Article

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

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Abstract

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 subjects (1:1.4 cases:controls) were included. Analyses revealed evidence of a non-linear association. After adjusting for demographic and clinical covariates, PZ level >2.5 µg/ml (90(th) %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.

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... Venous blood of 1.8 mL was collected in Vacutainer tube (Becton-Dickinson, NJ, USA) containing 0.2 mL of 3.2% tri-sodium citrate. Specimens were centrifuged at 25009g for 20 min, plasma supernatant was decanted and stored frozen at -70°C Diabetes mellitus is defined as non-fasting blood glucose C 200 mg/ dL, fasting blood glucose C 126 mg/dL, or hemoglobin A1c C 6.5%, current use of antidiabetic medication, or self-reported diabetes c Dyslipidemia is defined as LDL cholesterol C 160 mg/dL, HDL cholesterol \ 40 mg/dL in men or \ 50 mg/dL in women, total/HDL cholesterol C 4.0, or history of previous use of lipid-lowering medication d Family history of ACS is defined by the presence of at least one firstdegree relative developed ACS before the age of 55 years for men and 65 years for women [16] until PZ assay. The frozen plasma was thawed at 37°C for 15 min and tested within 4 h. ...
... a Negative correlation between protein Z levels and age of ACS patients; b lower protein Z levels in group B than group A ACS patients. ACS acute coronary syndrome Diabetes mellitus is defined as non-fasting blood glucose C 200 mg/dL, fasting blood glucose C 126 mg/dL, or hemoglobin A1c C 6.5%, current use of antidiabetic medication, or self-reported diabetes c Dyslipidemia is defined as LDL cholesterol C 160 mg/dL, HDL cholesterol \ 40 mg/dL in men or \ 50 mg/dL in women, total/HDL cholesterol C 4.0, or history of previous use of lipid-lowering medication d Family history of ACS is defined by the presence of at least one first-degree relative developed ACS before the age of 55 years for men and 65 years for women [16] p \ 0.01); and 4.2 lg/mL for predicting UA (100% sensitivity, 86.7% specificity, 73.3% PPV, 100% NPV, 0.983 area under curve, p \ 0.01). ...
... Finally, as PZ has been reported to increase with the intake of oral contraceptives [9], female patients on hormonal contraception were excluded. In accordance, a study by Zhang and colleagues [16] addressed the impact of PZ in unexplained cerebral infarction in young and middleaged adults and applied similar exclusion criteria to remove known or potential risk factors for cerebrovascular stroke, as well as to insure comparability of cases and controls. ...
Article
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 ≤ 55 years, and group B > 55 years). 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 3.7 μg/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.
... Also an association between family history of bleeding and low PZ seems probable and is also suggested by recent family-based association studies. 33 Nevertheless, due to the small sample size in our study, this association did not reach the level of significance ( Table 2). In patients with anamnestic haemorrhages and PZ levels below 1500 μg/L, in case of bleeding events, these become more severe. ...
... Determinations of PZ gene polymorphisms are a rather promising approach and have been applied with some success in ischaemic stroke. 33,34 More recent data obtained from family-based association studies demonstrated an association between several PZ single nucleotide polymorphism (e.g. PZ rs2273971) and cerebral haemorrhages in a Chan-Chinese population. ...
... PZ rs2273971) and cerebral haemorrhages in a Chan-Chinese population. 33 This association adds further evidence to the impact of PZ on bleeding complications. ...
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Background and objectives: Protein Z deficiency has been implicated both in bleeding diatheses and thrombophilia. Considering its ambiguous nature and the conflicting clinical data so far, we set out to evaluate the impact of low protein Z (PZ) on perioperative bleeding in patients who underwent surgical (ENT) interventions involving a high risk of bleeding. Patients and methods: 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. Results: Low PZ levels were associated with increased blood loss (p<0.001), increased need for blood transfusions (p<0.001), and a higher rate of surgical revisions (p=0.009) in a concentration dependent fashion. Low PZ caused earlier (within 24 h) and repetitive bleedings (p=0.005). The number of major bleeding episodes was significantly increased when low PZ was combined with bleeding history (p<0.05). Finally, ROC analyses confirmed the predictive validity of low PZ for bleeding complications and PZ-thresholds for clinical practice were determined. Conclusions: 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 remains inconclusive. This article is protected by copyright. All rights reserved.
... We also investigate the function of different genes involved in the duplicated 13q22-q34 region and their possible role on both immunological functions and coagulation pathways. Some of these genes are involved in the coagulation pathway as the Z protein (PROZ) and the Growth arrest-specific gene 6 protein (GAS6) genes, known to play an important role in regulating blood coagulation and in the regulation of thrombotic responses as well as in cerebral haemorrhage, thrombosis and in the genetic susceptibility of systemic lupus erythematosus (SLE) [5,[10][11][12][13][14][15]. In our patient cerebral vasculitis findings associated to LAC positivity could be related also to the involvement of the TNFSF13B (named also B lymphocyte stimulator, BLyS) gene that encodes a cytokine that belongs to the tumor necrosis factor (TNF) ligand family and it is reported to be significantly increased in the primary antiphospholipid syndrome (PAPS) and in LES, as confirmed by an animal model study [16][17][18][19]. ...
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The partial trisomy 13q encompasses an extensive variability of phenotypic and radiological findings including leukoencephalopathy and brain malformations such as holoprosencephaly, callosal dysgenesis, hippocampal hypoplasia, olfactory hypoplasia, and vermian hypoplasia. We report for the first time a case of a 23-year-old patient affected by de novo partial 13q22.1q34 trisomy (41.7 Mb, 72,365,975-114,077,122x3) presenting with hemiparesis related to both ischemic and haemorrhagic cerebral lesions compatible with cerebral vasculitis due to a possible combination of genetic and immunological interaction.
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An 8-month, double-blind, placebo-controlled, crossover trial of flunarizine in the prophylaxis of migraine has been performed in 70 children. After 4 weeks of medication-free base-line observation, 35 children (group A) received flunarizine (5 mg/day) and 35 (group B) received placebo over a 12-week period. After a 4-week washout they crossed treatments for another 12 weeks. Sixty-three patients completed the trial. In both groups flunarizine significantly reduced the frequency and average duration of headache attacks. In group A efficacy was maintained after placebo crossover for the last 4 months of the study. Five subjects in group B stopped placebo because of ineffectiveness; two children in group A discontinued flunarizine treatment, one because of excessive daytime sedation and the other because therapy was ineffective. The main side effects were daytime sedation and weight gain. It is concluded that flunarizine is an effective drug for the treatment of childhood migraine. In a study of this length no serious side effects were discovered.
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In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.
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Protein Z was purified from human plasma by a four-step procedure which included barium citrate adsorption, ammonium sulfate fractionation, DEAE-Sepharose chromatography, and blue agarose chromatography with a yield of 20%. It is a 62,000 mol wt protein with an extinction coefficient of 12.0. The concentration of Protein Z in pooled, citrated plasma is 2.2 micrograms/ml and its half-life in patients starting warfarin anticoagulation therapy is estimated to be less than 2.5 d. The NH2-terminal sequence is Ala-Gly-Ser-Tyr-Leu-Leu-(Gla)-(Gla)-Leu-Phe-(Gla)-Gly-Asn-Leu. Neither Protein Z nor its cleavage products, which were obtained by treatment of Protein Z with thrombin or plasmin, incorporated [3H]diisopropyl fluorophosphate. The physiological function of Protein Z remains unknown.
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Human protein Z (PZ) is a 62,000-Mr, vitamin K-dependent plasma protein whose structure is similar to coagulation factors VII, IX, X, protein C, and protein S, but whose function is not known. The procoagulant activity of factor Xa in a one-stage plasma coagulation assay is reduced when factor Xa is first incubated with PZ. This apparent inhibitory effect is time dependent, requires the presence of calcium ions and procoagulant phospholipids (rabbit brain cephalin), and appears predominantly related to the incubation period of PZ with cephalin. In serum the initial rate of inhibition of factor Xa with calcium ions and cephalin also is enhanced in the presence PZ. A PZ-dependent protease inhibitor (ZPI) has been isolated from plasma. ZPI is a 72,000-Mr single-chain protein with an N-terminal amino acid sequence of LAPSPQSPEXXA (X = indeterminate) and an estimated concentration in citrate-treated plasma of 1.0-1.6 microg/ml. In systems using purified components, the factor Xa inhibition produced by ZPI is rapid (>95% within 1 min by coagulation assay) and requires the presence of PZ, calcium ions, and cephalin. The inhibitory process appears to involve the formation of a factor Xa-PZ-ZPI complex at the phospholipid surface.
Article
Protein Z (PZ) is a vitamin K-dependent plasma protein whose function has been uncertain. The structure of PZ is very similar to that of the coagulation-related factors VII, IX, and X and PC, but PZ differs from these other proteins in that it is not the zymogen of a serine protease. We have shown recently that PZ forms a calcium ion-dependent complex with activated factor X at phospholipid surfaces and that this interaction leads to the inhibition of activated factor X activity through, in part, the action of a previously unidentified plasma protein named PZ-dependent protease inhibitor. Herein, we report that the presence of PZ dampens the coagulation response in human plasma and that concomitant PZ deficiency dramatically increases the severity of the prothrombotic phenotype of factor V(Leiden) mice. The results indicate that PZ plays a physiologically important role in the regulation of coagulation.
Article
Protein Z-dependent protease inhibitor (ZPI) is a 72-kd member of the serpin superfamily of proteinase inhibitors that produces rapid inhibition of factor Xa in the presence of protein Z (PZ), procoagulant phospholipids, and Ca(++) (t(1/2) less than 10 seconds). The rate of factor Xa inhibition by ZPI is reduced more than 1000-fold in the absence of PZ. The factor Xa-ZPI complex is not stable to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but is detectable by alkaline-polyacrylamide gel electrophoresis. The combination of PZ and ZPI dramatically delays the initiation and reduces the ultimate rate of thrombin generation in mixtures containing prothrombin, factor V, phospholipids, and Ca(++). In similar mixtures containing factor Va, however, PZ and ZPI do not inhibit thrombin generation. Thus, the major effect of PZ and ZPI is to dampen the coagulation response prior to the formation of the prothrombinase complex. Besides factor Xa, ZPI also inhibits factor XIa in the absence of PZ, phospholipids, and Ca(++). Heparin (0.2 U/mL) enhances the rate (t(1/2) = 25 seconds vs 50 seconds) and the extent (99% vs 93% at 30 minutes) of factor XIa inhibition by ZPI. During its inhibitory interaction with factor Xa and factor XIa, ZPI is proteolytically cleaved with the release of a 4.2-kd peptide. The N-terminal amino acid sequence of this peptide (SMPPVIKVDRPF) establishes Y387 as the P(1) residue at the reactive center of ZPI. ZPI activity is consumed during the in vitro coagulation of plasma through a proteolytic process that involves the actions of factor Xa with PZ and factor XIa.
Article
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.
Article
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 (</=1.46 microg/ml). The odds ratios were: 2.6 for all subjects (95% C.I. = 1.5-4.3); 3.8 for nondiabetic subjects (95% C.I. = 2.2-6.8); and 3.6 for males (95% C.I. = 2.0-6.4). This study also revealed high protein Z levels associated with high triglyceride levels in controls (P = 0.015). Protein Z is suggested to be a physiologic downregulator of blood coagulation and low protein Z levels are associated with increased risk of ischemic stroke, particularly in males and in the absence of diabetes.
Article
Protein Z is a vitamin K-dependent plasma protein whose significance in arterial thrombosis remains uncertain. The objectives of this study were to determine the association between protein Z, ischemic stroke, and etiologic subtypes of ischemic stroke. We conducted a case-control study of 173 hospital cases of first-ever ischemic stroke and 186 randomly selected community controls. Using established criteria, we classified cases of stroke by etiologic subtype. Protein Z concentrations were measured during the first 7 days and at 3 to 6 months after the acute stroke event. Blood levels of protein Z measured within 7 days of acute stroke were significantly higher in cases than in controls (geometric mean, 1.46 versus 1.16 microg/mL; P<0.0001). Compared with the lowest tertile, the upper 2 tertiles of protein Z were associated with an adjusted odds ratio (OR) of ischemic stroke of 1.75 (95% CI, 1.00 to 3.07) for the second tertile and 3.07 (95% CI, 1.73 to 5.45) for the upper tertile. The adjusted odds of ischemic stroke caused by large-artery atherothrombosis was nearly 8-fold greater for those with protein Z concentrations in the upper tertile compared with the lower tertile (OR, 7.91; 95% CI, 3.11 to 20.14). The adjusted odds of ischemic stroke due to small-artery disease (OR, 1.79; 95% CI, 0.83 to 3.87) and cardioembolism (OR, 1.80; 95% CI, 0.58 to 5.64) was also increased among individuals with protein Z concentrations in the upper tertile compared with the lower tertile, but not significantly so. There was no significant difference between mean protein Z concentrations among cases in the convalescent phase (3 months) after stroke and age- and sex-matched controls. There is a strong, independent relationship between elevated blood levels of protein Z and ischemic stroke during the acute phase, particularly ischemic stroke due to large-artery atherothromboembolism, which is no longer evident during the convalescent phase. These results are consistent with the notion that protein Z is either an important factor in the pathogenesis of ischemic stroke due to large-artery atherothromboembolism or an acute phase reactant. Further studies are required to elucidate whether protein Z has a causative or prognostic role in acute arterial thrombosis.
Article
The vitamin K-dependent protein Z (PZ) has been shown to possess anticoagulant as well as procoagulant properties. Plasma levels of PZ show a broad interindividual variation, but it is unknown to which extent this variation is under genetic control. Recent clinical studies revealed contradictory results on the association of PZ plasma levels and the risk of ischemic stroke. We performed a case-control study including 200 patients with cerebral ischemia aged < or =50 years and 199 control subjects from the same South German region. We investigated a possible association of 2 common single nucleotide mutations in the PZ gene with the risk of cerebral ischemia. Furthermore, enzyme-linked immunosorbent assay measurements were done in control subjects without vascular disease to detect a potential association of different genotypes with PZ plasma (antigen) levels. In patients, the frequency of the A allele of the intron F polymorphism G79A was significantly lower than in controls (15.7% versus 24.4%; odds ratio, 0.58; 95% CI, 0.39 to 0.86; P=0.007; adjusted for age, sex, and conventional risk factors). The G allele of the promoter polymorphism A-13G tended to be less common in patients (4.2% versus 7.0%; adjusted odds ratio, 0.56; 95% CI, 0.28 to 1.13; P=0.105). In 42 control subjects, the A allele of the intron F polymorphism was associated with lower PZ antigen levels (P=0.0032; Spearman correlation coefficient rs=-0.48). The A allele of an intron F polymorphism of the PZ gene appears to be a novel protective genetic marker for the risk of cerebral ischemia in young adults. In the context of juvenile stroke, high PZ plasma levels may represent a prothrombotic condition.
Article
PS levels cannot be said to have any relationship with thestudied endothelial activation markers.Therefore, acquired free PS deficiency may be associatedwith lipid profile levels and/or another variable common tolipids and PS, conferring an increased potential thrombotic riskon HIV-infected patients naive of treatment. Additionally, thisfree PS deficiency may have some role in the development ofavascular necrosis seen in HIV-infected patients naive of anyantiretroviral treatment.AcknowledgementsThe study was supported by a School-Grant from MSDCorporation (MSD) and by Roche Diagnostics Argentina.References
Article
** To cite this article: Morange PE, Juhan-Vague I on behalf of the PRIME Study Group. Protein Z plasma levels are not associated with the risk of coronary heart disease: the PRIME Study. J Thromb Haemost 2004; 2: 2050–1.
Article
We aimed to determine whether A-13G or G79A polymorphisms of the protein Z gene that have been reported to be an important determinant of blood concentrations of protein Z are associated with risk of ischemic stroke in a broad range of stroke patients and controls. We conducted a case control study of 151 hospital cases of first-ever ischemic stroke and 164 randomly selected community controls. Protein Z genotype was determined for the A-13G promoter polymorphism and the G79A intron F polymorphism, and plasma protein Z concentrations were measured during the first 7 days and at 3 to 6 months after the acute stroke event. Geometric mean concentrations of protein Z measured within 7 days of acute stroke were significantly higher in cases compared with controls (1.51 microg/mL versus 1.13 microg/mL; P<0.0001). Protein Z concentrations were highest among subjects with the A-13G AA genotype, intermediate among those with the AG genotype, and lowest among those with the GG genotype (1.39 microg/mL versus 1.05 microg/mL versus 0.76 microg/mL; P<0.0001); and highest among those with the G79A GG genotype, intermediate among those with the GA genotype, and lowest among those with the AA genotype (1.47 microg/mL versus 1.13 microg/mL versus 0.66 microg/mL; P<0.0001). The prevalence of A-13G and G79A genotypes was not significantly different between cases of ischemic stroke and controls. However, compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (odds ratio [OR], 0.83; 95% CI, 0.52 to 1.33) and the homozygote AA genotype (OR, 0.63; 95% CI, 0.20 to 1.98). A pooled analysis showed that compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (OR, 0.78; 95% CI, 0.57 to 1.07) and the homozygote AA genotype (OR, 0.31; 95% CI, 0.14 to 0.69). The consistency of the association between protein Z genotypes, blood concentrations of protein Z, and ischemic stroke, determined using 2 different methods that have different sources of bias strengthens the evidence that increased blood concentrations of protein Z concentrations are associated causally with an increased risk of ischemic stroke.
Article
Protein Z (PZ) serves as a cofactor for activated factor X inhibition by the PZ-dependent protease inhibitor. In vivo and in vitro studies aimed at investigating the role of PZ levels in venous thombosis have produced conflicting results. We investigated whether reduced PZ levels and PZ gene common variants are associated deep vein thrombosis (DVT). In 197 patients with DVT and in 197 age-matched and sex-matched controls, PZ plasma levels and gene polymorphisms were evaluated by means of an enzyme-linked immunosorbent assay and direct cycle sequence analysis. Similar PZ levels were found in controls (1.44; SD 0.63 microg mL-1) and in patients (1.44; SD 0.96 microg mL-1). The incidence of PZ levels below the 5.0 (0.52 microg mL-1) or the 2.5 percentile of controls (0.47 microg mL-1) was higher in patients (10.2% and 8.7%, respectively) than in controls {4.1% [odds ratio (OR) 2.7, 95% confidence interval (CI) 1.2-7.3], and 2.0% (OR 4.6, 95% CI 1.5-13.9), respectively}. This relationship was independent of the effect of age, sex, and factor V Leiden and FII A(20210) alleles [OR 2.8 (95% CI 1.1-7.3), and OR 4.9 (95% CI 1.4-17.3)]. PZ levels were associated with the intron C G-42A and the intron F G79A polymorphisms in cases (r2=0.129) and in controls (r2=0.140). However, frequencies of the PZ gene polymorphisms were similar in the two groups and were not associated with very low PZ levels. The present data suggest an association between very low PZ plasma levels and the occurrence of DVT, with PZ gene polymorphisms contributing little to this relationship.
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia: an international journal of headache. 1988; 8(Suppl 7):1-96.