PubMed · 1996521
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W J Quiõnes-Baldrich, R B Rutherford. 1991. Thrombolytic therapy.. https://pubmed.ncbi.nlm.nih.gov/1996521/
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Plasminogen, the zymogen form of the fibrinolytic enzyme plasmin, is known to undergo plasmin-mediated modification in vitro. The modified form, Lys-plasminogen, is superior to the native Glu-plasminogen in fibrin binding and as a substrate for activation by tissue-type plasminogen activator (t-PA). The present study was undertaken to determine the existence and significance of the Glu- to Lys-plasminogen conversion during t-PA-mediated lysis of plasma clots in vitro. When human plasma was supplemented with exogenous Lys-plasminogen and clotted, a dose-dependent shortening of lysis time was observed. Formation of Lys-plasminogen in situ during fibrinolysis was determined using 131I-Glu-plasminogen-supplemented plasma. By the time of lysis, Lys-plasminogen had accumulated to about 20% of the initial concentration of Glu-plasminogen. Quantitation of activation of both Glu- and Lys-plasminogen as well as the conversion of Glu- to Lys-plasminogen in plasma supplemented with both 131I-Glu-plasminogen and 125I-Lys-plasminogen was accomplished by determining the flux of the isotopically labeled species along three pathways: Glu-plasminogen-->Glu-plasmin, Glu-plasminogen-->Lys-plasminogen, and Lys-plasminogen-->Lys-plasmin. After a brief lag, the Glu-plasminogen activation rate was constant until lysis was achieved, at which point activation ceased. The Lys-plasminogen activation rate also was essentially constant until lysis but was not characterized by a lag phase. The rate of conversion of Glu- to Lys-plasminogen was nonlinear and correlated directly with the rate of fibrinolysis. By the time lysis had occurred, Glu-plasminogen consumption had been distributed equally between direct activation to plasmin and conversion to Lys-plasminogen, and 45% of the plasmin which had been formed was derived from Lys-plasminogen. These results demonstrate both the formation and the subsequent activation of Lys-plasminogen during fibrinolysis. As a result of improved fibrin binding and activation of Lys-plasminogen compared to Glu-plasminogen, the formation of Lys-plasminogen within a clot constitutes a positive feedback mechanism that can further stimulate the activation of plasminogen by t-PA as fibrinolysis progresses.
Earlier workers have suggested a possible fibrinolytic effect using prostaglandin or prostaglandin analogues. Despite using maximum tolerated doses of the prostaglandin analogue Iloprost, we have been unable to demonstrate any significant effect on fibrinolysis in patients with stage IV peripheral vascular disease (Fontaine classification).
In this report the history and clinical results of heterotopic liver transplantation (HLT) are reviewed and some special aspects of current research on HLT are high-lighted. The first laboratory experiments on liver transplantation were performed with auxiliary heterotopic grafts. The initial clinical results of HLT, however, were disappointing and orthotopic liver transplantation (OLT) evolved to be the procedure of choice. Of all the patients who received a heterotopic graft before 1980, only two survived. Since 1980, 50 HLTs are known to have been performed on 48 patients. Results of HLTs after 1986 are clearly better than earlier ones, and survival rates come within the range of those reported for OLT. Intraoperative fibrinolysis is found in the anhepatic phase of OLT, something which is absent in HLT. Tissue-type plasminogen activator (t-PA) is said to be responsible for this phenomenon, as well as for the postreperfusion hyperfibrinolysis. Parallel to the hemostatic changes, the intraoperative hemodynamic stability may be impaired by deleterious substances that arise during liver transplantation. Furthermore, the interaction between the two livers, the effect of HLT on portal pressure and hypersplenism, and the possible role of HLT in inborn errors of hepatic metabolism are described. Special attention is given to the treatment of acute hepatic failure. OLT, in an early phase of the disease, negates the possibility of spontaneous recovery, while delay of the decision to transplant may lead to further deterioration of the patient's clinical condition. As the procedure of HLT is reversible, the decision to transplant can be made more quickly. The clinical experience with HLT for acute liver failure is reported in detail.