Fibrin on Endomyocardial Biopsy: A Significant Predictor of Cardiovascular Mortality beyond pAMR Score

Abstract

Purpose Endothelial activation (EA) is the hallmark lesion of antibody-mediated rejection (AMR). Mediators of EA trigger a cascade of additional endothelial injury leading to plasma protein leakage and fibrin accumulation. We hypothesized that interstitial fibrin on endomyocardial biopsy (EMB) would correlate with AMR severity and worse outcomes. Methods and Materials The AMR scores of patients transplanted in the UTAH Cardiac Transplant Program between 1986 and 2012 were classified according to the new ISHLT nomenclature. A semiquantitative scale (0-5) was used to record the presence of fibrin in the interstitium (FInt) and vessels (FVasc) (0, no fibrin; 5, diffuse fibrin). Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable and the fibrin variables were included in separate models as additive continuous variables. Both pAMR and fibrin were measured from last biopsy and varied over the time of the study. Results 11,550 biopsies from 983 patients were analyzed. Across all pAMR values, the presence of any fibrin increased the risk of CV mortality (OR 2.8, p=0.002). On further analysis, for each one unit increase in the FInt score, an additional 20% increase in CV mortality, above that due to pAMR alone, was observed (p=0.005). In contrast, the severity of the Fvasc score did not further increase the risk of CV death beyond that due to pAMR score (p=0.359). Conclusions The presence of interstitial fibrin on EMB confers an incremental risk of CV mortality in heart transplant recipients above that due to pAMR severity alone. This may be related to a more severe and chronic form of AMR in certain patients. Whether fibrin should be required as part of the pAMR grading system warrants serious consideration. Odds ratio for CV mortality stratified by pAMR score and fibrin deposition Interstitial Fibrin 0 1 2 3 4 5 pAMR0 1.00 1.20 1.45 1.74 2.09 2.52 pAMR1 2.37 2.85 3.43 4.12 4.96 5.97 pAMR2 3.21 3.86 4.64 5.58 6.71 8.08 pAMR3 61.51 73.99 88.99 107.03 128.73 154.83