Mutations within the protein Z‐dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia

Water, Neil Van de; Tan, Tina; Ashton, Fern; O'Grady, Anna; Day, T.R. Julen; Browett, Peter; Ockelford, Paul; Harper, Paul

doi:10.1111/j.1365-2141.2004.05189.x

Cited by 59 publications

(29 citation statements)

References 13 publications

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“…[13][14][15] In conclusion, our results are consistent with the hypothesis that elevated protein Z concentrations are prothrombotic. Further advances in understanding of the underlying mechanisms of the association between protein Z and thrombosis 23 may provide new insights into the cause, pathogenesis, or prognosis of acute ischemic stroke and could potentially yield new therapeutic strategies in the future.…”

Section: Discussionmentioning

confidence: 99%

Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Staton

Sayer

Hankey

et al. 2005

Stroke

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Background and Purpose-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. Methods-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. Results-Geometric mean concentrations of protein Z measured within 7 days of acute stroke were significantly higher in cases compared with controls (1.51 g/mL versus 1.13 g/mL; PϽ0⅐0001). 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 g/mL versus 1.05 g/mL versus 0.76 g/mL; PϽ0.0001); 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 g/mL versus 1.13 g/mL versus 0.66 g/mL; PϽ0.0001). 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). Conclusion-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.

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Section: Discussionmentioning

confidence: 99%

Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Staton

Sayer

Hankey

et al. 2005

Stroke

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“…PZ and ZPI deficiency have been shown to enhance thrombosis in mouse models (15, 16), but whether PZ and ZPI are involved in clinical thrombotic disease is controversial, with some, but not all, studies suggesting such a relationship (17-23). The aim of our study was to investigate the potential role of PZ and ZPI in the sepsis-associated activation of the inflammation and coagulation cascades.…”

Section: Introductionmentioning

confidence: 99%

Contribution of Protein Z and Protein Z-Dependent Protease Inhibitor in Generalized Shwartzman Reaction

Butschkau

Nagel²,

Grambow³

et al. 2013

Critical Care Medicine

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Objective Sepsis, a leading cause of mortality in critically ill patients, is closely linked to the excessive activation of coagulation and inflammation. Protein Z (PZ), a cofactor for the protein Z-dependent protease inhibitor (ZPI), enhances the inhibition of coagulation factor Xa and ZPI inhibits factor XIa in a PZ-independent fashion. The functions of PZ and ZPI in the inflammatory and coagulant responses to septic illness have not been evaluated. Design For induction of generalized Shwartzman reaction (GSR), dorsal skinfold chamber-equipped mice were challenged twice with lipopolysaccharide (0.05 mg/kg bw on day −1 and 5 mg/kg bw 24 h later). Time-matched control animals received equal volumes of saline. Setting University research laboratory. Subjects, Interventions and Measurements Using intravital fluorescence microscopy in ZPI-deficient (ZPI−/−) and PZ-deficient (PZ−/−) mice as well as their wild-type littermates (ZPI+/+, PZ+/+), kinetics of light/dye-induced thrombus formation and microhemodynamics were assessed in randomly chosen venules. Plasma concentrations of CXCL1, IL-6 and IL-10 were measured. Liver and lung were harvested for quantitative analysis of leukocytic tissue infiltration and thrombus formation. Main Results After induction of GSR, all mice showed significant impairment of microhemodynamics, including blood flow velocity, volumetric blood flow and functional capillary density as well as leukocytopenia and thrombocytopenia. Thrombus formation time was markedly prolonged after induction of GSR in all mice, except of ZPI−/− mice, which also had a significantly higher fraction of occluded vessels in liver sections. PZ−/− mice developed the highest concentrations of IL-6 and IL-10 in response to GSR and showed greater leukocytic tissue infiltration than their wild-type littermates. Conclusions In this murine model of GSR, ZPI deficiency enhanced the thrombotic response to vascular injury, whereas PZ deficiency increased inflammatory response.

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“…Besides inhibiting FXa, ZPI inhibits FXIa (EC 3.4.21.27) in a reaction stimulated 2-fold by heparin and not requiring protein Z (3). Recently, mutations in ZPI that generate stop codons at residues Arg-67 or Trp-303 were found to be significantly associated with venous thrombosis (6), although a different study found no association between ZPI or protein Z levels and venous thrombosis (7).…”

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confidence: 99%

Down-regulation of Factor IXa in the Factor Xase Complex by Protein Z-dependent Protease Inhibitor

Heeb

Cabral

Ruan

2005

Journal of Biological Chemistry

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Protein Z-dependent protease inhibitor (ZPI) 2 was recently identified as a serpin that potently inhibits activated blood coagulation factor X (FXa) (EC 3.4.21.6) in a manner dependent on protein Z, Ca 2ϩ , and phospholipids (1-3) and the action of which is largely ablated in the presence of FVa (3). ZPI is estimated to be present at 3.8 g/ml (53 nM) in plasma, forms non-covalent complexes with protein Z in plasma, and has an apparent mobility of 72 kDa on SDS-PAGE (3, 4). ZPI is 25-35% homologous to human serpins (2) and 70% homologous to rat liver regeneration protein rasp-1 (5). It has an unusual P1 residue of Tyr-387, and the mutant Y387A did not inhibit FXa (2). Besides inhibiting FXa, ZPI inhibits FXIa (EC 3.4.21.27) in a reaction stimulated 2-fold by heparin and not requiring protein Z (3). Recently, mutations in ZPI that generate stop codons at residues Arg-67 or Trp-303 were found to be significantly associated with venous thrombosis (6), although a different study found no association between ZPI or protein Z levels and venous thrombosis (7).Protein Z is a 62-kDa vitamin K-dependent plasma protein that circulates almost entirely as a complex with protein Z-dependent protease inhibitor and has a wide range in plasma of 2.6 Ϯ 1 g/ml (4, 8). The cofactor role of protein Z in FXa inhibition by ZPI is the first clearly identified function for human protein Z, although bovine and not human protein Z enhances the binding of thrombin to membrane surfaces (9).Protein Z gene knock-out mice have no gross abnormalities, but thrombotic manifestations are exacerbated in an FV Leiden pedigree (10). For humans with FV Leiden, low protein Z is associated with an earlier age of first thrombosis and more frequent thrombotic events (11). Protein Z genetic polymorphisms that are associated with reduced protein Z plasma levels were recently reported (12, 13). Low protein Z was reported to be associated with ischemic stroke (14 -16), although there are conflicting reports of high protein Z in association with stroke (17) or with large artery stroke (18) and one report of no relationship between protein Z levels and stroke (19). Low protein Z is associated with anti-protein Z antibodies and unexplained early fetal loss, which could involve thrombosis (20). Low protein Z levels are associated with antiphospholipid antibodies in women (21) and with a 7-fold increased risk of arterial thrombosis in patients with antiphospholipid syndrome (22).Although ZPI was reported in preliminary studies not to inhibit FIXa (3) (EC 3.4.21.22), we investigated whether ZPI might inhibit FIXa in the FXase complex, as well as FXa in the prothrombinase complex. If so, we wondered whether FVIIIa might protect FIXa from ZPI inhibition, as FVa protects FXa from ZPI inhibition, and whether protein Z might be required for inhibition of FIXa. The homologous prothrombinase and FXase complexes work in tandem to generate thrombin (EC 3.4.21.5), and a physiologic inhibitor of both complexes could be particularly significant. EXPERIMENTAL PROCEDURESPlasma-de...

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Mutations within the protein Z‐dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia

Cited by 59 publications

References 13 publications

Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Contribution of Protein Z and Protein Z-Dependent Protease Inhibitor in Generalized Shwartzman Reaction

Down-regulation of Factor IXa in the Factor Xase Complex by Protein Z-dependent Protease Inhibitor

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