Variant von Willebrand’s Disease

Summary30 members of an Illinois kindred were studied with a battery of haemostatic tests including the template bleeding time, platelet retention by glass beads (PRGB), measurement of activities related to factor VIII, and crossed-immunoelectrophoresis (CIEP). 9 family members had a history of excessive bleeding, and all 9 had prolonged bleeding times and increased migration of their factor VIII-related antigen (VIIIR:Ag) on CIEP. Of the other tests performed, the VIII: Ristocetin Cofactor and the PRGB showed the best correlation with the bleeding time. 3 subjects who were not bleeders, but who came from a branch of the family where there were several affected members, also had an abnormal VIIIR: Ag. The pattern of inheritance of the altered VIIIR: Ag in this family was one of autosomal dominance with full penetrance. The CIEP is a valuable screening test for the detection of variant von Willebrand’s disease and the recognition of silent heterozygotes.

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Effect Of DDAVP In Patients With Von Willebrand’s Disease And Hemophilia A

10.1055/s-0038-1652989 ◽

1981 ◽

Author(s):

A I Warrier ◽

C Hillman ◽

J M Lusher

Keyword(s):

Side Effects ◽

Factor Viii ◽

Hemophilia A ◽

Blood Components ◽

Excessive Bleeding ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Crossed Immunoelectrophoresis ◽

Transient Improvement ◽

The U.S

European investigators have reported on the efficacy of l-deamino-9-D-arginine vasopressin (DDAVP) in von Willebrand’s disease (vWD) and mild hemophilia A. We have thus evaluated the effects of a single intranasal dose of DDAVP (200ugm of the more dilute form available in the U.S.), in 12 individuals with vWD and in 4 with moderate hemophilia A. Crossed immunoelectrophoresis of VIII: RAg demonstrated normal electrophoretic mobility in each of the vWD subjects. Components of the factor VIII system (VIII: C, VIII: RAg, VIII: R Cof.) were assayed pre - and 90 and 180 minutes post- DDAVP. Each of 11 subjects with mild or moderate vWD had an increase in VIII: C activity (avg. 2X increase), 8 of 11 had an increase in VIII: R Cof, and 9 of 11 had an increase in VIII: RAg. The twelfth vWD subject, who had severe vWD, had no rise in any of these components. Of 4 vWD subjects who had pre- and post-DDAVP template bleeding times (BT) performed, the only one who had a prolonged baseline BT showed a normal BT 90 minutes post-DDAVP. One vWD subject, in whom we had documented an increase in all F. VIII components after DDAVP, later underwent dental extractions 90 minutes after DDAVP. No excessive bleeding was noted. Four individuals with moderate hemophilia A (baseline VIII: C values of 0.02-0.10 u/ml) were also studied. Three had a rise in all components of the factor VIII system post-DDAVP while the fourth did not. No undesirable side effects were noted in any of the 16 subjects who received DDAVP. We conclude that even the more dilute form of DDAVP available in the U.S., when given intranasally, results in transient improvement in selected individuals with vWD or moderate hemophilia A. This drug thus warrants further study as an alternative to blood components in the management of vWD, as well as in mild and moderate hemophilia A.

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DDAVP in type IIa von Willebrand's disease

Blood ◽

10.1182/blood.v67.2.465.465 ◽

1986 ◽

Vol 67 (2) ◽

pp. 465-468 ◽

Cited By ~ 26

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.

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Serial studies in von Willebrand's disease: variability versus "variants"

Blood ◽

10.1182/blood.v56.4.712.bloodjournal564712 ◽

1980 ◽

Vol 56 (4) ◽

pp. 712-716 ◽

Cited By ~ 1

Author(s):

CF Abildgaard ◽

Z Suzuki ◽

J Harrison ◽

K Jefcoat ◽

TS Zimmerman

Keyword(s):

Factor Viii ◽

Repeated Testing ◽

Laboratory Findings ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Normal Individuals ◽

Coagulant Activity ◽

History Of ◽

Ristocetin Cofactor

The variability of laboratory findings in von Willebrand's disease (vWd) was evaluated by performing serial studies of bleeding time (BT), factor VIII coagulant activity (VIII:C), factor-VIII-related antigen (VIIIR:Ag) and ristocetin cofactor (VIIIR:Rcof) in 50 individuals from 25 families with this disorder. The types of results were characterized from 1 to 16 based on the possible combinations of findings using these four tests. The only patients observed to have consistently abnormal results of all four tests were three individuals with homozygous vWd. Individuals with autosomal dominant vWd were found to have a variety of results and all 16 possible types were observed. Although a consistent pattern was present within some families, others with equivalent history of bleeding demonstrated widely variable types of results. The results within some families, others with equivalent history of bleeding demonstrated widely variable types of results. The results of serial studies of the same tests in 10 normal individuals indicated relative stability, with nearly all values within the usual range of normal, but some independent variation of factor-VIII-related activities was observed. These studies indicate that: (1) the results of BT, VIII:C, VIIIR:Ag, and VIIIR:Rcof vary considerably from time to time in many individuals with vWd, (2) a classification of “variants” of vWd based solely on such studies may be inappropriate, particularly if the tests are not repeated, and (3) repeated testing may be required to establish the diagnosis of vWd in some individuals.

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DDAVP in type IIa von Willebrand's disease

Blood ◽

10.1182/blood.v67.2.465.bloodjournal672465 ◽

1986 ◽

Vol 67 (2) ◽

pp. 465-468 ◽

Cited By ~ 1

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

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.

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Serial studies in von Willebrand's disease: variability versus "variants"

Blood ◽

10.1182/blood.v56.4.712.712 ◽

1980 ◽

Vol 56 (4) ◽

pp. 712-716 ◽

Cited By ~ 106

Author(s):

CF Abildgaard ◽

Z Suzuki ◽

J Harrison ◽

K Jefcoat ◽

TS Zimmerman

Keyword(s):

Factor Viii ◽

Repeated Testing ◽

Laboratory Findings ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Normal Individuals ◽

Coagulant Activity ◽

History Of ◽

Ristocetin Cofactor

Abstract The variability of laboratory findings in von Willebrand's disease (vWd) was evaluated by performing serial studies of bleeding time (BT), factor VIII coagulant activity (VIII:C), factor-VIII-related antigen (VIIIR:Ag) and ristocetin cofactor (VIIIR:Rcof) in 50 individuals from 25 families with this disorder. The types of results were characterized from 1 to 16 based on the possible combinations of findings using these four tests. The only patients observed to have consistently abnormal results of all four tests were three individuals with homozygous vWd. Individuals with autosomal dominant vWd were found to have a variety of results and all 16 possible types were observed. Although a consistent pattern was present within some families, others with equivalent history of bleeding demonstrated widely variable types of results. The results within some families, others with equivalent history of bleeding demonstrated widely variable types of results. The results of serial studies of the same tests in 10 normal individuals indicated relative stability, with nearly all values within the usual range of normal, but some independent variation of factor-VIII-related activities was observed. These studies indicate that: (1) the results of BT, VIII:C, VIIIR:Ag, and VIIIR:Rcof vary considerably from time to time in many individuals with vWd, (2) a classification of “variants” of vWd based solely on such studies may be inappropriate, particularly if the tests are not repeated, and (3) repeated testing may be required to establish the diagnosis of vWd in some individuals.

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The Presence and Significance of Electrophoreticaily Normal and Abnormal Factor VIII Related Protein in von Willebrand’s Disease

10.1055/s-0039-1689537 ◽

1975 ◽

Author(s):

I. R. Peake ◽

A. L. Bloom ◽

J. C. Giddings

Keyword(s):

Platelet Aggregation ◽

Factor Viii ◽

Electrophoretic Mobility ◽

Bleeding Time ◽

Factor Vii ◽

Two Dimensional ◽

Related Protein ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Crossed Immunoelectrophoresis

The presence of normal amounts of a factor-VII related protein (FVIIIRP) which has abnormal electrophoretic mobility at pH 9.2 has been demonstrated on two dimensional crossed immunoelectrophoresis in some patiente with von Willebrand’s disease (vWd) and these investigations have now been extended to a study of over 14 patients. In those with reduced levels of FVIIIRP, concentrates were prepared by precipitation with 3% ethanol at -3°C. The results showed that in three of the patients with “typical vWd” in whom levels of procoagulant factor VIII and FVIIIRP were parallel and both always reduced the latter had abnormal electrophoretic mobility indistinguishable from that of the “atypical” cases. In all patients in whom abnormal FVIIIRP was demonstrated the bleeding time was grossly prolonged and ristocetin platelet aggregation grossly impaired. In patients in whom the mobility of FVTIIRP was indistinguishable from normal the bleeding times and ristocetin platelet aggregation were sometimes less severely impaired despite gross reduction of the circulating level of FVIIIRP. It is suggested that in vWd synthesis of abnormal variants cf FVIIIRP is relatively common but that in some patients there is reduced syntehsis of normal FVIIIRP.

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Factor VIII-Related Activities in Normal, Haemophilic and von Willebrand’s Disease Platelet Fractions

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648663 ◽

1978 ◽

Vol 40 (02) ◽

pp. 288-301 ◽

Cited By ~ 8

Author(s):

P Meucci ◽

I R Peake ◽

A L Bloom

Keyword(s):

Factor Viii ◽

Electrophoretic Mobility ◽

Concanavalin A ◽

Freezing And Thawing ◽

Von Willebrand's Disease ◽

Factor Viii Related Antigen ◽

Von Willebrand’S Disease ◽

Normal Plasma ◽

Significant Difference ◽

Ristocetin Cofactor

SummaryFactor VIII-related activities have been studied in platelet fractions in order to try to reconcile the conflicting findings of other workers, and to extend the studies. In platelets from 16 normal subjects procoagulant factor VIII was not detected. The amount of factor VIII-related antigen (FVIIIR: AG) in the cytosol per mg of protein was about twice that in the membrane fraction and about ten times that in the debris fraction. There was no significant difference between the amount of FVIIIR: AG and ristocetin cofactor (RistCof) activity in each fraction. The findings in haemophilic platelets were similar. In von Willebrand’s disease (vWd) one serverely affected patient had no detectable factor VIII related activities in any platelet fraction. In 5 patients with intermediate vWd results were normal. In a further 5, with more prolonged bleeding times, no FVIIIR: RistCof was detected in platelets, despite a normal amount of FVIIIR: AG in the cytosol and debris. The electrophoretic mobility of cytosol FVIIIR: AG was increased in all normals and patients, while that in the membrane and debris fractions had normal mobility. Cytosol FVIIIR: AG eluted later than normal FVIIIR: AG on gel filtration on Sepharose 2B, and also showed reduced antibody binding in an immunoradiometric assay. Precipitation of FVIIIR: AG by concanavalin A was incomplete in all platelet fractions from normals, and even more reduced in vWd platelet fractions. The results suggest the possibility of two types of platelet FVIIIR: AG.A factor VIII-related antigen was shown to be associated with normal washed platelets by immunofluorescence techniques (Bloom et al. 1973). Since then, several studies have been reported on the localisation of factor VIII related antigen (FVIIIR: AG), factor VIII procoagulant activity (FVIII: C) and factor VIII related ristocetin cofactor activity (FVIIIR: RistCof) within the platelets. Initially, Howard et al. (1974) indicated that FVIIIR: AG was firmly bound to the platelet membrane, and noted that in lysed platelets the level of FVIIIR: AG as measured by electroimmunodiffusion was higher than that in whole platelet suspensions. However, further studies by Nachman and Jaffe (1975) showed that FVIIIR: AG was also present to a considerable extent in the granules, and they detected none in the platelet cytosol. Bouma and colleagues (1975) were, however, able to find FVIIIR: AG and FVIIIR: RistCof in the cytosol upon freezing and thawing platelets. This FVIIIR: AG had an electrophoretic mobility comparable to that of normal plasma. They also noted that platelets which were air dried apparently had a granular FVIIIR:AG localisation by immunfluorescence; however, intact platelets in suspension did not stain by this method.Recently Ruggeri et al. (1977) and Sultan et al. (1977) have also found FVIIIR: AG in the cytosol, and the former authors reported it to have increased electrophoretic mobility when compared to normal plasma FVIIIR:AG. Results concerning the localisation of FVIIIR: AG in normal platelets have thus been conflicting. Similarly, in the few reports available concerning platelet FVIIIR: AG in von Willibrand’s disease variable results have also been obtained (Ruggeri et al. 1977, Howard et al. 1974, Shearn et al. 1974 and Bouma et al. 1975).In this study we report on the localisation of factor VIII-related activities in normal, haemophilic and von Willebrand’s disease platelets using available standard techniques as well as precipitation of FVIIIR: AG with the plant lectin concanavalin A, a procedure which has been shown to detect abnormal forms of FVIIIR:AG in certain types of von Willebrand’s disease (Peake and Bloom 1977).

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The Spectrum of von Willebrand’s Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655015 ◽

1967 ◽

Vol 18 (01/02) ◽

pp. 040-056 ◽

Cited By ~ 13

Author(s):

E. J Walter Bowie ◽

P Didisheim ◽

J. H Thompson ◽

C. A Owen

Keyword(s):

Factor Viii ◽

Bleeding Time ◽

Severe Bleeding ◽

Platelet Adhesiveness ◽

Platelet Activity ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

The Third ◽

Generation Test

SummaryPatients (from 5 kindreds) with variants of von Willebrand’s disease are described. In one kindred the depression of factor VIII was moderate (20 to 40% of normal) and transfusion of 500 ml of normal plasma led to an increase higher than anticipated and to an almost normal level of factor VIII 17 to 24 hrs later. This represents the usual type of von Willebrand’s disease.In the second kindred the concentration of factor VIII was less than 2 % of normal in the son and daughter, who had severe bleeding and hemarthroses.The third kindred was characterized by reduction of factor VIII and a long bleeding time as well as by a serum defect in the thromboplastin-generation test comparable to that seen in patients with hemophilia B, yet with normal levels of factors IX, X, and VII. The severity of the serum defect, the positive result with the Rumpel-Leede test, and the reduced platelet activity in the thromboplastin-generation test are all compatible with the diagnosis of thrombopathy or ‘‘thrombopathic hemophilia.” In two other kindreds, one patient had a long bleeding time and normal levels of factor VIII and another had a normal bleeding time and decrease of factor VIII. The last patient had the type of response to transfusion usually seen in von Willebrand’s disease.In four kindreds, platelet adhesiveness in vivo was found to be strikingly abnormal (virtually absent).It would appear, therefore, that von Willebrand’s disease forms a spectrum, and whether the kindreds reported simply reflect variations of a single genetic disease state or represent separate entities will be answered only by clarification of the underlying etiology of that disease.

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Increased Ristocetin Induced Binding of Factor VIII to Platelets in Von Willebrand’s Disease (vWd)

10.1055/s-0039-1687418 ◽

1979 ◽

Author(s):

Z.M. Ruggeri ◽

F.I. Pareti ◽

P.M. Mannucci ◽

T.S. Zimmerman

Keyword(s):

Platelet Aggregation ◽

Factor Viii ◽

Bleeding Time ◽

Human Platelet ◽

Bleeding Tendency ◽

Platelet Factor ◽

Induce Platelet Aggregation ◽

Prolonged Bleeding Time ◽

Crossed Immunoelectrophoresis ◽

Ristocetin Cofactor

Initial reports of ristocetin-induced platelet aggregation (RIPA) demonstrated it to be decreased in some patients with vWd. We now report 20 patients (from five unrelated families) in whom RIP A was increased, apparently as the result of an increased ristocetin-induced binding of Factor VIIIrelated antigen (VIIIR:Ag) to platelets. All the patients had a life-long bleeding tendency, with prolonged bleeding time, and an abnormal two-dimensional crossed immunoelectrophoresis (2DCIE). Increased RIPA was demonstrated by measuring the minimum ristocetin concentration necessary to induce platelet aggregation. This was 0.42 mg/ml á 0.11 SD in the patients, and 0.91 á 0.097 SD in 17 normals (t = 13.83; P < 0.001). VIIIR:Ag binding to platelets occurred at ristocetin concentrations (0.4 mg/mI) which were ineffective in normals (who required >0.6 mg/mI). In contrast, the VIIIR:Ag of other patients with abnormal 2DCIE and markedly decreased RIP A did not bind to platelets at ristocetin concentrations as high as I mg/ml. It has been previously demonstrated that 30% to 60% of normal VIIIR:Ag binds to isolated human platelet membranes in the absence of ristocetin or any other agent, and that binding is restricted to the larger forms of VIIIR:Ag. However, VIIIR:Ag from the patients with increased RIPA, including two with normal ristocetin cofactor activity, showed decreased or undetectable binding as did all other patients with abnormal 2DCIE. This study suggests that ristocetin induced platelet Factor VIII interaction does not accurately reflect the “bleeding time factor” defect in vWd.

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

Blood ◽

10.1182/blood.v59.6.1272.1272 ◽

1982 ◽

Vol 59 (6) ◽

pp. 1272-1278 ◽

Cited By ~ 241

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.

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