Type 2M vWD Resulting from a Lysine Deletion within a Four Lysine Residue Repeat in the A1 Loop of von Willebrand Factor

2000 ◽  
Vol 84 (08) ◽  
pp. 188-194 ◽  
Author(s):  
P. V. Jenkins ◽  
C. Gaucher ◽  
E. Meriane ◽  
P. W. Collins ◽  
K. J. Pasi ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Lysine Residue ◽  
Antigen Level ◽  
The Uk ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity

SummaryType 1 von Willebrand disease is characterized by a decreased plasma concentration of functionally normal von Willebrand factor (vWF) whereas type 2M is characterised by an abnormal vWF displaying decreased affinity for platelets. In these two types of patients, the multimeric structure of vWF is normal.We report here the identification, in two unrelated families from the UK and Algeria, of an in-frame 3 bp deletion, at the heterozygous state, resulting in the deletion of a lysine residue within a four lysine repeat at position 642-645 of the mature vWF subunit (del K1405-1408 in prepro vWF). The patients who have a discrepancy between vWF antigen level and vWF ristocetin cofactor activity exhibited decreased ristocetin-induced binding but only a slight decrease in the percentage of high molecular weight (HMW) multimers in plasma.Recombinant vWF harbouring this deletion did not bind to platelet GPIb in the presence of ristocetin or botrocetin although the protein is multimerized. Consequently, this lysine deletion was considered as a type 2M vWD mutation.

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

Blood ◽  
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

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.

Altered von Willebrand factor subunit proteolysis and multimer processing associated with the Cys2362Phe mutation in the B2 domain

2007 ◽  
Vol 97 (04) ◽  
pp. 527-533 ◽  
Author(s):  
Luigi Marco ◽  
Lisa Gallinaro ◽  
Maryta Sztukowska ◽  
Mario Mazzuccato ◽  
Monica Battiston ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Proteolytic Processing ◽  
Triplet Structure ◽  
Von Willebrand ◽  
A2 Domain ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity ◽  
Marked Drop

SummaryThe normal von Willebrand factor (vWF) multimer pattern results from the ADAMTS-13 cleavage of the Tyr1605-Met1606 bond in the A2 domain of vWF. We identified a patient with severe von Willebrand disease (vWD) homozygously carrying a Cys to Phe mutation in position 2362 of vWF with markedly altered vWF multimers and an abnormal proteolytic pattern. The proband’s phenotype was characterized by a marked drop in plasma vWF antigen and ristocetin cofactor activity, and a less pronounced decrease in FVIII. The vWF multimers lacked any triplet structure, replaced by single bands with an atypical mobility, surrounded by a smear, and abnormally large vWF multimers. Analysis of the plasma vWF subunit's composition revealed the 225 kDa mature form and a single 205 kDa fragment, but not the 176 kDa and 140 kDa fragments resulting from cleavage by ADAMTS-13.The 205 kDa fragment was distinctly visible, along with the normal vWF cleavage products, in the patient's parents who were heterozygous for the Cys2362Phe mutation. Their vWF levels were mildly decreased and vWF multimers were organized in triplets, but also demonstrated abnormally large forms and smearing. Our findings indicate that a proper conformation of the B2 domain, which depends on critical Cys residues, may be required for the normal proteolytic processing of vWF multimers.

Reduced von Willebrand factor survival in type Vicenza von Willebrand disease

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 180-184 ◽  
Author(s):  
Alessandra Casonato ◽  
Elena Pontara ◽  
Francesca Sartorello ◽  
Maria Grazia Cattini ◽  
Maria Teresa Sartori ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Normal Platelet ◽  
Cofactor Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity ◽  
Original Type

Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype.

scholarly journals A new variant of type II von Willebrand disease with aberrant multimeric structure of plasma but not platelet von Willebrand factor (type IIF)

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 269-274 ◽  
Author(s):  
PM Mannucci ◽  
R Lombardi ◽  
AB Federici ◽  
JA Dent ◽  
TS Zimmerman ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Normal Plasma ◽  
Von Willebrand Factor Antigen ◽  
Cofactor Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity

Abstract A patient with a lifelong bleeding disorder was diagnosed as having Type II von Willebrand disease. The larger multimers of von Willebrand factor were absent from her plasma but present in platelets. A high- resolution electrophoretic technique was used to study the complex structure of individual von Willebrand factor multimers. In normal plasma, each multimer could be resolved into five bands: a more intense central one and four less intense, two moving faster and two slower than the central band. In normal platelets, each multimer could also be resolved into five bands. The central one had a mobility similar to that in plasma, whereas the four satellite bands had a mobility that differed from that of the corresponding plasma bands. In the patient, platelet von Willebrand factor antigen content and ristocetin cofactor activity were normal, and von Willebrand factor showed the same structure of individual multimers as seen in normal platelets. On the other hand, plasma von Willebrand factor antigen and ristocetin cofactor activity were decreased, and the structure of individual von Willebrand factor multimers was different from that of normal plasma and similar to that seen in normal and patient's platelets. After infusion of 1-deamino-8-D-arginine vasopressin, the largest von Willebrand factor multimers, as well as new satellite bands with a mobility similar to those in normal plasma, appeared in the patient plasma, and the levels of von Willebrand factor antigen and ristocetin cofactor activity became normal. Yet no relevant change in the prolonged bleeding time was observed. This new variant of von Willebrand disease, therefore, is characterized by the presence of a dysfunctional von Willebrand factor molecule that exhibits unique structural abnormalities in plasma but appears to be normal in platelets. The designation of Type IIF is proposed for this type of von Willebrand disease in accordance with the terminology that has been previously used.

The possibility to obtain reagent from platelet concentrates with long storage time for determination of von Willebrand factor ristocetin cofactor activity (vWF:RCo)

2018 ◽  
Author(s):  
А.Л. Берковский ◽  
Е.В. Сергеева ◽  
А.В. Суворов ◽  
К.Н. Иевская ◽  
Е.В. Анисимова
Keyword(s):  
Shelf Life ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Platelet Concentrates ◽  
Cofactor Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity

Введение. Фактор Виллебранда (ФВ) является важным компонентом системы гемостаза, и отклонение от нормы его содержания или состава вызывает развитие различных типов болезни Виллебранда. Определение ристоцетин-кофакторной активности ФВ (ФВ:РКФА) является особенно значимым при выявлении таких типов болезни Виллебранда как 2А, 2В и 2М, при которых содержание антигена ФВ находится в нормальных пределах, а ФВ:РКФА значительно снижена. Цель исследования: получение реагента для измерения ФВ:РКФА из концентратов тромбоцитов с длительным сроком хранения, обеспечивающего правильность диагностики. Материалы и методы. Функционально полноценные тромбоциты получали из донорских тромбоцитарных концентратов со сроком хранения 7–14 суток. Результаты. При создании реагента для измерений ФВ:РФКА нами был подобран метод отбора функционально полноценных донорских тромбоцитов для получения фиксированных формальдегидом клеток. На основе таких тромбоцитов был разработан реагент, позволяющий измерять ФВ:РКФА с использованием как агрегационного, так и агглютинационного метода. Выявлено соответствие результатов определения ФВ обоими методами с коэффициентом корреляции 0,96. Проведена оценка агрегационного метода измерения ФВ:РКФА по результатам участия в международной программе внешнего контроля качества UK NEQAS for Blood Coagulation (Великобритания). Заключение. Показано, что использование полученного из фиксированных тромбоцитов реагента позволяет правильно измерять ФВ:РКФА. Introduction. Von Willebrand factor (vWF) is an important component of hemostatic system and deviations from the norm of its content or composition are the cause of various types of von Willebrand disease development. Determination of ristocetin-cofactor activity of vWF (vWF:RCo) is particularly important for identifying 2A, 2B and 2M types of von Willebrand disease, in which the content of vWF antigen is within the normal range, and vWF:RCo signifi cantly reduced. Aim: to obtain a reagent for the measurement of vWF:RCo from platelet concentrates with a long shelf life, providing correct diagnostics. Materials and methods. Fully functional platelets were obtained from donor platelet concentrates with a shelf life of 7–14 days. Results. We discovered the method for selection of fully functional donor platelets to produce formaldehyde-fi xed cells. On the basis of these platelets we developed a reagent that allows to measure vWF:RCo using both aggregation and agglutination methods. The appropriateness was found between the results of vWF determination by both methods with a correlation coeffi cient 0.96. The aggregation method of measuring vWF:RCo was evaluated by a result of participation in the international program of external quality control UK NEQAS for Blood Coagulation (United Kingdom). Conclusion. It is shown that the use of a reagent obtained from fi xed platelets allows for the correct measurement of vWF:RCo.

Evaluation of commercial von Willebrand factor collagen binding assays to assist the discrimination of types 1 and 2 von Willebrand disease

2010 ◽  
Vol 104 (11) ◽  
pp. 1009-1021 ◽  
Author(s):  
Emmanuel Favaloro
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Binding Assays ◽  
Collagen Binding ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Control Samples

SummaryThis study reports on the evaluation of seven commercial von Wille-brand factor (VWF) collagen binding (VWF:CB) assays to potentially assist the discrimination of types 1 and 2 von Willebrand disease (VWD). Samples from 25 patients with type 1 VWD, of varying severity, were co-tested with 16 samples from patients with types 2A or 2B VWD, plus various control samples, using each commercial VWF:CB assay assessed against our standard (reference) in-house VWF:CB assay, as well as our in-house VWF antigen (VWF:Ag) and ristocetin cofactor (VWF:RCo) assays. Commercial VWF:CB assays varied in their ability to discriminate types 1 and 2A/2B VWD. The optimal VWF:CB/VWF:Ag ratio at which optimal discrimination occurred also differed between assays, with some improvements observed with some (but not all) as-says following a harmonisation process that aimed to correct for different calibrator effects. Assay variability also compromised assay utility in some test occasions. Future standardisation and improvements in some commercial VWF:CB assays are needed before the VWF:CB assay can be more fully and globally utilised for discrimination of VWD types in diagnostic laboratories.

scholarly journals A new variant of type II von Willebrand disease with aberrant multimeric structure of plasma but not platelet von Willebrand factor (type IIF)

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 269-274
Author(s):  
PM Mannucci ◽  
R Lombardi ◽  
AB Federici ◽  
JA Dent ◽  
TS Zimmerman ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Normal Plasma ◽  
Von Willebrand Factor Antigen ◽  
Cofactor Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity

A patient with a lifelong bleeding disorder was diagnosed as having Type II von Willebrand disease. The larger multimers of von Willebrand factor were absent from her plasma but present in platelets. A high- resolution electrophoretic technique was used to study the complex structure of individual von Willebrand factor multimers. In normal plasma, each multimer could be resolved into five bands: a more intense central one and four less intense, two moving faster and two slower than the central band. In normal platelets, each multimer could also be resolved into five bands. The central one had a mobility similar to that in plasma, whereas the four satellite bands had a mobility that differed from that of the corresponding plasma bands. In the patient, platelet von Willebrand factor antigen content and ristocetin cofactor activity were normal, and von Willebrand factor showed the same structure of individual multimers as seen in normal platelets. On the other hand, plasma von Willebrand factor antigen and ristocetin cofactor activity were decreased, and the structure of individual von Willebrand factor multimers was different from that of normal plasma and similar to that seen in normal and patient's platelets. After infusion of 1-deamino-8-D-arginine vasopressin, the largest von Willebrand factor multimers, as well as new satellite bands with a mobility similar to those in normal plasma, appeared in the patient plasma, and the levels of von Willebrand factor antigen and ristocetin cofactor activity became normal. Yet no relevant change in the prolonged bleeding time was observed. This new variant of von Willebrand disease, therefore, is characterized by the presence of a dysfunctional von Willebrand factor molecule that exhibits unique structural abnormalities in plasma but appears to be normal in platelets. The designation of Type IIF is proposed for this type of von Willebrand disease in accordance with the terminology that has been previously used.

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

Blood ◽  
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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