Hyper-responsiveness to DDAVP for patients with type I von Willebrand's disease and normal intra-platelet von Willebrand factor

2009 ◽  
Vol 40 (2) ◽  
pp. 163-167 ◽  
Author(s):  
F. Rodeghiero ◽  
G. Castaman ◽  
E. Bona ◽  
M. Ruggeri ◽  
R. Lombardi ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand ◽  
Willebrand Factor

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 Platelet von Willebrand factor: an important determinant of the bleeding time in type I von Willebrand's disease

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 58-61 ◽  
Author(s):  
HR Gralnick ◽  
ME Rick ◽  
LP McKeown ◽  
SB Williams ◽  
RI Parker ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Time Factors ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen ◽  
Ristocetin Cofactor

Abstract We studied 17 patients with moderate to mild type I von Willebrand's disease (vWd) and correlated the bleeding time with the plasma von Willebrand factor antigen (vWf Ag), the plasma vWf activity (ristocetin cofactor), the platelet vWf Ag, and the platelet vWf activity. We found an excellent correlation between the bleeding time and the platelet vWf activity and, to a lesser extent, between the bleeding time and the platelet vWf Ag. The length of the bleeding time was inversely proportional to the level of the platelet vWf (P less than .001) or, to a lesser extent, the platelet vWf Ag (P less than .05). The plasma vWf Ag and activity did not correlate significantly with the bleeding time. These studies indicate that the platelet vWf is one of the important bleeding time factors in type I vWd and that the platelet vWf plays an important role in the early steps of hemostasis.

scholarly journals Type IIB von Willebrand's disease: differential clearance of endogenous versus transfused large multimer von willebrand factor

Blood ◽  
1982 ◽  
Vol 60 (6) ◽  
pp. 1453-1456 ◽  
Author(s):  
ZM Ruggeri ◽  
R Lombardi ◽  
L Gatti ◽  
R Bader ◽  
C Valsecchi ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Arginine Vasopressin ◽  
Binding Sites ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Molecular Abnormality ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Abnormal Tissue

The abnormal multimeric composition of plasma von Willebrand factor in type IIB von Willebrand's disease is transiently corrected after infusion of 1-deamino-[8-D-arginine]-vasopressin. However, the larger multimers released into the circulation disappear more rapidly in these patients than in type I von Willebrand's disease or normals. We demonstrate that the larger multimers of normal von Willebrand factor transfused into a type IIB patient are cleared from the circulation more slowly than multimers of similar size endogenously released from tissue stores. The rate of disappearance of large von Willebrand factor multimers after infusion of cryoprecipitate is similar in IIB, IIA, and severe homozygous-like von Willebrand's disease. Platelets from the IIB patient exhibited normal ristocetin-induced binding of normal von Willebrand factor. However, like normal platelets, they bound IIB von Willebrand factor at lower ristocetin concentrations than required for normal von Willebrand factor. These findings provide evidence that absence of the larger multimers from IIB plasma is related to a molecular abnormality of von Willebrand factor rather than to enhanced affinity of abnormal tissue or cellular binding sites, as is the case in the recently described “pseud” von Willebrand's disease and “platelet-type” von Willebrand's disease.

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.

scholarly journals Type IIB von Willebrand's disease: differential clearance of endogenous versus transfused large multimer von willebrand factor

Blood ◽  
1982 ◽  
Vol 60 (6) ◽  
pp. 1453-1456 ◽  
Author(s):  
ZM Ruggeri ◽  
R Lombardi ◽  
L Gatti ◽  
R Bader ◽  
C Valsecchi ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Arginine Vasopressin ◽  
Binding Sites ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Molecular Abnormality ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Abnormal Tissue

Abstract The abnormal multimeric composition of plasma von Willebrand factor in type IIB von Willebrand's disease is transiently corrected after infusion of 1-deamino-[8-D-arginine]-vasopressin. However, the larger multimers released into the circulation disappear more rapidly in these patients than in type I von Willebrand's disease or normals. We demonstrate that the larger multimers of normal von Willebrand factor transfused into a type IIB patient are cleared from the circulation more slowly than multimers of similar size endogenously released from tissue stores. The rate of disappearance of large von Willebrand factor multimers after infusion of cryoprecipitate is similar in IIB, IIA, and severe homozygous-like von Willebrand's disease. Platelets from the IIB patient exhibited normal ristocetin-induced binding of normal von Willebrand factor. However, like normal platelets, they bound IIB von Willebrand factor at lower ristocetin concentrations than required for normal von Willebrand factor. These findings provide evidence that absence of the larger multimers from IIB plasma is related to a molecular abnormality of von Willebrand factor rather than to enhanced affinity of abnormal tissue or cellular binding sites, as is the case in the recently described “pseud” von Willebrand's disease and “platelet-type” von Willebrand's disease.

Platelet Adhesion to Collagen in Subtypes of Type I von Willebrand’s Disease Is Dependent on Platelet von Willebrand Factor

1990 ◽  
Vol 64 (02) ◽  
pp. 227-231 ◽  
Author(s):  
Patrizia d'Alessio ◽  
Jaap Jan Zwaginga ◽  
Hetty C de Boer ◽  
Augusto B Federici ◽  
Francesco Rodeghierio ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Type I ◽  
Fibrillar Collagen ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Perfusion Studies ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Normal Controls

SummaryVon Willebrand’s disease type I, characterized by low levels of factor VIII coagulant activity (VTII :C), von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activity (RiCof) (1), can be subdivided on the basis of platelet von Willebrand factor into subtype platelet normal, platelet discordant, and platelet low (2). We have investigated the contribution of platelet von Willebrand factor in these various subtypes to platelet adhesion using the rectangular perfusion chamber of Sakariassen et al. (3) with fibrillar collagen or a fibroblast matrix as adhesive surfaces. Platelet adhesion to fibrillar collagen was decreased in all subtypes of von Willebrand’s disease, but not as low as in severe von Willebrand’s disease. A close correlation was observed between platelet adhesion to collagen and plasma vWF:Ag in severe von Willebrand’s disease, subtype platelet low, subtype platelet discordant, and normal controls. The platelet adhesion in subtype platelet normal was higher than expected from the plasma vWF: Ag level. Perfusions in which washed platelets were added to a human albumin solution together with red blood cells gave similar adhesion values in subtype platelet normal and normal controls; adhesion was decreased in subtype platelet discordant, and the lowest values were found in subtype platelet low and in severe von Willebrand’s disease. These data indicate that platelet von Willebrand factor may contribute to platelet adhesion, when plasma von Willebrand factor is low. Perfusion studies over a fibroblast matrix gave similar low adhesion values for subtype platelet low and platelet normal, indicating that the contribution of platelet von Willebrand factor can only be observed on a strongly activating surface such as fibrillar collagen.

Von Willebrand Factor Antigen Is Less Sensitive than Ristocetin Cofactor for the Diagnosis of Type I von Willebrand Disease -Results Based on an Epidemiological Investigation

1990 ◽  
Vol 64 (03) ◽  
pp. 349-352 ◽  
Author(s):  
Francesco Rodeghiero ◽  
Giancarlo Castaman ◽  
Alberto Tosetto
Keyword(s):  
Von Willebrand Factor ◽  
Type I ◽  
Epidemiological Investigation ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand Factor Antigen ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen ◽  
Ristocetin Cofactor

SummaryRecently, in an epidemiological investigation involving 1,218 children aged 11-14, we demonstrated that the prevalence of von Willebrand’s disease, based on a low ristocetin cofactor activity (RiCof) in children with a personal and/or family history of hemorrhage, was at least 1% (Blood 1987; 69: 454). All the diagnosed cases had multimeric patterns typical of type I von Willebrand’s disease (vWd). Since standardization of RiCof is difficult and the test is not easily performed in a clinical laboratory, we measured von Willebrand factor antigen (vWf: Ag) in all available unthawed plasma samples of previously investigated children by ELISA, to assess the relative sensitivity of this more simple test for diagnosing vWd.Separate normal ranges were calculated by non-parametric methods for 0 and non-0 subjects, and for children and adults, since values were higher in non-0 subjects and in children.Taking into account the 90% confidence interval around the lower limit of the normal range, 7 (50%) of the 14 cases diagnosed by RiCof were detected by vWf: Ag. Furthermore, two new cases would have been diagnosed by vWf: Ag, leading to a relative Ag/ RiCof global sensitivity of 64%. A similar figure was obtained when the two tests were compared in the group of relatives of the affected children.In conclusion, measurement of vWf: Ag seems to be definitely less sensitive than the RiCof assay for detecting patients with vWd, even in type I patients, and RiCof remains the test of choice for screening for vWd in hemorrhagic patients.

Mutations in Severe, Type III von Willebrand’s Disease in the Dutch Population: Candidate Missense and Nonsense Mutations Associated with Reduced Levels of von Willebrand Factor Messenger RNA

1992 ◽  
Vol 68 (04) ◽  
pp. 448-454 ◽  
Author(s):  
Jeroen C J Eikenboom ◽  
Hans K Ploos van Amstel ◽  
Pieter H Reitsma ◽  
Ernest Briët
Keyword(s):  
Von Willebrand Factor ◽  
Nucleotide Sequence Analysis ◽  
Polymorphism Analysis ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Type Iii ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Severe Type

SummaryThe von Willebrand factor (vWF) genes of nine unrelated, severe, type III von Willebrand’s disease (vWD) patients (six of Dutch origin) and four unrelated Dutch type I vWD patients were screened for mutations in exons that contain CGA codons (Arg), which are liable to mutation to TGA stop codons. The nine exons of the vWF gene (3, 8, 9, 10, 28, 31, 32, 43 and 45) that contain all the CGA codons (11 in total) of the vWF cDNA were amplified by the polymerase chain reaction and screened for mutations by single-strand conformation polymorphism analysis, restriction enzyme – and/or nucleotide sequence analysis. Three of the severe vWD patients were found to be heterozygous for a nonsense mutation: CGA Arg 2535 → TGA Stop. Three other severe vWD patients were homozygous for a single nucleotide substitution, AAC Asn 2546 → TAC Tyr. The transcription of these mutated alleles was tested by cDNA dependent amplification of platelet RNA. The level of transcription product was strongly reduced for either mutant allele.

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

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.

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