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Biomedical subjects

L W Hoyer

Publications and source records attributed to L W Hoyer.

At least 55 records · Page 3Linked to original sources
PubMed1987

Molecular pathology and immunology of factor VIII (hemophilia A and factor VIII inhibitors).

Factor VIII is a large procoagulant glycoprotein that circulates in plasma in a noncovalent complex with von Willebrand factor. It is essential for the efficient cleavage of coagulation factor X by factor IXa, and its absence causes a severe bleeding disorder. Plasma factor VIII is reduced from the normal range of approximately 100 to 200 ng/ml in patients with the hereditary coagulation defect, hemophilia A, as well as in patients who develop autoantibodies that inactivate factor VIII. The understanding of factor VIII structure has been enhanced by recent studies that have characterized the X chromosome gene responsible for its synthesis, and preliminary information is now available about specific genetic defects. The basis for antibody formation in approximately 15 per cent of repeatedly transfused hemophilic patients is less clear at this time, however, for these individuals appear to have a variety of genetic defects that are not characteristically different from the patients who do not develop inhibitors. Although the antibodies cause a serious problem for affected individuals, they have been very useful in characterizing normal factor VIII and nonfunctional factor VIII-like protein that is found in the plasmas of 10 per cent of patients with mild hemophilia. Moreover, they are very useful reagents that can be used for immunoassay of factor VIII that has been modified in ways that have destroyed its procoagulant function.

Chemical Phenomena↗
PubMed1987

von Willebrand factor abnormalities in primary pulmonary hypertension.

In primary pulmonary hypertension of recent clinical onset, pulmonary endothelial cells show injury. To characterize this phenomenon, we measured plasma von Willebrand factor (vWF) by immunologic and ristocetin cofactor assays in 6 patients with primary pulmonary hypertension, 17 patients with secondary pulmonary artery hypertension associated with congenital heart disease or cystic fibrosis, and 13 patients with congenital heart disease and normal pulmonary artery pressure. In selected cases, we also determined the vWF multimer pattern. In all 6 cases of primary pulmonary hypertension, the ristocetin cofactor activity was increased relative to the vWF antigen (vWF:Ag) concentration (a ratio of 2.55 +/- 0.36; normal range, 0.8 to 1.4); 4 of the 6 also had a similar and abnormal vWF multimer pattern--an increased proportion of the fastest moving bands. In the other 2, the multimer pattern was normal. Of the other 30 patients, a mild increase in ristocetin cofactor/vWF:Ag was seen in only 2 with secondary pulmonary hypertension and 1 with normal pulmonary artery pressure: these also had an abnormal vWF multimer pattern that was different from that observed in patients with primary pulmonary hypertension. The vWF abnormalities we describe in primary pulmonary hypertension offer a marker of the disease and could be helpful in understanding its pathogenesis.

Cystic Fibrosis↗
PubMed1986

Localization of binding sites within human von Willebrand factor for monomeric type III collagen.

Purified human plasma von Willebrand factor (vWf) binds to pepsin-digested monomeric type III collagen in a saturable (KD = 1 X 10(-8) M), specific, and rapid manner with a stoichiometry of approximately 1:15 [vWf subunit (Mr 270,000):collagen trimer (Mr 300,000)]. Two reduced and alkylated CNBr peptides of vWf, termed M11 residues 542-622 and M20 residues 948-998 [Titani, K., Kumar, S., Takio, K., Ericsson, L. H., Wade, R. D., Ashida, K., Walsh, K. A., Chopek, M. W., Sadler, J. E., & Fujikawa, K. (1986) Biochemistry 25, 3171-3184], inhibited vWf binding to collagen. With 125I-vWf (2 X 10(-9) M) as ligand, M11, M20, fragment III (a dimeric, V8 protease, NH2-terminal fragment, Mr 320,000 referenced above), and unlabeled vWf inhibited binding to collagen with EC50 values of 4.8 X 10(-7), 9.4 X 10(-7), 1.1 X 10(-7), and 0.2 X 10(-7) M, respectively. M11 and M20 bind to collagen directly when 125I-labeled peptides are used as ligands. Other CNBr fragments of vWf were less effective as inhibitors (5-fold or less) and bound less avidly to collagen (5-fold or less) compared to M11 and M20. A murine anti-human vWf monoclonal antibody (MR5), which blocks the binding of vWf to collagen, bound selectively to both M11 and M20 when tested in an enzyme-linked immunoadsorbent assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1986

von Willebrand factor and platelet function.

The complex interactions of platelets, von Willebrand factor (VWF), and vascular endothelium have been explored by many investigators during the last decade. With the development of better methods to assess these components has come an increased recognition of diseases associated with defects in the platelet-VWF interaction. Moreover, alternative therapeutic approaches have become available for the clinician who treats patients with disorders of VWF function.

Aminocaproic Acid↗
PubMed1985

Multicenter comparison of von Willebrand factor multimer sizing techniques. Report of the Factor VIII and von Willebrand Factor Subcommittee.

A multicenter study of various types of von Willebrand's disease (vWD) was conducted in order to compare the different electrophoretic techniques used to evaluate von Willebrand factor multimers in plasma. Seven laboratories participated in the blind study of eight plasma samples from two healthy subjects and six vWD types and subtypes (Ia, Ib, IIA, IIB, IIC and IID). From the results of the multimeric analysis of these samples, it appears that the differential diagnosis of vWD types and subtypes should be first approached by using a low-resolution electrophoretic technique, where each vWF multimer appears as a single band. Low-resolution techniques differentiate type I from type II, subtype Ia from Ib and also subtype IIA from other type II subtypes. When type II subtypes other than IIA are identified with these techniques, samples should be rerun using high resolution techniques that resolve each of the fastest migrating multimers in at least three subbands, and permit the differentiation of subtypes IIB, IIC and IID.

Electrophoresis, Agar Gel↗
PubMed1985

Prenatal diagnosis of haemophilia A by factor VIII gene analysis.

Cloned factor VIII deoxyribose nucleic acid (DNA) sequences were used as probes in the prenatal diagnosis of haemophilia A. Fetal DNA from cultured amniotic fluid cells was examined for a DNA polymorphism within the factor VIII gene which marked the haemophilia A gene in the pregnant obligate carrier. The fetus was predicted to be an affected male, and the diagnosis of haemophilia A was confirmed both in utero and after termination of the pregnancy.

Adult↗
PubMed1985

The effect of 1-deamino 8 D-arginine vasopressin (DDAVP) in a nonhaemophilic patient with an acquired type II factor VIII inhibitor.

DDAVP (1-deamino 8 D-arginine vasopressin) was administered on two occasions to a patient with an acquired factor VIII inhibitor. Because the patient's autoantibody was low titre (1.8 Bethesda units) and had type II kinetic properties, it was expected that endogenous factor VIII/VWF released by DDAVP would be inactivated at a slow enough rate to permit satisfactory haemostasis during dental procedures. In both instances there was a 7-9-fold increase in factor VIII above the baseline level (13 units/dl), and factor VIII activity remained above 35 units/dl for 5 h after the infusion. The inhibitor could not be detected in his plasma during this period and the activated PTT was shortened into the normal range. Our experience with this patient suggests that DDAVP has a role in the management of some patients with low titre autoantibodies that inactivate factor VIII.

Arginine Vasopressin↗
PubMed1985

Response of patients with mild and moderate hemophilia A and von Willebrand's disease to treatment with desmopressin.

Desmopressin was administered intravenously to 68 patients with hemophilia and von Willebrand's disease of mild or moderate severity to assess the safety, reproducibility, and range of response to this new therapeutic alternative. A rise in factor VIII-von Willebrand factor levels was seen in 64 patients, and the magnitude was sufficient to provide normal hemostasis in 55 to 68 spontaneous or traumatic bleeding episodes, dental procedures, or operations. Thus, our experience shows that most patients with mild or moderate hemophilia and von Willebrand's disease can be treated effectively without plasma derivatives. Patients who had two or more infusions of desmopressin at different times had similar responses each time, and members of the same family also had similar responses after desmopressin infusions. Because this drug can be administered without significant side effects, it should have an important role in the management of patients with mild or moderate hemophilia and von Willebrand's disease.

Adolescent↗
PubMed1985

Prenatal diagnosis of classic hemophilia (hemophilia A) by immunoradiometric assays.

During the period from 1978 to 1983, 92 pregnancies have been evaluated by fetoscopy for the prenatal diagnosis of hemophilia A. Satisfactory fetal plasma samples were obtained in 80 instances and the diagnosis--or exclusion--of hemophilia was made by immunoradiometric assay of the factor VIII coagulant protein (VIII:CAg). The accuracy of the diagnosis established by fetoscopy has been verified after delivery or termination, and there have been no misdiagnoses resulting from laboratory error. Additional evidence for the accuracy of the analysis was the observation that the frequency of hemophilia in pregnancies of obligate carriers of the hemophilia gene, and of women whose plasma assays were indicative of the carrier state, was 29 of 59 fetuses at risk. In one case of cross-reacting material-positive hemophilia, samples obtained at fetoscopy and from the newborn infant had normal VIII:CAg levels but the infant had decreased factor VIII procoagulant activity. There were five fetal deaths resulting from fetoscopy in 55 pregnancies not intentionally terminated. Although only a small percentage of pregnant hemophilia carriers in the United States have elected to undergo fetoscopy for prenatal diagnosis, this procedure has allowed a number of pregnancies to go to term with delivery of normal males in families that were not willing to accept the risk of a hemophilic child. In eight instances, fetoscopic evaluation was sought for two successive pregnancies.

Antigens↗
PubMed1984

New alternatives and strategies in the treatment of inhibitors.

It is clear that the challenge of factor VIII and factor IX inhibitors requires a multi-faceted approach. The emphasis on new data at this symposium has indicated that there are a number of ideas that are ready for laboratory and clinical testing. These opportunities will be explored as new approaches are considered for the identification of hemophiliacs at risk of inhibitor formation, the modification of the immune response in inhibitor patients and the treatment of inhibitor patients in a way that achieves more satisfactory hemostasis.

Antigens↗
PubMed1984

Immunochemical characterization of factor VIII inhibitors.

Factor VIII inhibitors are antibodies, predominantly of the IgG class, that inactivate factor VIII procoagulant activity. They do not fix complement and cannot be detected by standard immunoprecipitin assays. Their immunochemical properties are unusual, for the alloantibodies have consistent light chain restriction (kappa) and most allo- and auto- anti-VIII:C are predominantly or exclusively IgG4. This property may be responsible for the lack of complement fixation and immunoprecipitation. Human anti-VIII:C react with several different VIII:C antigenic determinants, and recent studies have begun to characterize the major epitopes. In addition, anti-VIII:C idiotypes have been identified using both rabbit anti-idiotype serum and monoclonal antibodies. These reagents provide a new way to obtain more precise immunochemical characterization.

Antigen-Antibody Complex↗
PubMed1984

The idiotypic characteristics of human antibodies to factor VIII.

We have prepared an antiidiotype antibody that specifically reacts with and inactivates a human autoantibody to factor VIII (VIII:C). The antiidiotype specificity of this rabbit antibody was evident in solution, as specific inhibition of anti-VIII:C activity, and in solid-phase studies. The antiidiotype antibody inhibited both plasma anti-VIII:C and Fab' fragments prepared from that plasma's IgG. Although the antibody had a greater inhibitory effect on the anti-VIII:C used for immunization than it did for other anti-VIII:C, partial inhibition was identified with ten of 25 other human anti-VIII:C. The demonstration that antiidiotype antibodies can be prepared to human anti-VIII:C indicates the feasibility of this approach to the immunochemical characterization of human anti-VIII:C inhibitors. Moreover, antiidiotype reagents have a potential role in the treatment of inhibitor patients.

Absorption↗