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ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 916-921

ADAMTS13 plasma level in maintenance hemodialysis patients: its relation to vascular access thrombosis


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Nephrology, Shebin El Kom Teaching Hospital, Shebin El Kom, Egypt

Date of Submission26-Oct-2017
Date of Acceptance17-Dec-2017
Date of Web Publication17-Oct-2019

Correspondence Address:
Sara M H. Kashkoush
Department of Nephrology, Shebin El Kom Teaching Hospital, Shebin El Kom, Menofuia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_730_17

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  Abstract 

Objective
The aim of this study was to evaluate ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) plasma level in patients under maintenance hemodialysis (HD) to determine its relation in the occurrence of vascular access thrombosis (VAT) in such patients.
Background
An increased thrombotic tendency is an important cause of complications in patients on chronic HD leading to thrombosis of the vascular access. VAT remains the main problem in vascular access for HD. Hypercoagulability in patients on chronic HD can be caused by a variety of factors, mainly consisting of platelet abnormalities and plasma factor abnormalities. Some of the plasma factor abnormalities are ADAMTS13 abnormalities. ADAMTS13 deficiency and/or the presence of antibodies against this enzyme may increase ultra large von Willebrand factor plasma levels, favoring the occurrence of thrombosis in small vessels.
Materials and methods
This case–control study was conducted on 60 patients on HD for more than 6 months classified into two groups: group I included 30 patients with VAT, and group II included 30 patients without VAT. Moreover, 20 healthy individuals served as a control group. History taking, clinical examination, and investigation were done.
Results
Mean ADAMTS13 serum level was found to be lower in HD groups of patients, with highly significant decrease in serum ADAMTS13 levels in group I (131.67 ng/ml) compared with group II (310.37 ng/ml) and group III (605.35 ng/ml), with P value of less than 0.001. A cut-off level at 200 ng/ml was accurate (95.00%) for occurrence of VAT in group I patients with sensitivity of 96.67%, specificity of 93.33%, positive predictive value of 93.55% and negative predictive value of 96.55%.
Conclusion
Low ADAMTS13 serum level was associated with occurrence of VAT.

Keywords: ADAMTS13, hemodialysis, vascular access thrombosis


How to cite this article:
El Hady HA, Yassin YS, El Zorkany KM, Montaser BA, Kashkoush SM. ADAMTS13 plasma level in maintenance hemodialysis patients: its relation to vascular access thrombosis. Menoufia Med J 2019;32:916-21

How to cite this URL:
El Hady HA, Yassin YS, El Zorkany KM, Montaser BA, Kashkoush SM. ADAMTS13 plasma level in maintenance hemodialysis patients: its relation to vascular access thrombosis. Menoufia Med J [serial online] 2019 [cited 2019 Nov 19];32:916-21. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/916/268840




  Introduction Top


Hemodialysis (HD) process is associated with increasing thrombotic trend especially owing to platelets and clotting factors activation [1].

An increased thrombotic tendency is an important cause of complications in patients on chronic HD leading not only to possibly fatal complications like ischemic heart disease, or stroke, but also to thrombosis of the vascular access [2].

Vascular access thrombosis (VAT) remains the main problem in vascular access for HD. In most cases, thrombosis is associated with low access blood flow. The most important reasons for a decreasing access blood flow are intimal hyperplasia and stenosis formation at the venous anastomosis or in the outflow tract of the graft. However, not all decreases in access blood flow are related to intimal hyperplasia or stenosis formation [3].

Other causes for low access flow leading to access thrombosis that have been proposed are hypotension, hypovolemia, and thrombotic events. Moreover, there has been a growing appreciation of the role of increased hypercoagulability found in these patients [4].

Hypercoagulability in patients on chronic HD can be caused by a variety of factors, mainly consisting of platelet abnormalities and plasma factor abnormalities. Some of the plasma factor abnormalities are ADAMTS13 and von Willebrand factor (VWF) abnormalities [5].

Patients with chronic kidney disease have been shown to have higher plasma levels of VWF and decreased ADAMTS13 activity compared with healthy controls. VWF and ADAMTS13 seem to be important players in the interface between diabetic nephropathy, hypercoagulability, and atherosclerotic cardiovascular disease [5].

ADAMTS13 is a proteolytic enzyme that is responsible for degradation of large multimers of VWF released in the plasma by endothelial cells and platelets [5].

ADAMTS13 deficiency and/or the presence of antibodies against this enzyme may increase ultra large VWF plasma levels, favoring the occurrence of thrombosis in small vessels [6].

The aim of this study was to evaluate ADAMTS13 plasma level in patients under maintenance HD to determine its relation in the occurrence of VAT in such patients.


  Materials and Methods Top


The present case–control study included all HD patients (N = 60) selected from two dialysis centers in Benha and Shebin El-Kom Teaching Hospitals, Egypt, from 2015 to 2016, according to the exclusion and inclusion criteria. The ethics committee of our institutions approved the study, and informed consent was obtained from all participants.

Classification of participants

The HD patients were allocated into two subgroups according to the occurrence of a previous episode of VAT (with and without VAT). HD patients with VAT consisted of 30 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 30 participants who were without VAT. Healthy participants without kidney disease (control group) (N = 20), age and sex-matched to HD patients, were included establish the range of ADAMTS13 plasma levels in our population.

Inclusion criteria

Patients on HD for more than 6 months with arteriovenous fistula, aged between 30 and 75 years, were included in this study.

Exclusion criteria

HD patients receiving oral anticoagulation therapy and those with chronic hepatic disease, malignant diseases, connective tissue disorder, acute infections, thyroid gland dysfunction, history of recent trauma (traffic accidents) less than 6 months, and recent myocardial infarction were excluded from the study.

Study protocol

All patients required regular HD sessions for 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 or high-flow polysulphone membranes with bicarbonate-buffered dialysate. All patients received regular doses of standard heparin (100–150 UI/kg) before HD session. A detailed history, clinical variables [age, sex, BMI, predialysis blood pressure levels, etiology of end stage renal disease (ESRD), presence of diabetes or not, type of vascular access, and interdialytic weight gain], and dialysis parameters (as urea reduction ratio) of each included patient were recorded retrospectively in a computer-specific data bank.

After informed consent, all participants were submitted to blood collection for the determination of plasma levels of ADAMTS13.

Blood sampling

Blood samples were drawn in sodium citrate (0.129 mol/l) in 9:1 volume ratio from HD vascular access before dialysis procedure at the first dialysis session of the week and before heparin administration. Samples were stored at −7°C until analysis. The determination of ADAMTS13 antigen was performed by enzyme-linked immunosorbent assay, using the ADAMTS13 Kit IMUBIND (American Diagnostica Inc., Stamford, Connecticut, USA).

Statistical analysis

The collected data were summarized in terms of mean ± SD and range for quantitative data and frequency and percentage for qualitative data. After the calculation of each of the test statistics, the corresponding distribution tables were consulted to get the 'P' (probability value). Statistical significance was accepted at P value less than 0.05 (significant). A P value less than 0.001 was considered highly significant, whereas a P value greater than 0.05 was considered nonsignificant.

The statistical analysis was conducted using personal computer using STATA/SE version 11.2 for Windows (STATA Corporation, College Station, Texas, USA).


  Results Top


From [Table 1], comparison between the two HD groups of patients showed the following: the first HD group with VAT consisted of 30 patients, with mean age of 53.73 ± 8.07 years, and has been on dialysis for different years with mean duration of 5.97 ± 2.02 (range: 2–11 years). Second, HD group without VAT consisted of 30 patients, with mean age of 46.07 ± 8.1 years, and has been on dialysis for different years, with mean duration of 4.83 ± 1.44 (range: 3–9 years). There was a statistically significant difference between both groups regarding age & dialysis duration (P < 0.001 and 0.01, respectively), and blood pressure (P = 0.004); the mean systolic blood pressure was higher in HD groups (group I: 130.67 ± 12.01 and group II: 122 ± 10.63). Regarding laboratory characteristics, results indicated that there is significant difference regarding mean low-density lipoprotein (LDL) (mg/dl) (Z = 3.53, P < 0.001), mean cholesterol (mg/dl) (F = 7.95, P < 0.001), 2 h postprandial (mg/dl) (Z = 2.71, P = 0.007), blood urea (mg/dl) (t = 2.72, P = 0.009), FBS (mg/dl) (t = 2.38, P = 0.02), and triglycerides (mg/dl) (t = 2.07, P = 0.04).
Table 1: Demographic and clinical characteristics of the studied groups

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From [Table 2], comparison among the three groups of patients showed the following: a highly significant decrease in serum ADAMTS13 levels in group I [131.67 ng/ml (13–200)] compared with group II (310.37 ng/ml) and group III (605.35 ng/ml) (P < 0.001).
Table 2: Serum ADAMTS13 levels in the studied groups

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[Table 3] shows a highly significant decrease of serum ADAMTS13 in group I patients, with Kt/V greater than or equal to 1.2 (131.67 ± 31.5), compared with group II patients, with Kt/V greater than or equal to 1.2 (310.37 ± 65.84) (P < 0.001).
Table 3: Serum ADAMTS13 levels in the studied patients groups according to Kt/V levels

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[Table 4] illustrates the accuracy of ADAMTS13 serum level for occurrence of VAT in group I, with best cut-off of 200 ng/ml, sensitivity of 96.67%, specificity of 93.33%, positive predictive value of 93.55%, negative predictive value of 96.55%, and area under the curve (AUC) of 0.9883.
Table 4: Accuracy of ADAMTS13 serum level for occurrence of vascular access thrombosis in group I

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Receiver operating characteristic analysis was carried out to evaluate the diagnostic performance of ADAMTS13 level for VAT screening among the group I patients, with sensitivity of 96.67%, specificity of 93.33%, and AUC of 0.9883 [Figure 1].
Figure 1: Receiver operating characteristics curve for ADAMTS13 in group I patients with vascular access thrombosis.

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  Discussion Top


HD requires a well-functioning vascular access that allows sufficient blood flow to achieve adequate clearance and blood dialysis. Vascular access complications increase morbidity and contribute to 20–25% of all hospitalizations in dialysis patients, of which ∼85% of cases is owing to thrombosis [7].

ESRD as well as HD itself may actually increase the risk of thrombosis. Among other factors, the increasing thrombotic trend in patients under HD is owing to platelets and clotting factors activation [1].

It is believed that almost all cases of thrombotic episodes in HD patients are associated with a reduction in vascular access blood flow owing to fibromuscular 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 [8].

Hypercoagulability in patients on chronic HD can be caused by a variety of factors, mainly consisting of platelet abnormalities and plasma factor abnormalities [1].

In 1998, Furlan et al. [9] and Tsai and Lian [10] isolated a protease that was able to cleave the peptide bond between tyrosine at position 1605 and methionine at position 1606 in the central A2 domain of VWF. In 2001, Zheng et al. [11], 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 ∼150 kDa [12].

Under physiological conditions, ADAMTS13 promptly cleaves and removes ultra-low-molecular-weight VWF from the circulation. These multimers of VWF are released from endothelial cells, and they are the only known substrates of this enzyme [6].

ADAMTS13 deficiency and/or the presence of antibodies against this enzyme may increase ultra-low-molecular-weight VWF multimers plasma levels, favoring the occurrence of thrombosis in small vessels [13].

Several studies have shown that diseases associated with low or absent activity of ADAMTS13, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, compromise the VWF multimers cleavage, elevating the plasma levels of these factors and consequently the thrombotic risk [14].

The aim of this study was to evaluate plasma levels of ADAMTS13 in patients with ESRD undergoing HD as a marker of the hypercoagulability state, as well as the association between this marker and VAT occurrence.

This case–control study was conducted on 60 patients with chronic renal failure who are undergoing chronic HD for more than 6 months and 20 healthy individuals who served as control.

According to the clinical characteristics of the studied groups of patients, there is a positive significant difference between the studied groups of patients regarding age (P < 0.001) and duration of dialysis (P < 0.01). In the study by Rios et al. [1] regarding ADAMTS13 and VWF in patients undergoing HD, there were also positive significant differences between the groups of patients regarding age and duration of HD.

There was a positive significant difference between HD groups of patients regarding predialysis SBP. According to Hemodialysis Adequacy 2006 Work Group [15], hypertension is the most frequently observed complication in chronic HD patients. Most of patients have hypertension due to high blood volume.

The mean blood urea in our study was significantly higher than normal in group I and group II (P = 0.009) which matched with the study by Amin et al. (2014) [16], which detected significant high level of blood urea.

Lipid profile in the studied groups (group I and II) showed high significant difference regarding serum LDL, cholesterol, and triglycerides, which matched with the study done by Koch et al. [17] where dyslipidemia represented an important risk factor for the development of cardiovascular complication. On the contrary, Farbakhsh et al. [18] reported that in the HD patients the serum lipid concentrations resemble those of predialysis patients with chronic kidney disease, which means that total and LDL cholesterol levels are generally normal.

Regarding ADAMTS13, there was a highly significant decrease in serum ADAMTS13 levels in group I [131.67 ng/ml (13–200)] compared with group II [310.37 ng/ml (147–400)] and group III [605.35 ng/ml (500 = 700)], with P value of less than 0.001. These results agree with the study done by Taniguchi et al. [19], about the association between reduced ADAMTS13 and diabetic nephropathy, who found lower ADAMTS13 levels in HD patients, suggesting a potential role of the kidneys function regarding ADAMTS13 synthesis or metabolism, regardless of other known sources of ADAMTS13. Our study also agree with the study done by Rios et al. [1] that shows ADAMTS13 plasma levels were reduced and VWF was increased in HD patients, as compared with healthy controls.

According to Kt/V, there was a highly significant decrease of serum ADAMTS13 in group I patients, with Kt/V greater than or equal to 1.2, compared with group II patients, with Kt/V greater than or equal to 1.2, with P value of less than 0.001.

According to stepwise logistic regression analysis for VAT in studied patients conditioned on ADAMTS13, potential risk factors were assessed and laboratory data were carried out to detect important predictors of VAT, and results was presented as odds ratio (0.92) and 95%CI (0.87–0.99), with P = 0.02.

Receiver operating characteristics analysis was carried out to evaluate the diagnostic performance of ADAMTS13 level for VAT screening among the group I patients curve, showing sensitivity of 96.67%, specificity of 93.33%, and AUC of 0.9883.

Overall, these findings support the raised hypothesis. However, HD patients are heterogeneous and have other comorbidities 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.

According to the study done by Ruggeri et al. (2007) [13], 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.


  Conclusion Top


Based on the results of the current study, it can be concluded that ADAMSTS 13 level was significantly decreased in the studied HD patients with VAT compared with those without VAT. There is no significant correlation between the studied clinical and laboratory parameters and serum ADAMTS13 in both groups of patients except a significant positive correlation with estimated glomerular filtration rate in group I patients. Thus, ADAMTS13 can be considered as a good predictor for the occurrence of VAT in HD patients, with accuracy of 95% at cut-off level of 200 ng/ml, with 96.67% sensitivity and 93.33% specificity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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