Biomedical subjects
J C Goldsmith
Publications and source records attributed to J C Goldsmith.
A new treatment strategy for hemophilia B: incorporation of factor IX into red cell ghosts.
Although patients with severe hemophilia B have lifelong spontaneous hemorrhage and crippling hemarthroses, patients with 0.01--0.03 U/ml Factor IX activity have a milder disease state. The clinical condition of severely affected individuals could potentially be improved by prolonging the half-life of transfused Factor IX. The feasibility of incorporating Factor IX into red cell ghosts was suggested by resealing experiments with similar sized molecules such as albumin. We have prepared resealed red cell ghosts containing human Factor IX and X. Human red cells were subjected to hypotonic lysis at 0 degrees C, pH 6.0. Commercial prothrombin complex concentrate was dissolved in the lysing medium immediately prior to the addition of the red cells. After being returned to isotonicity, the red cell ghosts were annealed at 37 degrees C for 30 minutes and then washed extensively. When intact red cell ghosts were tested, no Factor IX or X activity could be demonstrated. After disruption of the red cell ghost membranes with 3M urea or 2% Triton X-100, the procoagulants could be quantitatively recovered. Similar recovery of the clotting factors could be demonstrated from the lysate and the early wash samples. Red cells from Factor IX and X deficient patients served equally well as those from normal subjects. Red cell ghosts prepared in similar fashion but not exposed to the procoagulants had negligible clotting activity. We have demonstrated that human clotting factors can be incorporated into red cell ghosts. The ability of this system to prolong the biological half-life of Factor IX is under investigation.
Hemobilia complicating warfarin therapy.
This patient is the first case of endoscopically documented massive hemobilia exacerbated by inadvertent warfarin overdose. The true frequency of this disorder should become evident with the widespread use of endoscopy and a high index of suspicion.
Congenital deficiency of blood clotting factors II, VII, IX, and X.
A patient congenitally deficient in factors II, VII, IX, and X has been further investigated after a follow-up of 15 yr. At birth, these factors, when determined by clotting assays, were undetectable. Following therapy with vitamin K1, the clotting activity of these factors rose but never exceeded 18% of normal. Immunologic assays revealed much higher levels of these factors than did clotting assays, thus suggesting that the vitamin-K-dependent factors were present in abnormal forms. Two-dimensional crossed immunoelectrophoresis showed that at least two forms of prothrombin were present in the patient's plasma. One form was similar to normal prothrombin; the other had the same mobility as acarboxyprothrombin. In addition, the majority of this fast-migrating peak was not adsorbable onto insoluble barium salts. These observations suggested that some molecules of the patient's prothrombin lacked the normal complement of gamma-carboxyglutamic acid residues. This observation was confirmed by a specific assay for gamma-carboxyglutamate. Since malabsorption of vitamin K, warfarin intoxication, and hepatic dysfunction were excluded as causes of this patient's syndrome, this rare congenital abnormality could represent either a defective gamma-carboxylation mechanism within the hepatocyte or faulty vitamin K transport.
Antithrombin-III transfusion in disseminated intravascular coagulation.
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A simple assay for human factor IX: use of canine hemophilia B plasma as substrate.
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Purification and characterization of an abnormal factor IX (Christmas factor) molecule. Factor IX Chapel Hill.
Human Factor IX (Christmas factor) was isolated from the plasma of a patient with mild hemophilia B. The patient's plasma contained 5% Factor IX clotting activity but 100% Factor IX antigenic activity as determined by immunological assays, which included inhibitor neutralization and a radioimmunoassay for Factor IX. This abnormal Factor IX is called Factor IX Chapel Hill (Factor IXCH). Both normal Factor IX and Factor IXCH have tyrosine as the NH2-terminal amino acid. The two proteins have a similar molecular weight, a similar amino acid analysis, the same number of gamma-carboxyglutamic acid residues (10 gamma-carboxyglutamic acid residues), and a similar carbohydrate content. Both exist as a single-chain glycoprotein in plasma. The major difference between normal Factor IX and Factor IXCH is that the latter exhibits delayed activation to Factor IXa in the presence of Factor XIa and Ca2+. Thus, Factor IXCH differs from other previously described abnormal Factor IX molecules.
Prothrombin complex concentrates.
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Isolation and characterization of factor IX Chapel Hill: comparison to normal human factor IX.
A classification scheme for patients with hemophilia B has been devised. Assessment of factor IX antigen and factor IX coagulant activity has confirmed the genetic heterogeneity of hemophilia B and has shown that some affected patients have normal amounts of factor IX-like protein. An abnormal factor IX, factor IX Chapel Hill, has been isolated from one of these variants and compared structurally and functionally to the purified normal human factor IX molecule. The major difference between factor IX Chapel Hill and normal human factor IX appears to be defective activation of the abnormal molecule by factor XIa and calcium.
Thrombin - endothelial cell interactions: critical importance of endothelial cell vessel of origin.
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Successful cardiac surgery following plasmapheresis in a patient with hemophilia B.
A case of successful coronary artery bypass grafting in a patient with hemophilia B is described. The patient underwent preoperative plasmapheresis and replacement with fresh-frozen plasma. Fresh-frozen plasma was administered pre- and postoperatively. The use of factor IX concentrate was avoided.
False-positive enzyme-linked immunosorbent assay reactions for antibody to human immunodeficiency virus in a population of midwestern patients with congenital bleeding disorders.
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Successful conservative management of thrombocytopenia in adult hemophiliacs.
Hematologic abnormalities, including thrombocytopenia, have been reported in persons with acquired immune deficiency syndrome and in hemophiliacs. Seven of 92 adult hemophiliacs followed in a comprehensive hemophilia center developed mild to moderately severe thrombocytopenia in 1983. All had benign courses. None required therapy for thrombocytopenia, although several had increased cutaneous bleeding. Infection with human immunodeficiency virus may be important in the pathogenesis of these patients' thrombocytopenia as it has been in that of homosexual men.
Immunologic profiles of adults with congenital bleeding disorders.
An immunologic profile may be useful to predict the development of Acquired Immune Deficiency Syndrome (AIDS) in both high risk patient groups including homosexuals, hemophiliacs, Haitians, and users of illicit intravenous narcotics as well as the general population. We evaluated 76 consecutive, apparently healthy, adults with congenital bleeding disorders for serum beta-2 microglobulin concentration by competitive enzyme immunoassay, T-lymphocyte subpopulations with monoclonal antibodies and serum interferon by inhibition of vesicular stomatitis virus plaque forming units. Findings on physical examination were remarkable with 24% of the group having longstanding splenomegaly and 24% lymphadenopathy. beta-2 microglobulin levels were 3232 +/- 220 micrograms/l (mean +/- SEM) with normal controls 2134 +/- 119 micrograms/l. The ratio of Leu3a (helper/inducer) positive to Leu2a (suppressor/cytotoxic) positive T-lymphocytes was 1.33 +/- 0.1 (mean +/- SEM, median = 1.18). Normal control ratios were all greater than 1.35 with a mean +/- s.d. = 1.96 +/- 0.28. Abnormal ratios of T-lymphocyte subpopulations appeared to persist over time. Increases in beta-2 microglobulin correlated with an inverted helper/suppressor T-lymphocyte ratio, the presence of lymphadenopathy, and elevations in aspartate aminotransferase. Interferon was detected in 18% of patient sera. More frequently transfused and more severely affected patients had a higher frequency of immunologic abnormalities although abnormalities also occurred in some rarely and never transfused less severely affected patients. These studies document a high incidence of immunologic abnormalities in patients with inherited coagulation defects.
Restoring the human scale. Healthcare facilities will be designed as living spaces for families, not warehouses for sick people.
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The reshaping of healthcare. Part 1.
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Building integrated systems--driving the nitroglycerin truck.
Both sides of the bizarre, sadomasochistic relationship between physicians and hospitals bring baggage to the "arranged marriage" of the integrated healthcare system.
Technology & the end to entitlement.
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