ABSTRACT
At one end of the clinical spectrum of coronary artery disease [CAD] are subjects who have had repeated acute ischemic events [unstable angina, acute myocardial infarction or sudden death], and at the other end are those with longstanding stable angina who have never been unstable. The variability of serum level of thrombomodulin [TM] in various phases of ischemic heart disease [IHD] raised the question of variable pathphysiological role as vasoprotective, thromboresistant, and anti-inflammatory factor. To answer the question of TM variable levels in IHD, we studied 100 patients [90 males and 10 females, mean age 57 +/- 11.3 range 38 to 69 years,] with IHD including 5 groups [20 pts for each], Recurrent MI [RMI], Old stable MI [OSMI], Stable Angina [SAP], Acute MI [AMI], and a control group [normal coronary angiography]. Following clinical examination TM level was determined using ELIZA technique. Genetic studies using single strand conformation polymorphism [SSCP] method was done to determine mutation in TM gene G-33 A. Compared to control group, patients with IHD had significantly lower TM level [5.7 +/- 3.6 VS 3.06 +/- 2.8; p=0.002]. Serum TM in patients with SAP was significantly lower compared to control subjects [5.7 +/- 3.6 VS 3.92 +/- 2.8; p=0.004]. Compared to pts with OSMI., Pts with RMI had significantly higher levels of TM [4.52 +/- 4.3 VS 5.85 +/- 3.8; p=0.031]. Compared to pts with SAP, Pts with OSMI had significantly higher level of TM [3.06 +/- 2.8 VS 4.52 +/- 4.3; p=0.003]. In ischemic pts, there is a constant tendency of increased TM level from SAP to OSMI to RMI [3.06 +/- 2.8, 4.52 +/- 4.3 and 5.85 +/- 3.8, respectively]. There was no significant difference between pts with RMI and the control group [5.85 +/- 3.8 VS 5.7 +/- 3.6; p=0.93]. Compared to control group, pts with AMI had significantly lower level of TM [2.8 +/- 2.1 VS 5.7 +/- 3.6; p=0.0001] and significantly lower level of TM compared to pts with IHD not in the acute stage [p=0.026]. Regarding TM gene mutation, this study revealed that patients with a mutant TM gene have a significantly less TM level compared to patients with the mild type TM gene [2.85 +/- 2.1 vs 4.7 +/- 3.6, p=0.04] with the consequences of decreased surface expression of TM and decreased level of soluble TM in plasma. Our data point to the duality of the role of thrombomodulin in IHD as a thromboresistant and anti-inflammatory molecule. Reduced serum levels of TM could predispose to IHD and acute MI. Higher TM levels in normal population reflect activation of thrombin through protein C pathway activation [antithrombotic mechanism] whereas the lower levels of thrombomodulin in stable angina and acute MI might reflect a deficient anti thrombotic mechanism and may speak of the underestimated anti inflammatory role of thrombomodulin knocked down by inflammatory mediators released in the ischemic process. Recurrence of MI might explain the high levels of TM which serves as endothelial anti-inflammatory maker which is signaled by the continued inflammatory state caused by recurrent MI. The reduced TM expression on the coronary endothelium could facilitate thrombus formation at the site of plaque injury, highlighting the cardioprotective role played by TM at the coronary vasculature