Joel A. Spero

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.

Acute Renal Failure Due to High-Grade Obstruction Following Therapy With ϵ-Aminocaproic Acid

An 18-year-old man with mild factor VIII deficiency developed hematuria and, subsequently, acute renal failure due to high-grade urinary obstruction by clots during therapy with cryoprecipitate, ϵ-aminocaproic acid, and acetazolamide administered for ocular trauma. Discontinuation of therapy with the latter two agents and induction of a brisk diuresis with intravenous (IV) fluid therapy resulted in return of renal function concomitant with spontaneous clot passage. A review of previous literature suggests that hemophiliacs may be more susceptible than nonhemophiliacs to high-grade urinary obstruction due to clot formation when ϵ-aminocaproic acid is administered during episodes of hematuria. Acute flank pain, fever, and delayed dense nephrograms on IV pyelogram are characteristic of the syndrome and distinguish it from other forms of acute renal failure associated with ϵ-aminocaproic acid.

Ascites-induced LeVeen shunt coagulopathy.

Ten of 11 patients undergoing peritoneovenous (LeVeen) shunt placement for intractable ascites had disseminated intravascular coagulation (DIC) following the shunt procedure. Intraoperative ascitic fluid specimens revealed fibrin split products (FSP) in high titer (1:100–1:1600) in all patients. Endotoxin was found in 6 of 11 ascitic fluid samples but in no plasma samples. Activated clotting factors, clot inhibitors, excess protein, and fibrinolytic activity were not found in ascitic fluid. Clotting factor levels were much lower than in plasma. Bleeding occurred after operation in two patients; this appeared to be related to the severity of liver dysfunction as demonstrated by elevations of bilirubin, serum glutamic oxalocetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and preoperative DIC. It is concluded that the LeVeen shunt coagulopathy is DIC, and may be related to exposure of the systemic circulation to FSP-rich ascitic fluid that may activate the coagulation mechanism. Bleeding complications do not appear to be related to the severity of the post shunt coagulopathy, but rather to the severity of liver dysfunction and presence of preoperative DIC (probably caused by the liver disease).

Acquired immunodeficiency syndrome in the child of a haemophiliac

Oral thrush developed during the second month of life in the 5-month-old son of a patient with haemophilia A. He did not feed well, and interstitial pneumonitis, lymphadenopathy, hepatosplenomegaly, and a cellular immune defect consistent with the acquired immunodeficiency syndrome (AIDS) followed. Both parents had signs of pre-AIDS during the year before their sons illness. Transmission presumably occurred in 3 steps: parenterally, via factor VIII concentrate in the haemophiliac; heterosexually, from the haemophiliac to his wife; and vertically, from mother to infant, or via close paternal-infant or maternal-infant contact. This first report of AIDS in the child of a haemophiliac supports the theory that AIDS is caused by an infectious agent. Concentrate-treated haemophiliacs may transmit this agent to their spouses or children, resulting in pre-AIDS or AIDS.

Decreased helper/suppressor cell ratios after treatment with factor VIII and IX concentrates and fresh frozen plasma

The immunologic status of three groups of multiply transfused asymptomatic patients was evaluated. These included five with acquired inhibitors to factor VIII treated with both factor VIII and factor IX concentrates (Group A), seven with hemophilia B treated with factor IX concentrate (Group B), and six with hemophilia B treated with fresh frozen plasma (Group C). Mean helper/suppressor T cell ratios (+/- SEM) for the three groups were 0.72 +/- 0.09, 1.35 +/- 0.18, and 1.37 +/- 0.12, respectively. All three differed significantly (p less than 0.01) from the control mean ratio of 2.22 +/- 0.16. In addition, the mean ratio of Group A patients was significantly different (p less than 0.01) from those of Groups B and C. An inverted ratio (less than 1.00) was found in all Group A patients and only one Group B patient. Increased IgG levels were found in 80, 57, and 50 percent of each group, respectively. These immunologic findings bear a striking resemblance to those of the acquired immunodeficiency syndrome (AIDS) of homosexuals, intravenous-drug abusers, Haitian immigrants, and factor VIII concentrate-treated hemophiliacs. Transmission via a blood-borne infectious agent seems likely.

The high risk of chronic liver disease in multitransfused juvenile hemophiliac patients.

Eighty-seven asymptomatic children with either hemophilia A or B were treated before they were 21 years of age. Seventy-two received factor concentrates and 15 cryoprecipitate or fresh-frozen plasma only. Thirty-two of the 72 in the former group have persistently elevated alanine aminotransferase values compared to one of 15 in the latter group. In a subset of children treated with factor concentrates before five years of age, four of seven are chronically HBsAg positive. Liver biopsies were performed in 13 of the 32 asymptomatic patients with abnormal ALT values in the fraction group. It is recommended that until further data become available, children with mild hemophilia and all less than 5 years of age should receive only cryo or FFP.

A hemophiliac dog colony: Genetic studies and coagulation findings in hemophiliac and normal dogs

A colony of hemophiliac dogs was developed as descendants of a single affected Pomeranian. Over a 13 year period, a total of 29 hemophiliac dogs survived to the age of 6 months or longer. Eleven were female and 18 were male. All five of the possible matings in a sex-linked recessive inheritance pattern were accomplished and the offspring fell into the expected sex and disease groups. Twenty-one dogs died from untreated hemorrhages which usually occurred in loose tissues or body cavities during the night. Clinically, there were no hemarthroses but 22 other hemorrhages responded promptly to treatment with dog cryoprecipitate. Coagulation studies showed that the hemophiliac dogs averaged about 0.23 U/ml equivalents of human F VIII:C while normal dogs averaged 8.0 U/ml equivalents of human. Fs V, VII, II, X, IX, XI and XII were higher than human in both normal and hemophiliac dogs. Dog fibrinogen fell within the human range and Fletcher F was very low.

Prekallikrein (Fletcher factor) deficiency in clinical disease states

Abstract Plasma prekallikrein activity was measured in a clotting test in 315 consecutive patients undergoing coagulation profiles during the seven month period between January 1, 1979, and August 3, 1979, using substrate from one of our patients with severe Fletcher factor deficiency. Among the 68 patients with significantly reduced Fletcher factor activity (