Protein Z Levels Research Articles

Loss of Function in Protein Z (PROZ) is Associated with Increased Risk of Ischemic Stroke in the UK Biobank

BackgroundThe vitamin K-dependent coagulation factor protein Z (PZ), encoded by the PROZ gene, is canonically considered to have anticoagulant effects through negative regulation of factor Xa. Paradoxically, higher circulating PZ concentrations have repeatedly been associated with an elevated risk of acute ischemic stroke. ObjectiveWe performed a large-scale genetic association study to examine the relationship between germline genetic variants in PROZ and the risk of ischemic stroke. MethodsUsing whole exome sequencing and clinical data for 416,711 participants in the UK Biobank (UKB), we identified individuals with rare (MAF ≤ 0.1%) putatively function-altering variants in PROZ. Using Firth’s logistic regression and controlling for known stroke risk factors, we evaluated the association between variant carrier status and non-cardioembolic ischemic stroke (NCEIS). Additionally, we evaluated differences in the plasma levels of 1,472 proteins between PROZ variant carriers and non-carriers in a subset of 48,893 UKB participants. ResultsAfter accounting for missing data, qualifying variants in PROZ were identified in 414 UKB participants (99.0% heterozygous). Variant carriers had a significantly increased risk of NCEIS (OR=2.34, 95% CI: 1.15-4.13, P=0.02) but not of venous thromboembolism, myocardial infarction, or peripheral artery disease. Plasma proteomics analysis revealed that PROZ variant carriers had significantly elevated levels of two proteins related to the response to cerebral ischemia, peroxiredoxins 1 and 6 (PRDX1, fold-change=1.83, P=1.3 x 10-5 and PRDX6, fold-change=1.78, P=9.6 x 10-10). ConclusionsLifelong exposure to decreased PZ levels confers a significantly increased risk of NCEIS, consistent with the role of PZ as an anticoagulant factor.

Plasma levels and urinary excretion of protein Z in patients with urolithiasis.

Protein Z (PZ) is a γ-carboxyglutamic acid protein present in plasma that is involved in blood coagulation. Detailed analysis of urinary stones from patients with urolithiasis has revealed that PZ is often found in urinary stones composed of calcium oxalate monohydrate. In this study, we compared blood and urinary PZ concentrations between healthy individuals and patients with urolithiasis. Plasma and urine were collected from healthy individuals and patients with urolithiasis who provided informed consent. PZ was detected as a urinary stone matrix protein in some of the patients. PZ was quantified by ELISA, creatinine was measured by the enzymatic method, and the total protein concentration was measured by the Bradford method. The plasma PZ level was 2.54 ± 1.02 μg/mL in healthy individuals and that in urolithiasis patients classified by stone history were from 1.16 ± 0.77 to 3.73 ± 1.09 μg/mL, which was not significantly different. The urinary excretion of PZ (PZ/creatinine) was also not different in patients with urolithiasis and in healthy individuals (from 54.1 ± 40.9 to 95.4 ± 69.4 ng/mg vs. 73.3 ± 36.0 ng/mg). A positive correlation was found between the plasma PZ level and creatinine-corrected urinary PZ concentration (r = 0.46). Both the plasma level and urinary excretion of PZ in urolithiasis patients were not significantly different with normal individuals. PZ detected in urinary stones as a matrix protein is thought to be incorporated into urinary stones regardless of blood and urine levels of PZ.

Plasma Levels of Protein Z in Ischemic Stroke: A Systematic Review and Meta-Analysis.

The association between blood levels of protein Z (PZ) and risk of ischemic stroke remains poorly understood. We aimed to assess this potential relationship through a meta-analysis of case-control studies. PubMed, Scopus, Web of Science Core Collection, and the Cochrane Library were searched from April 1984 to April 2019. We selected case-control studies comparing PZ levels in adult patients with ischemic stroke and controls without ischemic stroke. Six case-control studies, with a total of 1,011 ischemic stroke patients and 1,128 controls, were included. Patients in the acute phase of ischemic stroke showed significantly higher levels of PZ compared with patients in the convalescent phase (standardized mean difference [SMD]: 0.289 mg/L; 95% confidence interval [CI]: 0.010, 0.569; p = 0.043). No significant differences in PZ levels were found between patients and controls in the acute phase (SMD: -0.059 mg/L; 95% CI: -0.570, 0.452; p = 0.821) or in the convalescent phase of ischemic stroke (SMD: -0.341 mg/L; 95% CI: -0.736, 0.055; p = 0.091). Subgroup analysis indicated that older patients (≥ 50 years old) had lower PZ levels than similarly aged controls. In contrast, when the study groups came from the United States and Australia or Europe no significant differences in PZ levels existed between patients and controls. No association between PZ and ischemic stroke was identified in this meta-analysis. The acute phase of ischemic stroke was associated with higher levels of PZ.

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.

Plasma Concentrations of Protein Z and Protein Z-Dependent Protease Inhibitor in Thalassemia Major Patients

Thalassemia is the most common congenital hemolytic disorder by a partial or complete deficiency in globin chain synthesis. Recent investigations have suggested a correlation between protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) deficiency and thrombosis. So, the aim of this study was to evaluate the PZ and ZPI levels in beta (β)-thalassemia patients. In this study, 40 patients with thalassemia major and 40 control subjects were selected. PZ and ZPI serum levels were measured by sandwich ELISA technique. PZ and ZPI were significantly higher in thalassemic patient group than control group. Also, PZ levels and PLT and Hb counts were significantly higher in splenectomized thalassemic patients than non-splenectomized ones. The exact mechanism of increased PZ and ZPI have an impact on hypercoagulable state in β-thalassemia major could not be found in our study. More studies are still needed to understand these challenges in β-thalassemia major patients.

PB1778 ESTIMATION OF PROTEIN Z LEVEL IN ADULT NAÏVE ACUTE MYELOID LEUKEMIA PATIENTS

Background:The occurrence of various coagulation abnormalities in acute leukemia is well established, but there are no data assessing the role of protein Z (PZ), a vitamin K‐dependent plasma protein in hemostatic disorder in hematology cancers, including acute leukemia, The potential role of alterations of PZ levels in the pathogenesis of disorders of coagulation has been investigated and revealed conflicting results as Protein Z (PZ) deficiency may induce bleeding as well as thrombosis.Aims:to estimate the level of protein Z in Acute Myeloid Leukemia (AML) patients and its correlation with bleeding tendency or thrombosisMethods:PZ level was measured by ELISA kits in 60 adult naïve (AML) patients aged above 16 years old and 30 healthy controls after informed consent from Clinical Hematology Unit, Ain‐Shams University Hospital and correlated it with bleeding and thrombotic episodes. Patient on oral anti‐coagulant regularly, Inherited bleeding disorder, Inherited thrombophilia were excluded.Results:The median PZ level was lower in AML Patients in comparison to healthy controls{205ng/L (150 – 340) vs 349.5ng/L (274 – 400) with p value &lt; 0.001}.No statistically significance correlation between protein Z level with initial platelet count(P value 0.323). A statistically significant correlation was detected between episodes of bleeding and PZ level (P value 0.008). By utilizing ROC curve, the best cutoff value for protein Z as a predictor for bleeding episodes during induction was found &gt;350ng/L.Summary/Conclusion:Conclusion: The results suggest that PZ level was lower in AML patients than healthy control and it was correlated with bleeding episodes. can be a cofactor associated with an increased bleeding tendency in AML patients.Summary: PZ can be a cofactor associated with an increased bleeding tendency in AML patients.

Association of Protein Z intronic G79A Polymorphism with susceptibility to deep vein thrombosis in Egyptian patients with Behcet's disease: A preliminary report

Behcet disease (BD) is a multi-systemic inflammatory disorder, which can affect all types of blood vessels. Thrombotic vasculopathy is one of the major causes complicating the clinical course of BD. This study aims to investigate potential associations between G79A polymorphisms of the protein Z (PZ) gene and venous thrombosis as well as other clinical manifestations in Egyptian patients with BD. Sixty patients who satisfied the International Study Group criteria for BD and sixty healthy age and sex- matched control subjects were genotyped for G79A polymorphisms of the PZ gene by restriction fragment length polymorphism PCR. Plasma levels of PZ were estimated using enzyme linked immunosorbent assay kit. Our preliminary data revealed that, compared to the GG genotype, the AA and AG PZ intron F genotypes were significantly associated with BD susceptibility and with reduced plasma PZ levels. The patients were then subgrouped according to Protein Z G79A genotypes to examine the G79A genotype frequencies according to the clinical characteristics, where there was a statistically significant association between AG and AA genotypes frequencies and deep venous thrombosis. In conclusion, our study nominates the minor A allele of the PZ G79A polymorphism as a discriminatory genetic marker for identification of BD patients at high risk for developing thrombotic events. However, large scaled studies are needed to verify these preliminary results.Key words: Behcet's disease; Protein Z; Deep vein thrombosis; intron F G79A polymorphism.

Low Protein Z Level: A Thrombophilic Risk Biomarker for Acute Coronary Syndrome.

Acute coronary syndrome (ACS) encompasses a range of thrombotic coronary artery diseases. Protein Z (PZ)/PZ-dependent protease inhibitor complex is a natural anticoagulant system with a presumptive role for PZ deficiency in the pathogenesis of ACS. We aimed to evaluate plasma PZ level and role as a risk biomarker in Egyptian patients with ACS. Hundred patients with stable ACS and 60 matched controls were enrolled. ACS patients were divided into 3 clinical subgroups (ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina), and 2 age subgroups (group A ≤ 55years, and group B > 55years). Plasma PZ levels were evaluated using enzyme linked immunosorbent assay. Lower PZ levels were found in ACS patients' group and clinical subgroups compared with controls. PZ levels showed a decrease with increasing age and were lower in females versus males. Lower PZ levels were found in hypertensive ACS patients in both age subgroups. Smokers and patients with family history of ACS in group A had lower PZ levels, while group B revealed lower PZ among diabetic patients. In group A, increased number of ACS conventional risk factors was associated with lower PZ levels. PZ level 3.7μg/mL was the best cut-off value for prediction of ACS. Logistic regression analyses approved PZ as an independent risk biomarker for ACS. PZ levels are reduced in stable ACS and are significantly and independently associated with increased susceptibility for ACS, denoting PZ deficiency as a reliable thrombophilic risk biomarker in Egyptian patients with ACS.

Low plasma protein Z levels are associated with an increased risk for perioperative bleedings.

Protein Z (PZ) deficiency has been implicated both in bleeding diatheses and in thrombophilia. Considering its ambiguous nature and the conflicting clinical data so far, we set out to evaluate the impact of low PZ on perioperative bleeding in patients who underwent surgical (ENT) interventions involving a high risk of bleeding. After exclusion of other coagulation disorders, 154 Patients were stratified into quartiles according to PZ plasma concentrations to evaluate the relation between PZ and bleeding complications. Low PZ levels were associated with increased blood loss (P<.001), increased need for blood transfusions (P<.001), and a higher rate of surgical revisions (P=.009) in a concentration-dependent fashion. Low PZ caused earlier (within 24hours) and repetitive bleedings (P=.005). The number of major bleeding episodes was significantly increased when low PZ was combined with bleeding history (P<.05). Finally, ROC analyses confirmed the predictive value of low PZ for bleeding complications and PZ-thresholds for clinical practice were determined. Low PZ appears to be an underestimated risk factor for perioperative bleeding. Determination of PZ plasma concentrations might be useful in the preoperative workup in patients with a bleeding history, when detailed clotting analyses remain inconclusive.

Low Protein Z levels in patients with plasma cell neoplasms are inversely correlated with IL-6 levels

Patients with multiple myeloma (MM) have an increased thrombotic risk, but pathogenesis remains uncertain. Low levels of Protein Z (PZ), a vitamin K-dependent plasma protein, are associated with venous as well as arterial thrombosis. The purpose of this study was to analyze PZ levels in patients with plasma cell neoplasms. Patients and methodsThe study consisted of 64 plasma cells neoplasm patients and 42 healthy individuals. Clinical investigations included measurement of plasma PZ and IL-6 levels. ResultsPZ levels in patients with plasma cell neoplasms were significantly lower compared to healthy controls in the entire cohort (1392±659 vs.2010±603ng/mL, P<0.01), as well as in specific disease subgroups; symptomatic MM (1428±652ng/mL, p<0.01), smoldering MM (1437±883ng/mL, p=0.045) and monoclonal gammopathy of undetermined significance (MGUS) (1247±593ng/mL, p=0.01). PZ was negatively correlated with IL-6 levels in MM patients (r=−0.7, P<0.01). There was no significant difference in PZ levels between patients with or without thrombotic event. ConclusionPlasma cell neoplasm patients have low levels of PZ. This is presumably related to the increased IL-6 production by the bone marrow microenvironment, and could have a potential role in the increased thrombotic tendency in those patients.

Assessment of the Procoagulant Activity of Microparticles and the Protein Z System in Patients Undergoing Off-Pump Coronary Artery Bypass Surgery.

To understand the coagulation changes after off-pump coronary artery bypass (OPCAB) surgery, we evaluated the procoagulant activity of microparticles (MPs) and microparticles exposing tissue factor (MPs-TF), together with the levels of total tissue factor (TF), protein Z (PZ), protein Z-dependent protease inhibitor (ZPI), and factor X (FX) before (first day) and 1 week after surgery (seventh day) in plasma samples from 30 patients. Twenty healthy controls were also included. Compared to the controls, patients scheduled for surgery had significantly higher MPs-TF procoagulant activity and lower TF levels ( P = .0006, P = .02, respectively). In the whole cohort, median procoagulant activity of MPs-TF and median levels of TF and ZPI were significantly lower ( P = .02, P = .0003, and P = .004, respectively), while median levels of PZ and FX were significantly higher ( P = .02 and P = .002, respectively) on the seventh day compared to the first day. Our results suggest that OPCAB surgery has a significant effect on the procoagulant activity of MPs-TF and the PZ system.

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.

Influence of protein Z plasma level on thrombin generation assay

Introduction: Protein Z (PZ) is a vitamin K-dependent factor, involved as a cofactor of PZ-dependent protease inhibitor (ZPI) that inhibits the activated factor X on phospholipid surface. A severe PZ deficiency could be associated with ischemic arterial diseases. The aim of this study was to evaluate the influence of PZ plasma levels on thrombin generation (TG) and to detect a hypercoagulable state in patients with PZ deficiency.Patients and Methods: Young patients with personal history of arterial thrombosis and PZ deficiency were included. PZ concentrations were assessed using ELISA method. TG assay was performed using PPP containing 5 pM or 1 pM tissue factor and 4 μM phospholipids with and without thrombomodulin. Then, we focussed on the influence of successive overloads with purified PZ in two patients with PZ deficiency (Pat1PZdef and Pat2PZdef) and industrial PZ deficiency (IndPZdef).Results: First, in 13 patients with PZ deficiency, none influence of PZ level was reported on TG assay parameters. Second, TG profiles performed on Pat1PZdef, Pat2PZdef and IndPZdef were close to the reference TG profile. In presence of TM, there was no difference in TG parameters according to PZ plasma levels. After each overload, real PZ plasma levels were underestimated; differences in standards of purified PZ between the two manufacturers might explain such results.Conclusion: The absence of influence of PZ concentration on TG assay is reliable to the absence of well-demonstrated clinical consequences of PZ deficiency in arterial thrombosis. Clinical consequences of protein Z deficiency warranted further studies.

Prominent protein Z-induced thrombin inhibition in cirrhosis: a new functional assay for hypercoagulability assessment.

Protein Z (PZ) is an anticoagulant that accelerates the inhibitory effect of PZ-dependent protease inhibitor (ZPI) on coagulation factor Xa. We assessed functional status of PZ system in 158 patients with liver cirrhosis and 59 healthy controls. Plasma PZ and ZPI levels were measured by enzyme immunoassay. Thrombin generation assays (TGA) were performed with and without thrombomodulin (TM) or PZ, and the ratios were calculated by dividing TGA values with TM or PZ by values without TM or PZ. PZ and ZPI levels were reduced and elevated in advanced cirrhosis, respectively. The lag time ratio-PZ was significantly higher in cirrhosis patients than controls and correlated with the model for end-stage liver disease score. The peak thrombin ratio-PZ and endogenous thrombin potential (ETP) ratio-PZ were significantly lower in cirrhosis patients than controls and correlated with the severity of liver cirrhosis. The peak thrombin ratio-PZ was dramatically reduced in advanced cirrhosis. Cirrhosis patients had a significantly higher ETP ratio-TM than the controls, although the ratio was not correlated with cirrhosis severity. The lag time ratio-PZ and peak time ratio-PZ were significantly correlated with the levels of all coagulation and anticoagulation factors. Interestingly, the lag time ratio-PZ and peak thrombin ratio-PZ were significantly associated with thrombotic events. The anticoagulant role of PZ is insufficient in advanced stages of cirrhosis. Our newly developed functional assay for measuring the PZ system is expected to reflect the ongoing hypercoagulability of cirrhosis.

Protein Z Variants Associated With Protein Z Plasma Levels and With Risk of Idiopathic Recurrent Miscarriage

Protein Z (PZ) deficiency due to anti-PZ autoantibodies and/or mutations in PZgene was linked with adverse pregnancy outcomes, including idiopathic recurrent miscarriage (IRM). We investigated the association of rs3024718, rs3024719, rs3024731, rs3024778, rs3024772, and rs3024735 (G79A) PZ variants and changes in PZ levels in 287 women with IRM, and 308 control women. Of the 6 single nucleotide polymorphisms (SNPs) analyzed, higher minor allele frequency of rs3024735 (G79A) and rs3024731 were seen in IRM cases than in control women. Significantly higher frequencies of rs3024735/G79A G/A and A/A (P< .001), rs3024719 G/A (P= .009), and rs3024731 A/A (P = .012), but not rs3024718 (P= .12), rs3024778 (P = .76), or rs3024772 (P= .27) genotype carriers were seen between IRM cases versus control women, respectively, and was linked with reduced PZ levels. Six-locus (rs3024718/rs3024719/rs3024778/rs3024731/rs3024735/rs3024772) PZhaplotypes analysis demonstrated increased frequency of GAGAAG and AGGTAG and reduced frequency of AGGTGC haplotypes in IRM cases, thereby conferring disease susceptibility and protective nature to these haplotypes, respectively. These results demonstrate that specific PZSNPs and haplotypes are significantly associated with IRM.

Protein Z, an anticoagulant protein with expanding role in reproductive biology

Protein Z (PZ) is a vitamin K-dependent factor characterized by its homology to other vitamin K-dependent factors (factors VII, IX, and X, protein C and protein S), but lacks any enzymatic activity. Instead, PZ acts as a cofactor for the inhibition of factor Xa through the serpin PZ-dependent protease inhibitor (ZPI). PZ deficiency is associated with a procoagulant state, highlighted by excessive FXa secretion and thrombin production, and is linked with several thrombotic disorders, including arterial vascular and venous thromboembolic diseases. A role for the PZ-ZPI complex in the regulation of physiological pregnancy has been demonstrated, highlighted by the progressive elevation in PZ levels in the first trimester of gestation, which then steadily decline toward delivery. An association between altered plasma PZ concentrations and adverse pregnancy outcomes (recurrent miscarriage, stillbirth, preeclampsia, intrauterine growth restriction, and placental abruption) has been reported. The mechanism by which PZ deficiency leads to adverse pregnancy outcomes is not clear, but it is multifactorial. It may be attributed to the anti-PZ IgG and IgM autoantibodies, which apparently act independently of classical antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies). PZ deficiency has also been reported to be constitutional, and a number of variants in the PROZ (PZ) gene and SERPINA10 (ZPI) gene are linked with specific adverse pregnancy complications. This review summarizes the relationship between adverse pregnancy outcomes and acquired and constitutional PZ-ZPI deficiency, in order to understand whether or not PZ deficiency could be considered as a risk factor for poor pregnancy outcomes.

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.

Protein Z Concentrations in Patients With Acute Leukemia

Protein Z (PZ) deficiency may induce bleeding as well as thrombosis. The aim of our study was to estimate the concentration of PZ in patients with acute leukemia. Plasma levels of PZ were determined in 76 patients with newly diagnosed acute leukemia ([AML], n = 50; acute lymphoblastic leukemia [ALL], n = 26) and 62 healthy participants. In the patients, mean plasma concentrations of PZ were statistically lower than in healthy individuals: AML (1.24 ± 0.11 μg/mL vs 1.58 ± 0.05 μg/mL P = .01) and ALL (1.19 ± 0.16 μg/mL vs 1.58 ± 0.05 μg/mL P = .01). Levels of PZ below the fifth percentile (0.873 μg/mL) of normal value distribution in control participants were found in 30% of patients with AML and ALL and in 3% of controls (P < .0001). In this AML subgroup, we found statistically significant correlation between episodes of bleeding and PZ level (P = .01). There was no such correlation in ALL group. The results suggest that PZ can be a cofactor associated with an increased bleeding tendency in patients with AML.

Protein-Z Deficiency and/or Protein Z Polymorphisms in First Trimester Pregnancy Complications

Abstract 1221 INTRODUCTION:Protein Z (PZ) is a vitamin K-dependent coagulation factor; it is a glycoprotein that inhibits activated factor Xa, acting as a co-factor to PZ-dependent protease inhibitor, enhancing its action approximately by 1000 times. PZ levels in normal individuals vary greatly, as a result of PZ gene polymorphisms. PZ deficiency has been involved in the pathogenesis of ischemic strokes and pregnancy complications. Gris et al [Blood 2002;99(7):2606–08] first described a possible role of PZ deficiency (PZ <= 1mg/L) in women with fetal loss between the beginning of the 10th and the end of the 15th week of gestation. In a recent meta-analysis [Sofi et al, Thrombosis and Haemostasis 2010;103(4):749–56] PZ deficiency was associated with increased risk of pre-eclampsia and fetal loss, as well as with increased risk of arterial and venous thrombotic events. MATERIALS-METHODS:We studied a total of 314 women, 70 women with three or more consecutive spontaneous abortions (group A), 145 women with less than 3 early spontaneous abortions (group B) and 99 control women with at least one normal pregnancy and negative history of a thrombotic complication (group C). All women were tested for congenital and acquired thrombophilia such as antithrombin, protein C and S levels, homocysteine levels, lupus anticoagulant (PTTLa), factor V Leiden mutation, prothrombin G20210A gene polymorphism and PZ levels. We also investigated protein Z polymorphism F79A in a subgroup of our patients. Measurements were made at least 3 months apart from a thrombotic event. Differences between groups were assessed with ANOVA and chi-squared tests for continuous and categorical variables respectively. RESULTS:Statistically significant difference was found in PZ levels between the three groups. Mean PZ level was 1.23mg/dL, 1.31mg/dL και 1.61mg/dL (p<0.00001) in groups A, B, C respectively. Post-hoc Bonferroni analysis revealed a significant difference between groups A and C (p=0.0003) and between groups B and C (p=0.001). The percentage of PZ deficiency (95% condidence interval) was 40% (28%–52%), 38% (30%–46%) and 18% (11%–26%) respectively (p=0.001). Both group A (OddsRatio[OR]=3) and group B (OR=2.75) have a statistically greater PZ deficiency than control group C. The other parameters did not differ significantly between the three groups. DISCUSSION/CONCLUSIONS:Spontaneous abortions are common in women especially in first trimester. Thrombophilia has a major role in pregnancy complications. In these women that one cannot find some of the well established thrombophilic factors, searching for other possible deficiencies is necessary. The role of PZ deficiency has been investigated thoroughly in the last decade with sometimes conflicting results. To the best of our knowledge, this is the first Greek study investigating the possible role of protein Z deficiency in women with early pregnancy losses. From our study it is evident that PZ deficiency is an independent risk factor for early pregnancy losses. From our study it seems that the other thrombophic factors may play a minor role. A plausible pathophysiologic explanation is the occurrence of microthrombi due to atherosclerotic lesions soon after the development of materno-placental circulation. The role of PZ gene polymorphisms in PZ levels and in thrombotic complications remains to be investigated further. According to preliminary results from a sub-group of our patients (Topalidou et al, Thrombosis Research 2009;124:24–27), the presence of the intron F79A polymorphism was associated with significantly lower PZ levels, but was unrelated to unexplained early pregnancy losses. Disclosures:No relevant conflicts of interest to declare.

Protein Z levels in pregnant Omani women: correlation with pregnancy outcome

Placental insufficiency resulting in fetal loss has been recognized in women with thrombophilic predisposition. Recent studies indicate that there is a high prevalence of protein Z (PZ) deficiency in patients with unexplained fetal loss. The objective of this study was to measure the PZ levels in pregnant Omani women in the first, second and third trimesters and correlate with the pregnancy outcome. The study enrolled 126 consecutive pregnant women after an informed consent prospectively. PZ was estimated in the first, second and third trimester in 15, 97 and 66 pregnant women respectively and they were followed for pregnancy outcomes including live birth, still birth, spontaneous abortion/induced abortion, maternal complications, fetal complications and health risks/complications in the newborn. The median PZ level (Mean±SD) in the first, second and third trimester were 0.98 (1.07±0.46), 1.3 (1.36±0.61) and 1.44 (1.43±0.69) (P<0.05, Student's t-test, between first vs. second and first vs. third trimester). PZ deficiency defined as PZ level below 0.54μg/ml (below 10th centile in the Omani population) was observed in 4 (4.7%) women, but interestingly all had a normal pregnancy outcome. Amongst the 43 subjects in whom paired PZ estimations were available, reducing PZ levels were observed from baseline values in 8 (33%) with normal pregnancy outcome; 5 (55%), with diabetes; 3 (50%) with hypertension and 2 (50%) with low birth weight respectively (P<0.05, chi square test). PZ values increased progressively during the three trimesters of pregnancy. However, this increase is blunted in patients with abnormal pregnancy outcome like low birth weight babies or pregnancies associated hypertension or diabetes. Isolated PZ deficiency alone did not result in an abnormal outcome in this cohort of subjects.