J Thromb Thrombolysis (2012) 34:73–78 DOI 10.1007/s11239-012-0682-1

ADAMTS13 and Von Willebrand factor in patients undergoing hemodialysis Danyelle R. A. Rios • Maria G. Carvalho • Roberta C. Figueiredo • Cla´udia N. Ferreira • Vale´rio L. Rodrigues • Regina A. Souza • Ana C. Simo˜es e Silva Ana Paula Fernandes • Karina B. Gomes • Luci M. S. Dusse

•

Published online: 2 February 2012 Ó Springer Science+Business Media, LLC 2012

Abstract Hemodialysis (HD) is associated with increasing thrombotic trend. Vascular access thrombosis (VAT) increases morbidity in HD patients. The aim of this study was to evaluate ADAMTS13 and VWF plasma levels from patients undergoing HD as putative biomarkers of the hypercoagulability state, as well the association between these markers and VAT occurrence. This study included 195 patients on HD for more than 6 months. HD patients were allocated into two groups according to the occurrence or not of previous episode of VAT; HD with VAT (N = 46) and HD without VAT (N = 149). ADAMTS13 and VWF were performed by ELISA. There was no significant difference between HD patients with and without VAT for ADAMTS13 and VWF levels. However, VWF levels were higher (P \ 0.001) and ADAMTS13 were lower (P \ 0.001) in HD patients, comparing to the control group composed by

D. R. A. Rios
M. G. Carvalho
C. N. Ferreira
A. P. Fernandes
K. B. Gomes
L. M. S. Dusse (&) Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil e-mail: [email protected]; [email protected] R. C. Figueiredo Department of Public Healthy, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil V. L. Rodrigues Instituto Mineiro de Nefrologia, Belo Horizonte, Brazil R. A. Souza Clinical Hospital of Universidade Federal de Minas Gerais, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil A. C. S. eSilva Department of Pediatric, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

healthy subjects without kidney disease, age and sex-matched (N = 80). Taken together our data suggest a potential role of the kidneys function compromised on ADAMTS13 synthesis or metabolism, regardless other known sources of ADAMTS13. The imbalance between ADAMTS13 and VWF levels does not explain the development of VAT in HD patients by itself, although it should contribute for the hypercoagulability state. Therefore, additional studies to identify other risk factors are warranted and essential for better management of HD patients. Keywords Hemodialysis
ADAMTS13
VWF
Vascular access thrombosis

Introduction Hemodialysis (HD) process is associated with increasing thrombotic trend especially due to platelets and clotting factors activation [1, 2]. Thrombotic episodes in HD patients are mainly related to a reduction in vascular access blood flow due to fibro muscular and intimal hyperplasia, which may result in vascular access stenosis. The blood flow reduction causes blood stasis and favors hypercoagulability, hypotension and hypovolemia, predisposing to a prothrombotic environment [3]. Von Willebrand factor (VWF) is an important component of the hemostatic system and a hypercoagulability state biomarker [4]. The VWF is a multimeric glycoprotein composed of identical subunits of 270 kDa each containing 2,050 amino acids synthesized by endothelial cells and megakaryocytes. The synthesis occurs initially in the endoplasmic reticulum, where there is the formation of preVWF dimers linked at the carboxy terminal disulfide. These pre-dimers migrate to the Golgi complex, where

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other disulfide bonds at the amino terminus link two dimers together to form multimers resulting in ultra-large multimers of the VWF (ULVWF), which are stored in endothelial cells and platelets. VWF dimers are secreted into the plasma and the subendothelium, whereas ULVWF are stored within the Weibel–Palade bodies of endothelial cells and their release to plasma is limited to sites of endothelial damage [5]. VWF directly contributes to thrombus formation by mediating platelet adhesion to subendothelial collagen and, indirectly, by being the carrier of FVIII and by preventing its plasmatic clearance [4]. Several clinical conditions are associated to increase of VWF secretion by endothelium, contributing to thrombus formation. This may explain the association of elevated levels of FVIII and VWF with thromboembolism, atherosclerosis and preeclampsia [6–9]. In 1996, Furlan et al. [10] and Tsai and Lian [11] isolated a protease that was able to cleave the peptide bond between tyrosine at position 1,605 and methionine at position 1,606 in the central A2 domain of VWF. In 2001, Zheng et al. [12] called this protease as ADAMTS13 (a disintegrin and metalloprotease with eight thrombospondin-1-like domains), a new member of the ADAMTS family of metalloproteases. ADAMTS13 normally circulates in plasma and has a mass of approximately 150 kDa [13, 14]. Under physiological conditions, ADAMTS13 promptly cleaves and removes ULVWF from the circulation. These multimers of VWF are released from endothelial cells and they are the only known substrate of this enzyme [15]. ADAMTS13 deficiency and/or the presence of antibodies against this enzyme may increase ULVWF plasma levels, favoring the occurrence of thrombosis in small vessels [4, 16]. Several studies have shown that diseases associated to low or absent activity of ADAMTS13, such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), compromise the VWF multimers cleavage, elevating the plasma levels of these factors and consequently the thrombotic risk [15–18]. The aim of this study was to evaluate plasma levels of ADAMTS13 and VWF in end stage renal disease patients undergoing hemodialysis (HD patients) as putative biomarkers of the hypercoagulability state, as well as the association between these markers and vascular access thrombosis occurrence.

Subjects and methods Study design The present cross-sectional study included all HD patients (N = 195) selected from two dialysis centers in Belo

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Horizonte/MG, Brazil from 2007 to 2009, according to the exclusion and inclusion criteria. The HD patients were allocated into two subgroups, according to the occurrence or not of a previous episode of vascular access thrombosis-VAT (with and without VAT). HD patients with VAT consisted of 46 individuals whose functioning dialysis access had, at least, one previous episode of thrombotic occlusion, which was defined by the absence of blood flow and the impossibility to use the access for dialysis. The remainder HD patients included 149 subjects who have not experienced this disturb (HD patients without VAT). Healthy subjects without kidney disease (control group) (N = 80), age and sex-matched to HD patients, were included in order to establish the range of ADAMTS13 and VWF plasma levels in our population. Ethical aspects The Ethics Committee of our institution approved the study and informed consent was obtained from all participants. The research protocol did not interfere with any medical recommendations or prescriptions. Inclusion criteria Patients on HD for more than 6 months with arteriovenous fistula, aged between 18 and 70 years, were included in this study. Exclusion criteria Hemodialysis patients receiving oral anticoagulation therapy or oral contraceptives, with prior history of arterial or venous thrombosis (except those with VAT), with acute or chronic hepatic disease, autoimmune and malignant diseases, vasculitis, acute infections, clinical instabilities, history of renal transplantation, HIV positive and pregnant women were excluded from the study. Study protocol All patients required regular HD sessions for 3–4 h, three times a week. Blood flow was usually 300–450 ml/min with a dialysate flow at a constant rate of 500 ml/min. Patients were dialyzed either with low-flux polysulphone membranes and high-flow polysulphone membranes with bicarbonatebuffered dialysate. All patients received regular doses of standard heparin (100–150 UI/Kg) before hemodialysis session. A detailed history, clinical variables (age, gender, body mass index (BMI), pre-dialysis blood pressure levels, etiology of end stage renal disease (ESRD), presence of diabetes or not, type of vascular access, time on hemodialysis, interdialytic weight gain, and main medications in use)

ADAMTS13 and Von Willebrand factor

and dialysis parameters (urea reduction ratio and normal protein catabolism rate) of each included patient were recorded retrospectively in a computer specific data bank. After informed consent, all subjects were submitted to blood collection for the determination of plasma levels of VWF and ADAMTS13. Blood sampling Blood samples were drawn in sodium citrate (0.129 mol/l) in 9:1 volume ratio from HD vascular access prior to dialysis procedure at the first dialysis session of the week and before heparin administration. Citrated blood samples were centrifuged at 2,5009g for 20 min at 4°C to obtain plasma. Samples were stored at -70°C until analysis. Blood samples from healthy volunteers were collected in arm veins in sodium citrate and processed in the same way described above. Assays The determination of VWF and ADAMTS13 antigens was performed by ELISA, using the VWF Kit IMUBINDÒ and ADAMTS13 Kit IMUBINDÒ, respectively (American Diagnostica Ò Inc., Stamford, USA). Statistical analysis Statistical comparisons were performed using the program SIGMA STAT (version 2.03) and STATA (version 10.0). Values were expressed as medians and 25–75th quartile or means and standard deviation, when appropriate. The normality of the distribution was evaluated by the Kolmogorov–Smirnov test for each group. Non-paired Student t test was used for the comparisons of means between two groups and the Mann–Whitney U test was used to compare medians. Categorical variables were compared using v2 test. Differences were considered significant when P \ 0.05.

Results Clinical variables and hemodialysis parameters did not differ between HD patients with and without VAT, as presented in Table 1. Age, gender, BMI, pre-dialysis blood pressure levels, etiology of ESRD, presence of diabetes, type of vascular access, time on hemodialysis, interdialytic weight gain, main medications in use and dialysis parameters were similar in both groups (P [ 0.05 for all comparisons, Table 1). There was not significantly different between HD patients with and without VAT for ADAMTS13 plasma

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levels, 299 ng/ml (244–330 ng/ml) versus 276 ng/ml (238–330 ng/ml, P = 0.503) and VWF, 1,134 mU/ml (760–1,381 mU/ml) versus 1,047 mU/ml (722–1,351 mU/ml, P = 0.462), respectively. However, VWF levels were significantly higher, 1,062 mU/ml (728–1,357 mU/ml) and ADAMTS13 levels significantly decreased in HD patients, 279 ng/ml (238–329 ng/ml) comparing to the median and interquartile range of the healthy control group (805 mU/ml, 683–1012 mU/ml, P \ 0.001 and 578 ng/ml 486–690 ng/ml, P \ 0.001, respectively), as showed on Figs. 1 and 2.

Discussion Knowing that HD constitutes a singular condition, it seems to be of great interest to investigate hemostatic alterations in HD patients and to establish the real role of laboratorial biomarkers in monitoring these patients. ADAMTS13 and VWF did not differ between HD patients with and without VAT. However, ADAMTS13 plasma levels were reduced and VWF were increased in HD patients, as compared to healthy control subjects. Although it is still not clear the mechanism that results on imbalance between ADAMTS13 and VWF plasma levels in HD patients, this probably contributes to the hypercoagulability state seen in these patients, who have increased risk of thrombosis [2]. It is known that chronic activation of platelet and endothelial cells, frequent in dialysis procedures, could continuously increase the VWF levels. Besides, inflammatory cytokines promote ULVWF release from endothelial cells to plasma, which could explain the higher VWF in HD patients, since they present inflammatory process [5]. Previous studies have shown that the endothelial injury in HD patients, probably resulting from uremia, dyslipidemia, hypertension, hyperparathyroidism, high levels of plasma interleukin-1 and tumor necrosis factor, increases VWF levels [19]. Increased endothelium expression of VWF, thrombomodulin and tissue factor have also been reported in these patients [20]. It should be highlighted that platelets do not adhere to small forms of VWF that circulate after cleavage of ULVWF by ADAMTS13. However, platelets bind to ULVWF, resulting in platelet aggregates, consisting basically of platelets and ULVWF, which may obstruct the microcirculation [5, 21]. It is worth mentioning that the antibody capture ELISA test used to detect VWF recognizes mainly ULVWF. However, no significant differences were detected in levels of these markers, comparing patients with and without VAT, suggesting that HD triggers a hypercoagulability state, regardless the development of VAT. Nevertheless, vascular access complications increase morbidity and contribute to 20–25% of all hospitalizations in HD patients, of which approximately 85% of these cases

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Table 1 Clinical characteristics and dialysis parameters of HD patients without VAT and with VAT

2000

Characteristics/Parameters

1500

HD patients with VAT (n = 46)

P value

52 (39-60)

50 (41–59)

0.979

750

0.100

500

Male [n(%)]

86 (58%)

20 (43%)

Female [n(%)]

63 (42%)

26 (57%)

24.2 ± 4.7

24.5 ± 5.7

Sex

BMI (Kg/m2) Cause of ESRD [n(%)] Hypertensive nephrosclerosis

vWF

HD patients without VAT (n = 149)

Age (years)

1250 1000

250 0

0.734 0.270

51 (34%)

14 (30%)

39 (26%)

7 (15%)

Diabetic nephropathy

21 (14%)

12 (26%)

900

Polycystic kidney disease Others or unknowns causes

7 (5%) 31 (21%)

3 (7%) 10 (22%)

800

500 400

140 (130–150) 80 (80–90)

0.060

34.0 (17.0–90.3)

39.5 (19.0–92.0)

0.226

Arteriovenous fistula

144 (97%)

42 (91%)

Arteriovenous graft

5 (3%)

4 (9%)

Type of vascular access

300 200

0.968

0.131

Kt/v

1.4 (1.3-1.6)

1.5 (1.3–1.6)

0.513

URR nPCR (g/Kg/day)

73.6 ± 5.9 1.1 (1.0–1.4)

74.0 ± 6.4 1.2 (1.0–1.6)

0.716 0.451

IWG (Kg)

3.2 ± 1.1

2.9 ± 1.4

0.165

Medications [n(%)] Antihypertensive drugs ACE inhibitor

69 (46%)

19 (41%)

0.551

b-blockers

64(43%)

21 (46%)

0.747

Calcium channel antagonists

65 (44%)

17 (37%)

0.423

Acetylsalicylic acid

38 (26%)

8 (17%)

0.257

Statins

31 (21%)

5 (11%)

0.129

Vitamin use

149 (100%)

46 (100%)

–

Insulin Erythropoietin

29 (19%) 129 (87%)

10 (22%) 41 (89%)

0.736 0.651

40 (27%)

15 (33%)

0.448

The normally distributed data were expressed as mean ± SD (t test). The non-Gaussian data were presented as median (range) (Mann–Whitney test). Frequencies (%) was evaluated by v2 test BMI body mass index, HD hemodialysis, URR urea reduction ratio, nPCR normal protein catabolism rate, IWG interdialytic weight gain, ACE angiotensin-converting enzyme, Kt/v clearance of urea

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*

600

130 (120–143) 80 (80–90)

Diabetes [n(%)]

Healthy subjects

700

Pre-dialysis arterial blood pressure

Time on hemodialysis (months)

HD patients

Fig. 1 VWF (mU/ml) plasma levels in HD patients and healthy subjects group. Bars median, whiskers minimum and maximum values, box interquartile range. * P \ 0.001

Glomerulopathies

Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

*

1750

100 0

HD patients

Healthy subjects

Fig. 2 ADAMTS13 (ng/ml) plasma levels in HD patients and healthy subjects group. Bars median, whiskers minimum and maximum values, box interquartile range. * P \ 0.001

are due to thrombosis [2]. Therefore, it is extremely relevant to fully understand the factors that synergizes with this hypercoagulability state in HD patients for thrombus formation. In our previous study, the prothrombin gene mutation (G20210A) was associated to development of vascular access thrombosis in HD patients [22]. It seems though, that ADAMTS13 and VWF levels imbalance is a common component of a hypercoagulability state in HD patients which, in addition to other genetic and acquired factors, could trigger the thrombotic events in these patients. However, few studies have investigated the association of genetic (Factor V Leiden, protein C, protein S and antithrombin deficiencies and ABO blood groups) and acquired risk factors (fistula infection, hypertension, dyslipidemia, uremia, anticardiolipin antibodies) with occurrence of VAT in HD patients, and the results are controversial [19, 23, 24]. Besides the scarcity of data, the hypercoagulability state established in these patients as a consequence of the vascular and cellular injury triggered by hemodialysis procedure may mask the effect of these less frequent factors, compromising this analysis.

ADAMTS13 and Von Willebrand factor

The cellular origin of ADAMTS13 antigen in plasma has not been completely elucidated. According to Uemura et al. [25], ADAMTS13 synthesis was firstly described in liver in 2000 [26]. Before 2004, it was known that ADAMTS13 synthesis occurred only in liver [27]. Later, three other groups indicated that ADAMTS13 mRNA was exclusively expressed in the liver [12, 28, 29] and more specifically in stellate cells [27]. In 2004, ADAMTS13 was detected in platelets [30] and in 2006 in endothelial cells [31, 32]. More recently, ADAMTS13 mRNA was also detected in kidney, including glomerular endothelial cells, podocytes, glomerular basement membrane and tubular epithelial cells [33, 34]. Although other sources of ADAMTS13 have been described, their relevance to the pathogenesis of thrombo-regulation remained unknown. Recently, we compared ADAMTS13 levels in four patients before and after kidney transplant. ADAMTS13 levels increased in all of them (386 vs. 757, 391 vs. 534, 277 vs. 679 and 185 vs. 450 ng/ml) [35]. Altogether, these findings and those presented herein indicated lower ADAMTS13 levels in HD patients, suggesting a potential role of the kidneys function compromised on ADAMTS13 synthesis or metabolism, regardless other known sources of ADAMTS13. In agreement with the hypothesis, reduced levels of ADAMTS13 antigen were also seen in patients with diabetic nephropathy [36]. Moreover, a relationship between renal function and ADAMTS13 in patients with TTP or HUS was also showed. Patients with severe ADAMTS13 deficiency had significantly higher serum creatinine levels than did patients with the ADAMTS13 activity levels higher than 20% [37]. Overall, these findings support the raised hypothesis. However, HD patients are heterogeneous and have other co-morbidities that could also affect ADAMTS13 levels. Therefore, a detailed analysis of ADAMTS13 antigen and activity, its metabolism and the relationship with parameters of renal function will be important to clarify this question. The imbalance between ADAMTS13 and VWF levels does not explain the development of VAT in HD patients by itself, although it should contribute for the hypercoagulability state. Therefore, additional studies to identify other risk factors are warranted and essential for better management of HD patients. The main limitation of this study was its cross-sectional design, since this usually provides association but not causal relationship. Therefore, a longitudinal approach would provide more significant information. However, it should be highlighted that cross-sectional studies are essential to guide the longitudinal studies that, in general, are more complex and expensive. Acknowledgments The authors thank FAPEMIG and CNPq/Brazil. LMSD, ACSS, APF and MGC are grateful to CNPq Research

77 Fellowship (PQ). The study was supported by FAPEMIG and the CNPq—BRAZIL.

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