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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 41  |  Issue : 4  |  Page : 180-186

Apolipoprotein M and transforming growth factor-β levels as predictive biomarkers in idiopathic recurrent venous thromboembolism


1 Department of Clinical Pathology, Faculty of Medicine, Tanta, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Tanta, Egyp
3 Department of Anesthesia & Surgical ICU, Faculty of Medicine, Tanta, Egypt
4 Department of Chest, Faculty of Medicine, Tanta, Egypt
5 Department of Surgery, Faculty of Medicine, Tanta, Egypt

Date of Submission26-Sep-2016
Date of Acceptance10-Oct-2016
Date of Web Publication20-Jan-2017

Correspondence Address:
Hossam Hodeib
Department of Clinical Pathology, Faculty of Medicine, El Geish Street, Tanta, 31511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.198653

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  Abstract 

Introduction Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is a common, acute, multifactorial, fatal disease, although treatable. The recurrence rate of VTE is about 17% after 2 years of follow-up and 30% after 8 years. Apolipoprotein M (ApoM) and transforming growth factor-β (TGF-β) could be prognostic biomarkers of recurrence of VTE.
Aim of the study The aim of this study was to assess the prognostic value of ApoM and TGF-β levels as predictors of recurrence of VTE among patients with first thrombotic event.
Patients and methods This prospective cohort study was carried out from December 2013 to December 2015 in the Internal Medicine, Chest, Anesthesia, Surgical ICU, and Surgery Departments, Tanta University Hospital, Egypt, on 78 patients of both sexes and age younger older than 18 years who were admitted in the hospital for DVT or PE. DVT was confirmed with imaging techniques, venography or compression ultrasonography, and PE was confirmed with ventilation/perfusion lung scan. They were initially treated with low molecular weight heparin and then with warfarin as an oral anticoagulant for 3–6 months. They were observed for 2 years at 3-month intervals in the first year and every 6 months in the second year or until the time of recurrence of VTE. We evaluated the plasma levels of ApoM, TGF-β1, TGF-β2, and TGF-β3 at 3–12 weeks after withdrawal of anticoagulant therapy.
Results The main finding in the present study was that the mean plasma levels of both TGF-β1 and TGF-β2 were significantly lower in patients with recurrence of VTE when compared with those without recurrence of VTE. However, the mean plasma levels of ApoM and TGF-β3 were not significantly different between patients with recurrence of VTE and those without recurrence of VTE.
Conclusion TGF-β1 and TGF-β2 could be useful prognostic biomarkers in VTE patients and can predict the recurrence of the thrombotic event.

Keywords: apolipoprotein M, transforming growth factor-β, venous thromboembolism


How to cite this article:
Hodeib H, Elshora O, Shahbah A, Ramadan E, Esam A, Hantera M, Elshoura AA. Apolipoprotein M and transforming growth factor-β levels as predictive biomarkers in idiopathic recurrent venous thromboembolism. Egypt J Haematol 2016;41:180-6

How to cite this URL:
Hodeib H, Elshora O, Shahbah A, Ramadan E, Esam A, Hantera M, Elshoura AA. Apolipoprotein M and transforming growth factor-β levels as predictive biomarkers in idiopathic recurrent venous thromboembolism. Egypt J Haematol [serial online] 2016 [cited 2019 Dec 14];41:180-6. Available from: http://www.ehj.eg.net/text.asp?2016/41/4/180/198653


  Introduction Top


Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is a common, acute, multifactorial, fatal disease, although treatable [1],[2]. According to the absence or presence of predisposing factors that may be transient or permanent, VTE can be either unprovoked (idiopathic) or provoked (secondary), respectively [3]. The recurrence rate of VTE, which is two-fold higher in unprovoked VTE in comparison with provoked ones, is over 25% at 5-year follow-up, with the highest hazard of recurrence during the first 6–12 months [4],[5],[6]. Although the anticoagulant therapy is effective in preventing recurrent VTE, the risk for recurrence after stopping the anticoagulant therapy is not influenced by the period of treatment; however, the incidence of uncontrolled bleeding is increased during anticoagulant therapy, and hence recurrence risk assessment is important before deciding to continue or stop anticoagulant therapy [7]. Atherosclerotic vascular diseases are one of the risk factors of VTE [8]. Apolipoprotein M (ApoM) is a lipocaline that mainly abides in plasma high-density lipoprotein (HDL) and to a lesser extent in apolipoprotein B containing lipoproteins − that is, low-density lipoprotein (LDL) and triglyceride-rich very-low-density lipoprotein [9],[10],[11]. ApoM connects to plasma lipoproteins through its hydrophobic NH2-signal peptide. HDL-bound ApoM has antiatherogenic effect; it is the physiological carrier of circulating sphingosine-1 phosphate (S1P), which provides endothelial protection and maintains vascular integrity [11],[12].

Transforming growth factor-β (TGF-β), which has three closely related isoforms (TGF-β1, TGF-β2, and TGF-β3), is a group of structurally related cytokines that exert a complex role on vessel wall biology through its effects on the endothelial cells and vascular smooth muscle cell [13]. All subtypes of TGF-β bind to same receptors and perform similar functions, including but not limited to immunomodulatory effects and anti-inflammatory role, in the process of atherogenesis [13],[14].

In this study, we investigated the effect of ApoM, TGF-β1, TGF-β2, and TGF-β3 levels as predictors for unprovoked VTE recurrence.

The objective of this study was to assess the prognostic value of ApoM and TGF-β levels as predictors of recurrence of VTE.


  Patients and methods Top


This prospective cohort study was carried out from December 2013 to December 2015 in the Internal Medicine, Chest, Anesthesia, Surgical ICU, and Surgery Departments, Tanta University Hospital, Egypt, on 78 patients of both sexes after approval by the hospital ethical committee. The study was performed according to the principles of the declaration of Helsinki; written informed consent of the patients was obtained.

Patients who were admitted in our hospital with DVT or PE were eligible for the study. None of them had any evidence of neoplastic or other systemic diseases. DVT was confirmed with imaging techniques, venography or compression ultrasonography, and PE with ventilation/perfusion lung scan. They were initially treated with low molecular weight heparin and then with warfarin as an oral anticoagulant for 3–6 months.

Exclusion criteria were as follows: inherited or acquired thrombophilic defect. Inherited thrombophilia such as antithrombin; protein C; or protein S deficiency; and homozygous/heterozygous or combined congenital clotting defects such as factor V Leiden polymorphism (rs6025) and/or the prothrombin G20210A polymorphism (rs1799963), and acquired thrombophilia such as antiphospholipid syndrome; major surgery; obesity; immobilization; long distance travel; cast therapy within the last month; malignancies; use of contraceptives pills; hormonal replacement therapy; pregnancy; and myeloproliferative disorders such as polycythemia vera and essential thrombocythemia.

All patients were asked to enter the study at the time of first thrombotic event. They were observed for a period of 2 years at 3-month intervals in the first year and every 6 months in the second year or until the time of recurrence of VTE, which is the endpoint of the study.

Blood collection and laboratory assay

Laboratory assays were performed in blood obtained at 1 month after withdrawal of anticoagulant therapy. Whole blood was collected by means of standard venipuncture in Vacuette Blood Collection Tubes (Greiner Bio-One, Kremsmuenster, Austria) containing 0.109 mol/l (3.2%) buffered sodium citrate solution, K2EDTA/Sep, and clot activator/Sep. d-Dimer, antithrombin, protein C, or protein S were evaluated on a fully automated blood coagulation analyzer (Sysmex CA 1500; Siemens Healthcare Global, Erlangen, Germany) at the Hematology Unit, Clinical Pathology Department, Tanta University Hospital, Egypt. Lipid profile was evaluated on a fully automated chemistry analyzer (konelab Prime 60i, Konelab; Vantaa, Finland) at the Clinical Chemistry Unit, the Clinical Pathology Department, Tanta University Hospital, Egypt. DNA samples were genotyped for factor V Leiden polymorphism (rs6025) or the prothrombin G20210A polymorphism (rs1799963) on Applied Biosystems StepOneReal-Time PCR Systems (Applied Biosystems, Foster City, California, USA), using TaqMan SNP Genotyping Assays kit (catalog No.4351379; Applied Biosystems) at the Molecular Biology Unit, Clinical Pathology Department, Tanta University Hospital, Egypt. Human ApoM levels were measured with enzyme-linked immunosorbent assay (ELISA) kit (catalogue no. E-EL-H0473, Elabscience; Elabscience Biotech Co., Wuhan, Hubei, China). Human TGF-β1 levels were measured with Human TGF-β1 Platinum ELISA (BMS249/4/BMS249/4TEN; ebioscience, Vienna, Austria). Human TGF-β2 levels were measured with Human TGF-β2 Platinum ELISA (BMS254; ebioscience). Human TGF-β3 levels were measured with ELISA kit (catalogue no. KA4402; Abnova, Taipei, Taiwan).

Statistical analysis

The data were collected, processed, and analyzed using (SPSS, version 23, Armonk, NY, USA). The χ2-test was used to examine the association between two categorical variables. The independent sample t-test was used to examine the difference in the age, ApoM, TGF-β1, TGF-β2, and TGF-β3 between the recurrence and nonrecurrence VTE groups. In addition, the correlation analysis was performed to study the relation between different variables. Finally, a full survival analysis was performed. The receiver operating characteristic (ROC)-curves were graphed and the best cutoff points that maximize (sensitivity+specificity) were determined. The Kaplan–Meier plots displayed the survival probabilities, and the hazard ratios were calculated and the Cox proportional-hazards models were written [15].


  Results Top


In total, 78 patients presented with first thrombotic event (53.8% female and 46.2% male) and the mean age was 53.49±7.49 years. They were followed up for 21.29±5.94 months. VTE recurred in 17 (21.8%) patients. There was no statistically significant difference on comparing the percentage of patients with recurrence of VTE below and those with recurrence of VTE above the cutoff value for both ApoM and TGF-β3 (P=0.784 and 0.915, respectively), whereas there was a statistically significant difference on comparing the percentage of patients with recurrence of VTE below and those with recurrence of VTE above the cutoff value for both TGF-β1 and TGF-β2 (P<0.001 and P=0.031, respectively). The mean plasma levels of total cholesterol, triglycerides, HDL, and LDL did not differ significantly in patients with recurrent VTE when compared with those without recurrence (P=0.837, 0.057, 0.8, and 0.874, respectively), whereas d-dimer levels were significantly increased in patients with recurrent VTE than in those without recurrence (P<0.001) ([Table 1]). The mean plasma levels of ApoM and TGF-β3 were not significantly different in patients with recurrence of VTE when compared with those without recurrence of VTE (P=0.533 and 0.685, respectively), whereas the mean plasma levels of both TGF-β1 and TGF-β2 were significantly lower in patients with recurrence of VTE than in those without recurrence of VTE (P<0.001 and P<0.001, respectively) ([Table 2]). There was a significant positive correlation between HDL and ApoM (r=0.442 and P<0.001) and a significant negative correlation between d-dimer and TGF-β1 (r=−0.364 and P<0.001). Furthermore, d-dimer showed correlation with TGF-β2 and TGF-β3, but these correlations did not reach significant value (r=−0.103, P=0.368, and r=−0.033, P=0.773). Interestingly, ROC curve illustrated the sensitivity and the specificity of ApoM, TGF-β1, TGF-β2, and TGF-β3 [(52.9 and 50.8%), (70.6 and 80.3%), (70.6 and 59.0%), and (58.8 and 42.6%), respectively] as prognostic biomarkers that could predict the recurrence of VTE. Furthermore, the greater the area under ROC curve, the more accurate the test. The results showed that the area under the ROC curves of both ApoM and TGF-β3 were not significant (P=0.561 and 0.908, respectively), whereas that of TGF-β1 and TGF-β2 were significant (P<0.001 and P=0.002, respectively), indicating that TGF-β1 and TGF-β2 were better prognostic biomarkers of recurrence of VTE compared with ApoM and TGF-β3 ([Figure 1]). The survival functions of the patients with ApoM and TGF-β3 below the cutoff (6.5 ng/ml and 31 pg/ml, respectively) were lower compared with the survival function of those above the cutoff. The hazards of VTE recurrence in those patients decreased when these two biomarkers increased. As the two survival curves overlapped, we could say that there were no significant differences between these two functions. Similarly, using the log-rank test (χ2) there were no significant differences between these two functions (P=0.713 and 0.899, respectively). The survival functions of the patients with TGF-β1 and TGF-β2 below the cutoff (5169 and 555 pg/ml, respectively) were lower compared with the survival function of those above the cutoff. The hazards of VTE recurrence in those patients decreased when these two biomarkers increased. As the two survival curves did not overlap, we could say that there were significant differences between these two functions. Similarly, using the log-rank test (χ2), there were significant differences between these two functions (P<0.001 and P<0.05, respectively) ([Figure 2]). Ultimately, to evaluate the predictive value of TGF-β1, TGF-β2, TGF-β3, ApoM, and d-dimer, the hazard ratios were calculated and the Cox proportional-hazards models were written. d-Dimer had a significantly increased risk for VTE recurrence (1.235-fold) [95% confidence interval (CI)=1.012–1.652]. Similarly, the risk for recurrence was increased among patients with TGF-β1 and TGF-β2 levels below the cutoff (1.001-fold and 1.011-fold, respectively) (95% CI=1.000–1.002 and 1.003–1.020, respectively). P-value was less than 0.05 for both markers, indicating that TGF-β1 and TGF-β2 were potential risk factors and predictive markers of recurrence for VTE.
Table 1 Plasma levels of cholesterol, triglycerides, HDL, LDL, and d-dimer among the studied patients with and those without recurrence of VTE

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Table 2 Plasma levels of ApoM, TGF-β1, TGF-β2, and TGF-β3 among the studied patients with and those without recurrence of VTE

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Figure 1 Receiver operating characteristic (ROC) curve of apolipoprotein M (ApoM), transforming growth factor-β1 (TGF-β1), TGF-β2, and TGF-β3.

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Figure 2 Survival analysis (Kaplan–Meier) of apolipoprotein M (ApoM), transforming growth factor-β1 (TGF-β1), TGF-β2, and TGF-β3.

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  Discussion Top


There are common risk factors for atherosclerotic vascular diseases and VTE that may help in identifying new risk factors for recurrent venous thrombosis [16]. The ability to stratify patients into risk groups would allow the proper use of VTE prophylaxis and selective management of high-risk patients. There is little information in the literature about risk stratification of patients for recurrent VTE. We tried in the present work by using simple, commercially available ELISA kit to measure ApoM, TGF-β1, TGF-β2, and TGF-β3 levels to identify patients in whom the risk for recurrent VTE is considerably elevated. The results obtained from the present work revealed that dyslipoproteinemia was not a significant risk factor for recurrence of VTE, whereas d-dimer had a significantly increased risk for VTE recurrence (1.235-fold) (95% CI=1.012–1.652). These results are in accordance with the study performed by Wattanakit et al. [17], who found that alcohol intake, diabetes, hypertension, HDL and LDL, and triglycerides were not associated with VTE risk. However, Doggen et al. [18] reported that elevated triglyceride levels were associated with a doubling of the risk for VTE in postmenopausal women, and another study by Eichinger et al. [19] found that elevated HDL-cholesterol decreased this risk. Palareti et al. [20] found that d-dimer levels had a high negative predictive value for recurrence in patients with unprovoked VTE. The main finding in the present study was that the mean plasma levels of both TGF-β1 and TGF-β2 were significantly lower in patients with recurrence of VTE than in those without recurrence for VTE. In the present study, the survival function of the patients with TGF-β1 and TGF-β2 below the cutoff was lower compared with the survival function of those with values above the cutoff. The hazards of VTE recurrence in those patients decreased when these two biomarkers increased, suggesting that these two biomarkers could be used as potential biomarkers of recurrent VTE. Our findings are supported by Memon et al. [21], who found an association between lower levels of TGF-β1 and TGF-β2 in recurrent VTE compared with nonrecurrent VTE. In the present work, the mean plasma levels of ApoM and TGF-β3 were lower in patients with recurrent VTE than in patients without recurrence, but our results did not reach significance. These findings were similar to that found by Memon et al. [22], who found an association between low levels of ApoM and an increased risk for unprovoked VTE in male patients. In the present work, there was a significant positive correlation between HDL and ApoM and a significant negative correlation between d-dimer and TGF-β1. Furthermore, d-dimer showed correlation with TGF-β2 and TGF-β3, but these correlations did not reach significance. Our results are supported by Huang et al. [23], who found that ApoM may affect HDL metabolism and exhibit antiatherosclerotic functions. Wolfrum et al. [24] found that ApoM is associated with HDL and plays an important role in lipid metabolism and protects against atherosclerosis. In addition, Grainger [25] and Vayalil et al. [26] suggested that, in atherosclerosis, TGF-β1 could be an antiatherogenic factor and, in hemostasis, it was considered as an antifibrinolytic factor. Other pieces of evidence that strengthen our results are provided by Bjorkerud [27] and Owens et al. [28] using cell culture studies; they suggested that TGF-β protects against atherosclerosis. Moreover, Mallat et al. [29] proved that suppression of TGF-β1 activity accelerates atherosclerosis by forming unstable plaque with increasing risk for its rupture.


  Conclusion Top


TGF-β1 and TGF-β2 could be useful prognostic biomarkers in VTE patients and can predict the recurrence of VTE in patients with first thrombotic event.

Limitations of the study

The limitations of our study were that this study involved a relatively small number of patients and our study period was only 2 years with short follow-up period; thus, we may have missed recurrent DVT that occurred afterward.

Acknowledgements

The authors thank the nurses at the Internal Medicine, Chest, Anesthesia, Surgical ICU, and Surgery Departments, Tanta University Hospital, for their assistance in conducting the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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