Recurrent myocardial infarction: new concepts in predisposing factors

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

Autoimmune thrombocytopenia: flow cytometric determination of platelet-associated CD 154/CD40L and CD40 on peripheral blood T and B lymphocytes: their role in immunological aspects of the disease

The CD40-CD40L system has pleiotropic effects in a variety of cells and biological processes including immune response. Within the immune system, these molecules represent a critical link between its humoral and cellular arms. Immune or idiopathic thrombocytopenic purpura [ITP] is an autoimmune disorder characterized by antibody-induced platelet destruction and clearance because of anti-platelet autoantibodies, which bind to circulating platelets resulting in their destruction by the reticuloendothelial system. Despites its clinical importance, the diagnosis of ITP is one of exclusion, thus, inevitably associated with potential difficulties, CD40 is a cell surface receptor that belongs to the tumor necrosis factor- receptor [TNF-R] family, and that was first identified and functionally characterized on B lymphocytes. CD40-ligand [CD40L/CD154], a member of the TNF superfamily is a cell membrane molecule expressed on activated CD4+ T lymphocytes and is essential for the T cell-dependent activation of B lymphocytes. Therefore it is now thought that CD40-CD40L interactions play a more important role in ITP immune regulation. The expressions of CD154 and CD40 on peripheral blood [PB] T and B lymphocytes, respectively, were measured using the technique of flow cytometry. An antigen-specific assay for platelet-associated antibody CD150 [CD40L] on CD4+ T lymphocytes and for CD40 on CD 19+ B lymphocytes was tested in 30 children patients with acute ITP, 30 adult patients with chronic ITP, and in 20 age-and sex-matched healthy controls. The results of this showed that the expressions of CD4+CD154+ and of CD4+CD154+/CD4+ on PB T lymphocytes, and of CD19+CD40+ and of CD19+CD40+/CD19+ on PB B lymphocytes were significantly higher in acute and chronic ITP patients compared to controls, and in acute patients compared to chronics [p<0.001]. CD40-CD40L interaction plays and important role in the pathology of certain autoimmune diseases. ITP is an autoimmune disease characterized by increased platelet destruction caused by anti-platelet auto antibodies, which mainly target a platelet surface antigen. It is speculated that platelet-associated CD154 is competent to induce the CD40-dependent proliferation of B lymphocytes. Therefore, platelet-associated CD154 expression is increased in ITP patients and is able to drive the activation of autoreactive B lymphocytes in this disease. These findings are particularly useful for clarifying the pathogenic process in ITP patients and for developing a therapeutic approach that blocks pathogenic anti-platelet antibody production. Blockade of the CD40/CD154 signal is a potential immunomodulatory strategy for T-cell mediated diseases, and many findings suggest that CD40/CD154 blockade therapy is potentially effective for ITP through selective suppression of autoreactive T and B lymphocytes to platelet antigens