chain vitamin K-dependent glycoprotein. Low PZ levels are reported to be a risk factor for thrombosis. The aim of this study was to investigate protein Z and other natural anticoagulant levels in children with NS. Thirty children aged between 1.5 and 12 years with NS (Groups I and II) and 19 age-and-sex-matched healthy controls (Group III) were enrolled into the study. Patients were divided into two groups: Group I (proteinuria >40 mg/m2/hr) and Group II (patients in remission). Plasma PZ levels in Group I were significantly lower than Group II (p=0.009) and group III (p=0.018). Plasma levels of AT III for Group I were significantly lower than for Groups II and III (p=0.009, p=0.005, respectively). Protein C levels in Group I were higher than in Group II and Group III (p=0.002, p=0.000, respectively). Protein Z levels positively correlated with serum total protein and albumin levels (p=0.003, p=0.003, respectively) and negatively with the degree of proteinuria (p=0.000). Protein Z levels were positively correlated with AT III (r=0.037, p=0.04). Along with the other coagulation abnormalities, decreased protein Z may contribute to increased risk of thromboembolic complications in children with NS. The negative correlation between proteinuria and PZ level suggests the possibility of renal PZ loss. Further studies are needed to investigate the mechanism and role of decreased PZ in NS.

Low Protein Z Levels and the Risk of Venous Thrombosis.

Background. Protein Z (PZ) is a vitamin-K dependent protein that serves as cofactor for PZ-dependent protease inhibitor, inactivating factor Xa. Therefore, deficiency of PZ could led to a prothrombotic phenotype. Contrasting data are available on the relationship between PZ and venous thromboembolism (VTE).Patients and Methods. We carried out a case-control study on 443 patients with deep vein thrombosis of the lower limbs and/or pulmonary embolism who discontinued oral anticoagulant therapy and 394 controls, similar for age and sex. PZ was measured with an enzyme immuno-assay (Diagnostica Stago, France). A thrombophilia screening including DNA testing for factor V Leiden and G20210A prothrombin mutation and measurements of plasma antithrombin, protein C, protein S, and homocysteine (fasting and post-methionine load) was performed. Pregnancy, oral contraceptive use, liver or renal disease were exclusion criteria.Results. 443 patients and 394 healthy controls who underwent thrombophilia screening were investigated. Median PZ levels (range) were 1.95 μg/mL (0.22–6.26 μg/mL) in patients and 1.79 μg/mL (0.25–7.82 μg/mL) in controls (p=0.07). The odds ratios (adjusted for age, sex and the presence of thrombophilia) for VTE in patients with PZ levels in the lowest quartile was 0.8 (95% CI 0.5–1.1), and remained statistically non significant considering PZ levels below the 10th percentile. However, low PZ levels (lowest quartile) increased the risk of VTE associated with factor V Leiden (odds ratio 14.6, 95% CI 1.9–113), prothrombin G20210A (odds ratio 3.2, 95% CI 1.0–10.3), and hyperhomocysteinemia (odds ratio 4.7, 95% CI 1.7–17.0). These interactions remained, apart for prothrombin G20210A, when PZ levels below the 10th percentile were considered.Conclusion. Low PZ levels are not an independent risk factor for VTE, but may enhance the relative risk due to already established risk factors, particularly factor V Leiden.

Antibodies against protein Z and fetal loss: current perspectives

Protein Z (PZ) is a vitamin K-dependent plasma protein that serves as a cofactor for the inactivation of factor Xa. A number of investigators found low PZ levels in patients with haemorrhagic as well as thromboembolic diseases, although there is no clear evidence of a pathogenic link between PZ deficiency and these clinical disorders. Nevertheless, low PZ levels have been found in association with early fetal losses, especially those occurring before the 15th week of gestation and in patients with detectable antiphospholipid and anti-PZ antibodies. The current diagnostic relevance and therapeutic consequences of these parameters will be discussed.

Autoimmune antiphospholipid antibodies impair the inhibition of activated factor X by protein Z/protein Z-dependent protease inhibitor

The hemostatic process is tightly regulated by several antithrombotic mechanisms. Among them, protein Z (PZ)-dependent protease inhibitor (ZPI) potently inhibits factor (F)Xa in a manner dependent on calcium ions, phospholipids and PZ. Autoimmune antiphospholipid antibodies (aPL) are mainly directed against phospholipid-binding plasma proteins such as beta2-glycoprotein I (beta2GPI) and prothrombin, and are known to interfere with phospholipid-dependent hemostatic pathways. In this study, we investigated whether purified aPL are able to interfere with inhibition of FXa by PZ/ZPI. beta2GPI modestly delayed the FXa inactivation by PZ/ZPI and most isolated aPL-IgGs were found to further increase the inhibitory potential of beta2GPI on PZ/ZPI activity. Without beta2GPI, the PZ/ZPI activity was unaffected by the addition of aPL-IgG. As PZ deficiency is hypothesized to lead to a prothrombotic state, we performed a case-control study to measure plasma levels of PZ and ZPI in 66 patients with autoimmune aPL and 152 normal controls. The prevalence of low PZ levels (below the 5th percentile of controls) was significantly greater in the 37 patients with definite antiphospholipid syndrome (APS) (24.3%) but not in the 29 aPL patients not fulfilling the criteria for APS (10.3%) compared with the normal group (4.6%, P < 0.001 vs. APS). ZPI antigen levels were similar in patients with aPL and normal controls. Concomitant PZ deficiency increased by approximately sevenfold the risk of arterial thrombosis in aPL patients. Taken together, these data suggest that the PZ/ZPI system is commonly impaired in aPL patients thus probably increasing the thrombotic risk.