text: Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID 19 Insights from Clinico histopathologic and Single Nuclei RNA Sequencing Analyses Cardiac injury is associated with critical COVID 19 yet its etiology remains debated To elucidate the pathogenic mechanisms of COVID 19 associated cardiac injury we conducted a single center prospective cohort study of 69 COVID 19 decedents Of six cardiac histopathologic features microthrombi was the most commonly detected n 48 70 We tested associations of cardiac microthrombi with biomarkers of inflammation cardiac injury and fibrinolysis and with in hospital antiplatelet therapy therapeutic anticoagulation and corticosteroid treatment while adjusting for multiple clinical factors including COVID 19 therapies Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi Using single nuclei RNA sequence analysis we discovered an enrichment of pro thrombotic anti fibrinolytic extracellular matrix remodeling and immune potentiating signaling amongst cardiac fibroblasts in microthrombi positive COVID 19 hearts relative to microthrombi negative COVID 19 Non COVID 19 non failing hearts were used as reference controls Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID 19 associated cardiac microthrombi 