Different Types of von Wiilebrand’s Disease (vWd): A Study of 101 Cases

1975 ◽  
Author(s):  
T. Barbui ◽  
F. Baudo ◽  
A. Capitanio ◽  
N. Ciavarella ◽  
P. M. Mannucci ◽  
...  
Keyword(s):  
Factor Viii ◽  
Glass Bead ◽  
Bleeding Time ◽  
Autosomal Dominant ◽  
Type I ◽  
Clinical Form ◽  
Different Types ◽  
Factor Viii Antigen ◽  
Willebrand Factor ◽  
Antihemophilic Factor

The following tests have been carried out in 101 patients with vWd: bleeding time (BT), ristocetin aggregation in PRP (RA), platelet retention to glass bead columns (PR), antihemophilic factor (VIIIAHF). factor-VIII antigen (VIIAGN) and Willebrand factor (VIIIVWF. measured with a washed platelet system), 86 patients had a clinical form of the disease of moderate severity and autosomal dominant pattern of inheritance. In 59 of them VIIIAHF. VIIIAGN and VIIIVWF were concomitantly reduced, PR was usually low and BT moderately prolonged (type I vWd). These patients could be further divided into three subtypes according to the behaviour of RA, which was normal in type la, decreased in type lb and increased in type lc. Typo I vWd is thought to represent an example of decreased synthesis of factor VIII, as suggested by the concomitant decreased of the three factor-VIII related properties. Since RA was found to be either decreased, normal or increased in presence of reduced plasma levels of VTIIVWF. the latter cannot bes solely responsible of the extent of RA in PRP, which may be also related to the variations of a platelet component.27 patients showed very prolonged BT, low PR and absent or markedly rudeced RA: VIIIVWF was much lower than VIIIAHF and VIIIAGN. 15 patients had no family history, a severe clinical form of the disease, unmeasurable levels of VIIIAHF, VIIIAGN and VIIIVWF and markedly abnormal BT, PR and RA. In the majority of their unaffected parents, VIIIVWF and VIIIAGN were much lower than VIIIAHF These patients are similar to the case of recessive vWd described by Veltkamp and Tilbury (N. Engl. J. Med. 289.. 882, 1973).Supported by a grant of the Fondazione Angelo Bianchi Bonomi.

Von Willebrand Disease (vWd) Characterized by Increased Ristocetin Aggregation: A Study of Eleven Cases

1975 ◽  
Author(s):  
N. Ciavarella ◽  
F. I. Pareti ◽  
Z. M. Ruggeri ◽  
P. M. Mannucci
Keyword(s):  
Factor Viii ◽  
Bleeding Time ◽  
Autosomal Dominant ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Laboratory Findings ◽  
Prolonged Bleeding Time ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Antihemophilic Factor

The defective ristocetin aggregation occurring in patients with vWd is thought to depend on the decrease of a plasmatic factor related to factor VIII (Willebrand factor, VIIIVWF) 10 patients from 3 families had a mild to moderate bleeding tendency with autosomal dominant pattern of inheritance and laboratory findings suggestive for vWd (decreased levels of antihemophilic factor, and factor- VIII related antigen reduced platelet retention to glass beads columns and prolonged bleeding time). However, ristocetin aggregation in PRP was markedly increased, although VIIIVWF plasma levels were decreased. Aggregation induced in PRP by other agents (such as ADP, adrenaline and collagen), and the release of 14C serotonin was normal; the addition of purified bovine factor VIII was followed by normal aggregation in patients’ PRP and washed platelets. Patients’ washed platelets added to normal plasma aggregated to ristocetin more than normal washed platelets with patients’ plasma; the most marked aggregation response, however, was obtained when patients’ washed platelets were mixed with their own plasma. These findings suggest that a, platelet component is involved in the hyperaggregation response to ristocetin of these patients; however, the interaction of platelets with patients’ plasma is needed to produce the maximum response.Supported by a grant of the Fondazione Angelo Bianchi Bonomi.

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.

Stabilization of the Antihemophilic Factor (VIII :AHF) by the Von Willebrand Factor (VIII :VWF): A Possible Model for Von Willebrand’s Disease

1977 ◽  
Author(s):  
H. J. Weiss ◽  
I. I. Sussman ◽  
L. W. Hoyer
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Crossed Immunoelectrophoresis ◽  
Factor Viii Antigen ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Antihemophilic Factor

When compared with VIII:AHF in normal citrated plasmas, VIII:AHF activity showed increased lability at 37°C in the ‘late’ post-transfusion plasmas (VIII:AHF≫VIII:VWF) of a patient with von Willebrand’s disease, but not in the ‘early’ post-transfusion plasmas in which VIII:AHF~VIII:VWF. VIII:AHF was also labile in the baseline plasmas of 3 patients with von Willebrand’s disease in whom VIII:AHF≫VIII:VWF. In two of these patients the mobility of Factor VIII antigen (on crossed Immunoelectrophoresis) was increased. (VIII:AHF was not excessively labile in 4 other patients in whom VIII :AHF~VIII:VWF). In all of the above cases, VIII:AHF was stabilized by the addition of either purified von Willebrand factor or plasmas of patients with hemophilia, but not by plasmas of patients with severe von Willebrand’s disease. Thus, VIII:VWF may serve to stabilize VIII:AHF and this might explain the post-transfusion findings in von Willebrand’s disease.

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 Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

1993 ◽  
Vol 69 (02) ◽  
pp. 173-176 ◽  
Author(s):  
Anna M Randi ◽  
Elisabetta Sacchi ◽  
Gian Carlo Castaman ◽  
Francesco Rodeghiero ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Autosomal Dominant ◽  
Genetic Defect ◽  
Von Willebrand Disease ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Gene ◽  
Low Levels ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

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 The factor VIII complex: structure and function

Blood ◽  
1981 ◽  
Vol 58 (1) ◽  
pp. 1-13 ◽  
Author(s):  
LW Hoyer
Keyword(s):  
Factor Viii ◽  
Complex Structure ◽  
Related Protein ◽  
Molecular Defects ◽  
Normal Human ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Antihemophilic Factor ◽  
Immunologic Properties

Abstract Normal human plasma contains a complex of two proteins that are important in hemostasis and coagulation. The factor VIII procoagulant protein (antihemophilic factor) and the factor VIII-related protein (von Willebrand factor) are under separate genetic control, have distinct biochemical and immunologic properties, and have unique and essential physiologic functions. While the nature of their interaction and the details of the biochemical structures remain to be determined, the information now available permits a preliminary understanding of the molecular defects in hemophilia and von Willebrand's diseases.

scholarly journals Multiple Molecular Forms of Factor VIII Antigen in Normal Individuals and Von Willebrand’s Disease Patients

1977 ◽  
Author(s):  
T. S. Zimmerman ◽  
J. R. Kimball ◽  
T. S. Edgington ◽  
C. F. Abildgaard
Keyword(s):  
Factor Viii ◽  
Small Sample ◽  
Molecular Forms ◽  
Type I ◽  
Type Ii ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Multiple Molecular Forms ◽  
Normal Individuals ◽  
Factor Viii Antigen

Factor VIII antigen is present in normal individuals in multiple molecular forms which can be separated according to size. The intermediate and larger forms preferentially bind to platelets in the presence of ristocetin. In order to evaluate the possibility that Factor VIII antigen forms of large size may be an artifact of in vitro aggregation, we have ultracentrifuged plasma on a 20% sucrose cushion at 37°C for 10 min at 254,000 xg (peak). The rate of clearing of Factor VIII antigen was compared to that of IgM, fibrinogen, IgG, α1-antitrypsin and the S rate calculated to be between 15 and 18. These results indicate that Factor VIII-related antigen forms of high S exist even when plasma is maintained at physiological temperature and analyzed with minimal delay, suggesting that these large molecular forms also exist as such in vivo.Two types of von Willebrand’s disease (vWd) have been identified according to size of Factor VIII antigen forms present in plasma. In Type I all forms of Factor VIII antigen are present but are decreased in quantity. In Type II large forms are missing and smaller forms are present in normal or increased quantities. Factor VIII antigen was isolated from plasma of one patient with Type I and two patients with Type II vWd by counter Immunoelectrophoresis. The Factor VIII antigen was then reduced and electrophoresed on SDS-containing polyacrylamide gels. The presence of carbohydrate was evaluated by staining with perchloric acid-Schiff’s reagent (PAS). The 210,000 MW Factor VIII antigen subunit from each patient was PAS-positive. Though subtle changes in carbohydrate content or composition could not be evaluated by this technique, a total defect of glycosylation is unlikely in this small sample of vWd patients.

scholarly journals New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 169-175 ◽  
Author(s):  
MR Ledford ◽  
I Rabinowitz ◽  
JE Sadler ◽  
JW Kent ◽  
F Civantos
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Autosomal Dominant ◽  
Disease Type ◽  
Von Willebrand Disease ◽  
Dominant Inheritance ◽  
New Variant ◽  
Von Willebrand ◽  
Willebrand Factor

A variant of von Willebrand disease (vWD) was identified in six members of a kindred spanning four generations. The proband was a 46-year-old woman with a lifelong history of bleeding, a prolonged bleeding time (> 15 minutes), markedly elevated von Willebrand factor (vWF) antigen (vWF:Ag = 2.09 U/mL), slightly reduced ristocetin cofactor activity, and a plasma vWF multimer pattern similar to that of vWD type IIC. Similar findings were observed in her three children, mother, and brother. In affected family members, platelet and plasma vWF multimer patterns were discrepant with higher molecular weight multimers observed in platelet vWF. Following a 1-Des-amino-8-D-arginine vasopressin (DDAVP) challenge, the proband failed to normalize her bleeding time even though vWF: Ag rose by 70% and higher molecular weight multimers were increased slightly. Genetic studies were consistent with autosomal dominant inheritance of a mutation within the vWF gene. By sequencing of cloned genomic DNA, mutations were excluded in exons 4, 5, 14, and 15, which encode regions of the vWF propeptide proposed to be important in multimer biosynthesis. Mutations also were excluded in exons 28 to 31, which encompass the known mutations that cause vWD types IIA, IIB, and B. This new variant of vWD, characterized by autosomal dominant inheritance, a qualitative defect that resembles vWD type IIC, and increased plasma vWF:Ag, was tentatively designated vWD type IIC Miami.

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