The Open Ophthalmology Journal




ISSN: 1874-3641 ― Volume 14, 2020

Protein Z Plasma Levels are Not Elevated in Patients with Non-Arteritic Anterior Ischemic Optic Neuropathy



Ioannis Asproudis1 , *, Taxiarchis L Felekis1, Spiridon Gorezis2, Lefkothea Dova3, Eleni Dokou3, Georgios Vartholomatos2, Miltiadis Aspiotis1, Nikolaos I Kolaitis2
1 University Eye Clinic of Ioannina, Greece
2 Epirus Vision Center, Ioannina, Greece
3 Haematology Laboratory of the University Hospital of Ioannina, Greece

Abstract

Background: Protein Z is a glycoprotein that acts as a co-factor for the inhibition of activated coagulation factor X. Protein Z circulating in abnormal levels has been associated with increased risk for acute ischemic events. Non-arteritic Anterior Ischemic Optic Neuropathy (N-AION) is caused by acute ischemic infarction of the optic nerve head, supplied by the posterior ciliary arteries.

Objectives: The aim was to investigate whether there is an association between N-AION and plasma protein Z levels.

Patients and Methods: Twenty-six cases of confirmed N-AION and fifty-two controls were included in the study group. Protein Z was estimated in thawed citrate plasma on both N-AION cases and controls by an enzyme immunoassay. The imprecision of the estimation was satisfactory (CV = 4, 6%).

Results: The controls’ protein Z values distributed within a range 340 to 4200 ng/ml (median = 1420, mean = 1673, SD = 1040 ng/ml). Patients’ protein Z values distributed within a range 420 to 3600 ng/ml (median = 1030, mean = 1520, SD = 939 ng/ml). There was no statistical difference between the two distributions (Independent t-test, p=0.529).

Conclusion: In our study, protein Z levels are not implicated in the pathogenesis of non-arteritic anterior ischemic optic neuropathy (N-AION).

Keywords: Protein Z, Non-arteritic anterior ischemic optic neuropathy.


Article Information


Identifiers and Pagination:

Year: 2009
Volume: 3
First Page: 15
Last Page: 19
Publisher Id: TOOPHTJ-3-15
DOI: 10.2174/1874364100903010015

Article History:

Received Date: 21/1/2009
Revision Received Date: 27/2/2009
Acceptance Date: 7/3/2009
Electronic publication date: 28/4/2009
Collection year: 2009

© Asproudis et al.; Licensee Bentham Open.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.


* Address correspondence to this author at the University Eye Clinic of Ioannina, Kosti Palama 1, Anatoli-Ioannina 45500, Greece; Tel: 0030- 2651067689; Fax: 0030-2651022928; E-mail: gorezis@hotmail.com





INTRODUCTION

Protein Z (PZ) is a single chain, vitamin K- dependent glycoprotein that was purified from human plasma in 1984 [1Broze GJ Jr, Miletich JP. Human protein Z J Clin Invest 1984; 4: 933-8., 2Miletich JP, Broze GJ Jr. Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy Blood 1987; 69: 1580-6.].

The amino acid sequence of PZ shows a wide homology with many vitamin K-dependent coagulation factors, such as factors VII, IX, X and anticoagulant protein C, but the protein does not act as expected for a zymogen form of a coagulation factor. PZ does not serve a proteolytic action because it lacks the proper amino acids residues of a serine protease on the active center [3Sejima H, Hayashi T, Deyashiki Y, Nishioka J, Suzuki K. Primary structure of vitamin K-dependent human protein Z Biochem Biophys Res Commun 1990; 171: 661-8., 4Ichinose A, Takeya H, Espling E, Iwanaga S, Kisiel W, Davie EW. Amino acid sequence of human protein z, a vitamin K-dependent plasma glycoprotein Biochem Biophys Res Commun 1990; 172: 1139-44.]. A cofactor role, in the inhibition of activated coagulation factor X (f Xa), dependent on phospholipids and calcium ions, was recognized for PZ in 1998 [5Han X, Fiehler R, Broze GH Jr. Isolation of a protein Z-dependent plasma protease inhibitor Proc Natl Acad Sci USA 1998; 95: 9250-5.].The inhibitory function is exerted by the Protein Z- dependent protease inhibitor (ZPI), which circulates in the human plasma in a complex with PZ [6Tabatabai A, Fiehler R, Broze GJ Jr. Protein Z circulates in plasma in a complex with protein Z-dependent protease inhibitor Thromb Haemost 2001; 85: 655-0.].The cofactor action of PZ is manifested after its binding to phospholipids and presumably involves the proper localization of ZPI-PZ complex on the phospholipid surface, for interaction with the fXa [5Han X, Fiehler R, Broze GH Jr. Isolation of a protein Z-dependent plasma protease inhibitor Proc Natl Acad Sci USA 1998; 95: 9250-5., 7Broze GJ Jr. Protein Z-dependent regulation of coagulation Thromb Haemost 2001; 86: 8-13.].

In experimental animal models [8Yin ZF, Huang ZF, Cui Z, et al. Prothrombotic phenotype of protein Z deficiency Proc Natl Acad Sci USA 2000; 97: 6734-8.]and in humans [9Pardos-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: 727-34.] several studies have suggested that low plasma PZ levels might contribute to venous or arterial thrombosis.

In cases of venous thrombosis a potential association with low PZ levels was only demonstrated in subgroups of patients (men and individuals older than 55 years) but no effect of a concomitant factor V Leiden (FVL) genotype was detected [10Al-Shanqeeti A, van Hylckama Vieg A, Bentrop E, Rosendaal FR, Broze GJ Jr. Protein Z and protein Z-dependent protease inhibitor: determinants of levels and risk of venous thrombosis Thromb Haemost 2005; 93: 411-3., 11Refaai MA, Ahn C, Lu L, Broze GJ Jr. Protein Z and ZPI levels and cardiovascular events J Thromb Haemost 2006; 4: 1628-9.].

A number of clinical studies which explore the role of PZ on coronary heart disease [12Fedi S, Sofi F, Brogi D, et al. Low protein Z plasma levels are independently associated with acute coronary syndromes Thromb Haemost 2003; 90: 1173-8.], ischemic stroke [11Refaai MA, Ahn C, Lu L, Broze GJ Jr. Protein Z and ZPI levels and cardiovascular events J Thromb Haemost 2006; 4: 1628-9.] and deep vein thrombosis [13Santacroce R, Sarno M, Cappucci F, et al. Low protein Z levels and risk of occurrence of deep vein thrombosis J Thromb Haemost 2006; 4: 2417-2.] patients have been published. Particularly in ischemic stroke, patients or at least subgroups of patients [11Refaai MA, Ahn C, Lu L, Broze GJ Jr. Protein Z and ZPI levels and cardiovascular events J Thromb Haemost 2006; 4: 1628-9.] with low levels [14Vasse M, Guegan-Messardier E, Borg JY, Woimant F, Soria C. Frequency of protein Z deficiency in patients with Ischemic stroke Lancet 2001; 357: 933-4., 15Heeb 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: 139-44.]or high levels [16Kobelt K, Demarmels Biasiutti FD, Mattle HP, Lammle B, Wuillemin WA. Protein Z in ischaemic stroke Br J Haematol 2001; 114: 169-73.-18Staton J, Sayer M, Hankey GL, Cole V, Thom J, Eikelboom JW. Protein Z gene polymorphisms, protein Z concentrations, and Ischemic stroke Stroke 2005; 36: 1123-7.] of PZ have been associated with increased risk of stroke. On the other hand, there are studies that claim no association between PZ levels and the risk for stroke [19Lopaciuk S, Bykowska K, Kwiecinski H, Clonkowska A, Kuczynska-Zardzewialy A. Protein Z in young survivors of ischemic stroke Thromb Haemost 2002; 88: 436-8.].

Although an absolute comparison of these studies is impossible, since a lot of differences exist between them, the opposing results that are presented are scientifically intriguing.

Anterior ischemic optic neuropathy (AION) is caused by acute ischemic infarction of the optic nerve head, which is supplied by the posterior ciliary arteries [20Salomon O, Huna-Baron R, Kurtz S, et al. Analysis of prothrombotic and vascular risk factors in patients with non- arteritic ischemic optic neuropathy Ophthalmology 1999; 106: 739-42., 21Nagy V, Steiber Z, Takacs L, et al. Thrombophilic screening for non- arteritic anterior ischemic optic neuropathy Graefes Arch Clin Exp Ophthalmol 2006; 244: 3-8.]. There are two different types of AION. The most frequent Non-arteritic anterior ischemic optic neuroparhy (N-AION) and arteritic anterior ischemic optic neuropathy (A-AION) usually associated with giant cell arteritis.

N-AION is the most common acute optic neuropathy in older age groups and may result in severe visual acuity or visual field loss [22Newman JN, Dickersin K, Kaufman D, Kelman S, Scherer R. Characteristics of patients with non- arteritic ischemic optic neuropathy eligible for the ischemic optic neuropathy decompression trial Arch Ophthalmol 1996; 114: 1366-74.].It is characterized by sudden, usually painless visual loss, relative afferent pupillary defect and optic disk edema [23Mojon SD, Hedges RT III, Ehrenberg B, et al. Association between sleep apnea syndrome and non- arteritic anterior ischemic optic neuropathy Arch Ophthalmol 2002; 120: 601-5.]. Optic nerve atrophy-generalized or sectorial- ensues within the next few weeks.

Arteriosclerosis, hypertension [24Hayreh SS, Joos MK, Podhajsky AP, Long RC. Systemic diseases associated with non- arteritic anterior ischemic optic neuropathy Am J Ophthalmol 1994; 118: 766-80.] diabetes mellitus, ischemic heart disease, hypercholesterolemia [20Salomon O, Huna-Baron R, Kurtz S, et al. Analysis of prothrombotic and vascular risk factors in patients with non- arteritic ischemic optic neuropathy Ophthalmology 1999; 106: 739-42.], “crowded” optic disk [25Beck WR, Savino JP, Repka XM, Schatz JN, Sergott CR. Optic disk structure in anterior ischemic optic neuropathy Ophthalmology 1984; 91: 1334-7.], nocturnal hypotension [26Hayreh SS, Podhajsky AP, Zimmerman B. Non-arteritic anterior ischemic optic neuropathy: time of onset of visual loss Am J Ophthalmol 1997; 124: 641-7.] and sleep apnea syndrome [23Mojon SD, Hedges RT III, Ehrenberg B, et al. Association between sleep apnea syndrome and non- arteritic anterior ischemic optic neuropathy Arch Ophthalmol 2002; 120: 601-5.]have been implicated as risk factors.

To our knowledge, there are extremely limited data, on the role of protein Z in ophthalmic disease. The aim of this study was to investigate whether alterations in protein Z might contribute to the enhanced risk of Non-arteritic anterior ischemic optic neuropathy.

MATERIALS AND METHODOLOGY

Study Design: Diagnostic and Exclusion Criteria

Diagnostic criteria for N-AION patients were as follows: sudden loss of vision, relative afferent pupillary defect, and visual field defects consistent with ischemic optic neuropathy and pale swollen optic disk. To exclude giant cell arteritis, a detailed history concerning the systematic symptoms of giant cell arteritis was aqcuired and C- reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were measured. ESR over 35mm/h and CRP levels above 5 mg/L were considered suspicious for A-AION and those patients were excluded. In addition, biopsy of temporal arteries, if necessary, wasperformed. The same criteria along with raised white blood cells (WBC) from the blood count, served to exclude inflammatory conditions in both patients and controls. Other exclusion criteria were liver disease, myeloproliferative disorders and use of anticoagulants and contraceptives. In all patients MRI was performed to exclude demyelinization and intracranial tumors. All the patients are under systematic follow–up in regular intervals in our Eye Clinic.

Laboratory Investigation

Blood samples from patients and controls were collected, approximately 2-3 days after original diagnosis, in sodium citrate and EDTA acid anticoagulants. A sample of citrated plasma from each patient was deep frozen for the determination of PZ.

A complete blood cell count, ESR and CRP were performed in all N-AION patients in a regular basis, using routine laboratory techniques [27Kesler A, Irge D, Rogowski O, et al. High-sensitivity C-reactive protein measurements in patients with non-arteritic anterior ischaemic optic neuropathy: a clue to the presence of a microinflammatory response Acta Ophthalmol 2008; 83: 499-502.].

Search for the thrombophilic polymorphisms for factor V Leiden polymorphism (G1691A) and for prothrombin gene polymorphism G20210A, were done by polymerase chain reaction amplification and restriction enzyme digestion.

Detection of factor V Leiden mutation:

In brief, a 267-basepair (bp) segment of the factor V gene was amplified using specific primers (5'-TGC CCA GTG CTT AAC AAG ACC A-3' and 5'-TGT TAT CAC ACT GGT GCT AA-3'), as previously described [28Alvarez F, Bernard O, Brunelle F, Hadchouel P, Odievre M, Alagille D. Portal obstruction in children I Clinical investigation and hemorrhage risk J Pediatr 1983; 103: 696-702.]. The PCR product (10 mL) was digested with 4 U of DNA restriction enzyme Mnl I (New England Biolabs, Beverly, MA, USA), at 37°C for 16 h, subjected to 2% low melting point agarose (Sigma, MO, USA) gel electrophoresis and viewed under ultraviolet light after staining the gel with ethidium bromide. The digested amplicon from wild-type DNA gives 3 bands of 163, 67 and 37 bp, respectively; in contrast, heterozygous and homozygous FVL mutations show four (200, 163, 67 and 37 bp) and two (200 and 67 bp) bands, respectively.

Detection of prothrombin gene mutation:

For detection of G20210 prothrombin gene mutation, we used a PCR-RFLP method that has been described previously [29Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. 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: 3698-703.]. In brief, a 345-bp genomic DNA fragment encompassing a part of the prothrombin gene that contains the mutation was amplified by PCR using specific primers (5'-TCT AGA AAC AGT TGC CTG GC-3' and 5'-ATA GCA CTG GGA GCA TTG AAG C-3'). The PCR product (10 mL) was digested with 20 U of Hind III (New England Biolabs, Beverly, MA, USA), at 37°C for 16 h, subjected to 3% low melting point agarose gel electrophoresis and read using ultraviolet light. Using this method, the wild-type DNA yields a solitary 345-bp band, heterozygous G20210A mutation yields two bands of 345 and 322 bp, respectively and homozygous mutation only one band of 322 bp.

The plasma PZ concentration was determined by a commercial enzyme immunoassay (Asserachrom Protein Z, Diagnostica Stago, France). This assay utilizes the quantitative sandwich enzyme immunoassay technique. Briefly, the standards and samples were incubated in duplicate wells of microtiter plate precoated with a monoclonal antibody specific for protein Z. Following incubation, repeated washings were performed to remove unbound materials and a second monoclonal antibody coupled with peroxidase directed against another epitope of protein Z was added to the assay plates. This step was followed by additional washes and an equal amount of stabilized chromogen; ortho-phenylenediamine (OPD) and urea peroxide substrate were added to each well. This initiates the development of color, which is halted at a set time by the addition of an acid solution. Optical densities were determined using a programmable micro plate reader (Bio-Tek Instruments, Winooski, Vermont, USA). Protein Z concentrations in the samples were determined by interpolation from individual standard curves. Since the sample size of our study is small, to minimize the inter-assay variation, we determined the protein Z values in one experiment, the same day by the same batch of reagents. One sample of thawedcitrate plasma was examined in duplicate, for each patient or control.Protein Z values were calculated from a standard curve provided by the kit and expressed in ng/ml of plasma. The inter-assay variation calculated from the values of normal plasma was satisfactory (CV= 4.6 %) We considered protein Z deficiency levels < 1000ngr/ml [14Vasse M, Guegan-Messardier E, Borg JY, Woimant F, Soria C. Frequency of protein Z deficiency in patients with Ischemic stroke Lancet 2001; 357: 933-4.].

Statistical Analysis was performed with Statistical Package for Social Sciences (SPSS version 14.0) using parametric (t-test) and non-parametric (Fisher’s exact test) statistic procedures where necessary.P-values less than 0.05 were considered statistically significant.

RESULTS

According to diagnostic criteria, three patients with possible giant-cell arteritis were not included in the study. One more patient with meningioma was also excluded from the study.

Twenty-six patients with definite diagnosis of N-AION and in accordance with the criteria described were included in the study.Those were eighteen males and eight females with a mean age of 65 years (range 47 to 83).

The control group consisted of fifty-two healthy individuals from the same geographic area who were referred to the University Eye Clinic for cataract operation and had no history of N-AION, retinal artery or vein occlusion. The control group consisted of thirty males and twenty-two females with a mean age of 70 years (range 47 to 85).

All patients and controls were free from autoimmune diseases, they were not taking anticoagulants and they had no other clinical or laboratory indication that they were under an acute inflammatory phase. In both groups WBC, ESR and CRP values were in the normal range.

Risk factors for atherosclerosis such as hyperlipidemia, (The United States NCEP guidelines for the diagnosis and treatment of hypercholesterolemia) diabetes mellitus, (Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus) hypertension, (2003 new European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines for the management of arterial hypertension ), defined according to strict criteria, were present in both groups with nearly the same incidence (Table1).

Table 1

Incidence of Vascular Risk Factors




The concentration values of plasma PZ for the control group were distributed in a range from 340 to 4200 ng/ml with a mean of 1673 ng/ml (median 1420 ng/ml) and a SD of 1040 ng/ml.

In N-AION patients the values of plasma PZ were also distributed in a range from 420 to 3600 ng/ml with a mean of 1520 ng/ml (median 1030 ng/ml) and a SD 931 ng/ml (Fig. 1). There was not any statistically significant difference between the PZ values of N-AION patients and the controls (Independent t-test, p=0.529).

Fig. (1)

Protein Z levels in controls and N-AION patients.



There was not any statistical difference in PZ levels between males and females in each individual subgroup of N-AION patients and controls (P=0.37 and P=0.55 respectively).

There was no statistically significant difference (P=0.18 using the Kruscal-Wallis test) between the protein Z levels in groups of N-AION patients that had the attack in the left eye, in the right eye or in both eyes.

There was not any statistical difference using the Fisher’s exact test concerning factor V Leiden polymorphism (G1691A) (p=0.26) and prothrombin gene polymorphism G20210A (p=1) between patients and controls.

In two patients and one control subject that were carriers of factor V Leiden polymorphism, the values of protein Z were 1020, 1040 and 960 ng/ml, respectively.

Finally, all patients and controls were negative for lupus anticoagulant.

DISCUSSION

N-AION is the most common acute optic neuropathy in older age groups which can affect both eyes in up to 40% of the patients [30Beri M, Klugman MR, Kohler JA, Hayreh SS. Anterior ischemic optic neuropathy VII: incidence of bilaterality and various influencing factors Ophthalmology 1987; 94: 1020-28.].

Recurrent attacks in the same eye, although uncommon, may also occur [31Lavin PJM, Ellenberger C. Recurrent ischemic optic neuropathy J Clin Neuroophthalmol 1983; 3: 193-8., 32Borchert M, Lessell S. Progressive and recurrent non- arteritic anterior ischemic optic neuropathy Am J Ophthalmol 1988; 106: 443-9.]. The subsequent visual acuity or visual field loss may be devastating and can lead to serious visual impairment. More than half of the patients discover visual loss upon first awakening or when they first use vision, critically in the morning [23Mojon SD, Hedges RT III, Ehrenberg B, et al. Association between sleep apnea syndrome and non- arteritic anterior ischemic optic neuropathy Arch Ophthalmol 2002; 120: 601-5., 26Hayreh SS, Podhajsky AP, Zimmerman B. Non-arteritic anterior ischemic optic neuropathy: time of onset of visual loss Am J Ophthalmol 1997; 124: 641-7.].This was also the case in our study, where 17 (65%) of the patients realized the loss immediately after awakening. The prognosis of N-AION is poor due to optic nerve atrophy ensuing within the next 2-4 weeks, and only a small number of the patients can show significant improvement.

The question whether there is an association between N-AION and thrombophilic risk factors- inherited or acquired- provides quite controversial results. Salomon et al. found no association between N-AION and thrombophilic risk factors [20Salomon O, Huna-Baron R, Kurtz S, et al. Analysis of prothrombotic and vascular risk factors in patients with non- arteritic ischemic optic neuropathy Ophthalmology 1999; 106: 739-42.]. On the other hand, Nagy et al. [21Nagy V, Steiber Z, Takacs L, et al. Thrombophilic screening for non- arteritic anterior ischemic optic neuropathy Graefes Arch Clin Exp Ophthalmol 2006; 244: 3-8.]suggested that hyperfibrinogenemia and factor V Leiden may contribute to the pathogenesis of N-AION, while Van Cott et al. [33Van Cott ME, Laposata M, Hartnett EM. Prothrombin gene mutation G20210A, homocysteine, antiphospholipid antibodies and other hypercoagulable states in ocular thrombosis Blood Coagul Fibrinolysis 2004; 5: 393-7.] recommend that testing for homocysteine and prothrombin G20210A mutation should be considered in these patients. J.F. Acheson and M.D. Sanders describe seven cases in which there is an associated thrombophilic state and non-arteritic anterior ischemic optic neuropathy [34Acheson FJ, Sanders DM. Coagulation abnormalities in ischemic optic neuropathy Eye 1994; 8: 89-92.].

N-AION is a multifactorial disease in which cerebrovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolemia and ischemic heart disease may play an important role. However, because vascular risk factors are more common in individuals of similar age as patients with N-AION, the design of studies of this kind is very difficult to address the issue of whether these systemic factors represent true risk factors for the pathogenesis of N-AION, as Jakobson et al. refer to in their study [35Jakobson MD, Vierkant AR, Belongia AE. Non-arteritic anterior ischemic optic neuropathy.A case control study of potential risk factors. Arch Ophthalmol 1997; 115: 1403-7.].

This is the first study, to our knowledge, to investigate whether there is an association between N-AION and plasma protein Z levels. The only study concerning PZ in ophthalmic disease, and specificallycentral retinal vein or artery occlusion, was held by Koren-Michowitz et al. [36Koren-Michowitz M, Eting E, Rahimi-Levene N, Garach-Jehoshua O, Volcheck Y, Kornberg A. Protein Z levels and control retinal vein or artery occlusion Eur J Haematol 2005; 75: 401-5.].

Although protein Z was characterized already in the 1980s, its role in normal and pathologic coagulation is still controversial. There are studies suggesting an association between low plasma PZ levels and acute coronary syndromes [12Fedi S, Sofi F, Brogi D, et al. Low protein Z plasma levels are independently associated with acute coronary syndromes Thromb Haemost 2003; 90: 1173-8., 13Santacroce R, Sarno M, Cappucci F, et al. Low protein Z levels and risk of occurrence of deep vein thrombosis J Thromb Haemost 2006; 4: 2417-2.],pregnancy complications (late fetal demise and intrauterine growth restriction) [37Paidas MJ, Ku DH, Lee MJ, et al. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications J Thromb Haemost 2005; 3: 497-501., 38Bretelle F, Arnoux D, Shojai RD, et al. Protein Z in patients with pregnancy complications Am J Obstet Gynenol 2005; 193: 1698-702.], and ischemic colitis [39Koutroubakis IE, Theodoropoulou A, Sfiridaki A, Kouroumalis EA. Low plasma PZ levels in patients with ischemic colitis Dig Dis Sci 2003; 48: 1673-6.].

Opposing results and conclusions, concerning the association of ischemic stroke and PZ plasma concentrations have been reported. The behavior of PZ during the acute phase is also a matter of disagreement [13Santacroce R, Sarno M, Cappucci F, et al. Low protein Z levels and risk of occurrence of deep vein thrombosis J Thromb Haemost 2006; 4: 2417-2., 18Staton J, Sayer M, Hankey GL, Cole V, Thom J, Eikelboom JW. Protein Z gene polymorphisms, protein Z concentrations, and Ischemic stroke Stroke 2005; 36: 1123-7.].

PZ concentration has a broad range in healthy individuals when samples of EDTA or citrate plasma are examined with immunofluoresence [2Miletich JP, Broze GJ Jr. Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy Blood 1987; 69: 1580-6.] or immunoenzymatic techniques [10Al-Shanqeeti A, van Hylckama Vieg A, Bentrop E, Rosendaal FR, Broze GJ Jr. Protein Z and protein Z-dependent protease inhibitor: determinants of levels and risk of venous thrombosis Thromb Haemost 2005; 93: 411-3.], respectively. A lot of opposing results also exist, concerning the PZ values on patients with the same disease. Since the inter-assay variation reported for citrate plasma and immunoenzymatic techniques determination is near to 11% [15Heeb 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: 139-44., 40Lichy 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: 40-5.], a part of this observed variability may be attributed to the unavoidable imprecision of the assays. We were able to minimize this inter-assay variation since we performed only one assay under very low variation (CV=4.6%).

On the other hand the accuracy of determination seems questionable since an International standard for PZ is lacking and as a consequence some researchers report their PZ results as percentages (%) of the mean, probably for comparison reasons [10Al-Shanqeeti A, van Hylckama Vieg A, Bentrop E, Rosendaal FR, Broze GJ Jr. Protein Z and protein Z-dependent protease inhibitor: determinants of levels and risk of venous thrombosis Thromb Haemost 2005; 93: 411-3., 11Refaai MA, Ahn C, Lu L, Broze GJ Jr. Protein Z and ZPI levels and cardiovascular events J Thromb Haemost 2006; 4: 1628-9.].

Our results showed no statistically significant difference concerning PZ levels between the N-AION patients and controls. In consistency with this observation are the findings of Lopaciuk et al. 2002 [19Lopaciuk S, Bykowska K, Kwiecinski H, Clonkowska A, Kuczynska-Zardzewialy A. Protein Z in young survivors of ischemic stroke Thromb Haemost 2002; 88: 436-8.] that the values of protein Z are not associated with the risk for stroke in young survivors and the observations of Refaai et al. 2006 [11Refaai MA, Ahn C, Lu L, Broze GJ Jr. Protein Z and ZPI levels and cardiovascular events J Thromb Haemost 2006; 4: 1628-9.]who did not find any association of PZ values and risk for stroke or coronary heart disease in older patients.

Contrary to our conclusions, due to small number of patients that we examined, there is always the possibility that some N-AION patients would have lower concentration values of PZ than the controls at the time of the attack. This would be observed in a minority of future patients, probably in less than 5%, according to our results. A none statistically significant trend for an increase of the levels of PZ as the time passed after the eye attack, that we observed, may support this, otherwise, small possibility. In contrast to this hypothesis and in analogy with our results, Refaai et al. 2006 [11Refaai MA, Ahn C, Lu L, Broze GJ Jr. Protein Z and ZPI levels and cardiovascular events J Thromb Haemost 2006; 4: 1628-9.] found that PZ levels were not associated with the time of development of coronary heart disease or stroke.

CONCLUSION

In conclusion, we compared a group of carefully selected N-AION patients, without inflammation, with a control group and we did not found a statistically significant difference (p=0.529) between the levels of protein Z.

ABBREVIATIONS

AION Anterior ischemic optic neuropathy
FVL Concomitant factor V Leiden
f Xa Activated coagulation factor X
N-AION Non-arteritic Anterior Ischemic Optic Neuropathy
PZ Protein Z
ZPI Protein Z- dependent protease inhibitor

REFERENCES

[1] Broze GJ Jr, Miletich JP. Human protein Z J Clin Invest 1984; 4: 933-8.
[2] Miletich JP, Broze GJ Jr. Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy Blood 1987; 69: 1580-6.
[3] Sejima H, Hayashi T, Deyashiki Y, Nishioka J, Suzuki K. Primary structure of vitamin K-dependent human protein Z Biochem Biophys Res Commun 1990; 171: 661-8.
[4] Ichinose A, Takeya H, Espling E, Iwanaga S, Kisiel W, Davie EW. Amino acid sequence of human protein z, a vitamin K-dependent plasma glycoprotein Biochem Biophys Res Commun 1990; 172: 1139-44.
[5] Han X, Fiehler R, Broze GH Jr. Isolation of a protein Z-dependent plasma protease inhibitor Proc Natl Acad Sci USA 1998; 95: 9250-5.
[6] Tabatabai A, Fiehler R, Broze GJ Jr. Protein Z circulates in plasma in a complex with protein Z-dependent protease inhibitor Thromb Haemost 2001; 85: 655-0.
[7] Broze GJ Jr. Protein Z-dependent regulation of coagulation Thromb Haemost 2001; 86: 8-13.
[8] Yin ZF, Huang ZF, Cui Z, et al. Prothrombotic phenotype of protein Z deficiency Proc Natl Acad Sci USA 2000; 97: 6734-8.
[9] 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: 727-34.
[10] Al-Shanqeeti A, van Hylckama Vieg A, Bentrop E, Rosendaal FR, Broze GJ Jr. Protein Z and protein Z-dependent protease inhibitor: determinants of levels and risk of venous thrombosis Thromb Haemost 2005; 93: 411-3.
[11] Refaai MA, Ahn C, Lu L, Broze GJ Jr. Protein Z and ZPI levels and cardiovascular events J Thromb Haemost 2006; 4: 1628-9.
[12] Fedi S, Sofi F, Brogi D, et al. Low protein Z plasma levels are independently associated with acute coronary syndromes Thromb Haemost 2003; 90: 1173-8.
[13] 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: 2417-2.
[14] Vasse M, Guegan-Messardier E, Borg JY, Woimant F, Soria C. Frequency of protein Z deficiency in patients with Ischemic stroke Lancet 2001; 357: 933-4.
[15] 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: 139-44.
[16] Kobelt K, Demarmels Biasiutti FD, Mattle HP, Lammle B, Wuillemin WA. Protein Z in ischaemic stroke Br J Haematol 2001; 114: 169-73.
[17] McQuillan AM, Eikelboom JW, Hankey GL, et al. Protein Z in ischemic stroke and its etiologic subtypes Stroke 2003; 34: 2415-9.
[18] Staton J, Sayer M, Hankey GL, Cole V, Thom J, Eikelboom JW. Protein Z gene polymorphisms, protein Z concentrations, and Ischemic stroke Stroke 2005; 36: 1123-7.
[19] Lopaciuk S, Bykowska K, Kwiecinski H, Clonkowska A, Kuczynska-Zardzewialy A. Protein Z in young survivors of ischemic stroke Thromb Haemost 2002; 88: 436-8.
[20] Salomon O, Huna-Baron R, Kurtz S, et al. Analysis of prothrombotic and vascular risk factors in patients with non- arteritic ischemic optic neuropathy Ophthalmology 1999; 106: 739-42.
[21] Nagy V, Steiber Z, Takacs L, et al. Thrombophilic screening for non- arteritic anterior ischemic optic neuropathy Graefes Arch Clin Exp Ophthalmol 2006; 244: 3-8.
[22] Newman JN, Dickersin K, Kaufman D, Kelman S, Scherer R. Characteristics of patients with non- arteritic ischemic optic neuropathy eligible for the ischemic optic neuropathy decompression trial Arch Ophthalmol 1996; 114: 1366-74.
[23] Mojon SD, Hedges RT III, Ehrenberg B, et al. Association between sleep apnea syndrome and non- arteritic anterior ischemic optic neuropathy Arch Ophthalmol 2002; 120: 601-5.
[24] Hayreh SS, Joos MK, Podhajsky AP, Long RC. Systemic diseases associated with non- arteritic anterior ischemic optic neuropathy Am J Ophthalmol 1994; 118: 766-80.
[25] Beck WR, Savino JP, Repka XM, Schatz JN, Sergott CR. Optic disk structure in anterior ischemic optic neuropathy Ophthalmology 1984; 91: 1334-7.
[26] Hayreh SS, Podhajsky AP, Zimmerman B. Non-arteritic anterior ischemic optic neuropathy: time of onset of visual loss Am J Ophthalmol 1997; 124: 641-7.
[27] Kesler A, Irge D, Rogowski O, et al. High-sensitivity C-reactive protein measurements in patients with non-arteritic anterior ischaemic optic neuropathy: a clue to the presence of a microinflammatory response Acta Ophthalmol 2008; 83: 499-502.
[28] Alvarez F, Bernard O, Brunelle F, Hadchouel P, Odievre M, Alagille D. Portal obstruction in children I Clinical investigation and hemorrhage risk J Pediatr 1983; 103: 696-702.
[29] Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. 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: 3698-703.
[30] Beri M, Klugman MR, Kohler JA, Hayreh SS. Anterior ischemic optic neuropathy VII: incidence of bilaterality and various influencing factors Ophthalmology 1987; 94: 1020-28.
[31] Lavin PJM, Ellenberger C. Recurrent ischemic optic neuropathy J Clin Neuroophthalmol 1983; 3: 193-8.
[32] Borchert M, Lessell S. Progressive and recurrent non- arteritic anterior ischemic optic neuropathy Am J Ophthalmol 1988; 106: 443-9.
[33] Van Cott ME, Laposata M, Hartnett EM. Prothrombin gene mutation G20210A, homocysteine, antiphospholipid antibodies and other hypercoagulable states in ocular thrombosis Blood Coagul Fibrinolysis 2004; 5: 393-7.
[34] Acheson FJ, Sanders DM. Coagulation abnormalities in ischemic optic neuropathy Eye 1994; 8: 89-92.
[35] Jakobson MD, Vierkant AR, Belongia AE. Non-arteritic anterior ischemic optic neuropathy.A case control study of potential risk factors. Arch Ophthalmol 1997; 115: 1403-7.
[36] Koren-Michowitz M, Eting E, Rahimi-Levene N, Garach-Jehoshua O, Volcheck Y, Kornberg A. Protein Z levels and control retinal vein or artery occlusion Eur J Haematol 2005; 75: 401-5.
[37] Paidas MJ, Ku DH, Lee MJ, et al. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications J Thromb Haemost 2005; 3: 497-501.
[38] Bretelle F, Arnoux D, Shojai RD, et al. Protein Z in patients with pregnancy complications Am J Obstet Gynenol 2005; 193: 1698-702.
[39] Koutroubakis IE, Theodoropoulou A, Sfiridaki A, Kouroumalis EA. Low plasma PZ levels in patients with ischemic colitis Dig Dis Sci 2003; 48: 1673-6.
[40] 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: 40-5.
Track Your Manuscript:


Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2020 Bentham Open