Download PDF
Thromb Haemost 2003; 90(06): 1173-1178
DOI: 10.1160/TH03-04-0237
Vascular Development and Vessel Remodelling
Schattauer GmbH

Low protein Z plasma levels are independently associated with acute coronary syndromes

Sandra Fedi
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Francesco Sofi
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Daria Brogi
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Irene Tellini
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Francesca Cesari
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Ilaria Sestini
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Alessandra Gazzini
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Marco Comeglio
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Rosanna Abbate
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
,
Gian Franco Gensini
1   Department of Medical and Surgical Critical Care, Section of Clinical Medicine and Cardiology, University of Florence; Thrombosis Centre, Azienda Ospedaliera Careggi, Florence, Italy
› Author AffiliationsFinancial support: This study was supported in part by a grant from Ministero dell’Istruzione, Università e Ricerca.
Further Information

Publication History

Received 18 April 2003

Accepted after resubmission 05 August 2003

Publication Date:
05 December 2017 (online)

    Permissions and Reprints

Summary

Protein Z (PZ) is a single chain vitamin-K-dependent glycoprotein synthesized by the liver. Studies in vivo and in vitro suggest that PZ plays an important role in inhibiting coagulation as it serves as cofactor for the inactivation of factor Xa by forming a complex with the plasma PZ-dependent protease inhibitor. Recently, conflicting findings on plasma PZ levels in patients with ischemic stroke have been published.

Aim of our study was to investigate the role of PZ in acute coronary syndromes (ACS). PZ plasma levels were determined in 223 (189 M; 34 F) patients with ACS referring to the Coronary Intensive Therapy Unit of University of Florence and in 265 (219 M; 46 F) healthy subjects. Patients under oral anticoagulation treatment as well as subjects with positivity for antiphospholipid antibodies were excluded. None had liver or kidney dysfunction. The mean PZ plasma level was lower in patients (1508 ± 730 ng/mL) than in controls (1728 ± 594 ng/mL) (p < 0.0001). PZ levels below the 5th percentile (565 ng/mL) of normal values distribution in control subjects were found in 15.7% of patients and in 4.9% of controls (p <0 .0001). At multivariate analysis, PZ levels below 565 ng/mL were associated with ACS (OR=3.3; 99%CI 1.1-9.7; p = 0.004). The contemporary presence of low PZ levels and smoking habit leads to an increased risk of ACS (OR=9.5; 99%CI 2.4-37.2; p < 0.0001). In conclusion, our results suggest a possible role of PZ in the occurrence of arterial thrombosis.

Keywords

Protein Z (PZ) - Protein Z-dependent protease inhibitor - Factor Xa - Acute Myocardial Infarction - Unstable Angina
 

  • References

  • 1 Prowse CV, Esnouf MP. The isolation of a new warfarin-sensitive protein from bovine plasma. Biochem Soc Trans 1997; 5 (01) 255-6.
    PubMedGoogle Scholar
  • 2 Broze Jr GJ, Miletich JP. Human protein Z. J Clin Invest 1984; 73 (04) 933-8.
    CrossrefPubMedGoogle Scholar
  • 3 Hojrup P, Jensen MS, Petersen TE. Amino acid sequence of bovine protein Z: a vitamin K-dependent serine protease homolog. FEBS Lett 1985; 184 (02) 333-8.
    CrossrefPubMedGoogle Scholar
  • 4 Fujimaki K, Yamazaki T, Taniwaki M. et al. The gene for human protein Z is localized to chromosome 13 at band q34 and is coded by eight regular exons and one alternative exon. Biochemistry 1998; 37 (19) 6838-46.
    CrossrefPubMedGoogle Scholar
  • 5 Ichinose A, Takeya H, Espling E. et al. Amino acid sequence of human protein Z, a vitamin k-dependent plasma glycoprotein. Biochem Biophys Res Commun 1990; 172 (03) 1139-44.
    CrossrefPubMedGoogle Scholar
  • 6 Miletich JP, Broze Jr GJ. Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy. Blood 1987; 69 (06) 1580-6.
    PubMedGoogle Scholar
  • 7 Hogg PJ, Stenflo J. Interaction of vitamin k-dependent protein Z with thrombin. Consequences for the amidolytic activity of throm-bin and the interaction of thrombin with phospholipids vescicles. J Biol Chem 1991; 266 (17) 10953-8.
    PubMedGoogle Scholar
  • 8 Tabatabai A, Fiehler R, Broze Jr GJ. Protein Z circulates in plasma in a complex with protein Z-dependent protease inhibitor. Thromb Haemost 2001; 85 (04) 655-60.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Kemkes-Matthes B, Matthes KJ. Protein Z deficiency: a new cause of bleeding tendency. Thromb Res 1995; 79 (01) 49-55.
    CrossrefPubMedGoogle Scholar
  • 10 Gamba G, Bertolino G, Montani N. et al. Bleeding tendency of unknown origin and protein Z levels. Thromb Res 1998; 90 (06) 291-5.
    CrossrefPubMedGoogle Scholar
  • 11 Ravi S, Mauron T, Lammle B. et al. Protein Z in healthy human individuals and in patients with a bleeding tendency. Br J Haematol 1998; 102 (05) 1219-23.
    CrossrefPubMedGoogle Scholar
  • 12 Yin ZF, Huang ZF, Cui J. et al. Prothrombotic phenotype of protein Z deficiency. Proc Natl Acad Sci USA 2000; 97 (12) 6734-8.
    CrossrefPubMedGoogle Scholar
  • 13 Vasse M, Guegan-Massardier E, Borg JY. et al. Frequency of protein Z deficiency in patients with ischaemic stroke. Lancet 2001; 357 9260 933-4.
    CrossrefPubMedGoogle Scholar
  • 14 Kobelt K, Biasiutti FD, Mattle HP. et al. Protein Z in ischaemic stroke. Br J Hematol 2001; 114 (01) 169-73.
    CrossrefPubMedGoogle Scholar
  • 15 Lopaciuk S, Bykowska K, Kwiecinski H. et al. Protein Z in young survivors of ischemic stroke. Thromb Haemost 2002; 88 (03) 536
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Falciani M, Gori AM, Fedi S. et al. Elevated tissue factor and tissue factor pathway inhibitor circulating levels in ischaemic heart disease. Thromb Haemost 1998; 79: 495-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Soejima H, Ogawa H, Yasue H. et al. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation 1999; 99: 2908-13.
    CrossrefPubMedGoogle Scholar
  • 18 Gori AM, Fedi S, Pepe G. et al. Tissue factor and tissue factor pathway inhibitor levels in unstable angina patients during short-term low-molecular-weight heparin administration. Br J Haematol 2002; 117: 693-8.
    CrossrefPubMedGoogle Scholar
  • 19 Newby LK, Alpert JS, Ohman EM. et al. Changing the diagnosis of acute myocardial infarction: implications for practice and clinical investigations. Am Heart J 2002; 144 (06) 957-80.
    CrossrefPubMedGoogle Scholar
  • 20 Braunwald E, Antman EM, Beasley JW. et al. ACC/AHA Guideline Update for the Management of Patients with Unstable Angina and Non-ST-segment Elevation of Myocardial Infarction-summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2002; 40 (07) 1366-74.
    CrossrefPubMedGoogle Scholar
  • 21 Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adult (Adult Treatment Panel III) final report. Circulation 2002; 106 (25) 3143-421.
    CrossrefPubMedGoogle Scholar
  • 22 Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 (01) Suppl S5-20.
    CrossrefPubMedGoogle Scholar
  • 23 Von Clauss A. Gerinnungsphysiologische Schellmethode zur bestimmung des fibrino-gens. Acta Haematol 1957; 17: 237-46.
    CrossrefPubMedGoogle Scholar
  • 24 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369 6475 64-7.
    CrossrefPubMedGoogle Scholar
  • 25 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88 (10) 3698-703.
    PubMedGoogle Scholar
  • 26 Steffano B, Forastiero R, Martinuzzo M. et al. Low plasma protein Z in patients with anti-phospholipid antibodies. Blood Coagul Fibrinolysis 2001; 12 (05) 411-2.
    CrossrefPubMedGoogle Scholar
  • 27 McColl MD, Deans A, Maclean P. et al. Plasma protein Z deficiency is common in women with antiphospholipid antibodies. Br J Haematol 2003; 120 (05) 913-4.
    CrossrefPubMedGoogle Scholar
  • 28 Heeb MJ, Paganini-Hill A, Griffin JH. et al. Low protein Z levels and risk of ischemic stroke: differences by diabetic status and gender. Blood Cells Mol Dis 2002; 29 (02) 139-44.
    CrossrefPubMedGoogle Scholar
  • 29 Gris JC, Quere I, Dechaud E. et al. High frequency of protein Z deficiency in patients with unexplained early fetal loss. Blood 2002; 99 (07) 2606-8.
    CrossrefPubMedGoogle Scholar
  • 30 Gris JC, Amadio C, Mercier E. et al. Anti-protein Z antibodies in women with pathological pregnancies. Blood 2003; 6 epub ahead of print
    PubMedGoogle Scholar
  • 31 Undar L, Karadogan I, Ozturk F. Plasma protein Z levels inversely correlate with plasma interleukin-6 levels in patients with acute leukaemia and non-Hodgkin’s lymphoma. Thromb Res 1999; 94 (02) 131-4.
    CrossrefPubMedGoogle Scholar
  • 32 Biasucci LM, Liuzzo G, Fantuzzi G. et al. Increasing levels of interleukin (IL)-Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 1999; 99: 2079-84.
    CrossrefPubMedGoogle Scholar
  • 33 Anguera I, Miranda-Guardiola F, Bosch X. et al. Elevation of serum levels of the anti-inflammatory cytokine interleukin-10 and decreased risk of coronary events in patients with unstable angina. Am Heart J 2002; 144 (05) 811-7.
    CrossrefPubMedGoogle Scholar
  • 34 Bertolino G, Montani N, Lorezutti F. et al. Behaviour of plasma protein Z levels in patients with abnormal haemostasis: correlation with coagulation screening times. Thromb Haemost 1997; 78 (01) suppl 235a abstr.
    PubMedGoogle Scholar
  • 35 Marco P, Marin F, Garcia A. et al. Do protein Z levels influence the prothrombotic state in atrial fibrillation?. Thromb Res 2002; 106 4-5 269-70.
    CrossrefPubMedGoogle Scholar
  • 36 Kemkes-Matthes B, Nees M, Kuhnel G. et al. Protein Z influences the prothrombotic phenotype in Factor V Leiden patients. Thromb Res 2002; 106 4-5 183-5.
    CrossrefPubMedGoogle Scholar
  • 37 Saito M, Kumabashiri I, Jokaji H. et al. The levels of protein C and protein S in plasma in patients with type II diabetes mellitus. Thromb Res 1988; 52 (05) 479-86.
    CrossrefPubMedGoogle Scholar
  • 38 Xu N, Dahlback B, Ohlin AK. et al. Association of vitamin K-dependent coagulation proteins and C4b binding protein with triglyceride-rich lipoproteins of human plasma. Arterioscler Thromb Vasc Biol 1998; 18 (01) 33-9.
    CrossrefPubMedGoogle Scholar
  • 39 Greten J, Kreis I, Liliensiek B. et al. Localisation of protein Z in vascular lesions of patients with atherosclerosis. Vasa 1998; 27 (03) 144-8.
    PubMedGoogle Scholar