Jessica H. Lewis

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 an-hepatic 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 thrornbelastography 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.

Mutation of antitrypsin to antithrombin: α1-antitrypsin Pittsburgh (358 Met→Arg), a fatal bleeding disorder

Our previous studies predicted a functional relationship between the plasma proteins alpha 1-antitrypsin and antithrombin III. To elucidate this relationship we investigated the plasma of a 14-year-old boy who had died from an episodic bleeding disorder. A variant alpha 1-antitrypsin was identified in which the methionine at position 358 had been replaced by an arginine. This had converted the alpha 1-antitrypsin from its normal function as an inhibitor of elastase to that of an inhibitor of thrombin. This finding indicates that the reactive center of alpha 1-antitrypsin is methionine 358, which acts as a bait for elastase, just as the normal reactive center of antithrombin III is arginine 393, which acts as a bait for thrombin. The independence of the new thrombin inhibitor from heparin control explains the bleeding disorder; it also indicates that heparin normally acts directly on antithrombin III, revealing its inherent inhibitory activity. The episodic nature of the bleeding was a consequence of the mutant proteins being an acute-phase reactant, the level of which increased several-fold after trauma.

Epsilon-aminocaproic Acid for Treatment of Fibrinolysis during Liver Transplantation

In 97 adult patients receiving liver transplants, the coagulation system was monitored by thrombelastography and by coagulation profile including PT; aPTT; platelet count; level of factors I, II, V, VII, VIII, IX, X, XI, and XII; fibrin degradation products; ethanol gel test; protamine gel test; and euglobulin lysis time. Preoperatively, fibrinolysis defined as a whole blood clot lysis index of less than 80% was present in 29 patients (29.9%), and a euglobulin lysis time of less than 1 h was present in 13 patients. Fibrinolysis increased progressively during surgery in 80 patients (82.5%) and was most severe on reperfusion of the graft liver in 33 patients (34%). When whole blood clot lysis (F < 180 min) was observed during reperfusion of the graft liver, blood coagulability was tested by thrombelastography using both a blood sample treated in vitro with &epsis;-aminocaproic acid (0.09%) and an untreated sample. Blood treated with &epsis;-aminocaproic acid showed improved coagulation without fibrinolytic activity in all 74 tests. When whole blood clot lysis time was less than 120 min, generalized oozing occurred, and the effectiveness of &epsis;-aminocaproic acid was demonstrated in vitro during the pre-anhepatic and post-anhepatic stages, &epsis;-aminocaproic acid (1 g, single intravenous dose) was administered. In all 20 patients treated with &epsis;-aminocaproic acid, fibrinolytic activity disappeared; whole blood clot lysis was not seen on thrombelastography during a 5-h observation period, and whole blood clot lysis index improved from 28.5 ± 29.5% to 94.8 ± 7.4% (mean ± SD, P < 0.001). None of the treated patients had hemorrhagic or thrombotic complications. In patients undergoing liver transplantation, the judicious use of a small dose of &epsis;-aminocaproic acid, when its efficacy was confirmed in vitro, effectively treated the severe fibrinolysis without clinical thrombotic complications.

Liver transplantation in a hemophiliac.

To the Editor: A cure rather than a treatment has long been the goal of those caring for and those suffering from hemophilia. Encouraging results were obtained some years ago with the transplantation of normal livers into a dog with mild hemophilia 1,2 and into four others with severe hemophilia.3 Two dogs given transplants survived more than 100 days and produced coagulation factor VIII in quantities sufficient to maintain normal levels. The first “cure” in a human being appears to have been achieved, at least temporarily, in a 15-year-old boy with hemophilia and severe chronic active hepatitis, who received a liver from a 9-year-old “normal” donor on March 5, 1985. The patient was given the diagnosis of hemophilia A in early childhood and has been followed at the Hemophilia Center, Children’s Memorial Hospital, Northwestern School of Medicine, Chicago, by Dr. John Paul Scott. In 1969 he had severe hepatitis B; positivity for hepatitis B surface antigen and antibody to hepatitis B e has persisted. In addition, therapy-related non A,non B hepatitis may have contributed to his liver disease. About four months before liver transplantation, a splenectomy was performed for chronic thrombocytopenia, which resolved postoperatively, but a residual pancreaticogastrocutaneous fistula remained. Liver transplantation and repair of the fistula were accomplished with less than the average blood loss. Before, during, and for 18 hours after liver transplantation, the patient’s factor VIII level was maintained at 0.54 to 1.60 U per milliliter by intermittent infusions of heat-treated factor VIII concentrate. From 18 hours after operation to the time of this writing (April 17), his level has been sustained at 1.0 to 3.0 U per milliliter without exogenous treatment. The high postoperative levels of factor VIII are similar to those seen after transplantation in patients without hemophilia. Eight days after operation the patient underwent repair of a bile duct. There was no increased hemorrhage, and he required no factor VIII treatment. Although in this case, at least temporarily, internal production of factor VIII has been achieved by the implanted liver, liver transplantation cannot be recommended as a “cure” for hemophilia. This drastic operation is justified only for end-stage liver disease because of the risks of lifelong immunosuppressive therapy, rejection, infection, and recurrence of disease. The duration of production of factor VIII is unknown. This case suggests that the antihemophilic activity (factor VIII:C) of the large factor VIII complex, synthesized in endothelium.4,5 is acquired in the liver.

THE RELATION OF PREOPERATIVE COAGULATION FINDINGS TO DIAGNOSIS, BLOOD USAGE, AND SURVIVAL IN ADULT LIVER TRANSPLANTATION

A group of 70 adults with end-stage liver disease received 87 homologous liver transplants from 7/11/81 and 7/11/83. The recipients fell into the following diagnostic categories: postnecrotic cirrhosis (PNC) in 22, primary biliary cirrhosis (PBC) in 18, cancer or neoplasia (CA) in 11, sclerosing cholangitis (SC) in 8 and miscellaneous (MISC) in 11. Survival for six months or longer was 46%: survival by group was PBC=67%, CA=55%, PNC=45%, SC=25%, and MISC=18%. Preoperative coagulation profiles were evaluated on 64 of the 70 first transplant patients by assigning a score derived from one point per abnormality in each of 8 tests. Mean coagulation abnormality scores (CAS) were strikingly elevated in the PNC and MISC groups. Mean intraoperative blood product usage was 43 units of RBCs, 40 units of fresh frozen plasma (FFP), 21 units of platelets, and 9 bags of cryoprecipitate. Direct correlations were found between CAS and RBC usage (+0.454, P=<.001), CAS, and survival of 6 months or longer (-0.281, P=<.02), and RBC usage and survival (-0.408, P=<.001). These findings indicate that the degree of coagulation abnormality and the type of liver disease may be predictive of intraoperative blood usage and survival in liver transplantation in adults.

Asymptomatic Structural Liver Disease in Hemophilia

In a study of persistent abnormalities of liver-function tests in hemophilic patients deficient in factor VIII or IX and treated with factor VIII or IX concentrates, we examined 14 liver biopsies from 13 anti-HBs-positive patients. None had any symptoms of liver disease. All had chronically abnormal levels of alanine aminotransferase. Histologic studies showed chronic persistent hepatitis in eight patients, chronic active hepatitis in four and fatty infiltration with portal fibrosis in one. Indirect immunofluorescence of antiserums containing anti-HBs or anti-HBc (or both) revealed nuclear and cytoplasmic fluorescence in the hepatocytes of eight of 12 patients. Specificity testing of these antiserums confirmed that hepatitis B viral markers are present in the hepatocytes of these anti-HBs-positive patients. These histologic derangements are probably related to frequent treatment with blood products obtained from multiple donors and to the persistance of hepatitis B virus in hepatocytes despite the presence of circulating anti-HBs.

Incidence, prevalence, and clinical course of hepatitis C following liver transplantation

Hepatitis C virus (HCV) is the agent responsible for posttransfusion hepatitis. The incidence, timing, and clinical course of HCV positive hepatitis in liver transplant recipients are unknown. Three hundred and seventeen donor-recipient liver transplant pairs were grouped on the basis of their pretransplant HCV antibody status. The biopsy findings were examined. Four distinct groups were identified on the basis of HCV serology: group I, both were negative; group II, donor was negative and recipient was positive; group III, donor was positive and recipient was negative; group IV, both were positive. The prevalence of anti-HCV positivity in recipients was 13.6%. The rate of seroconversion was 9.2%. Histologic hepatitis not ascribable to any specific cause other than non-A, non-B (NANB) hepatitis occurred in 13.8%. The incidence of histologic chronic active hepatitis was 1.6%, and none progressed to cirrhosis. The concordance rate for a positive anti-HCV serology and NANB hepatitis was 2.8%. Of the 35 patients (group II and IV) with positive anti-HCV serology pretransplant, only 17 were positive posttransplantation. Based on these data it can be concluded that posttransplant NANB hepatitis occurred in 13.8% of liver recipients. Twenty percent of these were anti-HCV positive. Progression to histologic chronic active hepatitis occurs over a period of 1-5 years in 1.6% of cases.

SUCCESSFUL TREATMENT OF HOMOZYGOUS PROTEIN C DEFICIENCY BY HEPATIC TRANSPLANTATION

A child with homozygous protein C deficiency was treated at age 20 months by orthotopic hepatic transplantation. Postoperatively there was complete reconstitution of protein C activity and resolution of the thrombotic condition.

Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder.

Our previous studies predicted a functional relationship between the plasma proteins alpha 1-antitrypsin and antithrombin III. To elucidate this relationship we investigated the plasma of a 14-year-old boy who had died from an episodic bleeding disorder. A variant alpha 1-antitrypsin was identified in which the methionine at position 358 had been replaced by an arginine. This had converted the alpha 1-antitrypsin from its normal function as an inhibitor of elastase to that of an inhibitor of thrombin. This finding indicates that the reactive center of alpha 1-antitrypsin is methionine 358, which acts as a bait for elastase, just as the normal reactive center of antithrombin III is arginine 393, which acts as a bait for thrombin. The independence of the new thrombin inhibitor from heparin control explains the bleeding disorder; it also indicates that heparin normally acts directly on antithrombin III, revealing its inherent inhibitory activity. The episodic nature of the bleeding was a consequence of the mutant proteins being an acute-phase reactant, the level of which increased several-fold after trauma.

Fibrinolytic and Coagulant Activities of Certain Snake Venoms and Proteases.

Summary Of the 16 snake venoms studied, 11 actively lysed human blood clots. However, only one of these, C. basiliscus, was devoid of thrombic, hemolytic, and hemaggluti-nating properties. This venom was fibrino-genolytic as well as fibrinolytic. The possible therapeutic use of certain venoms as dissolving agents for intravascular clots presents a theoretical advantage over most other fibrinolytic agents in that their fibrinolytic activity is not readily inhibited by human serum. Fractionation of a pure fibrinolytic principle may be possible.