Ddavp-Induced Alterations In The Multimeric Composition Of Factor Viii/Von Willebrand Factor In Normal And Von Willebrand’S Disease Plasma

1981 ◽  
Author(s):  
Z M Ruggeri ◽  
R Lombardi ◽  
P M Mannucci ◽  
T S Zimmerman
Keyword(s):  
Plasma Concentration ◽  
Von Willebrand Factor ◽  
Resting State ◽  
Type I ◽  
Normal Complement ◽  
Normal Individuals ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Insight Into ◽  
Rapid Correction

DDAVP is known to induce increases in plasma FVIII/von Willebrand Factor (FVIII/vWF) concentration by release of tissue stores. We have now found that the multimeric composition of plasma FVIII/vWF alters following DDAVP administration to resemble that seen in platelets. Multimers were resolved by thin-layer SDS-agarose and SDS-agarose acrylamide electrophoresis and were identified by reaction of the fixed gels with 125I-laben ej antibody followed by autoradiography. Fifteen minutes after DDAVP infusion, larger multimers appeared in normal plasma than were present during the resting state. These larger multimers were also present in resting normal platelets, suggesting that DDAVP causes their release from tissue stores. In Type I von Willebrand s disease (vWd), there is a decreased quantity of circulating FVIII/vWF but the multi meric composition is normal in plasma and platelets. The response to DDAVP was qualitatively similar to that in normal individuals. In Type IIA vWd large multimers are absent both from plasma and platelets. Even though DDAVP induced a threefold rise in FVIII/vWF plasma concentration, these large forms did not appear. In 11B vWd only intermediate and small multimers are present in plasma but there is a normal complement of multimers in platelets. Following DDAVP there was a rapid correction of the plasma multimeric composition so that it was identical with the pattern seen in normals after DDAVP. However, this correction was transitory and the abnormal basal pattern soon reappeared. These disparate changes in plasma FVIII/vWF multimeric composition following DDAVP suggest that platelet FVIII/vWF is representative of releasable tissue stores. They also provide insight into the variable hemostatic response to this agent and suggest different pathogenic mechanisms for the vWa subtypes.

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 Proteolytic degradation of von Willebrand factor after DDAVP administration in normal individuals

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 173-176 ◽  
Author(s):  
J Batlle ◽  
MF Lopez-Fernandez ◽  
A Lopez-Borrasca ◽  
C Lopez-Berges ◽  
JA Dent ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Resting State ◽  
Relative Proportion ◽  
The Other ◽  
Proteolytic Degradation ◽  
Normal Individuals ◽  
Rapid Clearance ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adult Volunteers

Abstract The infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) in normal individuals is followed by an increase in factor VIII/von Willebrand factor (vWF) in plasma, by an increase in intensity of all sizes of multimers, and by the appearance of larger multimers of vWF than those seen in the resting state. Since the larger multimers are rapidly cleared and proteolysis is known to cause disaggregation of large multimers, we evaluated the degree of vWF proteolysis after DDAVP administration. DDAVP was infused into eight normal adult volunteers, and the relative proportions of the intact 225 kilodalton (kDa) subunit and the 189, 176, and 140 kDa vWF fragments were compared before and at different times after DDAVP infusion. The relative proportion of the 176 kDa fragment was increased, whereas that of the other species was decreased, thereby indicating that proteolytic fragmentation had occurred. However, plasmin did not appear to be responsible because the vWF fragments characteristically produced by this enzyme could not be detected. Concomitant analysis of vWF multimeric structure showed that these changes were accompanied by an increase in the relative proportion of the satellite bands, which suggests that they were proteolytically generated. Proteolysis may explain, at least in part, rapid clearance of larger vWF multimers released by DDAVP.

scholarly journals Proteolytic degradation of von Willebrand factor after DDAVP administration in normal individuals

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 173-176 ◽  
Author(s):  
J Batlle ◽  
MF Lopez-Fernandez ◽  
A Lopez-Borrasca ◽  
C Lopez-Berges ◽  
JA Dent ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Resting State ◽  
Relative Proportion ◽  
The Other ◽  
Proteolytic Degradation ◽  
Normal Individuals ◽  
Rapid Clearance ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adult Volunteers

The infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) in normal individuals is followed by an increase in factor VIII/von Willebrand factor (vWF) in plasma, by an increase in intensity of all sizes of multimers, and by the appearance of larger multimers of vWF than those seen in the resting state. Since the larger multimers are rapidly cleared and proteolysis is known to cause disaggregation of large multimers, we evaluated the degree of vWF proteolysis after DDAVP administration. DDAVP was infused into eight normal adult volunteers, and the relative proportions of the intact 225 kilodalton (kDa) subunit and the 189, 176, and 140 kDa vWF fragments were compared before and at different times after DDAVP infusion. The relative proportion of the 176 kDa fragment was increased, whereas that of the other species was decreased, thereby indicating that proteolytic fragmentation had occurred. However, plasmin did not appear to be responsible because the vWF fragments characteristically produced by this enzyme could not be detected. Concomitant analysis of vWF multimeric structure showed that these changes were accompanied by an increase in the relative proportion of the satellite bands, which suggests that they were proteolytically generated. Proteolysis may explain, at least in part, rapid clearance of larger vWF multimers released by DDAVP.

scholarly journals Possible effect of secretor locus on plasma concentration of factor VIII and von Willebrand factor

Blood ◽  
1989 ◽  
Vol 73 (4) ◽  
pp. 990-993 ◽  
Author(s):  
KH Orstavik ◽  
L Kornstad ◽  
H Reisner ◽  
K Berg
Keyword(s):  
Plasma Concentration ◽  
Factor Viii ◽  
Blood Group ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Type I ◽  
Genetically Determined ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Blood Group H

Abstract A significant fraction (30%) of the genetically determined variance in plasma concentration of the von Willebrand factor antigen (vWf:Ag) has been shown to be related to ABH determinants. Individuals with blood group O, who have the highest amounts of blood group H substance, have the lowest concentration of vWf:Ag. The Lewis substances, Le(a) and Le(b), are biochemically closely related to the ABH substances as both can be produced from the same precursor substance. We studied the effect of the presence of the Lewis antigens on the plasma concentration of vWf:Ag and factor VIII antigen (VIII:Ag) in 323 individuals of different ABO groups from a series of twins and in 58 blood donors of blood group O. Among persons belonging to blood group O, those with the Le(a) antigen had a higher concentration of both vWf:Ag and VIII:Ag than individuals lacking Le(a). Le(a+b-) people are nonsecretors and Le(a-b+) people are secretors of ABH substance. Thus, the lowest concentration of vWf:Ag and VIII:Ag was found in group O secretors. The effect is most likely due to an effect of the secretor locus. This finding may be of importance for the detection of carriers of hemophilia A and for the diagnosis of type I von Willebrand disease.

Quantitative Analysis of von Willebrand Factor and Its Propeptide in Plasma in Acquired von Willebrand Syndrome

1998 ◽  
Vol 80 (09) ◽  
pp. 495-498 ◽  
Author(s):  
Ria Boertjes ◽  
Jan van Mourik ◽  
Perry van Genderen
Keyword(s):  
Quantitative Analysis ◽  
Von Willebrand Factor ◽  
Intravenous Immunoglobulins ◽  
Von Willebrand Disease ◽  
High Dose ◽  
Type I ◽  
Acquired Von Willebrand Syndrome ◽  
Normal Individuals ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryMeasurement of the von Willebrand factor (vWF) propeptide, also known as von Willebrand antigen II, has been suggested to be helpful in the discrimination of congenital von Willebrand disease type I from type 2 and in assessing the extent of activation of the endothelium. We performed a quantitative analysis of mature vWF and its propeptide in plasma in 8 patients with acquired von Willebrand syndrome (AvWS) and in 20 normal individuals. Mature vWF levels were significantly lower in AvWS as compared with normal individuals (13.4 ± 3.5 vs 35.6 ± 3.3 nM, p <0.001). In contrast, propeptide levels were significantly higher in AvWS (11.4 ± 1.1 vs 4.7 ± 0.2 nM, p < 0.001), probably reflecting a compensatory increase in vWF synthesis or increased perturbation of the endothelium in AvWS. After treatment with DDAVP, propeptide and mature vWF levels rose 5-fold in AvWS, whereas propeptide levels were not altered by the infusion of a vWF concentrate or treatment with high dose intravenous immunoglobulins, indicating that plasma propeptide levels are a reliable reflection of vWF synthesis. Measurement of propeptide levels may provide additional information in AvWS as to whether decreased levels of mature vWF in the circulation are due to a decrease in synthesis or due to an accelerated removal of vWF from the circulation.

scholarly journals Possible effect of secretor locus on plasma concentration of factor VIII and von Willebrand factor

Blood ◽  
1989 ◽  
Vol 73 (4) ◽  
pp. 990-993
Author(s):  
KH Orstavik ◽  
L Kornstad ◽  
H Reisner ◽  
K Berg
Keyword(s):  
Plasma Concentration ◽  
Factor Viii ◽  
Blood Group ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Type I ◽  
Genetically Determined ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Blood Group H

A significant fraction (30%) of the genetically determined variance in plasma concentration of the von Willebrand factor antigen (vWf:Ag) has been shown to be related to ABH determinants. Individuals with blood group O, who have the highest amounts of blood group H substance, have the lowest concentration of vWf:Ag. The Lewis substances, Le(a) and Le(b), are biochemically closely related to the ABH substances as both can be produced from the same precursor substance. We studied the effect of the presence of the Lewis antigens on the plasma concentration of vWf:Ag and factor VIII antigen (VIII:Ag) in 323 individuals of different ABO groups from a series of twins and in 58 blood donors of blood group O. Among persons belonging to blood group O, those with the Le(a) antigen had a higher concentration of both vWf:Ag and VIII:Ag than individuals lacking Le(a). Le(a+b-) people are nonsecretors and Le(a-b+) people are secretors of ABH substance. Thus, the lowest concentration of vWf:Ag and VIII:Ag was found in group O secretors. The effect is most likely due to an effect of the secretor locus. This finding may be of importance for the detection of carriers of hemophilia A and for the diagnosis of type I von Willebrand disease.

PROTEOLYTIC DEGRADATION OF VON WILLEBRAND FACTOR AFTER DDAVP ADMINISTRATION IN NORMAL INDIVIDUALS

1987 ◽  
Author(s):  
J Batlle ◽  
M F López-Fernández ◽  
C López-Berges ◽  
S D Berkowitz ◽  
Z M Ruggeri ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Resting State ◽  
Relative Proportion ◽  
The Other ◽  
Proteolytic Degradation ◽  
Normal Individuals ◽  
Rapid Clearance ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adult Volunteers

The infusion of l-Deamino-8-D-Arginine Vasopressin (DDAVP) in normal individuals is followed by an increase in factor VIII/von Willebrand factor in plasma and by the appearance of larger multimers of von Willebrand factor (vWF) than those seen in the resting state. Since the larger multimers are rapidly cleared and proteolysis is known to cause disaggregation of large multimers, we evaluated the degree of vWF proteolysis after DDAVP. DDAVP was infused into eight normal adult volunteers and the relative proportions of the intact 225 kDa subunit and the 189, 176 and 140 kDa fragments were compared before and at different times after DDAVP infusion. The relative proportion of the 176 kDa fragment was increased while that of the other species was decreased, indicating that proteolytic fragmentation had occurred. However, plasmin did not appear to be responsible because the vWF fragments characteristically produced by this enzyme could not be detected. Concomitant analysis of vWF multimeric structure showed that these changes were accompanied by an increase in the relative proportion of the satellite bands suggesting that they were ptoteolytically generated. Proteolysis may explain, at least in part, rapid clearance of larger vWF multimers released by DDAVP.

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.

The Interaction of Botrocetin with Normal or Variant von Willebrand Factor (Types IIA and IIB) and Its Inhibition by Monoclonal Antibodies that Block Receptor Binding

1992 ◽  
Vol 68 (04) ◽  
pp. 464-469 ◽  
Author(s):  
Y Fujimura ◽  
S Miyata ◽  
S Nishida ◽  
S Miura ◽  
M Kaneda ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Von Willebrand Factor ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Normal Individuals ◽  
Rag 1 ◽  
The One ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryWe have recently shown the existence of two distinct forms of botrocetin (one-chain and two-chain), and demonstrated that the two-chain species is approximately 30 times more active than the one-chain in promoting von Willebrand factor (vWF) binding to platelet glycoprotein (GP) Ib. The N-terminal sequence of two-chain botrocetin is highly homologous to sea-urchin Echinoidin and other Ca2+-dependent lectins (Fujimura et al., Biochemistry 1991; 30: 1957–64).Present data indicate that purified two-chain botrocetin binds to vWF from plasmas of patients with type IIA or IIB von Willebrand disease and its interaction is indistinguishable from that with vWF from normal individuals. However, an “activated complex” formed between botrocetin and IIB vWF expresses an enhanced biological activity for binding to GP Ib whereas the complex with IIA vWF has a decreased binding activity. Among several anti-vWF monoclonal antibodies (MoAbs) which inhibit ristocetin-induced platelet aggregation and/or vWF binding to GPIb, only two MoAbs (NMC-4 and RFF-VIII RAG:1) abolished direct binding between purified botrocetin and vWF. This suggests that they recognize an epitope(s) on the vWF molecule in close proximity to the botrocetin binding site.

Interventional Thermal Injury of the Arterial Wall: Unfolding of von Willebrand Factor and Its Increased Binding to Collagen after 55° C Heating

1996 ◽  
Vol 75 (03) ◽  
pp. 515-519 ◽  
Author(s):  
Mark J Post ◽  
Anke N de Graaf-Bos ◽  
George Posthuma ◽  
Philip G de Groot ◽  
Jan J Sixma ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Conformational Changes ◽  
Arterial Wall ◽  
Platelet Adhesion ◽  
Type I ◽  
Temperature Dependent ◽  
Collagen Types ◽  
Electron Microscopic ◽  
Von Willebrand ◽  
Willebrand Factor

Summary Purpose. Thermal angioplasty alters the thrombogenicity of the arterial wall. In previous studies, platelet adhesion was found to increase after heating human subendothelium to 55° C and decrease after heating to 90° C. In the present electron microscopic study, the mechanism of this temperature-dependent platelet adhesion to the heated arterial wall is elucidated by investigating temperature-dependent conformational changes of von Willebrand factor (vWF) and collagen types I and III and the binding of vWF to heated collagen. Methods. Purified vWF and/or collagen was applied to electron microscopic grids and heated by floating on a salt-solution of 37° C, 55° C or 90° C for 15 s. After incubation with a polyclonal antibody against vWF and incubation with protein A/gold, the grids were examined by electron microscopy. Results. At 37° C, vWF was coiled. At 55° C, vWF unfolded, whereas heating at 90° C caused a reduction in antigenicity. Collagen fibers heated to 37° C were 60.3 ± 3.1 nm wide. Heating to 55° C resulted in the unwinding of the fibers, increasing the width to 87.5 ± 8.2 nm (p < 0.01). Heating to 90° C resulted in denatured fibers with an enlarged width of 85.1 ± 6.1 nm (p < 0.05). Heating of collagen to 55° C resulted in an increased vWF binding as compared to collagen heated to 37° C or to 90° C. Incubation of collagen with vWF, prior to heating, resulted in a vWF binding after heating to 55° C that was similar to the 37° C binding and a decreased binding after 90° C. Conclusions. After 55° C heating, the von Willebrand factor molecule unfolds and collagen types I and III exhibit an increased adhesiveness for von Willebrand factor. Heating to 90° C denatures von Willebrand factor and collagen. The conformation changes of von Willebrand factor and its altered binding to collagen type I and III may explain the increased and decreased platelet adhesion to subendothelium after 55° C and 90° C heating, respectively.

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