Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A pharmacokinetic program that allows individualization of drug dosage regimens through the Bayesian method is described. The program, which is designed for the Hewlett-Packard HP-41 CV calculator, is based upon the one-compartment open model with either instantaneous or zero-order absorption. Individualized estimation of the patient's kinetic parameters (clearance and volume of distribution) is performed by analyzing the plasma levels measured in the patient as well as considering the population data of the drug. After estimating the individual kinetic parameters by the Bayesian method, the program predicts the dosage regimen that will elicit the desired peak and trough plasma levels at steady state. For comparison purposes, the least-squares estimates for clearance and volume of distribution are calculated, and dosage prediction can also be made on the basis of the least-squares estimates. The least-squares estimates can be used to calculate population pharmacokinetic parameters according to the Standard Two-Stage method. Several examples of clinical use of the program are presented. The examples refer to patients with classic hemophilia who were treated with Factor VIII concentrates. In these patients, the Bayesian kinetic parameters of Factor VIII have been estimated through the calculator program. The Bayesian parameter estimates generated by the HP-41 have been compared with those determined by a Bayesian program (ADVISE) designed for microcomputers.
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PMID:A calculator program for clinical application of the Bayesian method of predicting plasma drug levels. 392 43

We present the rare occurrence of an inhibitor of factor VIII procoagulant arising in a patient with mild haemophilia A and rheumatoid arthritis. The inhibitor was transient and behaved like a low titre, type II factor VIII procoagulant inhibitor similar to previously reported cases (Biggs et al, 1972b). In vitro studies confirmed the type II-like interaction of this inhibitor with the factor VIII procoagulant molecule. Factor VIII procoagulant antigen level was equal to the factor VIII procoagulant activity, which excluded dysproteinaemia as the cause. This patient's HLA type has no known association with abnormal immune responsiveness or autoimmune disease, and his clinical course as well as in vitro studies were similar to the eight previously reported cases of factor VIII procoagulant inhibitors arising in mild haemophilia A.
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PMID:Factor VIII antibody in a patient with mild haemophilia. 392 30

Factor VIII is generally believed to circulate in blood as a multimeric complex of two glycoproteins which are physiologically and immunologically distinct. One component of the factor VIII complex is factor VIII procoagulant activity (FVIII:C) which is associated with factor VIII/procoagulant antigen (FVIII:Ag, formerly FVIII/CAg). The second, larger unit of the complex is factor VIII/von Willebrand factor (vWF:Ag, formerly factor VIII-related antigen or FVIIIRAg). FVIII:C has anti-haemophilic activity and is defective or deficient in patients with classical haemophilia, and vWF:Ag is absent in patients with von Willebrand disease. FVIII:Ag was demonstrated recently in endothelial cells lining hepatic sinusoids, by using immunoperoxidase staining and light microscopy, whereas biochemical data had indicated its presence predominantly in the hepatocyte fractions and in lesser amounts in endothelial cells. Moreover, recent hybridization experiments detected FVIII:C messenger RNA in liver and kidney tissues. Despite several efforts, the cells responsible for FVIII:C synthesis have not been unequivocally identified. Here we use protein A-gold complex labelling to demonstrate the ultrastructural localization of FVIII:C in human liver cells; the results indicate that hepatocytes may synthesize FVIII:Ag.
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PMID:Ultrastructural localization of factor VIII procoagulant antigen in human liver hepatocytes. 393 86

Twenty-four total knee arthroplasties were performed in fourteen disabled patients with hemophilia. The average age of the patients at operation was thirty-five years. Twenty-one of the implants that were used were total condylar prostheses. Using The Hospital for Special Surgery knee-rating system after two to nine years of follow-up, the result in fifteen knees was rated as excellent; in six, as good; and in one, as fair. Two patients had a poor result that was attributable to late infection. Pain and function were markedly improved, and the average gain in range of motion was 23 degrees. Postoperative complications, in addition to the infections, included one subcutaneous hematoma, one hemolytic anemia, and one instance of inhibition to Factor VIII. The technical problems in treatment were formidable. Total knee arthroplasty in a hemophiliac can be successful, but it should be performed only with strict hematological supervision. The surgeon should be prepared to treat many potential postoperative complications.
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PMID:Total knee arthroplasty in hemophilia. 393 51

Factor VIII Leiden is a genetic variant of coagulation factor VIII which has been detected in the plasma of a patient with mild haemophilia A. In this patient's plasma factor VIII procoagulant antigen was in 5-fold excess over factor VIII procoagulant activity, indicating the presence of an abnormal factor VIII molecule. The variant factor VIII was isolated from the patient's plasma, and its functional properties were studied in a factor X-activating system consisting of purified components. The isolated factor VIII Leiden was normally activated by factor Xa and by thrombin, but the activity of the factor VIIIa was about 3% of normal. The defect of factor VIIIa Leiden was studied by comparison with normal factor VIIIa in kinetic experiments of factor Xa formation. The results support the hypothesis that factor VIIIa Leiden has a reduced affinity for phospholipid-bound factor IXa in the intrinsic factor X-activating complex.
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PMID:The functional defect of factor VIII Leiden, a genetic variant of coagulation factor VIII. 393 62

The authors reported a case of subacute subdural hematoma in a 14-month-old child suffering from mild hemophilia (Factor VIII, activity: 2.5%). Removal of hematoma under the cover of replacement therapy has been performed safely and has led to recovery without any clinical sequelae. Computerized tomography appeared very useful as an atraumatic method of examination in hemophiliacs. Discussion deals with the problems associated with management of intracranial hemorrhages in hemophiliacs and emphasizes the need of prompt adequate medical and surgical treatment to prevent irreversible damage to the brain.
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PMID:Subacute subdural hematoma as the first symptom in a child with hemophilia A. 406 Oct 21

Factor VIII in preparations from normal plasma is a large glycoprotein of greater than 2 million molecular weight which elutes in the exclusion volume of 4% agarose gels at an ionic strength of 0.15. Recent studies have demonstrated that the factor VIII in canine and bovine plasma is a macromolecular complex composed of a large inert carrier protein and a noncovalently bound small fragment which contains the procoagulant active site. This complex is dissociable in 0.25 M CaCl(2), and conditions for its recombination have been reported. The present study reports the dissociation characteristics of normal human factor VIII preparations in 0.25 M CaCl(2) and the ability to achieve quantitative recombination of the dissociated fragments of normal human and bovine factor VIII after the removal of Ca(2+). The recombination technique was used to characterize further the defect in hemophilia and von Willebrand's disease. Void volume preparations from human hemophilia A(-), canine hemophilia A, and human von Willebrand's plasma, with no factor VIII procoagulant activity, were mixed with the small active fragment prepared from the normal plasma of their respective species. Chromatography of the three mixtures in agarose gel showed that the fractions from the human hemophilic plasmas contained a molecule that bound the small active normal fragment, but neither the fractions from canine hemophilia A plasmas nor the fractions from the human von Willebrand's plasmas demonstrated evidence of such material. These data suggest that there is present in human hemophilia A plasma a normal functional carrier molecule which is absent or nonfunctional in the plasma of hemophilic dogs and humans with von Willebrand's disease.
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PMID:The defect in hemophilic and von Willebrand's disease plasmas studied by a recombination technique. 421 56

Two new monoclonal antibodies (M.Abs) 4F91C5 and 202D3 which are capable of inhibiting ristocetin cofactor activity have been raised against high molecular weight detergent denatured Factor VIII/von Willebrand preparations. Characterized in a simple solid phase radioimmune binding assay (RIA) the binding activity of the two M.Abs can be shown to be absorbed by normal plasma, and plasma from type A hemophilia patients but not by plasma from patients suffering from severe von Willebrand disease. Both monoclonal antibodies are capable of inhibiting strongly the FVIII.vWF associated ristocetin cofactor activity. Competition radioimmune assays have shown that the two monoclonal antibodies recognize different epitopes on the Factor VIII/vWF molecule. This has been confirmed by the differential binding of the two M.Abs observed to monkey plasma. Whilst inhibition curves for the two M.Abs with normal plasma and FVIII/vWF preparations in solid phase RIA are similar, quite different reactivities with commercially available F VIII preparations have been found. The high sensitivity of these reagents for the FVIII/vWF molecule and their ability to inhibit strongly the associated biological activity suggest the potential usefulness of these monoclonal antibodies as diagnostic reagents.
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PMID:Monoclonal antibodies against the human factor VIII von Willebrand molecule: characterization and potential for screening of von Willebrand patients. 608 22

Factor VIII related antigen has been measured and epitope distribution has been explored by testing the degree of parallelism between standard and test plasma dose response curves using an enzyme immunoassay. Normal plasma, plasma fractions, and plasma from patients with haemophilia and von Willebrand's disease have been tested. All showed parallelism except for plasma from patients with the variant type IIA von Willebrand's disease, of which 10 had parallel and five had non-parallel dose response curves when compared with that of normal plasma. In one family plasma from seven members showed parallelism but from four others did not. An unrelated patient was tested on three occasions, and although the samples were parallel to each other, no sample was parallel to the standard. No correlation was found between parallelism as shown by the enzyme immunoassay and differences in factor VIII related antigen multimeric pattern, including triplet configuration, seen in the type IIA patients.
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PMID:Lack of correlation between factor VIII related antigen multimeric analysis pattern and parallel or non-parallel dose response curves in an ELISA factor VIII related antigen assay. 619 41

Factor VIII (FVIII) procoagulant activity is the function of a plasma glycoprotein that is missing or inactive in patients with classic hemophilia. Numerous studies have shown that trace thrombin causes rapid enhancement followed by gradual inactivation of FVIII procoagulant activity. Recent evidence suggests that thrombin activation of the FVIII/von Willebrand factor (vWF) protein is required for inactivation to occur. All of these studies have used the one-stage partial thromboplastin time to assay FVIII activity. Other investigators have used the two-stage assay of FVIII activity and have been unable to demonstrate thrombin-induced enhancement of FVIII activity, although inactivation has consistently occurred. We performed experiments designed to help resolve this disagreement, using the two-stage assay specifically modified to detect thrombin potentiation of FVIII activity. The length of the first-stage incubation time was found to be critical in demonstrating the initial effect of thrombin on FVIII activity. Taking advantage of this finding we were able to show a 4.1 +/- 0.5-fold enhancement of FVIII activity upon incubating purified FVIII/vWF with 0.04 NIH unit thrombin per ml. The apparent enhancement of FVIII activity declined with increasing thrombin concentration. Incubation with 0.08, 0.16, and 0.32 NIH unit thrombin per ml resulted in only 3.2 +/- 0.5, 2.6 +/- 0.5 and 1.5 +/- 0.3-fold enhancement, respectively, of FVIII activity. As with results from the one-stage assay, activation was followed by slow inactivation of FVIII/vWF. Using the two-stage assay we also showed 100% inactivation and 100% inhibition of FVIII activity by plasmin and human anti-FVIII IgG, respectively. Plasmin inactivation of FVIII activity showed a dose-response effect. Thrombin was unable to activate plasmin-degraded FVIII/vWF. Our results show that thrombin potentiation of FVIII activity is easily demonstrable in the two-stage assay. These findings support the contention that activation of FVIII activity by thrombin is prerequisite for inactivation and underscore the importance of thrombin activation of FVIII/vWF in the intrinsic clotting system.
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PMID:Thrombin potentiation of factor VIII procoagulant activity: assessment by the two-stage assay. 621 66


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