Circulation, Vol 89, 1599-1608, Copyright © 1994 by American Heart Association
CA Labarrere, D Pitts, H Halbrook and WP Faulk
BACKGROUND: Tissue-type plasminogen activator (TPA) is the principal
activator of plasminogen. Since hemostasis in the microcirculation of
allografts is a well-recognized complication of transplantation, we asked
(1) whether the distribution and amount of cellular TPA in biopsies of
transplanted human hearts are associated with fibrin deposits in and around
the microcirculation, (2) whether such changes involve the physiological
inhibitors of TPA and plasmin, and (3) whether the presence of these
activators and inhibitors of fibrinolysis in tissue is correlated with
clinical outcome. METHODS AND RESULTS: We immunocytochemically quantified
the presence of fibrin, plasmin, TPA, and the TPA inhibitor 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 allografts maintained vascular TPA
reactivity consistent with time-zero biopsies of autologous donor hearts:
this was designated as the normal TPA group. In contrast, 33 of the 68
allografts significantly lost vascular 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 was 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 normal 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
biopsies from the normal TPA group did not. Plasmin-associated molecules
were rarely identified in biopsies of the normal TPA group but were present
in the depleted TPA group, and the fibrin-to-plasmin ratio in the normal
TPA group always was less than the fibrin-to-plasmin ratio in biopsies from
the depleted TPA group. Analysis of demographic and risk factors revealed
no significant differences between patients in the normal and depleted TPA
groups, but none of the 35 patients in the normal TPA group died or were
retransplanted, and 13 of the 33 patients in the depleted TPA group died or
required retransplantation (P = .0001). CONCLUSIONS: Time- zero hearts (n =
68) and 34 of 38 stable allografts contained immunocytochemically
detectable TPA only in vascular smooth muscle cells. Twenty-nine of 30
patients with normal TPA in their time-zero biopsies who subsequently
developed a poor clinical outcome were found to have depleted TPA in
biopsies evaluated during their first postoperative month and remained
depleted throughout the study. Of 33 patients with depleted TPA, 39% died
or required retransplantation. Depleted arteriolar TPA associated
significantly with vascular and interstitial deposits of fibrin, plasmin,
and endothelial TPA-PAI-1 complexes. These findings indicate that
hemostatic and fibrinolytic pathways are activated in falling allografts,
and they reveal evidence of depleted TPA before clinical or
histopathological signs of failure. Patients with such allografts were
found to be at high risk of death independently of other widely used
clinical/laboratory parameters of prediction.
ARTICLES
Tissue plasminogen activator, plasminogen activator inhibitor-1, and fibrin as indexes of clinical course in cardiac allograft recipients. An immunocytochemical study
Methodist Hospital of Indiana, Center for Reproduction and Transplantation Immunology, Indianapolis.
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