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Thrombophilia and the Risk for Hemodialysis Vascular Access Thrombosis

Greg A. Knoll^*,,, Philip S. Wells^,, Darlene Young, Sherry L. Perkins^||, Rachel M. Pilkey^¶, Jennifer J. Clinch and Marc A. Rodger^,

Divisions of ^* Nephrology; Hematology, Department of Medicine, University of Ottawa, Kidney Research Centre and Clinical Epidemiology Program, The Ottawa Health Research Institute, and ^|| Department of Pathology and Laboratory Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario; and ^¶ Division of Nephrology, Department of Medicine, Queens University, Kingston, Ontario, Canada

Address correspondence to: Dr. Greg A. Knoll, Division of Nephrology, The Ottawa Hospital, Riverside Campus, 1967 Riverside Drive, Ottawa, Ontario, Canada K1H 7W9. Phone: 613-738-8400 ext. 82536; Fax: 613-738-8337; gknoll{at}ottawahospital.on.ca

Received for publication November 24, 2004. Accepted for publication January 17, 2005.

	Abstract

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Vascular access thrombosis is the most common and costly complication in hemodialysis patients. The role of thrombophilia in access thrombosis is not established. A case-control study was conducted of 419 hemodialysis patients to determine whether thrombophilia was associated with arteriovenous fistula or graft thrombosis. Participants were enrolled from three in-center and five satellite dialysis units associated with a Canadian academic health science center that provides dialysis services in a catchment area of one million. Patients were tested for factor V Leiden, prothrombin gene mutation, factor XIII genotype, methylenetetrahydrofolate reductase genotype, lupus anticoagulant, anticardiolipin antibody, factor VIII, homocysteine, and lipoprotein (a) concentrations. Overall, 59 (55%) patients with access thrombosis had at least one thrombophilia compared with 122 (39%) patients without access thrombosis (unadjusted odds ratio [OR], 1.91; 95% confidence interval [CI], 1.23 to 2.98). After controlling for important risk factors, the association between any thrombophilia and access thrombosis remained (adjusted OR, 2.42; 95% CI, 1.47 to 3.99). For each additional thrombophilic disorder, the odds of access thrombosis increased significantly (adjusted OR, 1.87; 95% CI, 1.34 to 2.61). This study suggests that thrombophilia is associated with access thrombosis in dialysis patients. Large, multicenter, prospective cohort studies are needed to confirm the observations from this case-control study.

	Introduction

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The maintenance of adequate vascular access is crucial to patient survival on hemodialysis. The majority of hemodialysis patients in the United States have either a native arteriovenous fistula or a synthetic arteriovenous graft for vascular access (1). Complications related to vascular access account for 20 to 25% of all hospitalizations in dialysis patients (2,3) and cost >$1 billion annually in the United States (2). Thrombosis is the leading cause of arteriovenous fistula and graft failure (3), yet there are few well-established risk factors for access thrombosis (4). It is currently thought that most episodes of thrombosis are due to underlying anatomic abnormalities such as access stenosis from fibromuscular and intimal hyperplasia (5,6). However, access thrombosis can occur without anatomic abnormalities (3,6,7), and it is unknown why some patients with anatomic abnormalities experience access thrombosis whereas others do not (8).

Thrombophilias are inherited or acquired predispositions to thrombosis (9) and have been suggested as a possible cause of dialysis access thrombosis (4,10). Studies to date have been conflicting, with some suggesting a significant association (11–18) whereas others have not (19–22). Previous studies were limited by small sample size, absence of a control group, evaluation of only individual thrombophilias, or inadequate control of confounders (i.e., other potential risk factors for access failure). To clarify the role of thrombophilia in access thrombosis, we undertook an adequately powered case-control study that evaluated several thrombophilic disorders while simultaneously controlling for other potential risk factors for access thrombosis.

	Materials and Methods

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Study Design and Participants
This was a case-control study involving adult hemodialysis patients from three in-center and five satellite units associated with The Ottawa Hospital, a Canadian academic health science center that provides dialysis services in a catchment area of one million. All participants provided written informed consent. The study was approved by the Ottawa Hospital Research Ethics Board. Patients with a functioning permanent dialysis access (arteriovenous fistula or graft) were eligible to participate. Functioning access was defined as successful cannulation with two needles and a minimum blood flow of 250 ml/min for at least one complete dialysis treatment. Patients with a history of failed access (i.e., fistula or graft created but never functioned as defined above) were eligible to participate as long as they had one permanent access that at some point functioned. Patients were classified as cases when their first functioning dialysis access had a thrombotic occlusion. Control subjects were patients who never had a thrombotic occlusion of a functioning permanent dialysis access. Thrombotic occlusion was defined by the absence of flow on clinical examination and the inability to use the access for dialysis. The evaluation for thrombotic occlusion was determined by the clinical team, which was unaware of the patient’s thrombophilia status.

Screening for subclinical access dysfunction was not performed during the study. However, surveillance for clinical evidence of access dysfunction was carried out as described by Miller et al. (23) and Ram et al. (24). Patients with increased dialysis venous pressure, inability to achieve prescribed blood flow, swollen access site, prolonged bleeding from access needle site, or low urea reduction ratio were referred for angiography. When a clinically significant lesion (50% stenosis) was seen, the patient underwent angioplasty or surgical revision after consultation with the vascular surgeon and interventional radiologist (7,24,25).

Laboratory Tests
All participants had blood samples drawn predialysis. Samples for homocysteine were immediately placed on ice, and all samples were separated and stored at –70°C until analysis. DNA was isolated from leukocytes using standard methods. The single-nucleotide polymorphisms for factor V Leiden, factor XIII (Val34Leu), prothrombin (G20210A), and MTHFR (C677T) were determined using a single bp extension PCR-based method (SNaPshot Multiplex Kit; Applied Biosystems, Foster City, CA) (26). Primers for the single-nucleotide polymorphisms were designed and validated using recommended methods (27). DNA was sequenced using a capillary electrophoresis instrument (ABI PRISM 3100 Genetic Analyzer; Applied Biosystems) (26,27) and analyzed with an automated software protocol (Genotyper Software, version 3.7; Applied Biosystems). Factor VIII level was measured on an automated coagulation factor analyzer (BCS Coagulation System; Dade Behring, Deerfield, IL) using factor VIII–deficient plasma (28). Total homocysteine was measured using a fluorescence polarization immunoassay (29) (AxSym Immunoassay Analyzer; Abbott Laboratories, Abbott Park, IL). Lupus anticoagulant was measured with the DVVtest and DVVconfirm test kits (American Diagnostica, Stamford, CT). Fibrinogen concentration was measured on a BCS Coagulation System using the manufacturer’s reagents (Dade Behring). Anticardiolipin antibody concentrations (IgG and IgM) were measured using an ELISA kit (DiaSorin, Stillwater, MN). Lipoprotein (a) was measured using an ELISA kit (Macra Lpa, Trinity Biotech, Jamestown, NY). Albumin was determined using bromcresol purple dye binding method on a Beckman Coulter LX 20 analyzer using the manufacturer’s reagents (Beckman Coulter, Brea, CA). Folate and vitamin B₁₂ concentrations were measured on an Access 2 Immunoassay system using the manufacturer’s reagents (Beckman Coulter). The laboratory staff who performed the testing was not aware of the patient’s clinical status.

Statistical Analyses
Baseline dichotomous variables were compared with the ² test, and continuous variables were compared with a t test or the Mann-Whitney U test as appropriate. In the primary analysis, we examined whether the presence of any thrombophilic disorder was associated with access thrombosis. Unadjusted and multivariate-adjusted odds ratios (OR) and their 95% confidence intervals (CI) were determined using logistic regression. The primary analysis was determined a priori as part of a grant-funded research protocol. The sample size estimate was based on an 18 to 32% prevalence of the different thrombophilic disorders in the general population at the time of protocol submission (30–34). We estimated that 438 patients would be required to detect an increase in the adjusted OR of 2.0, with the conservative assumption that any thrombophilia was present in 18% of the control group, an error of 0.05 and a error of 0.2.

In the primary analysis, a thrombophilic disorder was defined as follows: The presence of factor V Leiden, prothrombin gene mutation, or lupus anticoagulant, an elevated factor VIII level, an elevated homocysteine concentration, an elevated lipoprotein (a) concentration, or an elevated anticardiolipin antibody (IgG or IgM) concentration. Factor VIII was defined as elevated when it was above the 90th percentile (28). Homocysteine and lipoprotein (a) were defined as elevated when they were 85th percentile (35). Anticardiolipin antibody level (IgG and IgM) was defined as elevated using a medium titer of 30 GPL or MPL U/ml (36,37). The logistic regression model was adjusted in three stages. First, factor XIII genotype was added to the model because it seems to modulate the risk for thrombosis in the presence of other thrombophilias (38,39). Next, we adjusted for age, gender, diabetes, and dialysis access type (arteriovenous fistula or graft). We then entered the following variables into the model when they showed a trend toward statistical significance (P < 0.2) on univariate testing: Body mass index; cause of ESRD; race; smoking status; history of failed dialysis access; time from access surgery to first cannulation; time from access surgery to thrombotic occlusion or end of observation period; operating surgeon; access location; access angiogram performed; angioplasty or surgical revision performed; warfarin use; antiplatelet therapy; B-vitamin or folic acid use; angiotensin-converting enzyme inhibitor use; oral contraceptive or hormone replacement therapy; erythropoietin dose; family history of venous thromboembolism; personal history of venous thromboembolism; malignancy; peripheral vascular disease; coronary artery disease or stroke; albumin, hemoglobin, folate, vitamin B₁₂, and fibrinogen concentrations; and urea reduction ratio. Finally, clinically important interaction terms were entered into the model. Specifically, we assessed whether the effect of any thrombophilia on access thrombosis was modified by the type of dialysis access. This was done by adding into the model an interaction term that incorporated access type (fistula or graft) and the presence of any thrombophilia. Additional interaction terms were created for age and any thrombophilia as well as gender and any thrombophilia. Only variables that reached statistical significance (P < 0.05) were retained in the final model.

In a secondary analysis, we determined whether the risk for access thrombosis increased when a patient had more than one thrombophilia. In this analysis, we counted the number of thrombophilic disorders per patient and entered the term into a logistic regression model. The model was adjusted using the same methods as described for the primary analysis.

Although not part of the a priori primary analysis, we conducted exploratory analyses to determine which, if any, of the individual thrombophilic disorders were associated with access thrombosis. These analyses were adjusted for the presence of all of the individual thrombophilias, age, gender, diabetes, and access type as well as any of the variables listed above that showed a trend toward significance (P < 0.2) on univariate testing. Interaction terms between each thrombophilia and access type, each thrombophilia and age, each thrombophilia and gender, vitamin use and homocysteine, and MTHFR genotype and homocysteine were entered in the model.

The protocol for this study was written by the authors and funded through a peer-reviewed competition by the Heart and Stroke Foundation of Ontario (grant NA4709). The authors maintained the database and performed all analyses independent of the funding agency.

	Results

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A total of 848 patients were screened for enrollment. Patients were ineligible for the following reasons: Fistula or graft never created or never functioned (n = 345) and access created but not yet used (n = 21). Of the 482 eligible patients, 63 refused or were unable to consent, leaving 419 participants in the study. A total of 107 cases had access thrombosis, and 312 control subjects never had access thrombosis.

The baseline characteristics of the cases and control subjects are depicted in Table 1. The cases were younger than the control subjects, but gender, race, weight, and presence of other comorbid conditions were similar between the groups. The cases were less likely to have a fistula for dialysis access than the control subjects, but the surgeon who created the access was not different between the cases and control subjects (P = 0.37). The time at risk for thrombosis was significantly longer in the control patients (Table 1). For the cases, the median number of days from access surgery to thrombosis was 548 (interquartile range, 281 to 1179), and for the control subjects, the median number of days from surgery to the end of the observation period was 1021 (interquartile range, 592 to 1654; P < 0.001). The mean vitamin B₁₂ (416.0 ± 221.3 versus 444.4 ± 246.6 pmol/L; P = 0.41), serum folate (39.2 ± 19.1 versus 37.3 ± 11.8 nmol/L; P = 0.59), and fibrinogen (3.8 ± 1.1 versus 3.7 ± 0.9 g/L; P = 0.69) concentrations were similar between the cases and control subjects.

View larger version (18K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Thrombosis-free survival of dialysis access stratified by the presence or absence of any thrombophilia.

Final exploratory analyses were performed to evaluate whether the individual thrombophilias were each associated with access thrombosis. After adjusting for each individual thrombophilia, age, gender, diabetes, access type as well as the clinical risk factors evaluated in the primary analysis, factor V Leiden (adjusted OR, 3.94; 95% CI, 1.08 to 14.35; P = 0.04), elevated factor VIII (adjusted OR, 2.40; 95% CI, 1.17 to 4.90; P = 0.02), elevated lipoprotein (a) (adjusted OR, 1.97; 95% CI, 1.04 to 3.74; P = 0.04), and elevated homocysteine (adjusted OR, 2.43; 95% CI, 1.26 to 4.67; P = 0.008) were associated with access thrombosis.

	Discussion

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To our knowledge, this is the largest and most comprehensive examination of the association between thrombophilic disorders and dialysis access thrombosis. After adjusting for important factors, we found that the presence of any thrombophilia was associated with an increased risk for dialysis access thrombosis.

Although we have shown a moderate association (OR <3) between thrombophilia and access thrombosis, this has not been a consistent finding in previous studies (11–22). The inconsistency in association may be due to the size of earlier studies. More than half of the studies to date have involved <100 patients and likely were not large enough to detect an effect of the thrombophilic disorders. We believe that further large case-control studies or prospective cohort studies need to be performed to confirm the association found in this study.

Arterial or venous thrombosis involves an interplay among stasis, vascular injury, and hypercoagulability (40). The roles of stasis and vascular injury have been studied extensively in relation to access thrombosis (3,5,41). It makes biologic sense that hypercoagulability would also play a role in access thrombosis. The thrombophilic disorders have been associated with both arterial and venous thrombosis (9,40,42), and the dialysis vascular access is a unique entity that involves components of both the arterial and the venous system. However, the moderate association demonstrated in this study suggests that thrombophilia is not the only cause of access thrombosis but rather a contributor to other factors. This would be consistent with the current understanding of access thrombosis in which anatomic abnormalities such as intimal hyperplasia and progressive stenosis have been well established (3,10). In addition, the association between thrombophilia and access thrombosis is strengthened by the biologic gradient that we have found. Each additional thrombophilic disorder was associated with nearly a two-fold increase in the odds of access thrombosis.

In this study, thrombophilias associated with venous disease (e.g., factor V Leiden and prothrombin gene mutation) as well as those associated with both venous and arterial disease (e.g., lipoprotein [a] [43,44] and homocysteine [34,45]) were evaluated. In the general population, thrombophilias associated with venous thrombosis are often treated with oral anticoagulants. However, the association that we found with homocysteine and lipoprotein (a) raises the possibility that antiplatelet agents, used to treat arterial disorders, might be beneficial in preventing access thrombosis. Because this was an observational study on risk factor identification, our data can provide no direct guidance on the prevention or treatment of access thrombosis. However, two recent randomized trials failed to show any benefit of low-intensity warfarin (46) or the combination of aspirin plus clopidogrel (47) in preventing access thrombosis. However, neither of these studies evaluated patients for thrombophilia. In a nonrandomized study, patients with one or more thrombophilic disorders and a history of dialysis access thrombosis were given high-intensity warfarin therapy (18). The thrombosis rate on warfarin was 1.2 events per year compared with 4.0 events per year in a similar group of hypercoagulable dialysis patients who were not given warfarin (18). All thrombotic events in the warfarin patients occurred when the international normalized ratio was <2.7. It may be that widespread use of antiplatelet agents or warfarin in all dialysis patients is ineffective but that selective use of these agents in patients with thrombophilia would prove beneficial. However, this hypothesis requires confirmation in properly designed randomized, controlled trials.

Limitations of this study should be noted. First, laboratory assessment for thrombophilia occurred after the dialysis access thrombosis for many of the case patients. This will not limit the analysis of the inherited thrombophilias, such as factor V Leiden, but it may affect how the acquired disorders (e.g., anticardiolipin antibodies) are interpreted. For example, we did not show a significant association between the presence of anticardiolipin antibodies and access thrombosis. However, it is possible that these antibodies were elevated before dialysis access thrombosis occurred, but at the time of measurement, they had normalized. Second, anticardiolipin antibodies were measured only once, and positives were not repeated as recommended (36). However, to reduce the number of false-positive results, we chose a medium rather than a low titer to classify patients as having elevated anticardiolipin antibodies. Third, we did not measure all known thrombophilias (i.e., excluded protein C, protein S, and antithrombin deficiencies). However, deficiencies of these inhibitors are rare in the general population (40) and likely would not have changed our findings given the prevalence of the other thrombophilias included in our study. Fourth, we used a case-control design that is efficient for examining several risk factors (48) but is generally not as practical when time at risk needs to be considered. For example, it might be argued that the control patients in this study were not evaluated for a long enough time and that eventually they will thrombose their access and become cases. However, we found that the median follow-up for the control patients was >2.5 yr and significantly longer than the cases. In addition, time with dialysis access was controlled for by its inclusion in the logistic regression model. Finally, a form of selection bias may have occurred as we chose our cases and control subjects from a group of patients who survived progressive renal failure and were currently on maintenance hemodialysis. If thrombophilia truly increases the risk for access thrombosis, then we might have missed enrolling patients who had thrombophilia and died or switched to peritoneal dialysis because of access failure. However, if this bias did occur, then it would have only weakened the association between thrombophilia and access thrombosis and therefore does not invalidate our findings.

In conclusion, this analysis has shown that the presence of thrombophilia is associated with hemodialysis access thrombosis. Although this was an adequately powered case-control study, the routine testing of dialysis patients for thrombophilic disorders cannot be recommended at this time. Large cohort studies, with the preoperative measurement of thrombophilic disorders, are needed to confirm the findings of this analysis.

	Acknowledgments

 
This study was funded by the Heart and Stroke Foundation of Ontario (grant NA4709). P.S.W. is a Canada Research Chair. M.A.R. is a recipient of the Maureen Andrew New Investigator Award from the Heart and Stroke Foundation of Canada.

We thank the staff and patients from the dialysis units that participated in the study. We acknowledge Rebecca Grimwood and Angela Shypipka for assistance with laboratory analysis; Marcella Cheng-Fitzpatrick for data management; and Judy Cheesman, Janet Graham, Darlene Hackett, Margo McCoshen, and Judy Tubman-Reid for invaluable assistance in conducting this study.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

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