scholarly journals Heterogeneity of the Factor VIII/Von Willebrand Factor Protein in Von Willebrand’s Disease

1977 ◽  
Author(s):  
H. R. Gralnick ◽  
Y. Sultan ◽  
B. S. Coller
Keyword(s):  
Molecular Weight ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Apparent Molecular Weight ◽  
Total Carbohydrate ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Parallel Reduction ◽  
Von Willebrand ◽  
Willebrand Factor

The recent advent of techniques to purify the factor VIII/von Willebrand factor (f.VIII/vWf) protein from plasma to quantitate the f.VIII/vWf protein and to measure the vWf (plasma ristocetin cofactor) have greatly added to our understanding of von Willebrand’s disease (vWd). The initial studies of antigen, procoagulant and vWf levels revealed a parallel reduction in all three activities in vWd suggesting a quantitative deficiency of the f. VIII/vWf protein and its biologic activities.Recent studies, however, have suggested three major forms of vWd. The first group of patients have a quantitative defect with a parallel reduction of the f.VIII/vWf protein and of the antigen, vWf and procoagulant activities. The second group of patients appear to have a qualitative defect of the f.VIII/vWf protein. These individuals have normal levels of the antigen and procoagulant activity; however, the vWf activity is reduced or absent. The third group of patients have a combination of a qualitative and quantitative deficiency. These variants resemble both previous groups in that there are reduced levels of the antigen, procoagulant and vWf activities but usually greater reduction of the vWf activity.Three major defects of the f.VIII/vWf protein have been recognized in vWd: 1) decreased plasma concentration of the f. VIII/vWf protein, 2) the apparent molecular weight of the protein is reduced and/or the largest molecular weight polymers are absent, and 3) there is a partial or total carbohydrate deficiency. For the f.VIII/vWf protein to express vWf activity, it must be of a minimal molecular size and have a specific carbohydrate content and/or sequence.

Current Knowledge of the AHF-Like Antigen

1975 ◽  
Author(s):  
Dominique Meyer
Keyword(s):  
Molecular Weight ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Hemophilia A ◽  
Factor Activity ◽  
Factor Viii Activity ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Factor VIII and von Willebrand Factor activities are associated with a high molecular weight protein which can be isolated from plasma and may be studied by immunological methods. Homologous antibodies to Factor VIII are directed towards the active site of the Factor VIII molecule; they do not neutralize Willebrand Factor activity and do not precipitate with normal plasma. The use of such antibodies has allowed the distinction between Hemophilia A+ and A-. Specific precipitation of Factor VIII antibodies using polyethylene glycol will be reported, allowing typing of heavy and light chains of purified antibodies. Heterologous antisera prepared in rabbits against purified human Factor VIII complex neutralize Factor VIII and von Willebrand Factor activities and precipitate with AHF-like antigen. Estimation of this antigen in plasma has allowed (1) the differenciation of the molecular abnormalities in Hemophilia A and classical von Willebrand’s disease; (2) the comparison between normal and Hemophilic AHF-like antigen; (3) the detection of carriers of Hemophilia A; (4) the study of variants of von Willebrand’s disease; (5) the demonstration of this antigen in platelets and in endothelial cells. Factor VIII activity and AHF-like antigen are probably separate entities, circulating as a complex in normal plasma, as suggested by the following experiments: transfusion studies in von Willebrand’s disease; immuno-adsorption studies; comparison of Factor VIII complex in cryoprecipitate and supernatant; and dissociation in high salt buffer, demonstrating that Factor VIII includes two biologically linked but distinct fragments, of high (HMW) and low (LMW) molecular weight. The non functional HMW subunit, controlled by an autosomal locus, is identified by the presence of AHF-like antigen and Willebrand Factor activity. The LMW subunit, product of an X-chromosome locus, does not contain AHF-like antigen, but it carries Factor VIII activity, as demonstrated by the following facts: inactivation by both human and rabbit antibodies to Factor VIII; transient activation by thrombin; obtention of antisera which specifically inactivate Factor VIII.

scholarly journals Properties of the Platelet Retention (von Willebrand) Factor and Its Similarity to the Antihemophilic Factor (AHF)

Blood ◽  
1973 ◽  
Vol 41 (6) ◽  
pp. 809-815 ◽  
Author(s):  
Harvey J. Weiss ◽  
John Rogers ◽  
Harvey Brand
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Apparent Molecular Weight ◽  
Retention Factor ◽  
Void Volume ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Antihemophilic Factor

Abstract The abnormal retention of platelets in glass-bead filters in von Willebrand’s disease was corrected by a fraction of normal cryoprecipitate that eluted, along with antihemophilic factor (AHF), in the void volume after chromatography on Bio-Gel 5 M. This platelet retention factor had an apparent molecular weight in excess of 5 x 106, was also present in hemophilic cryoprecipitate, but was not detectable in the void volume fractions of cryoprecipitate prepared from the plasma of a patient with von Willebrand’s disease. The adsorptive and thermal stability properties of the retention (von Willebrand) factor were similar to those of AHF. Platelet retention is the result of a complex interaction between red cells, platelets, and the von Willebrand factor, and it is suggested that the activity of the latter factor may be associated with the same high molecular weight protein that possesses coagulant (AHF) activity in normal subjects but that lacks this activity in hemophiliacs. The deficiency of this protein in von Willebrand’s disease may account for the hemostatic defect in this disorder.

scholarly journals Characterization of the defect of the factor VIII/von Willebrand factor protein in von Willebrand's disease

Blood ◽  
1982 ◽  
Vol 59 (3) ◽  
pp. 542-548 ◽  
Author(s):  
HR Gralnick ◽  
MC Cregger ◽  
SB Williams
Keyword(s):  
Sialic Acid ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Platelet Rich Plasma ◽  
Molecular Forms ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Platelet Receptor ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The factor VIII/von Willebrand factor (f.VIII/vWf) protein was purified from the plasma of a patient with von Willebrand's disease (vWd). The patient had all of the classic laboratory findings of vWd except for the ristocetin-induced platelet aggregation of his own platelet-rich plasma. The disease has been documented in three generations. Comparison of the purified normal and vWd f.VIIi/vWf protein revealed several abnormalities, including decreased concentration of f.VIII/vWf antigen; decreased specific vWf activity; absence of the larger molecular forms of the f.VIII/vWf protein; carbohydrate deficiencies affecting the sialic acid, penultimate galactose and N- acetylglucosamine moieties; and decreased binding of the f.VIII/vWf protein to its platelet receptor. These studies indicate the multiplicity of biochemical and functional abnormalities associated with the f.VIII/vWf protein in vWd. f.VIII/vWf protein to normal f.VIII/vWf protein that had been treated with 2-mercaptoethanol (2-ME) to reduce the multimer size and then treated with specific exoglycosidases to remove the sialic acid and penultimate galactose residues revealed similar biologic properties.

scholarly journals DDAVP in type IIa von Willebrand's disease

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 465-468 ◽  
Author(s):  
HR Gralnick ◽  
SB Williams ◽  
LP McKeown ◽  
ME Rick ◽  
P Maisonneuve ◽  
...  
Keyword(s):  
Factor Viii ◽  
Protease Inhibitors ◽  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Time Period ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

Abstract 1-D-Amino(8-D-arginine)-vasopressin (DDAVP) infusion in three patients with type IIa von Willebrand's disease (vWD) resulted in a normalization of the factor VIII coagulant, factor VIII-related antigen, and von Willebrand factor (vWF) (ristocetin cofactor) activities and the bleeding time. The normalization of these hemostatic parameters persisted for four hours. Over the same time period there was a marked increase in the quantity of the vWF multimers when blood was collected in the presence of protease inhibitors. The vWF multimers present were even larger than the normal. When blood was collected in the absence of protease inhibitors, a smaller increase in the plasma vWF multimers was observed and fewer of the intermediate and larger vWF multimers were seen; multimers larger than those present in normal plasma were not visualized. The platelet vWF multimers and activities did not change with or without inhibitors. These studies suggest that there is a subgroup of patients with type IIa vWD who respond to DDAVP with complete normalization of their hemostatic abnormalities and whose vWF is sensitive to proteolysis.

scholarly journals Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand's disease subtypes

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1272-1278 ◽  
Author(s):  
ZM Ruggeri ◽  
PM Mannucci ◽  
R Lombardi ◽  
AB Federici ◽  
TS Zimmerman
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Resting State ◽  
Bleeding Time ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Plasma Factor ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We have studied the modifications in the multimeric composition of plasma factor VIII/von Willebrand factor and the bleeding time response following administration of 1-Deamino-[8-D-arginine]-Vasopressin (DDAVP) to patients with different subtypes of von Willebrand's disease. In type I, all multimers were present in plasma in the resting state, though they were decreased in concentration. Administration of DDAVP resulted in an increased concentration of these forms as well as the appearance of larger forms than were previously present. There was concomitant correction of the bleeding time. In type IIA, large multimers were absent in the resting state, and although DDAVP induced an average threefold increase in the plasma concentration of factor VIII/von Willebrand factor, the larger multimers did not appear and the bleeding time, although shortened, was not corrected. In contrast, the larger multimers that were also absent from type IIB plasma in the resting state rapidly appeared following DDAVP administration. However, their appearance was transitory and the bleeding time, as in IIA patients, was shortened but not corrected. The characteristic multimeric composition of platelet factor VIII/von Willebrand factor in given subtypes predicted the alteration in plasma factor VIII/von Willebrand factor induced by DDAVP. These studies provide evidence that the different subtypes of von Willebrand's disease represent distinct abnormalities of factor VIII/von Willebrand factor. They also suggest that complete hemostatic correction following DDAVP can be routinely expected only in type I von Willebrand's disease, and only if factor VIII/von Willebrand factor can be raised to normal levels.

scholarly journals The complex multimeric composition of factor VIII/von Willebrand factor

Blood ◽  
1981 ◽  
Vol 57 (6) ◽  
pp. 1140-1143 ◽  
Author(s):  
ZM Ruggeri ◽  
TS Zimmerman
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Sodium Dodecyl ◽  
Factor Vii ◽  
Buffer System ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand ◽  
Willebrand Factor

We have analyzed the multimeric structure of factor VIII/von Willebrand factor in plasma by sodium dodecyl sulfate electrophoresis using gels of varying porosity and a discontinuous buffer system. Factor VIII/von Willebrand factor bands were identified by reaction with 125I-labeled affinity-purified antibody and subsequent autoradiography. In 1% agarose gels, normal plasma displayed a series of sharply defined oligomers. However, increasing the agarose concentration to 2.0% or utilizing mixtures of 0.8% agarose--1.75% acrylamide revealed two bands of lesser intensity interposed between the major bands. When the acrylamide concentration in the gels was increased to 2.5%, bands with a faster mobility than IgM and fibronectin were now evident. Type IIA von Willebrand's disease showed not only an absence of the larger multimers but also a relative increase in several of the newly identified bands as compared to type IIB, type I, and normal. These studies suggest that factor VII/von Willebrand factor in IIA von Willebrand's disease is structurally different from that in other forms of the disorder. They also indicate that the multimeric composition of factor VII/von Willebrand factor is more complex than can be explained by simple linear polymerization of a single protomer.

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