Relation between long-term steroid treatment after heart transplantation, hypofibrinolysis and myocardial microthrombi generation.
BACKGROUND
Thrombotic complications and transplant coronary artery disease are among the main causes of morbidity and mortality after heart transplantation. A thrombophilic state has been described in transplant recipients, and correlated to immunosuppressive therapy with cyclosporine A or azathioprine, whereas the prothrombotic effects of steroids, even though always given, have never been duly considered. A reduced fibrinolytic capacity due to high levels of PAI-1, the most important inhibitor of plasminogen activators, was suggested to play a role in the development of cardiovascular diseases and transplant coronary artery disease. A severe hypofibrinolytic state secondary to PAI-1 increase has been found in patients with Cushing's disease, and in hypercorticism secondary to long-term steroid treatment after renal transplantation.


METHODS
We evaluated plasma clotting and fibrinolytic behaviors in 2 groups of heart transplant patients treated with (26 cases) or without (23 cases) steroids together with cyclosporine A and azathioprine. Twenty-five healthy subjects were studied as normal controls. The following tests were assayed at least 1 year after transplantation: fibrinogen, factor VIII coagulant activity, von Willebrand factor antigen, euglobulin lysis time, tissue plasminogen activator antigen and activity, PAI-1 antigen and activity. In addition, the presence of cardiac microthrombi was evaluated on 2 endomyocardial biopsy specimens obtained in each patient both on day 7 after heart transplantation (first control) and usually 1 year or more later (last control).


RESULTS
Plasma levels of fibrinogen, factor VIII and von Willebrand factor were significantly higher in both groups of patients than in normal controls. Fibrinolytic activity was significantly reduced in transplant patients treated with steroids, compared with steroid-free patients and normal controls. In steroid-treated heart transplant recipients, the hypofibrinolytic state was due to a significant and pathological increase in PAI-1 antigen and activity levels. The fibrinolytic impairment was more evident in patients transplanted for ischemic heart disease and treated with steroids than in patients with previous dilated cardiomyopathy and treated either with or without steroids. Myocardial microthrombi were found in 2/49 cases at the first biopsy control, and in 12/49 cases at the last biopsy control after transplantation. This different prevalence was statistically significant (chi2 = 8.33, p = .003). Plasma PAI-1 activity was significantly higher and, as a consequence, euglobulin lysis time was more prolonged in microthrombi-positive patients than in microthrombi-negative ones. Among the 12 transplant recipients who developed cardiac microthrombi, 7 patients were treated with steroids and showed higher PAI-1 levels and more reduced fibrinolytic activity than the 5 steroid-free patients.


CONCLUSIONS
Our data confirm the prothrombotic state induced by long-term steroid treatment, characterized by an increase in PAI-1 levels and secondary impairment of fibrinolytic capacity. In heart transplant patients, steroid-related hypofibrinolysis might constitute a further risk factor for transplant coronary artery disease.
Sartori
T M
TM
Institute of Medical Semeiotics, University of Padua Medical School, Italy.
Maurizio
P G
PG
Sara
P
P
Ugolino
L
L
Annalisa
A
A
Panagiotis
T
T
Massimo
F
F
Antonio
G
G
D001379:Azathioprine / Q000009:adverse effects; D001706:Biopsy; D003324:Coronary Artery Disease / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D016572:Cyclosporine / Q000009:adverse effects; D004359:Drug Therapy, Combination; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects* / Q000502:physiology; D005938:Glucocorticoids / Q000009:adverse effects*; D006331:Heart Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D016027:Heart Transplantation / Q000502:physiology / Q000706:statistics & numerical data; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D011182:Postoperative Care / Q000009:adverse effects* / Q000379:methods; D011241:Prednisone / Q000009:adverse effects*; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D001379:Azathioprine; D011241:Prednisone