Background: Cells can generate phospholipid microparticles (MP) in vitro upon appropriate stimulation or during cell death. Recently, we have detected MP in vivo in normal and in pathophysiological conditions. Depending on the disease state, these MP appeared to generate thrombin via tissue factor, factor XII (Hageman factor) or via a pathway not fitting into our current knowledge of coagulation. Finally, MP generated in vivo were also found to interact with secretory phospholipase A2 (sPLA2) and C-reactive protein (CRP), pointing to a pro-inflammatory (via CRP-dependent complement activation) role of MP as well.
Hypothesis: Depending on their phospholipid composition, MP enhance coagulation and inflammation, and constitute an important link between these processes in the pathogenesis of cardiovascular diseases.
Objectives: To unravel the molecular background of the coagulant and inflammatory properties of MP generated in vivo during various cardiovascular and thromboembolic diseases.
Methods: Circulating MP will be isolated from patients with unstable angina pectoris and myocardial infarction from healthy volunteers, and analysed 1) for their thrombin generating properties (in normal or clotting factor-deficient plasma, with or without specific extrinsic or intrinsic pathway inhibitors, with purified components), 2) for their interaction with CRP and the complement system (in plasma either or not deficient for complement factors, with purified components), 3) regarding the influence of sPLA2 on clotting and complement activating properties of MP.
Expected results: 1) Understanding of the clotting and inflammatory properties of MP generated in vivo in cardiovascular disease; 2) delineation of an unknown pathway (independent of factor XII or tissue factor) of thrombin generation. |
