Abstract 19260: Prothrombotic Activity and Reduction in Coronary Flow Reserve Associated With Therapeutic Intracoronary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells is Ameliorated by Heparin Co-Administration in a Porcine Myocardial Infarction Model

Abstract

Cell therapy remains an evolving therapeutic option for cardiac repair in the case of acute myocardial infarction (AMI) associated with significant cardiomyocyte death. Mesenchymal stem cells (MSCs) are promising candidates for promoting myocardial salvage post AMI, but concerns regarding the safety of intracoronary MSC delivery remain. Surface expression of tissue factor (TF), a key initiator of the soluble coagulation cascade, has recently been implicated as a possible cause of MSC procoagulant activity. This study aimed to characterize the prothrombotic activity of MSC and identify means of managing any thrombotic side effects during therapeutic intracoronary delivery post AMI. Expression of TF on MSC was detected by immunoflourescence, flow cytometry and immunoblotting. TF antigen was catalytically active (252.4 ± 8.3 pM/2 x 105 MSC) and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet-driven thrombus deposition on collagen at arterial shear flow (12.67 ± 1.0% untreated vs 18.9 ± 0.9% surface coverage with MSC, p>0.001), an effect abolished by heparin co-administration (p<0.01 vs MSC alone). Infusion of 25 x 106 MSC via an intracoronary route in a porcine AMI model was associated with a decrease in coronary flow reserve when delivered during reperfusion (-0.7 ± 0.05) but not when coadministered with heparin (0.1 ± 0.02, p<0.01). Heparin also reduced MSC-associated thrombosis incorporating platelets and vWF in the microvasculature (p<0.05). Therapeutic MSC delivery was able to reduce apoptosis in the infarct border zone 24 post AMI (p<0.01). Procoagulant activity associated with therapeutic MSCs is independently associated with reduction in myocardial perfusion when delivered I.C. which may be successfully managed with heparin co-administration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic intracoronary MSC delivery for AMI.