title: Mechanical circulatory device thrombosis: a new paradigm linking hypercoagulation and hypofibrinolysis.
abstract: This review considers the perhaps unappreciated role of contact pathway proteins in the pathogenesis of thrombotic/thromboembolic morbidity associated with mechanical circulatory support. Placement of ventricular assist devices (VADs) has been associated with consumption of circulating contact proteins and persistent generation of activated contact proteins such as Factor XII and high molecular weight kininogen. Importantly, activated contact proteins are absorbed to the surface of VADs via the Vroman effect. Further, hyperfibrinogenemia and persistent platelet activation exist in patients with VADs, likely contributing to speed of clot growth. Using thrombelastographic-based analyses, it has been determined that contact pathway protein activated coagulation results in a thrombus that develops strength at a significantly faster rate that tissue factor initiated coagulation. Further, thrombelastographic analyses that include the addition of tissue-type plasminogen activator have demonstrated that contact protein pathway activation results in thrombin activatable fibrinolysis inhibitor activation to a far greater extent than that observed with tissue factor initiated coagulation, resulting in a thrombus that takes significantly longer to lyse. These observations serve as the rational basis for clinical investigation to determine if regional suppression of thrombin generation with FXII/high molecular weight kininogen inhibition in concert with thrombin-activatable fibrinolysis inhibitor inhibition may decrease mechanical circulatory support-associated thrombotic morbidity.
authors.affiliation: Departments of Anesthesiology, The University of Alabama at Birmingham, Birmingham, Alabama 35249-6810, USA. vnielsen@uab.edu
authors.forename: Vance G
authors.initials: VG
authors.lastname: Nielsen
authors.forename: James K
authors.initials: JK
authors.lastname: Kirklin
authors.forename: William L
authors.initials: WL
authors.lastname: Holman
authors.forename: Brad L
authors.initials: BL
authors.lastname: Steenwyk
authors.forename: James F
authors.initials: JF
authors.lastname: George
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.forename: Dale A
authors.initials: DA
authors.lastname: Parks
authors.forename: Truitt C
authors.initials: TC
authors.lastname: Ellis
mesh_terms: D000328:Adult; D001798:Blood Proteins / Q000378:metabolism*; D005260:Female; D005342:Fibrinolysis / Q000502:physiology*; D006333:Heart Failure / Q000601:surgery; D006353:Heart-Assist Devices / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019851:Thrombophilia / Q000209:etiology* / Q000503:physiopathology; D013927:Thrombosis / Q000209:etiology*
chemical_list: D001798:Blood Proteins