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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 40  |  Issue : 2  |  Page : 49-54

Thrombin-activatable fibrinolysis inhibitor antigen level in coronary artery disease


1 Department of Cardiology, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Hematology Unit, Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
3 Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission14-Feb-2015
Date of Acceptance16-Apr-2015
Date of Web Publication22-Jul-2015

Correspondence Address:
Deena Mohamed Mohamed Habashy
Hematology Unit, Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo 11566
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.161288

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  Abstract 

Background Thrombosis is one of the most serious complications associated with coronary artery disease (CAD), possibly arising from increased platelet activation and/or loss of the regulation of coagulation and fibrinolysis.
Objectives We aimed to measure total thrombin-activatable fibrinolysis inhibitor antigen (t-TAFI Ag) level in CAD Egyptian patients and correlate its level with the standard risk factors for CAD, to investigate its possible role in the occurrence of atherothrombosis in those patients.
Patients and methods Plasma t-TAFI Ag level was measured by enzyme-linked immunosorbent assay in 70 CAD patients and 20 healthy sex-matched and age-matched volunteers as a control group.
Results Plasma t-TAFI Ag level was higher in CAD patients [both acute coronary syndrome and stable angina groups (groups I and II, respectively)] compared with the control group (P = 0.001), whereas no difference was found in t-TAFI Ag level, neither between group I and II (P = 0.37) nor between subgroups of acute coronary syndrome (P = 0.66). Regarding correlation with risk factors, t-TAFI Ag level was inversely correlated with high-density lipoproteins only in group I (P = 0.02).
Conclusion t-TAFI Ag level is increased in CAD Egyptian patients and this increase may play an important role in the occurrence of thrombotic attacks in these patients.

Keywords: coronary diseases, fibrinolysis, thrombin-activatable fibrinolysis inhibitor, thrombosis


How to cite this article:
Sedky HA, Habashy DM, Ammar WS, El-Ashmawy EM. Thrombin-activatable fibrinolysis inhibitor antigen level in coronary artery disease. Egypt J Haematol 2015;40:49-54

How to cite this URL:
Sedky HA, Habashy DM, Ammar WS, El-Ashmawy EM. Thrombin-activatable fibrinolysis inhibitor antigen level in coronary artery disease. Egypt J Haematol [serial online] 2015 [cited 2019 Dec 12];40:49-54. Available from: http://www.ehj.eg.net/text.asp?2015/40/2/49/161288


  Introduction Top


It is well known that one of the most frequent and serious complications associated with cardiovascular disease (CVD) is thrombosis, possibly arising from loss of regulation of coagulation and fibrinolysis [1] . One important factor is thrombin-activatable fibrinolysis inhibitor (TAFI), which forms a link between blood coagulation and fibrinolysis. Thrombin forms fibrin to stabilize the platelet-rich thrombus and at the same time produces TAFI to protect that fibrin network [2] .

TAFI (plasma procarboxypeptidase B, carboxypeptidase U) is a single-chain glycoprotein zymogen that is synthesized in the liver [3] . It circulates as a procarboxypeptidase B zymogen, which is converted into an active form, carboxypeptidase U or activated thrombin-activatable fibrinolysis inhibitor (TAFIa), during coagulation after thrombin cleavage. Generation of TAFIa is dependent on the quantity of thrombin generated during coagulation and is drastically potentiated by thrombomodulin [4] .

Activated TAFI is a member of the family of metallocarboxypeptidases. These exopeptidases are zinc dependent and cleave carboxy-terminal peptide bond [5] . TAFI is proposed to play a key role in the interaction between procoagulant, anticoagulant, and fibrinolytic systems [3] . The direct action of TAFI as an inhibitor of clot lysis involves removal of carboxy-terminal lysyl and arginyl residues from partially degraded fibrin [6],[7] . Consequently, plasminogen binding sites are eliminated and plasminogen activation and fibrinolysis are inhibited [6] .

Endogenous fibrinolysis is a protective mechanism against lasting arterial thrombotic occlusion, which would otherwise lead to permanent tissue damage. Because arterial thrombogenesis is an active, ongoing, and dynamic process, a healthy endogenous fibrinolytic system can prevent the build-up of thrombus before complete occlusion occurs or break up the occlusive thrombus before lasting tissue damage ensues. Thrombin converts the inactive proenzyme plasminogen to active plasmin. This fibrinolytic system can be inhibited either by antagonizing plasmin through α2-antiplasmin or by specific plasminogen activator inhibitors or TAFI. Conflicting findings of either low or high TAFI levels have being associated with cardiovascular risk [2] .

Due to the confusing data in previous studies about the role of TAFI in CVD, we aimed to detect plasma total TAFI antigen (t-TAFI Ag) level in Egyptian patients with coronary artery disease (CAD) and correlate its level with the standard CAD risk factors, to investigate its possible role in the occurrence of atherothrombosis in those patients.


  Patients and methods Top


Patients

Seventy Egyptian patients with CAD were enrolled in this study. They were recruited from the Cardiology Department and the outpatient clinic of the Damietta Cardiology and Gastero-enterology Center (Damietta, Egypt). The patients were divided into two groups:

  1. Group I: this group comprised 35 patients who presented with acute coronary syndrome (ACS) [13 patients with ST elevation myocardial infarction (STEMI), 11 patients with non-ST elevation myocardial infarction (NSTEMI), and 11 patients with unstable angina (UA)].
  2. Group II: this group comprised 35 patients who presented with stable angina.


ACS and stable angina were diagnosed according to the criteria established by the American Heart Association/American College of Cardiology [8],[9] .

Twenty healthy age-matched and sex-matched volunteers with no evidence of CVD risk factors (diabetes mellitus, hypertension, hypercholesterolemia, obesity or smoking) were taken as a control group. All participants completed a questionnaire referring to their health status, personal and family history of CVD, presence of conventional cardiovascular risk factors, present and former smoking habits, and current use of medications. Height and weight were recorded and the BMI was calculated as kilograms per square meter.

Exclusion criteria

Patients were ruled out of the study if they had any of the following:

  1. Acute illness or fever.
  2. Malignancy.
  3. Hepatic or renal dysfunction.
  4. Known cardiomyopathy.
  5. Surgery or trauma within a month before the study.
  6. Taken oral anticoagulants in the 6-month period before participation in the study.


Hypertension was defined according to the guidelines of the European Society of Hypertension/European Society of Cardiology and/or according to current use of antihypertensive medication [10] . Dyslipidemia was defined according to the Third Report of the National Cholesterol Education Program [11] , and diabetes mellitus was defined according to the American Diabetes Association criteria [12] .

The procedures applied in this study were approved by the Ethical Committee of Human Experimentation of Ain Shams University and are in accordance with the Helsinki Declaration of 1975. All participants were informed about the objectives and procedures of the study and gave their written consent.

Methods

Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides (TG), and fasting blood glucose were determined following routine clinical chemical procedures.

Plasma total thrombin-activatable fibrinolysis inhibitor antigen detection

Blood samples were collected between 8 and 10 a.m. from the antecubital vein. Blood samples of 1.8 ml were anticoagulated with sodium citrate 3.2 mg/ml at a ratio of 9 : 1 (blood : anticoagulant) and were immediately centrifuged at 2500g for 20 min at 4°C. Plasma was frozen in small portions and stored at −20°C until the TAFI assay was performed.

Plasma t-TAFI Ag level was detected by Zymutest TAFI Ag (Hyphen BioMed, OH, USA), which is a sandwich enzyme-linked immunosorbent assay specific for human TAFI. Briefly, 200 μl of plasma was introduced into a microwell coated with a monoclonal antibody specific for human TAFI. When present, this protein was captured onto the solid phase. Following a washing step, 200 μl of the immunoconjugate, which is a goat polyclonal antibody coupled to horseradish peroxidase, was introduced, and binded to the free epitopes of immobilized TAFI. Following a new washing step, 200 ul of the peroxidase substrate tetramethylbenzidine in the presence of hydrogen peroxide was introduced and a blue color developed. The color turned yellow when the reaction was stopped with 50 μl of 0.45 mol/l sulfuric acid. Absorbance was read at 450 nm. The amount of color developed was directly proportional to the concentration of human TAFI in the tested sample.

Interpretation of results

Pooled plasma TAFI concentration varies from 4.4 to 15 μg/ml [13],[14],[15],[16] .

Statistical analysis

IBM SPSS (V. 21.0, 2012; IBM Corp., NY, USA) was used for data analysis. Data were expressed as mean ± SD for quantitative parametric measures and as percentage for nonparametric data. The level P less than 0.05 was considered nonsignificant, P less than 0.05 was significant, and P less than 0.01 was highly significant.

The following tests were conducted:

  1. The Student t-test: this was used to compare between two independent mean groups for parametric data.
  2. Analysis of variance (F): this was used to compare between more than two patient groups for parametric data.
  3. Pearson's correlation test (r): this was used to study the possible association between two variables in each group for parametric data.



  Results Top


The demographic and clinical data of all studied groups are shown in [Table 1].
Table 1 Demographic and clinical data of the studied groups


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Plasma t-TAFI Ag level was higher in CAD patients (groups I and II, respectively) compared with the control group (P = 0.001) ([Table 2]). No difference was found in TAFI level between group I and group II (P = 0.37) ([Table 3]), or between subgroups of ACS (P = 0.66) ([Table 4]). Mean HDL-cholesterol was higher in group II compared with group I (P = 0.02) ([Table 3]). The mean values of both systolic blood pressure (SBP) and diastolic blood pressure were higher in the UA group compared with the STEMI and NSTEMI groups (P = 0.01 and 0.005, respectively) ([Table 4]).
Table 2 Comparison between the control group and both group I and group II regarding plasma thrombin-activatable fibrinolysis inhibitor antigen level (µ g/ml)


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Table 3 Comparative analysis of the studied parameters between group I and group II


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Table 4 Comparative analysis of the studied parameters among the subgroups of acute coronary syndrome


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On correlating plasma t-TAFI Ag level with the rest of the studied parameters, it was found to be inversely correlated only to HDL-cholesterol in group I (P = 0.02) ([Table 5]). No correlation was found between t-TAFI Ag level and the rest of the standard risk factors for CAD in both groups (P > 0.05) ([Table 5]). Also, no difference was found between smokers and nonsmokers regarding t-TAFI Ag level in groups I and II (P > 0.05).
Table 5 Correlation between plasma thrombin-activatable fibrinolysis inhibitor antigen level and coronary artery disease risk factors in group I and group II


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  Discussion Top


Over the past few years, a large number of studies have investigated the role of TAFI as a possible risk factor for thrombotic disease. The results, however, are confusing. Several studies showed that high TAFI plasma levels are associated with increased risk for thrombosis, whereas others found the opposite [17] .

In this study, we detected plasma t-TAFI Ag level in CAD patients - those with ACS (STEMI, NSTEMI, and UA) and those with stable angina - with the aim to prove its possible role in the pathogenesis of atherothrombosis in those patients. We observed that plasma t-TAFI Ag level was significantly higher in patients with CAD compared with the control group ([Table 2]), whereas no difference in its level was found between ACS and stable angina groups ([Table 3]). Similar results have been reported by others, which found that CAD was associated with raised TAFI levels [17],[18],[19],[20],[21] . In addition, it was previously reported that higher TAFI levels were found in individuals with stable angina pectoris compared with healthy individuals [22] . Also, it was shown before that TAFI levels tended to be higher in CAD patients as compared with control individuals, especially in intracoronary blood samples. Furthermore, TAFI Ag levels were found to be lower, but functional TAFIa levels were significantly higher, in young patients with acute myocardial infarction compared with control individuals. In addition, in patients with stable angina undergoing percutaneous coronary intervention, preprocedural plasma TAFI Ag levels were significantly higher in those who developed restenosis [2] .

In contrast, other investigators did not find any association between TAFI and arterial thrombosis [23] , or any significant difference in TAFI Ag and activity levels between patients with acute CAD and controls [24] . This may be due to the short half-life reported for human TAFIa in vitro [25] . One could speculate that in the acute phase of CAD increased thrombin generation may lead to TAFI activation and consumption, thus blunting the detection of previously increased plasma levels [24]

Moreover, a previous study documented that TAFI Ag levels greater than the 90th percentile were associated with a significantly lower risk for myocardial infarction [26] , and another showed that individuals with low TAFI levels, as measured with a functional assay, had an increased risk for a first myocardial infarction compared with those with high TAFI levels [27] . In contrast, Tregouet et al. [28] demonstrated that only TAFIa levels are strongly associated with the risk for future cardiovascular death in CAD patients, and not plasma t-TAFI levels. This result supports the hypothesis that the amount of TAFIa plays a more crucial role in retarding fibrinolysis than the total amount of TAFI protein [29],[30] , as the TAFI pathway may play numerous roles besides inhibition of clot lysis, such as attenuation of inflammation, regulation of blood pressure, and vascular tone [20] . These effects could be responsible for the association between TAFIa level and the risk of cardiovascular death observed [28] .

These contradictory results regarding TAFI levels in CAD patients are possibly due to differences in the characteristics of patients investigated across studies (ACS, myocardial infarction, stable angina, mixed patients with acute and stable angina), the time of blood sampling in relation to activity of disease (baseline or acute phase) [17],[18],[19],[31] , or due to differences in the methods used to measure TAFI (antigenic or functional) [31] .

In this work, we did not find any differences in plasma t-TAFI levels between the subtypes of ACS ([Table 4]). Similarly, no differences were found between STE and non-STE ACS with respect to TAFI Ag level [31] .

In this study, no correlation was found between plasma TAFI Ag level and mean age in any of the studied groups ([Table 5]); similar results have been reported before for TAFI Ag [22] , activity [17],[27] , and both Ag and activity levels [24] . In contrast, a positive correlation was found between TAFI Ag level and age in women [4] . Another study showed that a significant variation in functional TAFI levels with age was found only in women, where older women had greater levels of TAFI. They suggested that this result was related to hormonal status [32] . TAFIa/inactive form of TAFI (TAFIai) increased with age, whereas an inverse relationship was observed for t-TAFI and TAFI activation peptide (TAFI-AP) [28] .

Regarding hypertension, our study reported no association between TAFI level and mean SBP and diastolic blood pressure in the studied groups ([Table 5]). Previously, it was stated that no association existed between TAFI Ag and SBP [22] , between TAFI activity and hypertension [17],[27],[32] , or between both Ag and activity levels and hypertension [24] . Others, however, have documented a positive correlation between TAFI Ag level and SBP in both men and women [4] , and between TAFIa/TAFIai and hypertension [28] .

The present study showed that mean HDL-cholesterol was inversely correlated with TAFI level in group I, whereas no association was found between TAFI Ag level and mean cholesterol, TG, low-density lipoprotein, and HDL-cholesterol in group II ([Table 5]). It was shown before that dyslipidemia had no significant influence on TAFI Ag or activity levels [24] , and there was no apparent association between TAFI activity and HDL-cholesterol [27] . In contrast, other studies proved a positive correlation between TAFI Ag level and total cholesterol in women [4] , and in the whole population [22] . Another study observed a significant correlation between TAFI and hypercholesterolemia [33] , and between dyslipemia and high TAFI levels [6] . Also, it was shown previously that cholesterol and TG levels were positively associated with TAFI activity [17],[27] , and higher functional TAFI levels were found in women with hypercholesterolemia [32] . Others found that only t-TAFI and TAFI-AP were correlated with total cholesterol and TG [28] .

This study observed no association between TAFI level and mean FBS in the studied groups ([Table 5]) as previously stated for TAFI Ag or activity [24] or TAFI activity alone [17],[27] . In contrast, it was documented before that TAFI is significantly elevated (50%) in patients with type 2 diabetes [34] .

In our study, no correlation was found between TAFI level and mean BMI in the studied groups ([Table 5]), as shown before for TAFI Ag [22] or activity [27] , whereas a positive correlation was found previously between both TAFI Ag [4] and activity levels [17],[33] and BMI. Also, it was detected previously that the circulating levels of TAFI Ag were significantly higher in obese than in nonobese individuals [35] .

The present study observed no significant difference between smokers and nonsmokers regarding TAFI level in either group I or group II. Similar results were reported before for both TAFI Ag [22] and functional TAFI levels [17],[27],[33] . In contrast, TAFIa/TAFIai levels were found to be increased in smokers [28] .

Study limitations

One of the major limitations of this study was measurement of plasma TAFI Ag without detection of TAFI activity and other hemostatic factors that may influence the activation of TAFI, such as protein C, which seems to be important to overview the complete role of TAFI in the occurrence of atherothrombosis in CAD patients. Also, our small sample size limited the probability of proving any positive correlation with standard CAD risk factors.


  Conclusion Top


This study showed that TAFI level is increased in Egyptian CAD patients and that this increase may play an important role in the occurrence of thrombotic attacks in such patients. Detection of functional TAFI and TAFI gene polymorphism, together with measurement of Ag levels, is mandatory for a better understanding of TAFI association with the pathophysiology of CAD and for designing a treatment protocol based on blockage of TAFI activation as a synergistic adjuvant in thrombolytic therapy.


  Acknowledgements Top


The facilities offered by the Clinical and Chemical Pathology Department, Hematology Unit of Ain Shams University Hospitals, Cairo, Egypt, and the Cardiology Department of the Damietta Cardiology and Gastero-enterology Center, Damietta, Egypt, which enabled us to carry out this work, are greatly appreciated.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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