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Principal Investigator: Miguel Angel Cruz
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $464,096
Funding agency: National Heart Lung and Blood Institute
A major complication of mechanical circulatory support devices (MCSD) for multi-organ
support is the dichotomous pathology of thrombosis and bleeding. Intravascular
hemolysis associated with MCSD produces free hemoglobin (fHb). Adsorption of
fibrinogen and von Willebrand factor (VWF) onto non-biological surfaces captures
platelets that may aggregate. We reported that high levels of fHb increased VWF-
mediated platelet adhesion and thrombus formation on fibrin(ogen)-coated surfaces at
high shear stress. Importantly, fHb increased the flow-dependent adhesion of formalin
fixed platelets to a VWF coated surface, suggesting that fHb directly enhances the VWF-
glycoprotein (GP)Ib interaction. VWF deficiency or antibodies against GPIb block the
enhancement of platelet adhesion by fHb, validating the role of VWF. Lastly, our
identification of ultra large VWF (ULVWF) in whole blood exposed to fHb and high shear
rates suggests that platelet derived ULVWF may contribute to the pathology of thrombosis
in the presence of high levels of fHb. Together, these findings provide the first evidence
that high levels of fHb are critical for VWF-mediated thrombosis on surfaces coated with
fibrin(ogen), and that ULVWF multimers from shear-activated platelets may enhance
thrombosis more robustly than plasma VWF in the presence of fHb. Our overarching
hypothesis is that fHb targets VWF, including the platelet-derived VWF, to promote
platelet adhesion via GPIb, and potentiate fibrin formation by facilitating the binding of
VWF to fibrinogen. We propose molecular, biochemical, and structural studies to
investigate the mechanisms by which fHb dysregulates the interactions between VWF,
fibrin(ogen), and platelets. Aim 1 will investigate the contributions of platelet VWF vs.
plasma VWF to thrombosis. We will test the hypotheses that fHb interaction with platelet
VWF enhances platelet adhesion to fibrin(ogen) and potentiates fibrin formation more
robustly than plasma VWF. Aim 2 will test the hypothesis that fHb-bound VWF has a
conformation that favors platelet adhesion. Aim 3 will determine the mechanism by which
fHb dysregulate VWF-fibrin(ogen) interaction. We will test the hypotheses that fHb
promotes VWF-fibrin(ogen) association and modulates the VWF-mediated fibrin
formation. These studies will describe new mechanisms related to thrombosis in patients
on MCSD and identify new, potential targets for therapeutic interventions in fHb-induced
thrombosis.
Terms: <Adhesions><Adsorption><Angiohemophilia><Antibodies><Anticoagulation><Antithrombotic Agents><Antithrombotic Drugs><Artificial Heart Ventricle><Artificial Ventricles><Avidity><Binding><Biochemical><Bleeding><Blood><Blood Coagulation Factor I><Blood Coagulation Factor One><Blood Factor One><Blood Plasma><Blood Platelets><Blood Reticuloendothelial System><Circulation><Clotting><Coagulation><Coagulation Factor I><Coagulation Factor One><Coagulation Process><Complex><Complication><Cryo-electron Microscopy><Cryoelectron Microscopy><Death Rate><Development><Devices><Electron Cryomicroscopy><Environment><Exposure to><Extracorporeal Membrane Oxygenation><Factor I><Factor One><Fibrin><Fibrinogen><Fibrinolytic Agents><Fibrinolytic Drugs><Formalin><Foundations><Glycoproteins><Hemoglobin><Hemoglobin A><Hemoglobin concentration result><Hemolysis><Hemolysis Induction><Hemorrhage><Hemostasis><Hemostatic Agents><Hemostatic function><Hemostatics><Intervention><Intervention Strategies><Investigation><Marrow platelet><Measures><Mediating><Mice><Mice Mammals><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monitor><Murine><Mus><Organ><Outcome><Pathology><Patients><Plasma><Plasma Serum><Platelets><Process><Proteins><Publishing><Reaction><Recombinant Proteins><Reporting><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Ristocetin Cofactor><Ristocetin-Willebrand Factor><Role><Surface><Testing><Therapeutic><Therapeutic Intervention><Thrombocytes><Thrombolytic Agents><Thrombolytic Drugs><Thrombosis><Thrombus><VWF receptor><Variant><Variation><Vascular Hemophilia><Ventricle-Assist Device><Visualization><Von Willebrand binding site><Von willebrand factor deficiency><Whole Blood><Willebrand disease><Work><age group><antithrombotic medication><antithrombotics><blood loss><conformation><conformational><conformational state><conformationally><conformations><cryo-EM><cryoEM><cryogenic electron microscopy><developmental><enhancing factor><erythrolysis><hemoglobin level><intervention therapy><interventional strategy><mechanical cardiac support><mechanical circulatory assist><mechanical circulatory support><mechanical circulatory therapy><mechanical heart support><mortality rate><mortality ratio><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><shear stress><social role><surface coating><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thromboembolic complications><thrombosis complications><thrombotic><thrombotic complications><thrombotic disease><thrombotic disorder><ventricular assist device><von Willebrand Disease><von Willebrand Factor><von Willebrand Protein><von Willebrand factor receptor>