FUNCTIONS OF MULTIMERIN 1 (MMRN1) IN PLATELET ADHESION AND THROMBUS FORMATION, THROUGH INTERACTIONS WITH VON WILLEBRAND FACTOR (VWF)

Abstract

Multimerin 1 (MMRN1) is a massive, homopolymeric platelet and endothelial cell protein with functions that are emerging to support platelet adhesive processes. MMRN1 supports platelet adhesion under arterial flow conditions by a mechanism dependent on interactions with von Willebrand factor (VWF). The goals of this thesis were to further define the platelet adhesive functions of MMRN1 by: 1) characterizing the molecular mechanisms of VWF interactions with MMRN1; and 2) investigating if multimerin 1 is important for platelet adhesive functions using mice with and without a selective multimerin 1 (Mmrn1) deficiency. Studies of the mechanism of MMRN1-VWF binding indicated that MMRN1 bound to shear exposed VWF, and that MMRN1 interacted with the A1 and A3 domains in the VWF A1A2A3 region. VWF A1A2A3 also bound to MMRN1 with a physiologically relevant binding affinity, and supported platelet adhesion to MMRN1 at a high shear rate. The selective loss of Mmrn1 in mice had limited effects on tail bleeding times, although it impaired collagen-induced aggregation of washed platelets, as well as high shear platelet adhesion of whole blood on collagen surfaces, in vitro. Additionally, the selective loss of Mmrn1 in mice was associated with impaired and delayed platelet-rich thrombus formation in vivo, in arterioles treated with ferric chloride. These findings provide new insights on platelet adhesive, haemostatic functions at arterial shear rates, and the involvement of the platelet and endothelial cell protein, multimerin 1, to support these processes.