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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 7  |  Issue : 4  |  Page : 117-123

Thrombin generation and endothelial dysfunctional markers in different stages of nephrotic syndrome


1 Physiology Department, College of Medicine, Alqassim University, Buraidah; King Saud University, Riyadh, Saudi Arabia
2 College of Medicine, Center of Excellence in Thrombosis and Hemostasis, King Saud University, Riyadh, Saudi Arabia
3 Physiology Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia
4 Hematology, Alfaisal University, Riyadh; Hematology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
5 Department of Medicine, King Saud University, King Salman Chair for Kidney Disease Research, Riyadh, Saudi Arabia

Date of Web Publication18-Jan-2017

Correspondence Address:
Dr. Ashwag S Alsharidah
Physiology Department, College of Medicine, Alqassim University, Buraidah 51491, Al-Qassim
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1658-5127.198509

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  Abstract 

Objectives: Venous thromboembolism is an important and potentially life-threatening complication of nephrotic syndrome (NS). This study aims to evaluate the functional test of thrombin generation (TG) in different stages of NS; determine its relation with the coagulation screening tests (prothrombin time [PT] and activated partial thromboplastin time), hemostatic activation markers (thrombin–antithrombin complex [TAT] and prothrombin fragment 1+2 [PF1+2]), and von Willebrand factor (vWF) and its proteolytic enzyme ADAMTS-13; and determine the correlation between TG and NS severity, as reflected by the levels of proteinuria and albumin.
Materials and Methods: This case–control cross-sectional study included 125 patients (n = 40, nephrotic range proteinuria; n = 45, NS; n = 40, remission) and 80 controls. Calibrated automated thrombogram assay (endogenous thrombin potential [ETP]) was performed to determine TG. TAT, PF1+2, vWF, and ADAMTS-13 were measured using enzyme-linked immunosorbent assay.
Results: TG (ETP), TAT, PF1+2, and vWF levels were significantly higher in all of the patient groups (P < 0.0001) than in the control group. ADAMTS-13 levels were significantly lower in the NS group (P < 0.0001) than in the control group.
Conclusion: Our findings confirm activation of the coagulation pathway in nephrotic patients. However, the degree of hypercoagulopathy (especially TG [ETP]) is positively correlated with proteinuria. Proteinuria could be considered an indirect indicator of the highest risk of thrombotic disease in patients with NS.

Keywords: Nephrotic syndrome, proteinuria, thrombin generation, thrombophilia


How to cite this article:
Alsharidah AS, Bayoumy NM, Alzogaibi MA, Owaidah T, Alghonaim M. Thrombin generation and endothelial dysfunctional markers in different stages of nephrotic syndrome. J Appl Hematol 2016;7:117-23

How to cite this URL:
Alsharidah AS, Bayoumy NM, Alzogaibi MA, Owaidah T, Alghonaim M. Thrombin generation and endothelial dysfunctional markers in different stages of nephrotic syndrome. J Appl Hematol [serial online] 2016 [cited 2020 Jun 1];7:117-23. Available from: http://www.jahjournal.org/text.asp?2016/7/4/117/198509


  Introduction Top


Nephrotic syndrome (NS) is one of the common presentations of glomerulonephritis with significant implications for morbidity.[1],[2] It affects both children and adults with a reported worldwide incidence of 3/100,000 cases per year in adults.[1],[3],[4] It results from failure of the glomerular filtration barrier (GFB), either from primary defects in the kidney or secondary to systemic diseases, and is characterized by massive proteinuria (>3–3.5 g/day), hypoalbuminemia (serum albumin <3 g/dl), generalized edema, and hyperlipidemia (serum cholesterol >200 mg/dl).[5],[6] Proteinuria only without these manifestations is known as nephrotic range proteinuria (NRP).

One-third of the primary cases of NS are due to membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS).[7] Minimal change nephrotic syndrome accounts for approximately 25% of NS cases.[8] The complex and varied NS pathogenesis is associated with multiple hemostatic indicators of the loss of various coagulation inhibitors, which can lead to an imbalance between procoagulants and anticoagulants.[9] This imbalance leads to hypercoagulability in NS and is considered secondary to the glomerular dysfunction and the resulting breakdown in the selectivity of the GFB.[10] These patients are prone to venous and arterial thrombosis[11] as well as thromboembolism, which is considered a major life-threatening complication of NS, with an incidence ranging from 10 to 60% in adult patients;[12],[13] however, the pathophysiology of thromboembolism in NS remains unknown.[9] Despite the proven prothrombotic tendency in NS, prophylactic anticoagulation and thrombosis treatment have not shown any benefit, because large randomized trials and guidelines are lacking in this area.[10]

It is now commonly understood that thrombin is the key enzyme of the coagulation system, responsible mainly for the conversion of fibrinogen to fibrin. Thrombin is generated from its inactive precursor prothrombin by prothrombinase complex, with the release of a single activation fragment designated as prothrombin fragment 1+2 (PF1+2).[14] The neutralization of thrombin by antithrombin results in the formation of thrombin–antithrombin complexes (TAT).[15] For many years, the laboratory measurements of PF1+2 and TAT (considered hemostatic activation markers) have been employed as an indirect measure of hemostatic activation and the generation of thrombin at a given moment in time.[16] However, they do not express the full hemostatic potential. Furthermore, the traditional coagulation screening tests, prothrombin time (PT), and activated partial thromboplastin time (aPTT), monitor the integrity of the extrinsic and intrinsic coagulation pathways, respectively.[17] PT and aPTT can only provide information about how long the blood takes to clot.[18]

Regarding the assessment of hemostasis, there was a recent shift from these traditional coagulation tests to alternative tests that estimate the process in a rather holistic and physiological manner,[19] including the thromboelastogram, clot waveform analysis, and thrombin generation (TG) test.[18] These newly introduced techniques are beneficial for understanding and investigating “global hemostasis,”[2],[18] as they reflect the entire dynamics of the coagulant process beyond initial clot formation. Their potential relies mostly on the fact that they are gradually replacing diagnostic tests of clotting time-based assays.[20]

The TG test depends on the fact that, after initiation of the coagulation system and following a lag, a significant amount of thrombin is formed quickly. At the very beginning of that formation process, the clot starts to appear. Routine clotting time does not monitor the entire quantity of thrombin generated within the clot.[20],[21] Determining the quantity of thrombin activity more accurately reflects this dynamic process to measure the coagulation system function than routine clotting times.[22]

In NS, monitoring blood TAT, PF1+2, prolonged PT, and aPTT levels do not provide conclusive direct evidence regarding the activation of the hemostatic pathway mainly because of the heterogeneity of the patient groups.[23],[24],[25] To the best of our knowledge, the levels of these markers have not been studied for NRP.

Another elevated hemostatic marker in patients with NS is von Willebrand factor (vWF),[26] which is a multimeric glycoprotein that plays a significant role in primary hemostasis, especially in the recruitment of platelets to the growing thrombus and as a carrier in plasma for clotting factor VIII, thereby protecting it from proteolysis.[27] The ultra-large vWF multimers possess potent thrombogenic properties. The primary mechanism regulating vWF size and function is because of a cleaving protease identified in 1996 as A disintegrin and metalloproteinase with thrombospondin (ADAMTS-13).[28]

We believed that simultaneously measuring all these markers of hemostasis at different stages of NS would provide a more precise view of the NS-associated hemostatic abnormalities. Thus, this study aims to evaluate the functional test of TG in different stages of NS; determine its relation with coagulation screening tests (PT and aPTT), hemostatic activation markers (TAT and PF1+2), and vWF and its proteolytic enzyme ADAMTS-13; and determine the correlation between TG and NS severity, as reflected by the levels of proteinuria and albumin.


  Materials and Methods Top


This case–control, cross-sectional study included 125 patients divided into the following three groups: 40 patients with NRP, 45 patients with NS, and 40 patients in remission; 80 healthy individuals were included in the control group. Patients were recruited from the Nephrology Clinic and Medical Ward at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia. Ten patients were followed from the initiation of the treatment of NS until remission. In all patients, the histological diagnosis of NS was confirmed using renal biopsy. The healthy individuals were volunteers randomly recruited from blood donors and academic staff. They were age and sex matched with the patient groups.

The study protocol was approved by the Institutional Review Board of Faculty of Medicine, King Saud University, Riyadh. Informed consent was obtained from all of the participants. All subjects underwent a complete physical examination and routine laboratory testing. The demographic data and characteristics of the participants are shown in [Table 1].
Table 1: Characteristics and biochemical parameters of the control and study groups

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The exclusion criteria for all groups were secondary causes of NS such as diabetes mellitus, hepatitis, preeclampsia, human immunodeficiency virus, and the use of any of the following medications: heparin, warfarin, or antiplatelet therapy.

Blood collection and plasma preparation

Ten ml blood was obtained by venipuncture directly into a sodium citrate tube with a citrate ratio of 9:1. Blood samples were transported within 1 h of collection to the Research Laboratory, College of Medicine. Platelet poor plasma (PPP) was prepared by centrifuging the samples at 3000 rpm (1000 g relative centrifugal force) for 15 min. Plasma was stored using plastic pipettes, and aliquots of plasma were immediately stored at 80°C until analysis at a later date. All plasma specimens were thawed at 37°C for 15 min before assay.

Thrombin generation test

The thrombinoscope BV reagent (Maastricht, The Netherlands) used for the determination of TG was supplied by Diagnostica Stago (Catalogue number 86193, Asnières, France).

In a 96-well round bottom plate, 20 μl prewarmed trigger solution (PPP reagent containing 5 picomol [pM]/l of tissue factor and 4 μM phospholipids) was added to one well and 20 μl of prewarmed calibrator (Thrombin Calibrator, α2M–thrombin complex) to another well; 80 μl plasma (platelet-rich plasma or PPP) was added to both wells. Ca2+ was added together with the fluorogenic substrate (FluoSubstrate) immediately before the beginning of the measurement (zero time) (Fluca Solution). The readings were conducted at 37°C temperature using a microtiter plate fluorometer (Fluoroscan Ascent, Thermolabsystems, Helsinki, Finland).

Thrombin generation markers measured using calibrated automated thrombogram (CAT)

The markers measured using CAT were lag time (clotting time, i.e., the moment at which TG begins), endogenous thrombin potential (ETP − the total amount of thrombin generated, in nM/min), peak height (maximum thrombin concentration, in nanomolars), time to peak (time to reach maximum thrombin concentration), and start tail (time at which the generation of thrombin had come to an end in minutes) [Figure 1].
Figure 1: Markers of thrombin generation. The image was obtained from the thrombinogram guide. ETP = endogenous thrombin potential

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Coagulation tests

A STA-Neoplastine CI Plus kit (Catalogue number 00370, Diagnostic Stago, Asnières, France) was used for the determination of PT. A STA-PTT kit was used for the determination of APTT using a STA analyzer supplied by Diagnostica Stago (Catalogue number 00595, Asnières, France). TAT, PF1+2, vWF, and ADAMTS-13 were measured using enzyme-linked immunosorbent assay.

Statistical analysis

Data were analyzed using the Statistical Package for the Social Sciences version 21 (IBM Corp., Armonk, NY, USA). Data are expressed as median (25–75th percentile). Kolmogorov–Smirnov tests of normality showed that the results did not follow a normal distribution, with skewness factors ranging from −0.09 to 3.6. Kruskal–Wallis tests were used for analysis of variance (ANOVA) and post-ANOVA pairwise comparisons between the groups. Mann–Whitney tests were used to compare values between two groups. Pearson’s correlation coefficients were used to test the correlations between relevant variables in each group. P < 0.05 was considered significant.


  Results Top


The results of renal biopsy in the patient groups were as follows: 64 (51.2%) had FSGS, 37 (29.6%) had MN, 14 (11.2%) had MCD, and 10 (8%) had immunoglobulin A (IgA). The hemostatic and biochemical parameters of the control and patient groups are shown in [Table 1].

No significant difference in PT levels between the groups was found, while aPTT level was significantly higher in the NS group (35.3 s) than in the control group (33.8 s) (P = 0.02) [[Figure 2]a]. However, the median TG (ETP) level was significantly higher in the NS group (2001 nM/min) than in the control group (1426 nM/min) (P < 0.0001) [[Figure 2]b]. Plasma TAT levels were significantly higher in all patient groups (NRP, 0.46 ng/ml; NS, 0.56 ng/ml; remission, 0.53 ng/ml) than in the control group (0.36 ng/ml) (P < 0.0001) [[Figure 2]b]. PF1+2 levels were also significantly higher in all patient groups (NRP, 2.7 ng/ml; NS, 1.5 ng/ml; remission, 5.7 ng/ml) than in the control group (1.01 ng/ml) (P < 0.0001) [[Figure 2]b]; vWF levels were significantly higher in all patient groups (NRP, 129%; NS, 208%; remission, 120%) than in the control group (90.5%) (P < 0.0001) [[Figure 2]c]. Plasma ADAMTS-13 levels were significantly lower in the NS group (387 ng/ml) than in the control group (800 ng/ml) (P < 0.0001) [[Figure 2]c].
Figure 2: Median levels of hemostatic markers in the control and patient groups. NS = nephrotic syndrome, NRP = nephrotic range proteinuria, TG (ETP) = thrombin generation (endogenous thrombin potential), TAT = thrombin–antithrombin complex, PF1+2 = prothrombin fragment 1+2, PT = prothrombin time, aPTT = activated partial thromboplastin time, vWF = von Willebrand factor, ADAMTS-13 = A disintegrin and metalloproteinase with thrombospondin-13, PT = prothrombin time, aPTT = activated partial thromboplastin time, ― = median, □ = 25–75th percentile, I = min–max. Kruskal–Wallis test was used for ANOVA and post-ANOVA pairwise to non-parametric statistical tests to compare between the groups. *Statistically significant at P ≤ 0.05

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Hemostatic changes in the group followed from nephrotic syndrome until remission

TG and vWF levels significantly decreased for the NS patients who went into remission (1417 nM/min to 2001 nM/min, P < 0.0001; 138–250%, P = 0.005, respectively) [Figure 3]. However, the plasma levels of ADAMTS-13 were significantly higher for patients who went into remission (843.5 ng/ml) than in patients with NS (397.5 ng/ml) (P ˂ 0.0001) [Figure 3]. However, no significant difference was found in median TAT, PF1+2, PT, or aPTT levels between the groups.
Figure 3: TG (ETP), vWF, and ADAMTS-13 levels in the patients followed-up from the initiation of the treatment of NS until remission. NS = nephrotic syndrome, TG (ETP) = thrombin generation (endogenous thrombin potential), vWF = von Willebrand factor, ADAMTS-13 = A disintegrin and metalloproteinase with thrombospondin-13, ― = median, □ = 25–75th percentile, I = min–max. Mann–Whitney tests were used to compare between the two groups. *Statistically significant at P ≤ 0.05

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Correlations between thrombin generation and severity parameters (proteinuria and albumin)

No significant correlations were found between TG (ETP) and the other measured hemostatic parameters. However, median TG (ETP) and vWF levels were significantly, positively correlated with proteinuria (P < 0.0001). ADAMTS-13 levels were significantly, negatively correlated with proteinuria (P < 0.0001). No significant correlations between these levels and albumin level were found [Table 2].
Table 2: Pearson’s correlation coefficients between hemostatic factors and proteinuria and albumin levels

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  Discussion Top


We aimed to characterize the prothrombotic changes in different stages of NS using a functional and holistic test of coagulation (TG [ETP]) with newly introduced assay techniques. This assay technique was designed to overcome the disadvantage of the older routine coagulation tests such as PT and aPTT.

PT and aPTT measured clotting time rather than the quantities of thrombin needed for clot formation. In this study, there was no significant difference in PT between patient groups and the control group, with significantly prolonged aPTT in the NS group. Similarly, previous studies have reported significantly prolonged aPTT;[25],[29] however, the underlying mechanism has not been clarified.

Regarding the markers of thrombin activation (TAT and PF1+2) that indirectly measure TG, the levels of both markers were significantly higher in all patient groups than in the healthy controls. These findings confirm those of similar earlier reports.[23],[24],[30],[31] However, no previous studies measured these parameters in NRP. Our findings provide evidence of hypercoagulability not only in NS but also in NRP. Interestingly, TAT and PF1+2 levels were still significantly higher in the remission group, indicating that the hemostatic imbalance in NS remains in patients in clinical remission and increases their risk for thrombosis.

The TG test is a functional assay that determines the total amount of generated thrombin and is denoted as ETP. This test has recently gained in popularity and acceptance for assessing normal hemostasis and its disorders.[17] A literature search did not identify any similar studies of this global hemostatic test in patients with NS. In this study, TG (ETP) levels were significantly higher in the NS group than in the healthy controls, but significantly lower in the remission group than in the NS group. However, the levels decreased during remission in the patients who were followed from NS until remission, demonstrating that hypercoagulability resolves slowly toward normal in response to treatment. Kerlin et al.[32] studied TG in the puromycin aminonucleoside and adriamycin rat model of NS. They found elevated levels of TG and an increased risk of thrombosis, particularly with the presence of vascular injury. Other studies using the TG test revealed elevated production of thrombin in some diseases that present with proteinuria such as preeclampsia.[33]

The vascular endothelium plays a critical role in the etiology of thrombosis. In this respect, vascular endothelial activation markers such as vWF have frequently been studied in prothrombotic states. vWF is a protein that exemplifies the thin line between the normal hemostatic process and an overly active system that results in thrombotic events.[34] In this study, all patient groups had higher vWF levels than the control group. These results confirm and extend those of many earlier reports.[26],[35],[36] In contrast, plasma levels of the vWF cleaving protease, ADAMTS-13, were lower in patients with NS than in the control group and started to normalize when patients go into remission. Therefore, the presence of endothelial dysfunction can occur with NS, which aggravates the hypercoagulable state in those patients. To the best of our knowledge, this is the first study to report ADAMTS-13 levels in NS.Collectively, these findings indicate that NS is associated with a high risk for thrombosis, given the presence of endothelial dysfunction, as evidenced by higher vWF levels and lower ADAMTS-13 levels, which are associated with increased TG (ETP) production.

Another interesting finding is a possible relationship between fluctuations in the levels of markers of hypercoagulability and disease severity, as evidenced by proteinuria (TG [ETP] and vWF). This is similar to the findings of Kerlin et al.[32] and Tkaczyk et al.[26] Plasma ADAMTS-13 levels were significantly and negatively correlated with proteinuria. Therefore, proteinuria could be used as indirect clinical biomarker of thrombosis in patients with NS. These findings should be confirmed with a larger sample size. A limitation of our study includes the patient subgroups.

In summary, patients with NS had higher levels of TG, TAT, PF1+2, and vWF and lower levels of ADAMTS-13, indicating a high risk for thromboembolic disease. Patients in remission still had significantly high levels of TAT and PF1+2. Further investigations are needed to clarify these findings regarding TG in the different disease stages. Plasma PF1+2 and TAT levels were significantly higher with NRP; although TG levels were higher in these patients, the difference was not significant. However, the clinical frequency of thromboembolic disease in patients with NRP requires further investigation. Finally, TG levels were correlated with the levels of proteinuria in all patient groups, indicating that hypercoagulability worsens with disease severity.

Acknowledgements

The financial support of Alqassim University is sincerely acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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