Enzymatic degradation of the factor-VIII-von-Willebrand protein: a unique tryptic fragment with ristocetin cofactor activity

Abstract A previously healthy elderly man with mucocutaneous bleeding was found to have a benign monoclonal IgG gammapathy associated with criteria for severe von Willebrand disease (Factor VIII procoagulant activity, Factor-VIII-related antigen, and ristocetin cofactor activity, less than 10% of normal). Associated qualitative abnormalities of factor VIII/von Willebrand factor were demonstrated by radiocrossed immunoelectrophoresis and immunoradiometric assay. The late clinical onset and negative family history are in favor of an acquired form of vWD. The monoclonal gammapathy and abnormalities of factor VIII/von Willebrand factor have been stable over a 10-yr period. No inhibitor to Factor VIII procoagulant activity, ristocetin cofactor activity, or Factor-VIII-related antigen could be demonstrated. Following transfusion of cryoprecipitate (with a normal cross immunoelectrophoretic pattern), there was a rapid removal of the large forms of Factor.-VIII-related antigen, paralleled by a decay of ristocetin cofactor activity. The transfusion study of this patient with acquired von Willebrand disease type II (variant of von Willebrand disease) serves to emphasize the relationship between polydispersity of Factor VIII/von Willebrand Factor and functional heterogeneity.

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Correlation between von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity and factor VIII activity in plasma

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-007-0090-0 ◽

2007 ◽

Vol 26 (2) ◽

pp. 150-153 ◽

Cited By ~ 7

Author(s):

Giuseppe Lippi ◽

Massimo Franchini ◽

Gian Luca Salvagno ◽

Martina Montagnana ◽

Giovanni Poli ◽

...

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Factor Viii Activity ◽

Von Willebrand Factor Antigen ◽

Cofactor Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen ◽

Ristocetin Cofactor ◽

Ristocetin Cofactor Activity

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Von Willebrand Activity of Low Molecular Weight Human Factor VIII Increases by Binding to Gold Granules

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650179 ◽

1981 ◽

Vol 45 (03) ◽

pp. 242-246 ◽

Cited By ~ 8

Author(s):

Miha Furlan ◽

Beat A Perret ◽

Eugene A Beck

Keyword(s):

Molecular Weight ◽

Factor Viii ◽

Human Factor ◽

Low Molecular Weight ◽

Human Factor Viii ◽

Large Factor ◽

Cofactor Activity ◽

Von Willebrand ◽

Ristocetin Cofactor ◽

Ristocetin Cofactor Activity

SummaryHuman factor VIII/von Willebrand protein is a population of multimers which vary in size but contain apparently identical subunits. Large-molecular-weight forms possess higher ristocetin cofactor/von Willebrand activity than the native smaller oligomers. Disulfide reduction of large factor VIII multimers results in progressively decreasing molecular size and a loss of ristocetin cofactor activity. Small molecular forms of factor VIII were adsorbed onto gold granules (average diameter 20-30 nm) and thereby increased their ristocetin cofactor activity. The amount of adsorbed material and the extent of activation were dependent on the pH of the colloid suspension. The maximum recovery of von Willebrand activity was observed at pH 4.75. Aggregation of fixed human platelets by factor VIII-coated gold particles was dependent on ristocetin concentration and was not competitively inhibited by unbound low-molecular-weight factor VIII. These results suggest that the subunits of the native small factor VIII species possess potential binding affinity for platelet receptors, which is manifested following formation of large factor VIII polymers. We conclude that an optimal size of remarkably high molecular weight is required for efficient aggregation of platelets by factor VIII as occurs during the primary phase of hemostasis.

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Standards for Assay of von Willebrand Factor Concentrates: A Collaborative Study

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649579 ◽

1993 ◽

Vol 70 (02) ◽

pp. 351-356 ◽

Cited By ~ 1

Author(s):

W A Fricke ◽

M A Lamb ◽

S C Rastogi

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Collaborative Study ◽

Von Willebrand Factor Antigen ◽

Cofactor Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen ◽

Ristocetin Cofactor ◽

Ristocetin Cofactor Activity

SummaryA multilaboratory collaborative study was undertaken to assess the feasibility of using a plasma standard for expressing the results of assays for the von Willebrand factor content of von Willebrand factor concentrates and of factor VIII concentrates. Thirteen laboratories tested six concentrates for von Willebrand factor antigen, ristocetin cofactor activity, and multimer content using the World Health Organization plasma standard for factor VIII/von Willebrand factor, 87/718, as a standard. Only a few assays were invalid because of nonparallelism or nonlinearity. Significant interlaboratory and interassay differences were found for both von Willebrand factor antigen and ristocetin cofactor activity. There was generally good agreement between the laboratories with respect to the multimer content in the preparations. With respect to assay validity, a plasma standard could be suitable for assaying concentrated preparations of von Willebrand factor.

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Selective absence of large forms of factor VIII/von Willebrand factor in acquired von Willebrand's syndrome. Response to transfusion

Blood ◽

10.1182/blood.v54.3.600.bloodjournal543600 ◽

1979 ◽

Vol 54 (3) ◽

pp. 600-606

Author(s):

D Meyer ◽

D Frommel ◽

MJ Larrieu ◽

TS Zimmerman

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Procoagulant Activity ◽

Factor Viii Related Antigen ◽

Cofactor Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

Ristocetin Cofactor ◽

Ristocetin Cofactor Activity

A previously healthy elderly man with mucocutaneous bleeding was found to have a benign monoclonal IgG gammapathy associated with criteria for severe von Willebrand disease (Factor VIII procoagulant activity, Factor-VIII-related antigen, and ristocetin cofactor activity, less than 10% of normal). Associated qualitative abnormalities of factor VIII/von Willebrand factor were demonstrated by radiocrossed immunoelectrophoresis and immunoradiometric assay. The late clinical onset and negative family history are in favor of an acquired form of vWD. The monoclonal gammapathy and abnormalities of factor VIII/von Willebrand factor have been stable over a 10-yr period. No inhibitor to Factor VIII procoagulant activity, ristocetin cofactor activity, or Factor-VIII-related antigen could be demonstrated. Following transfusion of cryoprecipitate (with a normal cross immunoelectrophoretic pattern), there was a rapid removal of the large forms of Factor.-VIII-related antigen, paralleled by a decay of ristocetin cofactor activity. The transfusion study of this patient with acquired von Willebrand disease type II (variant of von Willebrand disease) serves to emphasize the relationship between polydispersity of Factor VIII/von Willebrand Factor and functional heterogeneity.

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Plasma Derived von Willebrand Factor Preparations: Collagen Binding and Ristocetin Cofactor Activities

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657654 ◽

1997 ◽

Vol 78 (02) ◽

pp. 930-933 ◽

Cited By ~ 11

Author(s):

Ping Chang ◽

D L Aronson

Keyword(s):

Von Willebrand Factor ◽

Functional Activity ◽

Binding Activity ◽

Collagen Binding ◽

Binding Function ◽

Cofactor Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

Ristocetin Cofactor ◽

Ristocetin Cofactor Activity

SummaryFive plasma preparations (11 lots) used in the treatment of von Willebrand’s disease (vWD) were evaluated. The collagen binding function of von Willebrand factor (vWF) containing preparations was compared with the ristocetin cofactor activity and the vWF antigen. Some preparations have higher ratio of functional activity (ristocetin cofactor and collagen binding) relative to the antigen than is found in normal plasma. The ristocetin cofactor activity and the collagen binding activity are tightly correlated (r = .95). Ultracentrifugal (UCF) analysis was used to compare the size distribution of vWf antigen, ristocetin cofactor and collagen binding activity. The sedimentation of all of the vWF parameters in the plasma products was slower than in plasma. In plasma products the ristocetin cofactor activity sediments the most rapidly, the collagen binding activity is slower and the antigen the slowest. The collagen/antigen ratio decreases with decreasing vWF size. Assignment of potency to vWF containing preparations utilizing the collagen binding activity may be more precise and as accurate as with the traditional ristocetin cofactor assay.

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Variant von Willebrand's disease and pregnancy

Blood ◽

10.1182/blood.v58.5.873.873 ◽

1981 ◽

Vol 58 (5) ◽

pp. 873-879 ◽

Cited By ~ 27

Author(s):

W Hanna ◽

D McCarroll ◽

T McDonald ◽

P Painter ◽

J Tuller ◽

...

Keyword(s):

Factor Viii ◽

Half Life ◽

Clinical Course ◽

Procoagulant Activity ◽

Von Willebrand's Disease ◽

Factor Viii Related Antigen ◽

Coagulation Profile ◽

Cofactor Activity ◽

Ristocetin Cofactor ◽

Ristocetin Cofactor Activity

Abstract The clinical course and coagulation profile of a pregnant patient with variant von Willebrand's disease were followed from the second trimester through puerperium. The clinical course was characterized by a normal delivery and absence of abnormal bleeding or need for replacement therapy. The coagulation profile demonstrated an increase in factor VIII procoagulant activity, factor-VIII-related antigen, and platelet aggregation activity in response to ristocetin prior to delivery. Postpartum, these factors decreased to prepregnancy values with distinctly different patterns. Factor VIII procoagulant activity continued to rise for 5 days after delivery and then decreased with a half-life of approximately 6 days. Factor-VIII-related antigen began to decrease just prior to delivery, displaying a half-life or approximately 6 days. Ristocetin cofactor activity, however, dropped immediately postpartum and displayed a half-life of approximately 6 hr. The ristocetin cofactor activity was associated with factor-VIII- related antigen, which displayed a significantly smaller molecular weight than does normal factor-VIII-related antigen. Larger aggregates of factor-VIII-related antigen. Larger aggregates of factor-VIII- related antigen did not appear during the pregnancy, and ristocetin cofactor activity could not be demonstrated in fragments of less than 0,8 x 10(6).

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