MECHANISMS OF CEREBROVASCULAR EVENTS AS ASSESSED BY PROCOAGULANT ACTIVITY, CEREBRAL MICROEMBOLI, AND PLATELET MICROPARTICLES IN PATIENTS WITH PROSTHETIC HEART-VALVES

Background and Purpose-Cerebrovascular events (CVE) in patients with p rosthetic heart valves (PHV) have remained a severe and frequent compl ication despite oral anticoagulation with or without aspirin. We studi ed the possible pathophysiological involvement of platelet-derived mic roparticles (PMP) as a contributing factor for the increased incidence of CVE in patients with PI-IV. Methods-We compared in a retrospective , case-control study the clinical outcome after the implantation of th e PHV with several different independent morphological and functional methods, including simultaneous transcranial Doppler monitoring of bot h middle cerebral arteries, PMP detection by flow cytometry with use o f platelet-specific antibodies, coagulation markers, and determination of the procoagulant activity by Russell's viper venom time, a phospho lipid-dependent coagulation assay. Results-Eight of 26 patients with P HV had 9 CVE during 136 person-years of observation. Transcranial Dopp ler monitoring revealed an increased frequency of microembolic signals recorded over a 30-minute period in patients with CVE (75+/-25; media n, 55; range, 27 to 248) compared with those without CVE (23+/-12; med ian, 7; range, 0 to 153; P<0.05) or with control subjects (0; P<0.001) . Flow cytometry analysis showed increased levels of PMP in patients w ith compared to these without CVE (4.1+/-0.6% versus 2.4+/-0.4% of all fluorescence-positive events gated; P<0.05). Increased procoagulant a ctivity was documented by the shortened Russell's viper venom time exp ressed as an increased level of platelet equivalents per microliter of plasma in patients compared with control subjects (+24.7+/-14.9%; P<0 .01). Subgroup analysis revealed that patients with CVE had a higher e xcess of platelet equivalents per microliter of plasma than patients w ithout CVE in relation to the controls (+68.7+/-36.7%; P<0.05). Mildly elevated thrombin-antithrombin III complexes (2.9+/-0.7; median, 2.3; normal, <2.0 mu g/L) suggested incompletely suppressed thrombin forma tion, and fibrin generation (fibrinopeptide A) was in the upper normal range (2.1+/-0.2; median, 1.8; normal, <2.0 ng/mL), despite adequate anticoagulation (INR=3.6+/-0.1). Conclusions-Our data show increased m icroembolic signals, platelet microparticles, and procoagulant activit y in symptomatic patients with PI-IV and provide a potential pathophys iological explanation of CVE.