Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation

Orthotopic liver transplantation is frequently associated with hyperfibrinolysis, the origin and clinical relevance of which is largely unknown. In 20 orthotopic liver transplantations, we studied the occurrence and systemic effects of hyperfibrinolysis. Severe fibrinolysis was defined to be present when the euglobulin-clot lysis time and the whole-blood-clot lysis time, as measured by thrombelastography, were shorter than 60 and 90 min, respectively, at some time during the operation. Based on these criteria, 7 patients had minimal fibrinolysis (group I), and 13 patients had severe fibrinolysis (group II). In group II a gradual increase of tissue-type plasminogen activator (t-PA) activity was seen during the anhepatic stage, followed by an “explosive” increase immediately after graft reperfusion (P=0.0004, compared with group I), and a reduction of plasminogen activator inhibitor (PAI) activity. Plasma degradation products of fibrinogen and fibrin increased parallel to t-PA activity, and levels were significantly higher at 45 min after graft reperfusion in group II compared with group I (P<0.04). Thrombin-antithrombin III complexes showed an identical steady increase in both groups, indicating that increased t-PA activity was not related to thrombin formation. A combination of increased endothelial release and reduced hepatic clearance may have caused the increased t-PA activity. The t-PA—associated destruction of fibrinogen and fibrin after graft reperfusion is consistent with the clinical signs of severe oozing often seen in this period. These observations may have important clinical implications for the treatment of bleeding in patients undergoing orthotopic liver transplantation. © 1989 by The Williams and Wilkins Co

Intraoperative blood transfusions in highly alloimmunized patients undergoing orthotopic liver transplantation.

Intraoperative blood requirements were analyzed in patients undergoing primary orthotopic liver transplantation and divided into two groups on the basis of panel reactive antibody of pretransplant serum measured by lymphocytotoxicity testing. One group of highly sensitized patients (n = 25) had PRA values of over 70% and the second group of patients (n = 26) had 0% PRA values and were considered nonsensitized. During the transplant procedure, the 70% PRA group received considerably greater quantities of blood products than the 0% PRA group--namely, red blood cells: 21.1 +/- 3.7 vs. 9.8 +/- 0.8 units (P = 0.002), and platelets: 17.7 +/- 3.2 vs. 7.5 +/- 1.5 units (P = 0.003). Similar differences were observed for fresh frozen plasma and cryoprecipitate. Despite the larger infusion of platelets, the blood platelet counts in the 70% PRA group were lower postoperatively than preoperatively. Twenty patients in the 70% PRA group received platelet transfusions, and their mean platelet count dropped from 95,050 +/- 11,537 preoperatively to 67,750 +/- 8,228 postoperatively (P = 0.028). In contrast, nearly identical preoperative (84,058 +/- 17,297) and postoperative (85,647 +/- 12,445) platelet counts were observed in the 17 0% PRA patients who were transfused intraoperatively with platelets. Prothrombin time, activated partial thromboplastin time, and fibrinogen levels showed no significant differences between both groups. These data demonstrate that lymphocytotoxic antibody screening of liver transplant candidates is useful in identifying patients with increased risk of bleeding problems and who will require large quantities of blood during the transplant operation

Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation

The blood coagulation system of 66 consecutive patients undergoing consecutive liver transplantations was monitored by thrombelastograph and analytic coagulation profile. A poor preoperative coagulation state, decrease in levels of coagulation factors, progressive fibrinolysis, and whole blood clot lysis were observed during the preanhepatic and anhepatic stages of surgery. A further general decrease in coagulation factors and platelets, activation of fibrinolysis, and abrupt decrease in levels of factors V and VIII occurred before and with reperfusion of the homograft. Recovery of blood coagulability began 30-60 min after reperfusion of the graft liver, and coagulability had returned toward baseline values 2 hr after reperfusion. A positive correlation was shown between the variables of thrombelastography and those of the coagulation profile. Thrombelastography was shown to be a reliable and rapid monitoring system. Its use was associated with a 33% reduction of blood and fluid infusion volume, whereas blood coagulability was maintained without an increase in the number of blood product donors

Intraoperative blood transfusion requirements and deficient hemostasis in highly alloimmunized patients undergoing liver transplantation

During orthopic liver transplantation (OLT) a large transfusion of different blood components is frequently necessary. From 1981 to 1985 at the University Health Center in Pittsburgh, 4,318 units of RBCs and 4,788 units of platelets were administered during 366 OLT performed in adults. This results in a mean of 25 units of RBCs and 30 units of platelets per operation. The majority of adult liver transplant patients receive multiple transfusions of whole blood and/or blood components during their pretransplant course because of complications relating to their original disease. The exposure of these patients to different antigens from random donors facilitates the development of alloimmunization. The heightened alloimmune state can be identified by preoperative values of panel reacting antibodies (PRA). Since platelets possess the HLA antigens of donor specificity, platelets may function as the target of host antibodies, resulting in platelet alteration and subsequent dysfunction. Thus, the effect of alloimmunization on platelet function may be one of the factors responsible for significant blood loss after large transfusions of different blood components. In this retrospective study we compared blood loss and platelet transfusion during OLT with preoperative alloimmunization against random donor antigens, indicated by PRA values

Liver transplantation: Intraoperative changes in coagulation factors in 100 first transplants

Six intraoperative blood samples were obtained at intervals from each of 100 individuals undergoing their first liver transplants. The patients fell into the following diagnostic categories: postnecrotic cirrhosis 28, primary biliary cirrhosis 20, sclerosing cholangitis 19, miscellaneous diseases 14, carcinoma/neoplasia 12 and fulminant hepatitis 7. Coagulation factor values in the initial (baseline) blood samples varied by patient diagnosis. In general, all factor levels were reduced except factor VIII:C, which was increased to almost twice normal. The slight intraoperative changes in factors II, VII, IX, X, XI and XII suggested that a steady‐state relationship existed between depletion (consumption/bleeding) and repletion (transfusion, transit from extra‐ to intravascular space), even in the anhepatic state. In contrast, there were rapid and very significant falls in factor VIII and fibrinogen and a less pronounced decrease in factor V, all reaching their nadirs in early to mid‐Stage III. The cause of these coagulation changes appears to be activation of the fibrinolytic system. Copyright © 1989 American Association for the Study of Liver Disease

Glucose metabolism during liver transplantation in dogs

Arterial and hepatic venous blood levels of glucose were studied in 12 dogs during orthotopic liver transplantation peformed under ketamine anesthesia without exogenous glucose administration. During the early part of surgery, arterial blood glucose levels were stable: 161 ± 12 mg/dl (mean ± SEM) after laparotomy and 183 ± 16 mg/dl 5 min before the anhepatic stage. During the anhepatic stage, arterial blood glucose levels decreased progressively to 135 ± 9 and 88 ± 8 mg/dl, 5 min in the anhepatic stage and 5 min before reperfusion of the graft liver, respectively (P < 0.05). Reperfusion of the graft liver resulted in an increase in arterial glucose levels to 206 ± 17 and 240 ± 24 mg/dl, 5 and 30 min after reperfusion, respectively (P < 0.05). Hepatic venous blood glucose levels increased after reperfusion (405 ± 37 and 346 ± 41 mg/dl, 5 and 30 min after reperfusion, respectively) and were significantly higher than in arterial blood (P < 0.05). Arterial lasma insulin, measured in 5 animals, did not change significantly during the procedure, whereas plasma glucagon levels, stable during the preanhepatic and anhepatic stages, increased steadily after reperfusion of the graft liver, from 66.1 ± 14.2 to 108.4 ± 38.1 pg/ml (P < 0.05). This study shows that in dogs with ketamine anesthesia mild hypoglycemia occurs during the anhepatic stage of liver transplantation without exogenous glucose administration followed by hyperglycemia on reperfusion of the graft liver, possibly secondary to the release of glucose from the donor liver

Advantages of venous bypass during orthotopic transplantation of the liver.

Venous bypass restores normal hemodynamic physiology during the critical anhepatic phase of orthotopic transplantation of the liver. Its routine use in adults undergoing transplantation in Pittsburgh has resulted in lower operative blood losses, a lower frequency of postoperative renal failure, and a greater probability of survival for all but the highest risk patients. Because it allows for a longer anhepatic phase, the surgeon has the option of tailoring the native hepatectomy to the needs of the individual case, even to the point, in difficult cases, of obtaining most of the hemostasis after removal of the native liver, but before sewing in the donor organ. Selective use of bypass in children may offer similar advantages