Subscribe to RSS
DOI: 10.1055/s-0040-1708878
Plasma Levels of Protein Z in Ischemic Stroke: A Systematic Review and Meta-Analysis
Funding None.Publication History
02 October 2019
13 February 2020
Publication Date:
05 May 2020 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/202005/lookinside/thumbnails/10-1055-s-0040-1708878_190576-1.jpg)
Abstract
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.
-
References
- 1 Benjamin EJ, Muntner P, Alonso A. , et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: a report from the American Heart Association. Circulation 2019; 139 (10) e56-e528
- 2 Sommer CJ. Ischemic stroke: experimental models and reality. Acta Neuropathol 2017; 133 (02) 245-261
- 3 Lansberg MG, O'Donnell MJ, Khatri P. , et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012. ;141: 601-636
- 4 Huang X, Swanson R, Kroh HK, Bock PE. Protein Z-dependent protease inhibitor (ZPI) is a physiologically significant inhibitor of prothrombinase function. J Biol Chem 2019; 294 (19) 7644-7657
- 5 Han X, Fiehler R, Broze Jr GJ. Characterization of the protein Z-dependent protease inhibitor. Blood 2000; 96 (09) 3049-3055
- 6 Sofi F, Cesari F, Abbate R, Gensini GF, Broze Jr G, Fedi S. A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis. Thromb Haemost 2010; 103 (04) 749-756
- 7 Vasse M, Denoyelle C, Corbière C, Litzler PY, Legrand E, Vannier JP. Human endothelial cells synthesize protein Z, but not the protein Z dependent inhibitor. Thromb Haemost 2006; 95 (03) 519-523
- 8 Butschkau A, Wagner NM, Genz B, Vollmar B. Protein z exerts pro-angiogenic effects and upregulates CXCR4. PLoS One 2014; 9 (12) e113554
- 9 Vasse M, Guegan-Massardier E, Borg JY, Woimant F, Soria C. Frequency of protein Z deficiency in patients with ischaemic stroke. Lancet 2001; 357 (9260): 933-934
- 10 Lopaciuk S, Bykowska K, Kwiecinski H, Czlonkowska A, Kuczynska-Zardzewialy A. Protein Z in young survivors of ischemic stroke. Thromb Haemost 2002; 88 (03) 536
- 11 Kobelt K, Biasiutti FD, Mattle HP, Lämmle B, Wuillemin WA. Protein Z in ischaemic stroke. Br J Haematol 2001; 114 (01) 169-173
- 12 Heeb MJ, Paganini-Hill A, Griffin JH, Fisher M. Low protein Z levels and risk of ischemic stroke: differences by diabetic status and gender. Blood Cells Mol Dis 2002; 29 (02) 139-144
- 13 McQuillan AM, Eikelboom JW, Hankey GJ. , et al. Protein Z in ischemic stroke and its etiologic subtypes. Stroke 2003; 34 (10) 2415-2419
- 14 van Goor MP, Dippel DW, Jie KS, de Maat MP, Koudstaal PJ, Leebeek FW. Low protein Z levels but not the protein Z gene G79A polymorphism are a risk factor for ischemic stroke. Thromb Res 2008; 123 (02) 213-218
- 15 Zhang L, Segal AZ, Leifer D. , et al. Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults. Thromb Haemost 2017; 117 (01) 149-157
- 16 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med 2009; 6: 1000097
- 17 Broze Jr GJ, Miletich JP. Human Protein Z. J Clin Invest 1984; 73 (04) 933-938
- 18 Wells GA, Shea B, O'Connell D. , et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp . Accessed May 1, 2019
- 19 Luo X, Ou R, Dutta R, Tian Y, Xiong H, Shang H. Association between serum vitamin D levels and Parkinson's disease: a systematic review and meta-analysis. Front Neurol 2018; 9: 909
- 20 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315 (7109): 629-634
- 21 Kemkes-Matthes B, Matthes KJ. Protein Z, a new haemostatic factor, in liver diseases. Haemostasis 1995; 25 (06) 312-316
- 22 Miletich JP, Broze Jr GJ. Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy. Blood 1987; 69 (06) 1580-1586
- 23 Vossen CY, Hasstedt SJ, Rosendaal FR. , et al. Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-deficient family. J Thromb Haemost 2004; 2 (02) 242-247
- 24 Santacroce R, Cappucci F, Di Perna P, Sessa F, Margaglione M. Protein Z gene polymorphisms are associated with protein Z plasma levels. J Thromb Haemost 2004; 2 (07) 1197-1199
- 25 Santacroce R, Sarno M, Cappucci F. , et al. Low protein Z levels and risk of occurrence of deep vein thrombosis. J Thromb Haemost 2006; 4 (11) 2417-2422
- 26 Le Cam-Duchez V, Barbay V, Bal Dit Sollier C. , et al. Haplotypic or genotypic combinations of three protein Z polymorphisms influence protein Z plasma level. Thromb Haemost 2009; 101 (01) 212-214
- 27 Lichy C, Kropp S, Dong-Si T. , et al. A common polymorphism of the protein Z gene is associated with protein Z plasma levels and with risk of cerebral ischemia in the young. Stroke 2004; 35 (01) 40-45
- 28 Staton J, Sayer M, Hankey GJ, Cole V, Thom J, Eikelboom JW. Protein Z gene polymorphisms, protein Z concentrations, and ischemic stroke. Stroke 2005; 36 (06) 1123-1127
- 29 Greten J, Kreis I, Liliensiek B. , et al. Localisation of protein Z in vascular lesions of patients with atherosclerosis. Vasa 1998; 27 (03) 144-148
- 30 Husain S, Andrews NP, Mulcahy D, Panza JA, Quyyumi AA. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation 1998; 97 (08) 716-720
- 31 Reriani MK, Dunlay SM, Gupta B. , et al. Effects of statins on coronary and peripheral endothelial function in humans: a systematic review and meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil 2011; 18 (05) 704-716
- 32 Peller M, Ozierański K, Balsam P, Grabowski M, Filipiak KJ, Opolski G. Influence of beta-blockers on endothelial function: A meta-analysis of randomized controlled trials. Cardiol J 2015; 22 (06) 708-716
- 33 Pardos-Gea J, Ordi-Ros J, Serrano S, Balada E, Nicolau I, Vilardell M. Protein Z levels and anti-protein Z antibodies in patients with arterial and venous thrombosis. Thromb Res 2008; 121 (06) 727-734
- 34 Cesari F, Gori AM, Fedi S, Abbate R, Gensini GF, Sofi F. Modifications of protein Z and interleukin-6 during the acute phase of coronary artery disease. Blood Coagul Fibrinolysis 2007; 18 (01) 85-86
- 35 Girard TJ, Lasky NM, Tuley EA, Broze Jr GJ. Protein Z, protein Z-dependent protease inhibitor (serpinA10), and the acute-phase response. J Thromb Haemost 2013; 11 (02) 375-378