title: Mechanisms of cerebrovascular events as assessed by procoagulant activity, cerebral microemboli, and platelet microparticles in patients with prosthetic heart valves.
abstract: OBJECTIVE
  Cerebrovascular events (CVE) in patients with prosthetic heart valves (PHV) have remained a severe and frequent complication despite oral anticoagulation with or without aspirin. We studied the possible pathophysiological involvement of platelet-derived microparticles (PMP) as a contributing factor for the increased incidence of CVE in patients with PHV.
  
  
  METHODS
  We compared in a retrospective, case-control study the clinical outcome after the implantation of the PHV with several different independent morphological and functional methods, including simultaneous transcranial Doppler monitoring of both middle cerebral arteries, PMP detection by flow cytometry with use of platelet-specific antibodies, coagulation markers, and determination of the procoagulant activity by Russell's viper venom time, a phospholipid-dependent coagulation assay.
  
  
  RESULTS
  Eight of 26 patients with PHV had 9 CVE during 136 person-years of observation. Transcranial Doppler monitoring revealed an increased frequency of microembolic signals recorded over a 30-minute period in patients with CVE (75+/-25; median, 55; range, 27 to 248) compared with those without CVE (23+/-12; median, 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 with compared to those without CVE (4.1+/-0.6% versus 2.4+/-0.4% of all fluorescence-positive events gated; P<0.05). Increased procoagulant activity was documented by the shortened Russell's viper venom time expressed 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 excess of platelet equivalents per microliter of plasma than patients without 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 microg/L) suggested incompletely suppressed thrombin formation, 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 microembolic signals, platelet microparticles, and procoagulant activity in symptomatic patients with PHV and provide a potential pathophysiological explanation of CVE.
authors.affiliation: Department of Internal Medicine, University Hospital, Bern, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Geiser
authors.forename: M
authors.initials: M
authors.lastname: Sturzenegger
authors.forename: U
authors.initials: U
authors.lastname: Genewein
authors.forename: A
authors.initials: A
authors.lastname: Haeberli
authors.forename: J H
authors.initials: JH
authors.lastname: Beer
mesh_terms: D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000502:physiology*; D016022:Case-Control Studies; D002536:Cerebral Arteries / Q000000981:diagnostic imaging; D002560:Cerebrovascular Circulation; D002561:Cerebrovascular Disorders / Q000503:physiopathology*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis; D005344:Fibrinopeptide A / Q000032:analysis; D005434:Flow Cytometry; D006350:Heart Valve Prosthesis / Q000009:adverse effects*; D006801:Humans; D002542:Intracranial Embolism and Thrombosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000032:analysis; D011516:Prothrombin / Q000032:analysis; D011517:Prothrombin Time; D012189:Retrospective Studies; D013917:Thrombin / Q000378:metabolism; D017585:Ultrasonography, Doppler, Transcranial; D001620:beta-Thromboglobulin / Q000032:analysis
chemical_list: C046193:antithrombin III-protease complex; D001620:beta-Thromboglobulin; D005344:Fibrinopeptide A; D000990:Antithrombin III; D011516:Prothrombin; D005337:Fibrin; D010447:Peptide Hydrolases; D013917:Thrombin