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      Association of Thrombomodulin Gene Polymorphism (C1418T) With Coronary Artery Disease in Pakistani Population

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          To find out the association between Thrombomodulin gene polymorphism (C1418T) with coronary artery disease in population of Karachi, Pakistan.


          This case-control study was conducted in Tabba Heart Institute in collaboration with the National Institute of Blood Diseases, Karachi. We compared C/T dimorphism in 92 cases with 90 control subjects by allele-specific amplification. The results of PCR were confirmed by Gene sequencing. All the laboratory methods were strictly in compliance with the international standards. All variables that were either statistically significant in the univariate analyses or potentially important with respect to prevention or biologically relevant variables were included in logistic-regression analyses. Potential confounding was assessed with the use of multivariate models adjusted for participant’s characteristics and other major risk factors for coronary artery disease. All reported p values are two-tailed, with statistical significance at p value < 0.05.


          The frequency of CC, C/T and TT genotype was 81 (90%), 6 (6.7%) 3 (3.3%) in controls and 67 (72.8%), 20 (21.7%) and 5 (5.4%) in cases respectively. In cases group the CT/TT genotypes were found to be significantly highly represented among the patients with coronary artery diseases when compared with control group (p-value 0.009).


          TM C1418T polymorphism emerges as a risk marker in Coronary Artery Disease patients in the population of Karachi, Pakistan.

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          Most cited references 20

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          Genetics of coronary artery disease and myocardial infarction--2013.

          Coronary artery disease is a complex disease influenced by modifiable risk factors as well as genetic susceptibility. The genetics of coronary artery disease and myocardial infarction have long been enigmatic. Recent advances in molecular genetics and biology, bioinformatics, and statistics have allowed us to study the interaction of exogenous and endogenous factors. Recent genome-wide association studies and their meta-analyses have included thousands of patients and healthy individuals and provided the statistical power to identify genetic variants, each associated with a rather small increase in risk. Thus far, more than 45 risk loci have been identified. Nevertheless, the search for genetics-based improvements in therapy and prevention has just begun. Hitherto unrecognized mechanisms may provide promising drug targets and early interventional strategies. Furthermore, the sum of risk alleles may facilitate risk assessment as they provide complementary information to traditional risk scores.
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            Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation.

            Protein C is activated rapidly when thrombin binds to a specific cell surface cofactor protein, thrombomodulin. Studies were initiated to determine the influence of thrombin-thrombomodulin complex formation on the substrate specificity of thrombin. When thrombin binds to thrombomodulin, the resultant complex retains less than 1% of the fibrinogen clotting activity of free thrombin. Permanent alteration of the thrombin molecule is not involved since full clotting activity is regenerated by incubation of the complex with excess diisopropyl phosphothrombin. Unlike the activation of protein C by the thrombin-thrombomodulin complex which is dependent on Ca2+, inhibition of fibrinogen clotting activity is not dependent on the presence of divalent metal ions. Formation of the thrombin-thrombomodulin complex also inhibits thrombin activation of factor V. Despite these changes in macromolecular substate specificity, no significant change in the hydrolysis of the synthetic substrates p-tosyl-L-arginine methyl ester and N alpha-benzoyl-L-arginine ethyl ester is detected upon formation of the thrombin-thrombomodulin complex. Formation of this complex results in a slight increase in the Km (from 9.0 +/- 0.4 to 10.2 +/- 0.6 microM) and Vmax (from 230 +/- 10 to 270 +/- 10 mol/s/mol of thrombin) for the specific thrombin substrate H-D-Phe-Pip-Arg-p-nitroanilide. These studies suggest that thrombomodulin has two distinct anticoagulant functions: 1) to inhibit the ability of thrombin to clot fibrinogen and to activate factor V; and 2) to accelerate the formation of the anticoagulant, activated protein C.
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              Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface.

               C Esmon (1995)
              The protein C anticoagulant system generates an "on demand" physiologic anticoagulant response. The pathway is initiated when thrombin binds to the endothelial cell thrombin binding protein, thrombomodulin. The complex exhibits dramatically altered macromolecular specificity. It rapidly cleaves the protein C zymogen to form the anticoagulant, activated protein C. Complex formation between thrombin and thrombomodulin also prevents thrombin, the enzyme responsible for clot formation and a potent platelet activator, from being able to clot fibrinogen or to activate platelets. Structural, kinetic, and competition studies suggest that thrombomodulin blocks these clotting reactions by masking the binding sites for fibrinogen and the platelet thrombin receptor. Stimulation of protein C activation appears to occur through conformational changes in the extended binding pocket of thrombin. This prevents repulsive interactions with protein C that exist when the free enzyme attempts to dock with this substrate. In addition to protein-protein interactions, thrombomodulin has a covalently associated chondroitin sulfate moiety. Chondroitin sulfate binds to a basic surface on thrombin that is also involved in heparin interaction. The chondroitin sulfate enhances the affinity of thrombin for thrombomodulin approximately 10- to 20-fold, making thrombomodulin a more potent inhibitor of coagulation, altering thrombin's conformation and specificity, and accelerating thrombin inhibition by the serpin, antithrombin. These properties make thrombomodulin a molecular switch ideally suited to trigger an anticoagulant response when too much thrombin is generated. The importance of the system is documented by the clinical observation that patients deficient in protein C often die of massive thrombotic complications that can be reversed or prevented by infusion of protein C.

                Author and article information

                [1 ]Dr. Muhammad Akbar Mughal, MBBS, MPhil. Associate Professor, Department of Physiology, Karachi Medical & Dental College, Karachi, Pakistan
                [2 ]Prof. Dr. Muhammad Saleh Soomro, Ph.D. Chairman. Department of Physiology, Baqai Medical University, Karachi, Pakistan
                [3 ]Dr. Syed Muhammad Ashraf Jahangeer AlSaani, MBBS, FCPS. Assistant Professor, Dow University of Health Sciences (DUHS), Karachi, Pakistan
                [4 ]Dr. Saba Shahid, Ph.D. Assistant Professor, Genomics and Molecular Pathology Lab, National Institute of Blood Disease (NIBD), Karachi, Pakistan.
                [5 ]Shariq Ahmed, MSc, Clinical Scientist/Lab. Supervisor, Genomics and Molecular Pathology Lab, National Institute of Blood Disease (NIBD), Karachi, Pakistan
                Author notes
                Correspondence: Dr. Muhammad Akbar Mughal, Department of Physiology, Karachi Medical & Dental College (K.M.D.C), Karachi, Pakistan. E-mail: allahoghani@
                Pak J Med Sci
                Pak J Med Sci
                Pakistan Journal of Medical Sciences
                Professional Medical Publications (Pakistan )
                May-Jun 2018
                : 34
                : 3
                : 730-735
                Copyright: © Pakistan Journal of Medical Sciences

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Original Article


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