TISSUE-PLASMINOGEN ACTIVATES, PLASMINOGEN-ACTIVATOR INHIBITOR-1, AND FIBRIN AS INDEXES OF CLINICAL COURSE IN CARDIAC ALLOGRAFT RECIPIENTS -AN IMMUNOCYTOCHEMICAL STUDY

Background Tissue-type plasminogen activator (TPA) is the principal ac tivator of plasminogen. Since hemostasis in the microcirculation of al lografts is a well-recognized complication of transplantation, we aske d (1) whether the distribution and amount of cellular TPA in biopsies of transplanted human hearts are associated with fibrin deposits in an d around the microcirculation, (2) whether such changes involve the ph ysiological inhibitors of TPA and plasmin, and (3) whether the presenc e of these activators and inhibitors of fibrinolysis in tissue is corr elated with clinical outcome. Methods and Results We immunocytochemica lly quantified the presence of fibrin, plasmin, TPA, and the TPA inhib itor PAI-1 in 938 biopsies from 68 consecutive cardiac allografts over a 54-month period. The localization, distribution, and quantification of TPA in arteriolar smooth muscle cells revealed that 35 of the 68 a llografts maintained vascular TPA reactivity consistent with time-zero biopsies of autologous donor hearts: this was designated as the norma l TPA group. In contrast, 33 of the 68 allografts significantly lost v ascular TPA reactivity compared with time-zero biopsies of autologous donor hearts: this was designated as the depleted TPA group. Analysis of sequential biopsies from both groups during 54 months revealed that the mean cumulative quantitative TPA value for the normal TPA group w as 1.0+/-0.01, whereas the depleted TPA group value was 1.9+/-0.02 (P= .0001), and the mean cumulative quantitative fibrin value for the norm al TPA group was 1.0+/-0.01, whereas the depleted TPA group value was 1.5+/-0.05 (P=.0001). Biopsies of allografts in the depleted TPA group contained endothelial reactivity for TPA-PAI-1 complexes, whereas bio psies from the normal TPA group did not. Plasmin-associated molecules were rarely identified in biopsies of the normal TPA group but were pr esent in the depleted TPA group, and the fibrin-to-plasmin ratio in th e normal TPA group always was less than the fibrin-to-plasmin ratio in biopsies from the depleted TPA group. Analysis of demographic and ris k factors revealed no significant differences between patients in the normal and depleted TPA groups, but none of the 35 patients in the nor mal TPA group died or were retransplanted, and 13 of the 33 patients i n the depleted TPA group died or required retransplantation (P=.0001). Conclusions Time-zero hearts (n=68) and 34 of 38 stable allografts co ntained immunocytochemically detectable TPA only in vascular smooth mu scle cells. Twenty-nine of 30 patients with normal TPA in their time-z ero biopsies who subsequently developed a poor clinical outcome were f ound to have depleted TPA in biopsies evaluated during their first pos toperative month and remained depleted throughout the study. Of 33 pat ients with depleted TPA, 39% died or required retransplantation. Deple ted arteriolar TPA associated significantly with vascular and intersti tial deposits of fibrin, plasmin, and endothelial TPA-PAI-1 complexes. These findings indicate that hemostatic and fibrinolytic pathways are activated in failing allografts, and they reveal evidence of depleted TPA before clinical or histopathological signs of failure. Patients w ith such allografts were found to be at high risk of death independent ly of other widely used clinical/laboratory parameters of prediction.