Simultaneous occurrence of human antibodies directed against fibrinogen, thrombin, and factor V following exposure to bovine thrombin: effects on blood coagulation, protein C activation and platelet function.

We describe a patient with severe epistaxis, prolonged coagulation tests and decreased plasma factor V following exposure to bovine topical thrombin. Patient IgG, but not normal IgG, showed binding to immobilized thrombin (bovine > human) and fibrinogen, and to factor V by Western blotting; the binding to thrombin was inhibited by hirudin fragment 54-65. Electron microscopy of rotary shadowed preparations showed complexes with IgG molecules attached near the ends of trinodular fibrinogen molecules. Patient IgG inhibited procoagulant, anticoagulant and cell-stimulating functions of thrombin demonstrated by inhibition of fibrinogen clotting, protein C activation and platelet aggregation; thrombin hydrolysis of S-2238 was not inhibited. The results suggest that the antibody is targeted against anion-binding exosite and not catalytic site of thrombin. Antifibrinogen antibodies have not been reported in patients exposed to bovine thrombin. There is a pressing need to re-evaluate the role of bovine thrombin as a therapeutic agent.

Serum-ascites albumin gradients in nonalcoholic liver disease.

Several studies performed in alcoholics with advanced liver disease have demonstrated a positive correlation between the serum-ascites albumin gradient (SAAG) and measured portal venous pressure. A single study performed in 15 patients with exudative malignant ascites and 29 patients with alcoholic liver disease demonstrated that a SAAG of less than 1.1 was essentially diagnostic of a malignant origin of the ascites. In an effort to confirm and extend these observations to individuals with nonalcoholic liver disease, 24 patients with nonalcoholic liver disease and 11 with alcoholic liver disease undergoing orthotopic liver transplantation (OTLx) were studied. At the time of liver transplantation, each had their serum and ascitic fluid albumin levels determined, the gradient calculated, and their portal venous pressure (PVP) as well as the corrected portal venous pressure (PPc) measured directly. A significant correlation (r = 0.624) between the PPc and the SAAG was found in the 11 alcoholics (P less than 0.05). No such correlation existed for those with nonalcoholic liver disease (r = 0.398). Moreover, a SAAG less than 1.1 was found in three of nonalcoholics with cirrhosis in the absence of an abdominal malignancy. We conclude that (1) the SAAG and PPc are statistically related to each other in individuals with alcoholic liver disease but not in those with a nonalcoholic cause for cirrhosis, and (2) SAAG less than 1.1 is not diagnostic of abdominal malignancy but can occur in those with advanced nonmalignant hepatic disease.

Combined upper and lower gastrointestinal endoscopy: a prospective study in alcoholic and nonalcoholic cirrhosis.

Upper gastrointestinal hemorrhage is one of the more important complications of cirrhosis. Most of the available data regarding the prevalence of upper and lower gastrointestinal sites of bleeding in cirrhotic patients have been obtained in individuals with alcoholic cirrhosis evaluated in the course of an acute gastrointestinal bleeding episode. Few data exist, however, as to the prevalence of either potential bleeding sites or of normal endoscopic findings in hemodynamically stable individuals with cirrhosis of any etiology. Five hundred ten cirrhotic subjects, who were evaluated for possible liver transplantation (OLTx) between January 1985 and June 1987, were included in this study. Seventy-five had alcoholic cirrhosis and 435 had nonalcoholic cirrhosis of various etiologies. Of these 510 patients, 412 underwent combined upper and lower gastrointestinal endoscopy and 98 underwent upper gastrointestinal endoscopy alone. Gastritis, gastric and duodenal ulcer disease were found significantly (each at least p less than 0.025) more often in patients with alcoholic liver disease than in those with nonalcoholic liver disease. The prevalence of the various lower gastrointestinal lesions in both groups was similar. Of particular interest is the fact that in alcoholic cirrhotics, the prevalence of gastritis, gastric ulcer and duodenal ulcer disease was unrelated to the degree of portal hypertension, whereas in the nonalcoholic cirrhotics the prevalence of gastritis and duodenal ulcer disease but not gastric ulcer disease was associated significantly with the degree of portal hypertension as assessed by the presence or absence of large esophageal varices, ascites, and hepatic encephalopathy.

Role of serum complement, immunoglobulins, and cell-mediated immune system in the pathogenesis of spontaneous bacterial peritonitis (SBP).

Spontaneous bacterial peritonitis (SBP) is a common complication of advanced liver disease, which has a reported prevalence of between 4 and 27%. Frequent bacteremias due to inadequate host defense mechanisms, particularly the reticuloendothelial system (RES), with seeding of an ascitic fluid that lacks a normal opsonic activity, is believed to be the principal cause of SBP. Little data exist as to the role of serum levels of complement and immunoglobulins as well as the cell-mediated immune system in the pathogenesis of SBP. The aim of this study was to determine the serum levels of the third and fourth components of complement (C3, C4), total hemolytic complement activity (CH100), and properdin factor B (PFB) and immunoglobulins G, A, and M and various T-cell parameters in individuals admitted to hospital with ascites and advanced liver disease and to determine whether one or more of these factors could be used to predict the development of SBP in patients with advanced liver disease. Fourteen consecutive patients (nine male and five female; age 47.5 +/- 3.1 years, mean +/- SEM) with end-stage liver disease and ascites, who were evaluated for possible liver transplant at the University of Pittsburgh and who developed SBP, comprised the study group. The diagnosis of SBP was determined by positive ascitic fluid culture (three patients) and/or ascitic fluid neutrophil count of greater than 250 cells/mm3 (all patients). The control group consisted of 14 patients, matched for type of liver disease, age, and sex, who did not develop SBP.(ABSTRACT TRUNCATED AT 250 WORDS)

Midazolam versus diazepam for combined esophogastroduodenoscopy and colonoscopy.

This study compares the effects of two different benzodiazepines used for conscious sedation during combined upper gastrointestinal endoscopy (EGD) and colonoscopy. Subjects were assessed for their degree of analgesia and amnesia for the procedure, prior experience with endoscopy, and willingness to undergo another similar procedure should such be necessary. The patients were randomized single blind to receive either midazolam or diazepam for their preprocedure sedation. The amount of preprocedure sedation utilized was determined by titration of the dose to achieve slurring of speech. Prior to receiving either agent, the subjects were shown a standard card containing pictures of 10 common objects, were asked to name and remember them, and were told they would be "quizzed" (at 30 min and 24 hr) after being sedated for their recollection as to the objects pictured on the card. Each subject filled out a questionnaire addressing their perceived discomfort during the endoscopic procedure and their memory of the procedure 24 hr after the procedure. Sixty-three percent of the midazolam-sedated subjects reported total amnesia for their colonoscopy vs 20% of diazepam-sedated patients (P less than 0.001). Fifty-three percent of midazolam-sedated patients reported total amnesia of their upper gastrointestinal endoscopy vs only 23% of diazepam-sedated subjects (P less than 0.05). The midazolam-sedated subjects reported experiencing less pain with both upper gastrointestinal endoscopy (P less than 0.05) and colonoscopy (P less than 0.001) than did the diazepam-sedated group. Most importantly, the midazolam group was more willing to undergo another similar endoscopic procedure should they be asked to do so by their physician (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of different types of hepatic injury on the estrogen and androgen receptor activity of liver.

Mammalian liver contains receptors for both estrogens and androgens. Hepatic regeneration after partial hepatectomy in male rats is associated with a loss of certain male-specific hepatic characteristics. In this study we investigated the effects of lesser forms of hepatic injury on the levels of estrogen and androgen receptor activity in the liver. Adult male rats were subjected to portacaval shunt, partial portal vein ligation, hepatic artery ligation, or two-thirds partial hepatectomy. Another group of animals was treated with cyclosporine. At the time of sacrifice the livers were removed and used to determine the estrogen and androgen receptor activity in the hepatic cytosol. A significant reduction (p less than 0.05) in the hepatic cytosolic androgen receptor activity and a slight increase in the estrogen receptor activity occurred following total portosystemic shunting. Partial ligation of the portal vein, which produces a lesser degree of portosystemic shunting, had no effect on the levels of the estrogen and androgen receptor activity present within hepatic cytosol. Cyclosporine-treated animals had significantly greater (p less than 0.01) levels of estrogen receptor activity in the hepatic cytosol compared to vehicle-treated control animals. Levels of estrogen and androgen receptor activity within the hepatic cytosol remained unchanged after ligation of the hepatic artery. The reduction in the cytosolic estrogen and androgen receptor activity in the liver after partial hepatectomy was confirmed. In summary, certain types of hepatic injury are associated with profound changes in the estrogen and androgen receptor content within the liver.

Effect of partial portal vein ligation on hepatic regeneration.

To evaluate the effect of portal hypertension and diminished portal venous blood flow to the liver on hepatic regeneration, male rats were subjected to partial portal vein ligation and subsequently to a two-thirds partial hepatectomy. The levels of ornithine decarboxylase activity at 6 h after partial hepatectomy were greater (p less than 0.001) in the rats with prior partial portal vein ligation than in those without portal hypertension. The rats with prior partial portal vein ligation also had greater (p less than 0.005) levels of thymidine kinase activity at 48 h after partial hepatectomy than did those without portal hypertension. Hepatic sex hormone receptor activity was not affected by prior partial portal vein ligation either before or after partial hepatectomy. The reductions in both estrogen and androgen receptor activity observed in the hepatic cytosol after partial hepatectomy were similar to those observed in control animals. These data indicate that animals with portal hypertension having a diminished hepatic portal blood flow have a normal capacity to regenerate hepatic mass following a hepatic resection.

Inhibitor treatment using unactivated prothrombin complex concentrates: the Pennsylvania experience--1978-1982.

Data were analyzed on 48 patients with Factor VIII:C inhibitors, 31 of whom were treated with more than 6.7 million units of unactivated prothrombin complex concentrates (PCC) during the years 1978 through 1982 for more than 1,000 bleeding episodes. Twelve of the patients who were on home therapy used 3.1 million units, or 47% of the total PCC usage. Only one patient had a severe life-threatening allergic reaction to PCC, and no thrombotic complications were observed, supporting the concept that these products are safe when used in doses of 50-75 u/Kg. Fifty percent of hemarthroses and 65% of muscle hemorrhages were treated with no more than two infusions per episode, suggesting that PCC was effective at least half of the time. Comparison of the number of days hospitalized per year for inhibitor and non-inhibitor patients also indicated that PCC was effective, although not as effective as AHF therapy in non-inhibitor patients. The life styles of PCC treated patients were comparable to what might be expected for non-inhibitor patients with severe disease, and no deaths were attributed to PCC treatment failure during the four year period. Of major concern, however, was the cost of therapy. In 1981-82, the average use of PCC for inhibitor patients was 106,000 units per treated patient per year, compared to 40,000 AHF units for all Factor VIII deficient treated patients per year. Much of this usage was for recurrent hemarthroses in a small number of patients requiring eight or more infusions per episode.

Liver dysfunction in Pennsylvania's multitransfused hemophiliacs.

Transaminase values [alanine amino transferase (ALT) and aspartate amino transferase (AST)] and markers for hepatitis B were serially determined in 558 hemophiliacs exposed to blood products. Hepatitis B surface antigen (HBsAg) persistent for over 12 months was present in 6% of the patients. Antibody to hepatitis B surface antigen (anti-HBs) was noted in 90% of the 259 patients treated with factor VIII or IX concentrates but in only 49% of the 43 patients treated with fresh frozen plasma (FFP) or cryoprecipitate. Persistently abnormal transaminase values were noted in 31% of the patients treated with commercial concentrates but in only one (2%) of the patients exposed to cryoprecipitate or FFP. This difference continued even when the two groups of patients were matched for the amount of blood products, up to 50,000 units, which they had received in the study period. In the concentrate-treated patients, no correlation could be found between transaminase values and the number of units of factor VIII or IX they had received during the six years of the study (1973-1978).

The Pennsylvania hemophilia program 1973-1978.

In Pennsylvania, the prevalence of hemophilia is one per 10,000 males. Factor VIII deficiency is five times more frequent than Factor IX deficiency, and 34% of the patients have no relatives affected with the disease. The mean age is 23 years old, and 50% of the patients are less than 20 years old. Approximately one-third of the patients with Factor VIII deficiency and one fourth of the patients with Factor IX deficiency have levels of less than 0.01 mu/ml. By clinical criteria, 55% of those with Factor VIII deficiency are severe compared to 45% of those with Factor IX deficiency. Factor VIII-deficient patients are treated an average of 18 times per year compared to ten times per year for patients with Factor IX deficiency. Hemarthroses account for 70% of the hemorrhages treated and for 40% of the concentrate usage. Home therapy patients use an average of 45,950 Factor VIII units per year at a cost of ø170 per patient and their use accounts for 60% of the total Factor VIII usage of 1.7 million units. Less than five days per patient per year are lost from school or work because of bleeding, and patients are hospitalized for bleeding an average of only two to three days per patient year. Adverse immediate reactions to therapy are infrequent. Five percent of patients have persistence of the hepatitis B virus, and 7.5% have inhibitors. The mortality rate is 0.04% per year, with half of the deaths being hemophilia-related.

Further studies of platelet rosettes around granulocytes in Behcet's syndrome.

Rosettes of platelets around granulocytes-platelet satellitism-previously described in Behcet's syndrome led to the discovery of a case that may have been 80 years in duration. A strong relationship between calcium ions and the phenomenon was suggested by its specificity in edetic-acidanticoagulated blood, and the subsequent migration of platelets on supravital preparation from around neutrophils upon addition of 0.2 M calcium chloride to heparinized EDTA-treated blood. Plasma from the patient was able to cause the phenomenon with donor granulocytes and platelets. Platelet agglutinins were also demonstrable. Specificity in Behcet's syndrome is possible, but remains unproved.