Biomedical subjects
Publications and source records attributed to J H Lewis.
AT-P is a potent inhibitor of factor XIa. It has a greater affinity for factor XIa (5.1 X 10(5) M-1 sec-1), than it does for thrombin (3.1 X 10(5) M-1 sec-1). This recently cloned protein may be clinically valuable in the management of disorders involving activation of the contact system of plasma proteolysis.
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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.
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Total and free (unbound) anticonvulsant drug levels in serum (361 analyses) were measured in a series of 117 patients who attended for routine management of epilepsy. Comparison of predetermined therapeutic ranges for the two types of level demonstrated disagreement in as many as 30% of assessments. The clinical significance of this finding is discussed and wider acceptance of the use of free drug levels in the management of epilepsy is advocated.
Fibronectin levels were measured in 151 hospitalized patients with liver disease, sepsis, malignancy, leukemia, and following trauma or surgery, using heterologous precipitating antibody in an immunoassay. The mean (+/- S.E.M.) in 25 controls was 0.95 +/- 0.06 U/ml, with females, 0.83 +/- 0.07 U/ml, lower than males, 1.09 +/- 0.09 U/ml. Mean fibronectin levels were decreased in all disease groups except in obstructive liver disease. The reduced levels in hepatocellular disease and the restoration of levels to normal after orthotopic liver transplantation in patients with hepatocellular disease supports the theory that hepatic synthesis contributes significantly to plasma fibronectin levels. Following cryoprecipitate infusion in four hemophiliac patients, plasma fibronectin levels rose to 32% to 45% of the levels predicted. In patients with reduced fibronectin and poor clinical response to standard treatment (antibiotics, chemotherapy), cryoprecipitate infusions may raise the levels of fibronectin and, perhaps, contribute to clinical improvement.
The unique finding of normal proalbumin in human plasma provides an insight into the mechanism of propeptide cleavage. Proalbumin, present as 1-5% of the total albumin, was found in a boy whose prime problem was the presence of a mutant proteinase inhibitor, alpha 1-antitrypsin Pittsburgh (358 Met----Arg) [2]. The inferred structure of human proalbumin was confirmed as Arg-Gly-Val-Phe-Arg-Arg-Alb. On incubation with various enzymes (trypsin, tryptase, thrombin, chymotrypsin, chymase and cathepsin B), only trypsin was capable of converting proalbumin to albumin. There was no conversion when proalbumin was incubated with whole blood, plasma or serum. However, intravenous injection of proalbumin into a rat resulted in complete conversion to albumin, the half-life of this process being 6 h. We conclude that propeptide cleavage is dependent on a serine proteinase which is inhibited intracellularly, by the mutant inhibitor, and that all the albumin in the boy was secreted as proalbumin, but was subjected to a separate cleavage process after export from the hepatocyte.
Eight adult patients with chronic idiopathic thrombocytopenic purpura have been treated with an intravenous gamma globulin preparation. All patients received at least one "induction" course of intravenous gamma globulin for five consecutive days at a dose of 400 mg/kg per day. There were a total of 12 induction treatments. In five instances, patients also received single "maintenance" infusions of intravenous gamma globulin at the same dose. The mean peak increment in platelet count (X 10(3)/microliters) after induction was 87.3 +/- 42.37; after maintenance therapy it was 62.2 +/- 12.99. In only one instance was the platelet count increment less than 50 X 10(3)/microliters. In 13 of 17 intravenous gamma globulin treatments (both induction and maintenance), the platelet count returned to baseline or near-baseline levels within one to two weeks. In four instances, more prolonged remissions were observed. Measurements of platelet-associated IgG demonstrated the following: when platelet-associated IgG was greater than 100 ng/10(6) platelets, platelet-associated IgG usually decreased markedly after intravenous gamma globulin therapy. When platelet-associated IgG was less than 20 ng/10(6) platelets, platelet-associated IgG usually increased with therapy. There was no correlation between starting platelet-associated IgG levels or changes in platelet-associated IgG levels with therapy and the increment in the patient's platelet count.
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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.
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The diagnosis of a bleeding Meckel's diverticulum containing ectopic gastric mucosa by 99m-Tc pertechnetate imaging is reported to have a diagnostic accuracy of 90% for patients in the pediatric age group. The usefulness of Meckel's scanning in adults is, however, less certain. We present two patients who illustrate some of the difficulties inherent in Meckel's scanning in adults; one had a false-negative scan despite the presence of ectopic gastric mucosa and the other had a false-positive scan, both confirmed by laparotomy. The available literature indicates that false-positive and false-negative scans occur relatively frequently in adults, but no comprehensive review on this subject exists. Based on our findings, it is suggested that Meckel's scanning be supplemented with small bowel infusion or arteriography or both to improve preoperative diagnosis in adult patients in whom a diverticulum is suspected.
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Ketoconazole has only recently been recognized as a cause of hepatic injury, with most reports coming from outside the United States. In order to characterize more fully the U.S. experience, we undertook an analysis of 54 reports of alleged ketoconazole-induced liver injury submitted to the Food and Drug Administration from the time of initial marketing in 1980. Thirty-three reports were considered likely instances of ketoconazole-induced hepatitis. The majority of these cases occurred in women more than 40 yr of age. Jaundice was recorded in 27 individuals after therapy of 11-168 days with an average daily dose of 200 mg. Anorexia, malaise, nausea, and vomiting accompanied liver injury in one-third of cases. No instances of rash or eosinophilia were recorded. Serum transaminase and alkaline phosphatase values were consistent with acute hepatocellular injury in 18 patients, with primarily cholestatic injury in 5 patients, and with a mixed pattern in 9 individuals. Only one death seemed attributable to ketoconazole. In that patient, the drug was continued after the appearance of clinical and biochemical evidence of hepatic injury and massive hepatocellular necrosis was present at autopsy. The incidence of symptomatic, potentially serious hepatic injury appears to be very low, perhaps 1 in 15,000 exposed individuals. The presumed mechanism of injury is metabolic idiosyncrasy, although hypersensitivity has not been completely dismissed in some cases reported in the literature. The incidence of mild, asymptomatic, reversible elevations in serum transaminases occurring in ketoconazole recipients has been estimated to be 5%-10%. Periodic biochemical testing and monitoring for symptoms of hepatitis during ketoconazole therapy is recommended to help prevent the development of serious or fatal hepatic injury.
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.
We report the phenomenon of transient resistance to cimetidine in a 27-year-old healthy, asymptomatic woman who underwent a 5-day gastric intubation study as part of a research protocol. Despite normal blood levels after orally administered cimetidine, this subject had no gastric acid suppression in response to the drug on 2 days of the protocol. On two other occasions, however, she responded appropriately to cimetidine by raising her intragastric pH, reaching peak cimetidine blood levels that were similar to those on the days that she had not responded. The cause for this variable effect of cimetidine on intragastric pH is not known, but might reflect a cholinergic response to stress. Other mechanisms for cimetidine resistance are also discussed.
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