Abstract
Background: In this study, we investigated the relationship between early arteriovenous fistula (AVF) thrombosis with angiotensin-converting enzyme (ACE) gene and thrombophilic factor gene polymorphisms. Methods: Thirty-five patients who suffered from three or more fistula thrombosis episodes in the early period after AVF operation and 33 control patients with no history of thrombosis for at least 3 years were enrolled in this study. Results: Factor V G1691A Leiden, factor V H1299R (R2), prothrombin G20210A, factor XIIIV34L, β-fibrinogen-455 G-A, glycoprotein IIIa L33P human platelet antigens (HPA-1), methylenetetrahydrofolate reductase C677T, and methylenetetrahydrofolate reductase A1298C gene polymorphisms were similar in both groups (p > 0.05). Plasminogen activator inhibitor 1 (PAI-1) 4G/5G genotype in the study group and 4G/4G genotype in the control group were significantly higher (p = 0.014). No significant difference was detected in terms of the 5G/5G genotype. With regard to the ACE gene polymorphism, the control group showed more ID genotype (19/33, 57.6%), whereas the study group showed more DD genotype (17/35, 48.6%). II genotype was similar in both groups (x2 = 7.40, p = 0.025). The rate of ACE inhibitor-angiotensin II receptor blockers use was 5/35 in the study group (14.3%) and 5/33 in the control group (15.2%). Individuals with PAI-1 4G/5G genotype showed 5.03 times more risk of thrombosis when compared with 4G/4G and 5G/5G genotypes [p = 0.008, OR = 5.03, 95% confidence interval (1.44:17.64)]. Individuals with ACE DD genotype showed 4.25 times more risk of thrombosis when compared with II and ID [p = 0.008, OR = 4.25, 95% confidence interval (1.404:12.83)]. Conclusion: PAI-1 4G/5G and ACE DD genotypes are associated with increased risk for early AVF thrombosis.
INTRODUCTION
Vascular access is vital for patients with end-stage renal failure who require hemodialysis (HD) because it is the only route for HD application.Citation1 In the United States, arteriovenous fistula (AVF) or synthetic graft is used for vascular access in HD.Citation2 In dialysis patients, 20–25% of hospitalization is caused by vascular access and its cost exceeds $1 billion.Citation3,Citation4 Thrombosis is the main cause of AVF and graft failure.Citation4 Venous stenosis and thrombosis caused by intimal hyperplasia are the initiating causes of vascular dysfunction.Citation5 Causes of the stenosis are proliferation of smooth muscle cells, cell migration from the media to intima, and proliferation in the intima, which occludes the vein lumen.Citation6 The renin–angiotensin–aldosterone system induces extracellular system and growth factors, and has an important role in proliferation.Citation7 Plasma level of the key enzyme, renin, is controlled by the 17th chromosome, which has insertion (I)/deletion (D) polymorphism. The I/D polymorphism is characterized by the absence of a base couple (287) in the 16th intron; II, DD, and ID are the genotypes and DD is characterized by high antithrombin II levels.Citation8 The renin–angiotensin–aldosterone system's vasoconstrictive effect causes an increase in fibrinolysis and activates platelets and results in thromboembolism.Citation9 There have been a number of studies about the plasminogen activator inhibitor (PAI-1) mutation and its relation with thrombotic diseases. The most common mutation is in the beginning part of the PAI-1 gene, monobase double insertion (5G)/deletion (4G) polymorphism. The 4G allele is responsible for high plasma PAI-1 levels.Citation10–12 It is shown that PAI-1 expression increases in fistula stenosis in dialysis patients.Citation13 These thrombophilic factors have not been searched as much as other diseases in vascular access problems. Increase in PAI-1 levels and angiotensin-converting enzyme (ACE) DD phenotype raises the risk of coronary artery problems.Citation14,Citation15 ACE DD phenotype is related with hypofibrinolysis because of the increase in PAI-1 levels.Citation16 The studies in the literature on this subject are contradictory. In this study, we investigated the effects of ACE gene polymorphism, thrombophilic factor gene polymorphisms, and homocysteine level on AVF function in HD patients.
MATERIALS AND METHODS
In this retrospective study, we designed a case group and a control group by studying 520 patients from Cumhuriyet University, Nephrology Department, Hemodialysis and Peritoneal Dialysis Unit, Sivas Numune Hospital, and private dialysis centers in Sivas. All the patients were informed about the study and agreed to the terms of the study.
Exclusion criteria for this study were as follows: older age, myocardial infarction and cerebrovascular disease history, organ damage caused by diabetes (diffuse atherosclerosis, visual loss, peripheral arterial damage, and diabetic foot), immobilization, heart failure, and hypotension attack history. The case group comprised 35 patients who had no AVF problem in the first month, but experienced at least three AVF attacks in the following 2 months. The control group included 33 patients with no AVF problem in 3 years. In both groups, AVF operations were performed in the same center by the same surgical team.
For both groups, age, sex, smoking habit, and medicines used during dialysis (angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARB], erythropoiesis-stimulating agents, vitamin D, phosphorus-binding medicines, antiplatelet agents, vitamin B, folic acid, iron agent) were recorded. The reasons for end-stage renal failure were grouped as diabetes mellitus, hypertension, familial Mediterranean fever, glomerulonephritis, polycystic kidney disease, nephrolithiasis, and unknown. HD parameters, Kt/V, dialysis duration, and access localizations were evaluated. Access localizations were classified as forearm proximal, forearm distal, and forearm medial lines. Calcium × phosphate product, low-density lipoprotein, intact parathyroid hormone, hemoglobin, and albumin values were obtained from patient files. Plasma homocysteine level analysis was done in microbiology laboratories using AXSYM device and MACRO ELISA kit (Abbott, India). Two milliliters of peripheral blood was taken from the patients into ethylenediamine tetra acetic acid (EDTA) tubes. First, isolation of genomic DNA from peripheral blood lymphocyte cells was done with Invitek Invisorb Spin Blood DNA Isolation kit (Invitek GmbH, Berlin), and then a DNA bank was created. Thrombophilic factor mutations for both groups were searched and ACE gene regions were multiplied by polymerase chain reaction. The thrombophilic mutations that were searched included factor V G1691A Leiden (FVL), factor V H1299R (R2), prothrombin (PT) G20210A, factor XIII V34L, β-fibrinogen-455 G-A, PAI-1 4G/5G, glycoprotein IIIa L33P (HPA-1), methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C.
Statistical Analysis
SPSS for Windows (version 14.0) was used in analysis. Chi-square test was used to assess the statistical significance of two average values and odds ratios (ORs) were determined. Our data were recorded in the tables as arithmetic average ± SD, test subject quantity, and percentage (%), and error rates lower than 0.05 were accepted as significant.
RESULTS
We compared the case and control groups with regard to ACE gene polymorphisms and determined that the control group had mostly ID genotype (19/33, 57.6%), whereas the case group had mostly DD genotype (17/35, 48.6%) (p = 0.025). On the contrary, there was no difference between the two groups in ACE II gene polymorphism (). PAI-1 4G/5G was detected more in the case group and 4G/4G in the control group, but there was no significant difference in 5G/5G between the groups (). The subjects with ACE DD genotype had 4.25 times the increased risk for thrombosis when compared with those with ID and II genotypes [x2 = 7.0, p = 0.008, OR = 4.25, 95% confidence interval (CI) (1.404:12.83)] ().
Table 1. Distribution of ACE and PAI-1 gene polymorphisms in the case and control groups
Table 2. Evaluation of the case and control groups for ACE polymorphism (odds ratio)
When we compared the subjects with PAI-1 4G/5G genotype to those with 4G/4G and 5G/5G genotypes, the risk was detected as 5.03 times higher [x2 = 7.08, p = 0.008, OR = 5.03, 95% CI (1.44:17.64)] ().
Table 3. Evaluation of the case and control groups for PAI-1 polymorphism (odds ratio)
When we compared the groups for FVL, factor V H1299R (R2), PT G20210A, factor XIII V34L, β-fibrinogen-455 G-A, glycoprotein IIIa L33P (HPA-1), MTHFR C677T, and MTHFR A1298C, no significant differences were determined (p > 0.05) ().
Table 4. Distribution of case and control groups for thrombophilic factor gene polymorphisms
Age, sex, smoking habit, renal failure etiology, access location, HD duration, and Kt/V did not differ between the two groups (p > 0.05) ().
Table 5. Comparison of basic characteristics of case and control groups
There were also no differences between the groups with regard to ACEI–ARB, vitamin D, erythropoiesis-stimulating agents, phosphorus-binding medicines, antiplatelet agents, B complex, folic acid, use of parenteral iron, calcium × phosphate product, intact parathyroid hormone, hemoglobin, low-density lipoprotein, albumin, and homocysteine values (p > 0.05) ().
Table 6. Comparison of medication and laboratory parameters of the case and control groups
DISCUSSION
The ACE I/D gene polymorphism has been studied often in chronic renal failure patients. In other studies, it was shown that the DD genotype increased the risk of cardiovascular disease and mortality, and progression in renal failure in diabetic patients.Citation17–19 Nowadays, it is definitely understood that intimal hyperplasia and mitral stenosis cause access thrombosis.Citation4,Citation20
The data of the studies about the ACE I/D gene polymorphism in the general population are controversial.Citation21,Citation22 Dilley et al. determined a relationship between the ACE DD genotype and venous thrombosis (DD against ID and II) (OR = 2.8, 95% CI = 1.2–6.2; p = 0.01) in the African-American population.Citation23 On the contrary, Gonzales studied 148 thromboembolism subjects and 240 control subjects among Caucasians and could not detect any difference between the groups (p = 0.65).Citation24 This may be due to the difference of this polymorphism in different ethnic groups.
Makris et al. showed that in untreated hypertension subjects, the ACE DD gene polymorphism caused endothelial damage and hypercoagulability, thus harming the homeostatic balance.Citation25
Philipp et al. showed that thrombosis was a high risk factor in patients with ACE DD genotype who had undergone total hip arthroplasty.Citation21
A group of 517 subjects with venous thromboembolism and a control group of 478 were investigated regarding the presence of ACE DD, II, and ID genotypes. DD genotype was seen in 27.3% of the case group and in 28.2% of the control group. D allele frequency in the case group was 0.53 (95% CI = 0.50–0.56) and in the control group was 0.54 (95% CI = 0.50–0.57). For D allele, OR was 0.97 (95% CI = 0.81–1.16). Thus, it was thought that the ACE I/D gene polymorphism was not a risk factor in patients with thromboembolism.Citation26
In another study, Isbir et al. determined a relationship between arteriovenous graft (AVG) thrombosis and ACE I/D genotype. They found higher risks in the ID genotype when compared with II and DD genotypes.Citation27 The low number of subjects is an important limitation of their study. Furthermore, their study was on synthetic graft fistulas whereas ours involved native AVFs, a property distinguishing these two studies.
In one study, the investigators also studied the relationship between radiocephalic wrist AVFs (RCAVFs) permanency and ACE gene polymorphism. The study was a retrospective study with 56 patients [24 male, 32 female, average age = 49.8 (12–81)]. The patients with working RCAVFs 2 months postoperatively were selected and followed. The average follow-up period was 71.3 months (8–222 months). Vascular occlusions were confirmed by angiography. In 18 patients, average occlusion time was found as 33.6 months (7–72 months). AVF thrombosis was higher in DD genotype when compared with the others, but they could not determine a significant relationship between RCAVF thrombosis and ACE polymorphism (χ2 = 1.027, dt = 2, p = 0.598).Citation28 The limitation of their study was the thrombosis criteria. They considered difficulty in flow as thrombosis without considering intimal hyperplasia. The difference of this study from ours is that they studied late-stage function loss. It was seen that ACE DD may be a risk factor for late-stage thrombosis.
A current retrospective analysis showed that ACE inhibition could decrease AVG failure, but they could not support this analysis with the case–control group study performed afterward.Citation29,Citation30 In summary, according to DOPPS (Dialysis Outcomes and Practice Patterns Study), ACE inhibition increases secondary AVF patency (the time from the first opening of the fistula to the total loss of fistula or preparing a new access), whereas in primary AVF patency (time to the first access thrombosis or first saving process) and primary or secondary AVG patency, they could not detect any benefit of ACE inhibition.Citation31
In a cohort study including 137 patients, the main endpoint was decided as a fistula working without intervention (the period from opening of fistula to first failure episode). Twelve months after fistula operation, functional fistulas were determined in 72% in DD, 65% in ID, and 73% in II (p = 0.33). Long-term ACE inhibition and angiotensin type 1 (AT-1) receptor blockers were seen as insufficient for maintaining fistula patency (p = 0.33). In this study, renin–angiotensin system inhibition was observed as having limited ability to prevent AV stenosis.Citation32 The limitations of this study were insufficient II allele and lack of information in some patients about the usage of ACEI and AT-1 antagonist. We also noticed that usage of ACEI and ARB did not prevent early-stage AVF thrombosis.
In another study, consisting of 60 HD patients who experienced episodes of vascular access thrombosis (VAT) in 12 months proven by ultrasonography and physical examination and 41 individuals with no VAT in 3 years (as control group), they could not find any relationship between the ACE I/D polymorphism and VAT. The ID genotype was seen more than the others in both groups (>50%).Citation33 In their study, they evaluated AVF, AVG, and permanent vascular catheter; permanent vascular catheter was seen more in the case group, which could affect the reliability of the study. The number of the subjects was also limited. The other limitation was the lack of information regarding VAT history in the control group before the 3-year period.
In Moon et al.’s study with 155 subjects after a 58-month follow-up period, the rates of fistulas saved were 47.0% in the DD genotype, 71.8% in the ID genotype, and 82.9% in the II genotype (p < 0.01). This study indicated the benefits of ACE inhibition and ARB usage on AVF functions (p = 0.003).Citation34 We did not detect this benefit of ACEI and ARB usage. The reason for the protective effect of ACEI and ARB in Moon et al.’s study may have been due to its characteristics of being a prospective study involving late-stage AVF thrombosis.
In harmony with the studies that indicate ACE DD as a risk factor for venous thromboembolism, endothelial damage, and hypercoagulability in hypertensive patients and AVF thrombosis, we found DD genotype to be more frequent in patients having early-stage AVF thrombosis. We can state that the ACE DD genotype is a potent risk factor for early-stage AVF thrombosis, but there are studies that did not find any relationship between the I/D polymorphism and AVF thrombosis, VAT, or venous thromboembolism. Prospective studies with more subjects are needed to draw firm conclusions regarding this relationship.
In chronic renal failure, patients have higher PAI-1 levels when compared with others, so the issue of whether thrombogenesis and intravascular reactions are seen more commonly in this group was investigated previously.Citation35
Stegnar et al. studied 158 patients and 145 controls. They determined a relationship between 46–56 genotypes and deep vein thrombosis (DVT), but they obtained the same 46–56 genotype distribution in both groups. They thus concluded that this polymorphism is not a risk factor for DVT.Citation36
In a study by Yılmaz et al., it was demonstrated that the risk of thrombosis in patients having PT 620210A and PAI-1 4G/4G genotypes together increased from 3.4 to 8.46.Citation37 Pfeffer et al. demonstrated in myocardial infarction patients that the PAI-1 46 allele decreased the fibrinolytic activity.Citation38 Akar et al. stated that PAI-1 46 allele carriers do not have a risk of DVT, but if they have this 46 homozygote with factor V G1691A, the risk increases.Citation39
Lazo-Langer et al. determined that transforming growth factor β1 haplotype production is a risk factor for access thrombosis and that PAI-1 4G/4G genotype adds additional risk (OR = 8.23, 95% CI = 1.47–45.97; p = 0.016). On the other hand, when PAI-1 4G/5G was evaluated alone, there was no difference between the case and control groups. In their study, there was also no relationship between VAT and FVL and PT 20210A mutations.Citation40 The limitations of their study can be considered as follows: the case subjects were chosen after only one thrombosis event, the thromboses were diagnosed only with physical examination, and the accesses in the case group were in the forearm versus the arm in the control group, and the differences in these conditions were statistically significant; an additional limitation was that thrombosis times were not defined exactly as late or early. These limitations decrease the power of the study. In our study, we preferred patients who had experienced at least three thrombosis episodes. Fistula thrombosis was diagnosed with physical examination and ultrasonography support. In our study, which avoided the limitations of Lazo-Langer et al.’s study, we showed that PAI-1 4G/5G genotype increases the AVF thrombosis risk in early-stage thrombosis 5.03 times. Similar to Lazo-Langer's study, we found no relationship between AVF thrombosis and FVL and PT 20210A mutations.
Fukasawa et al. related VAT and MTHFR 677 CT point mutation in chronic renal failure patients. VAT was demonstrated to be related mostly with the TT genotype and least with the CC genotype.Citation41
Brophy et al. did not reveal any statistically significant relationship between MTHFR 677 CT and VAT in their study of 60 VAT patients as the case group and 41 patients without VAT as a control group (p = 0.78).Citation33 In our study, we also concluded that there was no relationship between MTHFR 677 CT and A1298C polymorphism and early-stage AVF (p = 0.155 and p = 0.879, respectively).
The FVL mutation is the most common hereditary procoagulant defect.Citation42 Ishimitsu et al. studied the incidence of this mutation in 152 HD patients. In 7 (5%) patients heterozygote for this mutation, they did not see any permanent vascular catheter or fistula thrombosis (), but the number of their study subjects was limited and there was also no patient group with homozygote, arg 506 mutation prevalence was higher (case group 13% and control group 4%), and PT 20210A heterozygote mutation was seen in the case group (case group 9% and control group 0%).Citation19 In a case presentation, the effect of FVL mutation on relapsing fistula thrombosis was supported.Citation43
The PT G20210A mutation is the second most common coagulopathy that predisposes to venous thrombosis. It is well known that FVL mutation and PT G20210A mutation are risk factors for DVT but their effects on the arterial system are not well known.Citation44,Citation45 In our study, we did not determine any relationship between these mutations and early-stage fistula thrombosis. We believe that this is because both groups have normal genotypes (>88%).
In a study in chronic renal failure patients who were awaiting transplantation, after a 3-year follow-up period, a relationship between FVL mutation and access thrombosis was shown (p = 0.01), whereas no relationship was seen for PT 20210A, MTHFR, and ACE gene mutations. In the follow-up period, 62 of 109 patients had VAT.Citation46 The criteria for thrombosis diagnosis and state of the peritoneal dialysis patients were not clarified. We found that the ACE DD genotype increases AVF thrombosis risk 4.25 times, whereas FVL, PT 20210A, and MTHFR gene polymorphisms did not have any effect on early-stage fistula thrombosis.
Brophy et al. conducted a study on 60 patients and 41 control subjects. Control subjects were selected from the HD patients who did not have access thrombosis for 3 years. The case group was selected using fistulography, Doppler ultrasonography, and physical examination and included the following: those with two or more VAT attacks in 12 months or requiring new dialysis access in 2 years or with AVG-AVF patency lasting less than 2 months and directed to permanent vascular catheter or peritoneal dialysis. They did not determine any relationship between FVL and PT 20210A mutations and VAT.Citation33 It should be stated that the thrombosis time in these patients was not comparable, with thromboses seen in early stage in some patients and in late stage in others. The access localization of the groups differed, with AVG more frequent in the case group (49.2%) and AVF (45%) in the control group (p < 0.001). In our study, FVL and PT 20210A mutations were unrelated with AVF thrombosis as well, but our case group consisted of patients with early-stage thrombosis and there was no difference in access localization between the two groups. Another similarity of this study with ours is the method of fistula thrombosis diagnosis.
In another study with 107 patients and a control group of 312 subjects without thrombosis, FVL, PT 20210A mutation, factor XIII genotype, MTHFR genotype, lupus anticoagulant, anticardiolipin antibody, factor VIII levels, homocysteine, and lipoprotein (a) were studied. For each thrombophilia added, the OR of thrombosis risk increased (OR = 1.87, 95% CI = 1.34–2.61; p < 0.0001). For important factors after arrangement, access thrombosis risk increased to mid-level.Citation47
To the best of our knowledge, this is the first broad study on early-stage fistula thrombosis. The limitations of this study are that 20% of the study subjects had diabetes mellitus, it was a retrospective study, and the number of subjects was limited.
We determined in this study that ACE DD genotype and PAI-1 4G/5G gene polymorphism increases the risk of fistula thrombosis. Prospective, multicentered studies based on observation and with more subjects are needed to decide the effect of ACE and thrombophilic factors on access thrombosis. In the near future, chronic renal failure patients with thrombophilic genetic background can be directed to peritoneal dialysis or preempt transplantation. In this patient group, to determine the effectiveness of antiplatelet, anticoagulant, and ACEI–ARB treatment, separate prospective studies will be needed.
Declaration of interest:The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES
- Smits J, van der Linden J, Blankestijn PJ, Rabelink TJ. Coagulation and hemodialysis access thrombosis. Nephrol Dial Transplant. 2000;15:1755–1760.
- US Renal Data System. Excerpts from the USRDS 2003 Annual Data Report: Atlas of end-stage renal disease in the United States. Am J Kidney Dis. 2003;42:S1–S230.
- Feldman HI, Kobrin S, Wasserstein A. Hemodialysis vascular access morbidity. J Am Soc Nephrol. 1996;7:523–535.
- Schwab SJ. Vascular access for hemodialysis. Kidney Int. 1999;55:2078–2090.
- LeSae CJ, Merrick HW, Smith MR. Thrombotic complications resulting from hypercoagulable states in chronic hemodialysis vascular access. Am Coll Surg. 1999;189:73–81.
- Weiss MF, Scivittaro V, Anderson JM. Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access. Am J Kidney Dis. 2001;37:970–980.
- Daemen MJ, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991;68:450–456.
- Tiret L, Rigat B, Visvikis S, Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51:197–205.
- Wiwanitkit V. Angiotensin-converting enzyme gene polymorphism: I and D alleles from some different countries. Clin Appl Thromb Hemost. 2004;10(2):179–182.
- Kohler HP, Grant PJ. Mechanisms of disease: Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 2000;342:1801–1972.
- Eriksson P, Kalling B, van't Hooft FM, Allele-specific increase in basal transcription of the plasminogen activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA. 1995;92:1851–1855.
- Mansfield MW, Stikland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin dependent diabetes. Thromb Hemost. 1995;74:1032–1034.
- Ikegaya N, Yamamoto T, Takeshita A, Elevated erythropoietin receptor and transforming growth factor-1 expression in stenotic arteriovenous fistulae used for hemodialysis. J Am Soc Nephrol. 2000;11:928–935.
- Aznar J, Estelles A, Tormo G, Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J. 1988;59:535–541.
- Cambien F, Poirier O, Lecerf L, Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359:641–644.
- Kim DK, Kim JW, Kim S, Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol. 1997;17:3242–3247.
- Van der Sman-de Beer F, Verhagen C, Rombach SM, ACE I/D polymorphism is associated with mortality in a cohort study of patients starting with dialysis. Kidney Int. 2005;68:2237–2243.
- So WY, Ma RC, Ozaki R, Angiotensin-converting enzyme (ACE) inhibition in type 2, diabetic patients: Interaction with ACE insertion/deletion polymorphism. Kidney Int. 2006;69:1438–1443.
- Ishimitsu T, Hosoya K, Matsuoka H. The deletion allele of angiotensin-converting enzyme gene polymorphism as a cardiovascular risk factor in patients undergoing long-term hemodialysis. Ann Intern Med. 2000;133:924.
- Paulson WD. Prediction of hemodialysis synthetic graft thrombosis: Can we identify factors that impair validity of the dysfunction hypothesis? Am J Kidney Dis. 2000;35:973–975.
- Philipp CS, Dilley A, Saidi P, Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Hemost. 1998;80:869–873.
- Koppel H, Renner W, Gugl A, The angiotensin-converting enzyme insertion/deletion polymorphism is not related to venous thrombosis. Thromb Hemost. 2004;91:76–79.
- Dilley A, Austin H, Hooper WC, Relation of three genetic traits to venous thrombosis in an African-American population. Am J Epidemiol. 1998;147:30–35.
- Gonzales Ordonez AJ, Fernandez Carreira JM, Medina Rodriguez JM, Risk of venous thromboembolism associated with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene. Blood Coagul Fibrinolysis. 2000;11(5):485–490.
- Makris TK, Stavroulakis GA, Dafni UG, ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial dysfunction in patients with untreated hypertension. Am Heart J. 2000;140:760–765.
- Jackson A, Brown K, Langdown J, Luddington R, Baglin T. Effect of the angiotensin-converting enzyme gene deletion polymorphism on the risk of venous thromboembolism. Br J Hematol. 2000;111:562–564.
- Isbir CS, Akgun S, Yilmaz H, Is there a role of angiotensin-converting enzyme gene polymorphism in the failure of arteriovenous femoral shunts for hemodialysis? Ann Vasc Surg. 2001;15:443–446.
- Baek SH, Kye YH, Ahn SH. Role of ACE gene polymorphism on failure of arteriovenous fistula for maintenance of hemodialysis. Korean J Nephrol. 2003;22(6):664–670.
- Gradzki R, Dhingra RK, Port FK, Roys E, Weitzel WF, Messana JM. Use of ACE inhibitors is associated with prolonged survival of arteriovenous grafts. Am J Kidney Dis. 2001;38:1240–1244.
- Paulson WD, Ram SJ, Faiyaz R, Caldito GC, Atray NK. Association between blood pressure, ultrafiltration, and hemodialysis graft thrombosis: A multivariable logistic regression analysis. Am J Kidney Dis. 2002;40:769–776.
- Saran R, Dykstra DM, Wolfe RA, Gillespie B, Held PJ, Young EW. Association between vascular access failure and the use of specific drugs: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2002;40:1255–1263.
- Heine GH, Ulrich C, Kohler H, Girndt M. Is AV fistula patency associated with angiotensin-converting enzyme (ACE) polymorphism and ACE inhibitor intake? Am J Nephrol. 2004;24:461–468.
- Brophy DF, Bukaveckas BL, Ferreira-Gonzalez A, Archer KJ, Martin EJ, Gehr TW. A pilot study of genetic polymorphism and hemodialysis vascular access thrombosis. Hemodial Int. 2009;13:19–26.
- Moon JY, Jeong KH, Paik SS, Arteriovenous fistula patency associated with angiotensin-converting enzyme I/D polymorphism and ACE inhibition or AT1 receptor blockade. Nephron Clin Pract. 2009;111:c110–c116.
- Tomura S, Nakamura Y, Doi M, Fibrinogen, coagulation factor VII, tissue plasminogen activator inhibitor-1, and lipid as cardiovascular risk factors in chronic hemodialysis and continuous ambulatory peritoneal dialysis patients. Am J Kidney Dis. 1996;27(6):848–854.
- Stegnar M, Uhrin P, Peternel P, The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: Relationship to plasma PAI-1 level in venous thromboembolism. Thromb Hemost. 1998;79(5):975–979.
- Yılmaz E, Akar E, Akar N. Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thromboembolic patients with and without prothrombin 20210 G-A. Turk J Hematol. 2004;21(2):83–86.
- Pfeffer MA, Braunwald E, Moye LA, Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1992;327:669–677.
- Akar N, Yılmaz E, Akar E, Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thrombotic patients with and without FV 1691 G-A. Thromb Res. 2000;97:227–230.
- Lazo-Langer A, Knoll AG, Wells SP, Carson N, Rodger AM. The risk of dialysis access thrombosis is related to the transforming growth factor-beta 1 production haplotype and is modified by polymorphism in the plasminogen activator inhibitor-type 1 gene. Blood. 2006;108:4052–4058.
- Fukasawa M, Matsushita K, Kamiyama M, The methylenetetrahydrofolate reductase C677T point mutation is a risk factor for vascular access thrombosis in hemodialysis patients. Am J Kidney Dis. 2003;41:637–642.
- Girndt M, Heine GH, Ulrich C, Köhler H, DialGene Consortium. Gene polymorphism association studies in dialysis: Vascular access. Semin Dial. 2007;2(1):63–67.
- Bremer C, Schaefer RM. Heterozygosity for factor V Leiden in a hemodialysis patient with recurrent shunt thrombosis. Nephrol Dial Transplant. 1997;12:1775–1776.
- Atac B, Yakupoglu U, Ozbek N, Ozdemir FN, Bilgin N. Role of genetic mutations in vascular access thrombosis among hemodialysis patients waiting for renal transplantation. Transplant Proc. 2002;34:2030–2032.
- Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: A meta-analysis of published studies. Am Heart J. 2003;146:948–957.
- Akman B, Afsar B, Ataç FB, Predictors of vascular access thrombosis among patients on the cadaveric renal transplantation waiting list. Transplant Proc. 2006;38:413–415.
- Knoll AG, Wells SP, Young D, Thrombophilia and the risk for hemodialysis vascular access thrombosis. J Am Soc Nephrol. 2005;16:1108–1114.