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The handle http://hdl.handle.net/1887/31463 holds various files of this Leiden University
dissertation.
Author: Ocak, Gürbey
Title: Vascular complications in kidney disease
Issue Date: 2015-01-14
Chapter 6
Venous and arterial thrombosis
in dialysis patients
Gürbey Ocak
Carla Y. Vossen
Joris I. Rotmans
Willem M. Lijfering
Frits R. Rosendaal
Karien J. Parlevliet
Ray T. Krediet
Els W. Boeschoten
Friedo W. Dekker
Marion Verduijn
Thromb Haemost. 2011; 106(6): 1046-1052
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Chapter 6
ABSTRACT
Background: Whether the risk of both venous and arterial thrombosis is increased in dialysis
patients as compared to the general population is unknown. In addition, it is unknown which
subgroups are at highest risk. Furthermore, it is unknown whether having a history of venous
thrombosis or arterial thrombosis prior to dialysis treatment increases mortality risk.
Methods: A total of 455 dialysis patients were followed for objectively verified symptomatic
thrombotic events between January 1997 and June 2009.
Results: The incidence rates in dialysis patients as compared to the general population
was 5.6-fold (95% CI 3.1-8.9) increased for venous thrombosis, 11.9-fold (95% CI 9.3-14.9)
increased for myocardial infarction, and 8.4-fold (95% CI 5.7-11.5) increased for ischemic
stroke. The combination of hemodialysis, lowest tertile of albumin, history of venous
thrombosis, and malignancy was associated with subsequent venous thrombosis. Increased
age, renal vascular disease, diabetes, high cholesterol levels, history of venous thrombosis,
and history of arterial thrombosis were associated with subsequent arterial thrombosis. The
all-cause mortality risk was 1.9-fold (95% CI 1.1-3.3) increased for patients with a history of
venous thrombosis and 1.9-fold (95% CI 1.4-2.6) increased for patients with a history of arterial
thrombosis. A potential limitation of this study was that in some risk categories associations
with venous thrombosis did not reach statistical significance due to small numbers.
Conclusion: Dialysis patients have clearly elevated risks of venous thrombosis and arterial
thrombosis and occurrence of venous thrombosis or arterial thrombosis prior to the start of
dialysis is associated with an increased mortality risk.
88
Venous and arterial thrombosis in dialysis patients
INTRODUCTION
In the past, venous and arterial thrombosis have been regarded as separate diseases with
different causes.1 In the last decade, however, several investigators suggested that venous
and arterial thrombosis might not be fully separate entities as several studies have shown
that patients with venous thrombosis have an increased risk of arterial thrombosis and vice
versa.2-6 Additional studies have shown that arterial and venous thrombosis share some risk
factors, although this has only consistently been shown for obesity.7-11
Early stages of chronic kidney disease have been associated with both venous and arterial
thrombosis.12,13 However, end-stage renal disease has only been associated with arterial
thrombosis,14-20 and not with venous thrombosis including deep vein thrombosis and pulmonary
embolism. One study in the US Renal Data System (USRDS) showed that dialysis patients
had an age-adjusted 2.3-fold increased risk of for a primary discharge diagnosis of pulmonary
embolism occurring within the first year of dialysis treatment as compared to the general
population.21 However, deep vein thrombosis was not assessed in this study.
Therefore, the primary aim of this study was to assess the absolute risk of deep vein
thrombosis and pulmonary embolism (venous thrombosis) and myocardial infarction and
ischemic stroke (arterial thrombosis) in a cohort of end-stage renal disease patients receiving
dialysis treatment. We also assessed whether venous thrombosis and arterial thrombosis
shared risk factors in dialysis patients. Finally, we determined whether having a history of
venous and arterial thrombosis prior to start of dialysis treatment increased the mortality risk.
METHODS
Patients
The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) is a prospective
multicenter cohort study in which incident adult end-stage renal disease patients in the
Netherlands were included. Eligibility included age older than 18 years, and no previous
renal replacement therapy. All patients gave informed consent and the study was approved
by all local medical ethics committees. We followed 455 patients, from January 1997 in
three dialysis centers that participated in NECOSAD, until a thrombotic event (venous
thrombosis, myocardial infarction, and ischemic stroke), death, or censoring, i.e. transfer to
a nonparticipating dialysis center, withdrawal from the study, transplantation, or end of the
follow-up period (June 2009). These three centers were chosen for logistic reasons, i.e. they
provided a large number of patients.
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Chapter 6
Demographic and clinical data
Data on age, sex, primary kidney disease, smoking status, diabetes, medication, and history
of thromboembolic events (venous thrombosis, myocardial infarction, or ischemic stroke)
were collected at the start of dialysis treatment. Primary kidney disease was classified
according to the codes of the European Renal Association-European Dialysis and Transplant
Association (ERA-EDTA).22 We grouped patients into four classes of primary kidney disease:
glomerulonephritis, diabetes mellitus, renal vascular disease, and other kidney diseases.
Other kidney diseases consisted of patients with interstitial nephritis, polycystic kidney
diseases, other multisystem diseases and unknown diseases.
Serum albumin, hemoglobin, creatinine, urea, total cholesterol, and triglycerides were routinely
measured in the dialysis centers at 3 months after start of dialysis. Total protein, urea, and
creatinine levels were also routinely measured in 24-hour urine samples. Renal function,
expressed as glomerular filtration rate (GFR), was calculated as the mean of creatinine and
urea clearance corrected for body surface area (ml/min per 1.73 m2).
Venous thrombosis and arterial thrombosis
Symptomatic venous thrombosis (deep vein thrombosis of the leg and pulmonary embolism)
and symptomatic arterial thrombosis (myocardial infarction and ischemic stroke) during
follow-up were identified from hospital diagnosis registration systems and from chart review
of all 455 patients. Moreover, we used medical records to validate the thrombotic events.
Peripheral vascular atherosclerotic diseases were not considered as arterial events due to
lack of detailed information of these disease entities in our patients charts.
Venous thrombosis was considered confirmed when diagnosed by compression ultrasound
for deep vein thrombosis of the leg and/or when diagnosed by spiral computed tomography
or ventilation-perfusion lung scanning for pulmonary embolism. Venous thrombosis
was considered unprovoked in the absence of surgery, trauma, presence of a catheter,
immobilization for >7 days or hospitalization, oral contraceptives, hormone therapy, pregnancy,
malignant disease, or long-distance travel for >4 hours at or within one month before the
development of venous thrombosis. Medical records were reviewed with a standardized
check-list to categorize venous thrombosis into provoked or unprovoked.
Myocardial infarction had to be confirmed by typical symptoms, electrocardiogram features,
elevated levels of cardiac enzymes, radionuclide imaging techniques, or coronary angiography.
Ischemic stroke had to be diagnosed by computed tomography or magnetic resonance
imaging.
90
Venous and arterial thrombosis in dialysis patients
Mortality
We classified causes of death according to the codes of the European Renal AssociationEuropean Dialysis and Transplantation Association (ERA-EDTA) which is a standardized
classification of death causes in dialysis patients.22 We grouped death causes into
cardiovascular and non-cardiovascular. Cardiovascular mortality was defined as death due to
myocardial ischemia and infarction (code 11); cardiac arrest/ sudden death (code 15); cardiac
failure/ fluid overload/ pulmonary edema (codes 14,16,18); hyperkalemia /hypokalemia (code
12,17); pulmonary embolism (code 21); cerebrovascular accident (code 22); hemorrhage
from ruptured vascular aneurysm (code 26); mesenteric infarction (code 29); cause of death
uncertain/unknown (code 0). Non-cardiovascular mortality was defined as death caused by
pulmonary infection (code 31-33); infections elsewhere (code 34); septicemia (code 35);
tuberculosis (code 36-37); generalized viral infection (code 38); peritonitis (code 39); suicide
(code 52); treatment cessation (code 51, 53-54) ; cachexia (code 64) ; malignancies (codes
66-68); miscellaneous (codes 13, 23-28, 41-46, 61-63, 69-73, 81-82, 99-102).
Statistical analysis
Continuous variables are presented as mean with standard deviation (SD) or as median
and interquartile rage (IQR) depending on the normality of the data. Categorical variables
are presented as counts with corresponding percentages. The observation time for venous
thrombosis in each participant was calculated as the time elapsed between the start of
dialysis and a censoring event (withdrawal from the study, transplantation, death, or June
2009), or the first episode of venous thrombosis during dialysis. The observation time for
arterial thrombosis in each participant was calculated as the time elapsed between the start
of dialysis and a censoring event (withdrawal from the study, transplantation, death, or June
2009), or the first episode of arterial thrombosis during dialysis. Incidence rates for arterial
and venous thrombosis were calculated by dividing the number of patients with a venous
thrombosis or arterial thrombosis by the total observation time at risk. When calculating the
incidence rates for venous thrombosis, we ignored the occurrence of arterial thrombosis
and vice versa. Incidence rates and 95% confidence intervals (95% CIs) were calculated
with Poisson regression models for venous thrombosis, myocardial infarction, and ischemic
stroke in dialysis patients. We used indirect standardization to compare these incidence rates
to the age- and sex-weighted incidence rates in the general population obtained from the
HUNT2 study for venous thrombosis23 and the Framingham study for myocardial infarction24
and ischemic stroke.25 The presented incidence rates in the general population are based on
the age- and sex-distribution of the dialysis patients in our study. Cumulative incidences for
venous thrombosis and arterial thrombosis were analyzed by using time-to-event analyses
accounting for competing risk of transplantation and death.26 Furthermore, we calculated
adjusted hazard ratios (HRs) with 95% CIs to evaluate the effect of clinical and laboratory
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Chapter 6
characteristics on the development of venous thrombosis and arterial thrombosis. Finally, we
determined whether having a history of venous and arterial thrombosis prior to start of dialysis
treatment increased the (cardiovascular and non-cardiovascular) mortality. SPSS statistical
software (version 17.0; SPSS, Chicago, Illinois) was used for the analyses.
RESULTS
Baseline characteristics of the 455 patients are shown in Table 1. Overall, the mean age
was 60.4 years, 65.7% were male, 64.6% had hemodialysis treatment at initiation of dialysis
including 85 patients with a catheter (18.7%) and 209 patients with an arteriovenous access
(45.9%), and 18.2% of patients had diabetes as primary kidney disease. Of the 455 patients, 23
(5.1%) had a history of venous thrombosis and 116 (25.5%) had a history of arterial thrombosis
prior to the start of dialysis therapy. Patients were followed for a median observation period of
2.4 years (range 0.1 to 11.7 years).
During the observation period, 15 patients developed venous thrombosis, of whom seven
had pulmonary embolism, seven deep vein thrombosis, and one presented with both. Four
patients (26.7%) with pulmonary embolism died. Of the 15 venous thrombotic events, 5 were
unprovoked and 10 were provoked (hospitalization, n=4; catheter-related, n=4; surgery, n=2,
presence of malignancy, n=2). Of the 4 patients who developed venous thrombosis during
hospitalization, one had an exacerbation of ulcerative colitis, one patient had sepsis, one had
a pancreatitis, and one had an exacerbation of Wegener’s disease. Of the 4 patients who
developed catheter associated venous thrombosis, three had a deep vein thrombosis and one
had a pulmonary embolism. One patient developed venous thrombosis during hospitalization
after coronary artery bypass grafting and another patient developed venous thrombosis
shortly after thrombectomy of a thrombosed dialysis shunt. Of note, none of the patients had
an arteriovenous access in the lower limb. Furthermore, 96 patients developed an arterial
thrombosis (72 patients developed myocardial infarction of which 15 were fatal (20.8%) and
33 patients developed ischemic stroke of which 6 were fatal (18.2%).
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Venous and arterial thrombosis in dialysis patients
Table 1. Baseline characteristics
Age, years
Sex
Male
Female
Dialysis modality (%)
Hemodialysis
Peritoneal dialysis
Primary kidney disease (%)
Diabetes mellitus
Glomerulonephritis
Renal vascular disease
Other
Body mass index, kg/m2
Diabetes mellitus as comorbidity
Malignancy
History of venous thrombosis
History of arterial thrombosis
Smoking
Never
Ever
Hemoglobin, mmol/L
GFR, ml/min
Proteinuria, gram per day
Anticoagulation use
Erythropoietin use
Erythropoietin dose, IU/week
Albumin, g/L
Cholesterol, mmol/L
Triglycerides, mmol/L
N=455
60.4
± 15.1
299
156
(65.7%)
(34.3%)
294
161
(64.6%)
(35.4%)
83
48
75
249
25.0
122
24
23
116
(18.2%)
(10.5%)
(16.5%)
(54.7%)
± 5.2
(26.8%)
(5.3%)
(5.1%)
(25.5%)
174
254
6.9
3.3
1.1
21
276
6000
33.0
4.4
1.9
(40.7%)
(59.3%)
± 1.0
(1.9-5.6)
(0.5-2.4)
(6.7%)
(60.7%)
(4000-8000)
(29.0-37.0)
(3.6-5.4)
(1.3-2.6)
6
Figure 1 shows the incidence rates per 1000 person-years for venous thrombosis (combination
of deep vein thrombosis and pulmonary embolism), deep vein thrombosis (alone), pulmonary
embolism (with or without deep vein thrombosis), myocardial infarction, and ischemic stroke
in dialysis patients as compared to the estimated age- and sex-weighted incidence rates
in the general population (HUNT2 study23 for venous thrombosis and Framingham study24,25
for myocardial infarction and ischemic stroke). The incidence rate of venous thrombosis
(12.3 (95% CI 7.2-19.9) per 1000 person-years) in dialysis patients was 5.6 (95% CI 3.18.9) times higher than the estimated age- and sex-weighted annual incidence rate in the
general population (HUNT2 study,23 2.2 per 1000 person-years). The incidence of both
provoked venous thrombosis (8.2 per 1000 person-years; 95% CI 4.2-14.6) and unprovoked
venous thrombosis (4.0 per 1000 person-years; 95% CI 1.4-8.9) were higher than the age-
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and sex-weighted annual incidence rates of provoked and unprovoked venous thrombosis
in the general population (HUNT2 study,23 1.1 per 1000 person-years for provoked venous
thrombosis
and 1.1rates
per 1000
person-years
forfor
unprovoked
Figure 1. Incidence
per 1000
person-years
venous andvenous
arterialthrombosis).
thrombosis inThe absolute
risk
of myocardial infarction (62.1 (95% CI 49.0-77.8) per 1000 person-years) was 11.9 (95%
dialysis patients as compared to the age- and sex- weighted incidence rates in the general
CI
9.3-14.9)
timesrates
higher
dialysis
patients
theand
estimated
age- and insex-weighted
Figure
1. Incidence
per in
1000
person-years
forthan
venous
arterial thrombosis
population
dialysis patients as compared to the age- and sex- weighted incidence rates in the general
incidence rate in the general population (the Framingham study,24 5.2 per 1000 person-years).
Moreover, the absolute risk of ischemic stroke (27.6 (95% CI 19.3-38.4) per 1000 personpopulation
years) was 8.4 (95% CI 5.7-11.5) times higher in dialysis patients than the estimated age- and
sex-weighted annual incidence rate in the general population (the Framingham study,25 3.3
per 1000 person-years). The cumulative incidence at eight years of follow-up was 4.1% for
venous thrombosis and
24.8%
for arterial
VENOUS
THROM
BOSISthrombosis.
VENOUS THROM BOSIS
80
Incidence
Incidence
per 1000
perperson-years
1000 person-years
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Chapter 6
ARTERIAL THROM BOSIS
ARTERIAL THROM BOSIS
80
60
60
40
40
20
20
0
0
VT
DVT (alone)
PE (± DVT)
MI
STROKE
VT
DVT (alone)
PE (± DVT)
MI
STROKE
Incidence dialysis patients
Incidence general population (HUNT2)
Incidence dialysis patients
Incidence general population (Framingham)
 Incidence general population (HUNT2)
Figure 1. Incidence rates per 1000 person-years for venous and arterial thrombosis in dialysis
patients as compared to the age-Incidence
and sex- weighted
incidence
rates in the general population
(Framingham)
MI indicates myocardial infarction; STROKE, general
ischemicpopulation
stroke; VT,
venous thrombosis; DVT, deep
MI indicates myocardial infarction; STROKE, ischemic stroke; VT, venous thrombosis; DVT, deep vein
thrombosis;
PE, pulmonary
embolism
vein thrombosis;
PE, pulmonary
embolism

MI indicates myocardial infarction; STROKE, ischemic stroke; VT, venous thrombosis; DVT, deep
vein thrombosis; PE, pulmonary embolism
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Venous and arterial thrombosis in dialysis patients
Table 2 shows the risk of venous or arterial thrombosis for different baseline variables after
adjustment for age and sex. Venous and arterial thrombosis did not share risk factors in these
dialysis patients, except for history of venous thrombosis which was associated with both
venous and arterial thrombosis. Hemodialysis therapy, highest tertile of albumin, malignancy,
and history of venous thrombosis were associated with venous thrombosis after adjustment
for age and sex, although not significant. The combination of hemodialysis, highest tertile
of albumin, history of venous thrombosis, and malignancy were associated with a 12.0-fold
(95% CI 1.7-84.9) increased risk of venous thrombosis as compared with the absence of
these risk factors. History of arterial thrombosis was not associated with subsequent venous
thrombosis (hazard ratio 1.0; 95 CI 0.3-3.9). However, after exclusion of vitamin K antagonist
users (anticoagulation use), the hazard ratio increased to 1.6 (95% CI 0.3-8.0). Increased
age, diabetic nephropathy, renal vascular disease, history of arterial and venous thrombosis,
diabetes as comorbidity, and the highest tertile of cholesterol were associated with arterial
thrombosis. The combination of increased age (≥65 years), renal vascular disease, history of
arterial and venous thrombosis, diabetes, and the highest tertile of cholesterol was associated
with an 11.3-fold (95% CI 1.8-72.3) increased risk of arterial thrombosis as compared with the
absence of these risk factors.
During the observation period, 197 patients died (99 cardiovascular mortality and 98 noncardiovascular deaths). Patients with a history of venous or arterial thrombosis before starting
dialysis had an increased mortality risk while on dialysis after adjustment for age, sex,
diabetes, and primary kidney disease (Table 3): the all-cause mortality risk was 1.9-fold (95%
CI 1.1-3.3) increased for patients with a history of venous thrombosis and 1.9-fold (95% CI
1.4-2.6) increased for patients with a history of arterial thrombosis as compared to patients
without a history of venous or arterial thrombosis. Patients with a history of venous thrombosis
had a non-significantly 2.0-fold (95% CI 0.9-4.4) increased risk of cardiovascular mortality and
a non-significantly 1.8-fold (95% CI 0.8-4.0) increased risk for non-cardiovascular mortality.
Patients with a history of arterial thrombosis had a 2.4-fold (95% CI 1.6-3.7) increased risk for
cardiovascular mortality and a 1.5-fold (95% CI 1.0-2.4) increased risk for non-cardiovascular
mortality.
95
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Chapter 6
Table 2. Association of baseline characteristics with subsequent venous and arterial thrombosis
after adjustment for age and sex
Venous thrombosis Arterial thrombosis
Hazard ratios*
Hazard ratios*
(95% CI)
(95% CI)
Age, years
Sex
Dialysis modality
Primary kidney disease
Body mass index, kg/m2
< 65
65-75
>75
Male
Female
Hemodialysis
Peritoneal dialysis
Diabetes mellitus
Glomerulonephritis
Renal vascular disease
Other
<30.0
≥30.0
Diabetes mellitus as comorbidity
Malignancy
History of venous thrombosis
History of arterial thrombosis
Smoking
Erythropoietin use
Hemoglobin, mmol/L
<6.5
≥6.5 to 7.2
>7.2
GFR, ml/min
0 to 5
>5 to 10
>10
Proteinuria, gram per day
0 to 0.3
>0.3 to 3.5
≥3.5
Albumin, g/L
<30.1
≥30.1 to 35.5
>35.5
Cholesterol, mmol/L
<3.9
≥3.9 to 5.0
>5.0
Triglycerides, mmol/L
<1.4
≥1.4 to 2.3
>2.3
1.0
0.3
1.2
0.8
1.0
2.6
1.0
0.5
0.4
NE
1.0
1.0
1.6
1.5
3.0
3.4
1.0
1.2
0.8
1.0
0.7
0.6
1.0
0.9
1.6
1.0
0.3
0.8
1.0
0.8
0.4
1.0
0.9
1.6
1.0
1.1
1.3
(reference)
(0.1-1.6)
(0.3-4.5)
(0.3-2.1)
(reference)
(0.7-9.7)
(reference)
(0.1-2.2)
(0.1-2.2)
(reference)
(reference)
(0.4-5.8)
(0.5-4.3)
(0.6-13.8)
(0.7-15.5)
(0.3-3.9)
(0.4-3.6)
(0.3-2.3)
(reference)
(0.2-2.3)
(0.2-2.0)
(reference)
(0.3-3.3)
(0.2-12.4)
(reference)
(0.1-1.1)
(0.2-3.2)
(reference)
(0.2-2.5)
(0.1-1.6)
(reference)
(0.2-3.6)
(0.5-5.7)
(reference)
(0.2-5.0)
(0.3-5.7)
NE indicates not estimable. *hazard ratios adjusted for age and sex.
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1.0
1.1
1.6
1.3
1.0
0.7
1.0
2.0
1.2
2.5
1.0
1.0
0.8
1.5
0.6
2.3
2.9
1.5
1.2
1.0
1.0
1.3
1.0
1.0
0.9
1.0
1.3
1.2
1.0
0.7
0.8
1.0
1.1
1.6
1.0
0.8
1.1
(reference)
(0.7-1.7)
(1.0-2.8)
(0.9-2.1)
(reference)
(0.4-1.1)
(reference)
(1.2-3.4)
(0.5-2.5)
(1.5-4.2)
(reference)
(reference)
(0.4-1.6)
(1.0-2.3)
(0.2-1.7)
(1.1-4.9)
(1.9-4.5)
(0.9-2.3)
(0.8-1.8)
(reference)
(0.6-1.7)
(0.8-2.1)
(reference)
(0.6-1.6)
(0.3-2.3)
(reference)
(0.7-2.3)
(0.6-2.6)
(reference)
(0.5-1.2)
(0.5-1.2)
(reference)
(0.6-1.9)
(1.0-2.8)
(0.6-1.7)
(0.5-1.4)
(0.7-1.9)
Venous and arterial thrombosis in dialysis patients
Table 3. History of venous and arterial thrombosis prior to start of dialysis treatment and mortality
risk after adjustment for age and sex
All-cause mortality
CV mortality
Non CV mortality
Hazard ratios* (95% CI) Hazard ratios* (95% CI) Hazard ratios* (95% CI)
No history venous or arterial
thrombosis
1.0
History of venous thrombosis 1.9
History of arterial thrombosis 1.9
(reference)
1.0
(reference)
1.0
(reference)
(1.1-3.3)
(1.4-2.6)
2.0
2.4
(0.9-4.4)
(1.6-3.7)
1.8
1.5
(0.8-4.0)
(1.0-2.4)
*hazard ratios adjusted for age, sex, diabetes, and primary kidney disease.
DISCUSSION
In the present study, we observed that dialysis patients had absolute risks of more than one
percent per year for venous thrombosis, myocardial infarction and ischemic stroke, with 6-fold
increase of venous thrombosis, 8-fold increase of ischemic stroke, and 12-fold increase of
myocardial infarction risk as compared to the age- and sex-weighted incidence rates in the
general population. Finally, our data showed a strong association between a history of venous
and arterial thrombosis prior to the start of dialysis and mortality during dialysis.
To our knowledge, this the first study that assessed the incidence of both deep vein thrombosis
and pulmonary embolism in end-stage renal disease patients. One other study has examined
the incidence of only pulmonary embolisms in end-stage renal disease patients. It showed that
dialysis patients had a 2.3-fold increased risk for pulmonary embolism,21 which is lower than in
our study. However, as they only assessed pulmonary embolism in case of primary discharge
diagnosis in the first year of dialysis, this could have resulted in an underestimation of the
number of pulmonary embolisms. The observed risk of venous thrombosis in dialysis patients
in our cohort is in contrast with previous autopsy studies.27-30 These studies showed that
pulmonary embolism was less common in dialysis patients than in non-dialysis patients.27-30
However, the incidence of venous thrombosis may be underestimated in these autopsy
studies, since only a small and selective proportion of dialysis patients undergo postmortem
examination. Furthermore, postmortem diagnosis often provides little information about the
clinical significance of thrombotic events. The increased risk for myocardial infarction and
ischemic stroke in our Dutch cohort of dialysis patients is in line with previous studies.14-20
Studies revealed that cardiovascular mortality rates were 8 to 20 times higher than in the
general population.15-17
A possible explanation for the increased risk of venous thrombosis is the high rate of
hospitalization, surgery, and immobilization resulting in stasis of the blood and in subsequent
venous thrombosis. However, we also found an increased incidence of unprovoked venous
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Chapter 6
thrombosis suggesting that also other factors play a role in the development of venous
thrombosis in dialysis patients. One of these other factors could be hypercoagulability.
Several studies have shown that there is a hypercoagulable state in dialysis patients.31,32
Another explanation for the increased risk of venous thrombosis in dialysis patients could be
that the high usually rate of thrombus formation in grafts and fistulas in hemodialysis patients
may cause pulmonary embolisms through dislodgement of thrombi.33 An important finding that
strengthens this hypothesis was that venous thrombosis was more frequent in hemodialysis
patients than in peritoneal dialysis patients. Moreover, deep vein thrombosis and pulmonary
embolism occurred in a similar frequency in this cohort of dialysis patients, whereas in the
general population deep vein thrombosis is twice as frequent as pulmonary embolism.23 In
addition, one patient had a symptomatic pulmonary embolism shortly after a thrombectomy of
a thrombosed dialysis shunt.
Recent studies have challenged the historical dichotomy of arterial and venous thrombosis as
two different entities with distinct risk factors.2-6 Indeed, arterial cardiovascular risk factors such
as hypertension, smoking, and diabetes appeared to be risk factors for venous thrombosis as
well.7-11 In our study, venous and arterial thrombosis did not share risk factors in these dialysis
patients, except for a history of venous thrombosis prior to the start of dialysis which was
associated with both venous and arterial thrombosis. “Classic” cardiovascular risk factors in the
general population, such as an increased age, diabetic nephropathy, renal vascular disease,
history of arterial thrombosis, diabetes as comorbidity, and highest tertiles of cholesterol were
associated with subsequent arterial thrombosis and not with venous thrombosis. Malignancy,
a “classic” risk factor for venous thrombosis in the general population was associated with a
non-significantly increased risk of subsequent venous thrombosis. Furthermore, we found a
non-significant inverse association between serum albumin levels and venous thrombosis.
Also in patients with nephrotic syndrome, serum albumin has been inversely associated with
venous thrombosis.34,35
We showed that both a history of arterial thrombosis and venous thrombosis before the start of
dialysis increased the mortality risk during dialysis. Prior studies also found that dialysis patients
who had suffered cardiovascular disease had a poor long-term survival.36,37 This finding is in
agreement with previous studies that showed that venous thrombosis was associated with an
increased risk for arterial thrombosis3-5 and an increased long-term mortality risk in the general
population.38 Therefore, it is tempting to suggest that a history of venous thrombosis before the
start of dialysis could be marker of underlying atherosclerosis which results in an increased risk
of subsequent arterial thrombosis and an increased mortality risk. Atherosclerosis in patients
with a history of venous or arterial thrombosis could also explain why the hazard ratios were
higher for cardiovascular mortality than for non-cardiovascular mortality. We did not find an
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association between a history of arterial thrombosis and subsequent venous thrombosis.
This might be explained by the high prevalence of anticoagulation use in patients with a
history of arterial thrombosis preventing also venous thrombosis. Indeed, after exclusion of
vitamin K antagonist users, the risk of venous thrombosis for patients with a history of arterial
thrombosis was 1.6-fold increased, but as numbers in this subgroup analysis became small,
the results should be handled with caution.
A strength of this study is its prospective design in which objectively confirmed venous and
arterial thrombotic events were considered as outcome measures. Nevertheless, our study
has some potential limitations that should be addressed. A limitation of this study was that we
could not measure levels or activity of coagulation factors or markers of hypercoagulability
to investigate the role of these factors in the development of thrombotic events in dialysis
patients. Another limitation of this study was that confidence intervals around the hazard ratios
were wide for risk factors of venous and arterial thrombosis, indicating a limited power for
detecting underlying risk factors for venous and arterial thrombosis in dialysis patients. Small
numbers also restricted us to not perform further analyses of potential risk factors (such as
hemodialysis or peritoneal dialysis) on mortality in patients with previous venous or arterial
thrombosis. Nevertheless, this study is the largest to date that analyzed risk factors for both
venous and arterial thrombosis and subsequent mortality in dialysis patients.
In conclusion, we showed that dialysis patients had high risks for venous and arterial
thrombosis, while occurrence of these thrombotic diseases prior to the start of dialysis was
associated with an increased mortality risk in this patient group. Furthermore, we showed that
venous and arterial thrombosis did not share risk factors in these dialysis patients.
ACKNOWLEDGMENTS
We thank the investigators and study nurses of the participating dialysis centers and the data
managers of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)
for collection and management of data. Furthermore, we thank Willem Vis for his assistance
in the collection of data for this study. The Netherlands Cooperative Study on the Adequacy
of Dialysis was supported in part by an unrestricted grant from the Dutch Kidney Foundation.
The funding source was involved in neither the collection, interpretation, and analysis of the
data nor the decision for the writing and submission of this report for publication.
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Chapter 6
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