scholarly journals Platelet dysfunction in platelet-type von Willebrand disease due to the constitutive triggering of the Lyn-PECAM1 inhibitory pathway

Haematologica ◽  
2021 ◽  
Author(s):  
Loredana Bury ◽  
Emanuela Falcinelli ◽  
Anna Maria Mezzasoma ◽  
Giuseppe Guglielmini ◽  
Stefania Momi ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Platelet Dysfunction ◽  
Platelet Disorder ◽  
Granule Secretion ◽  
Inhibitory Signaling ◽  
Von Willebrand ◽  
First Time ◽  
Willebrand Factor

Platelet-type von Willebrand disease (PT-VWD) is an inherited platelet disorder characterized by macrothrombocytopenia and mucocutaneous bleeding, of variable severity, due to gain-of-function variants of GP1BA conferring to glycoprotein Ibα (GPIbα) enhanced affinity for von Willebrand factor (VWF). The bleeding tendency is conventionally attributed to thrombocytopenia and large VWF-multimers depletion. Some clues, however, suggest that platelet dysfunction may contribute to the bleeding phenotype but no information on its characteristics and causes are available. Aim of the present study was to characterize platelet dysfunction in PT-VWD and shed light on its mechanism. Platelets from a PT-VWD patient carrying the p.M239V variant and from PT-VWD mice carrying the p.G233V variant showed a remarkable platelet function defect, with impaired aggregation, defective granule secretion and reduced adhesion under static and flow conditions. VWF-binding to GPIbα is known to trigger intracellular signaling involving Src-family kinases (SFKs). We found that constitutive phosphorylation of the platelet SFK Lyn induces a negative-feedback loop downregulating platelet activation through phosphorylation of PECAM1 on Tyr686 and that this is triggered by the constitutive binding of VWF to GPIbα binding. These data show for the first time that the abnormal triggering of inhibitory signals mediated by Lyn and PECAM1 may lead to platelet dysfunction.In conclusion, our study unravels the mechanism of platelet dysfunction in PT-VWD caused by deranged inhibitory signaling triggered by the constitutive binding of VWF to GPIbα which may significantly contribute to the bleeding phenotype of these patients.

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.

Autoantibody Selectively Inhibits Binding of von Willebrand Factor to Glycoprotein Ib. Recognition Site Is Located in the A1 Loop of von Willebrand Factor

1997 ◽  
Vol 77 (04) ◽  
pp. 760-766 ◽  
Author(s):  
Hiroshi Mohri ◽  
Etsuko Yamazaki ◽  
Zekou Suzuki ◽  
Toshikuni Takano ◽  
Shumpei Yokota ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Significant Inhibition ◽  
Von Willebrand Disease ◽  
Recognition Site ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Virtual Absence ◽  
Heavy Chains ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryA 20-year-old man with severe von Willebrand disease recently presented a progressive bleeding tendency, characterized recurrent subcutaneous hemorrhages and cerebral hemorrhage. Mixing and infusion studies suggested the presence of an inhibitor directed against vWF:RCo activity of von Willebrand factor (vWF) without significant inhibition of the FVIII:C. The inhibitor was identified as an antibody of IgG class. The inhibitor inhibited the interaction of vWF in the presence of ristocetin and that of asialo-vWF with GPIb while it partially blocked botrocetin-mediated interaction of vWF to GPIb. The inhibitor reacted with native vWF, the 39/34kDa fragment (amino acids [aa] 480/ 481-718) and the recombinant vWF fragment (MalE-rvWF508-704), but not with Fragment III-T2 (heavy chains, aa 273-511; light chains, aa 674-728). A synthetic peptide (aa 514-542) did not inhibit vWF-inhibitor complex formation. We conclude that this is the first autoantibody of class IgG from human origin that recognizes the sequence in the A1 loop of vWF, resulting in a virtual absence of functional vWF and a concomitant severe bleeding tendency although recognition site is different from the residues 514-542 which is crucial for vWF-GPIb interaction.

scholarly journals Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen

Blood ◽  
1994 ◽  
Vol 84 (10) ◽  
pp. 3378-3384 ◽  
Author(s):  
PJ van Genderen ◽  
T Vink ◽  
JJ Michiels ◽  
MB van 't Veer ◽  
JJ Sixma ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Low Grade ◽  
Bleeding Tendency ◽  
Glycoprotein Ib ◽  
Acquired Von Willebrand Disease ◽  
Recurrent Epistaxis ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract An 82-year-old man with a low-grade malignant non-Hodgkin lymphoma and an IgG3 lambda monoclonal gammopathy presented a recently acquired bleeding tendency, characterized by recurrent epistaxis, easy bruising, and episodes of melena, requiring packed red blood cell transfusions. Coagulation studies showed a von Willebrand factor (vWF) defect (Ivy bleeding time, > 15 minutes; vWF antigen [vWF:Ag], 0.08 U/mL; ristocetin cofactor activity [vWF:RCoF], < 0.05 U/mL; collagen binding activity [vWF:CBA], 0.01 U/mL; absence of the high molecular weight multimers of vWF on multimeric analysis). Mixing experiments suggested the presence of an inhibitor directed against the vWF:CBA activity of vWF without significantly inhibiting the FVIII:C, vWF:Ag, and vWF:RCoF activities. The inhibitor was identified as an antibody of the IgM class by immunoabsorption of vWF and inhibitor-vWF complexes from the plasma of the patient. Subsequent immunoprecipitation experiments using recombinant fragments of vWF showed that the inhibitor reacted with both the glycoprotein Ib binding domain (amino acids [aa] 422–826) and the A3 (aa 909–1112) domain of vWF, but not with the A2 (aa 716–908) or D4 (aa 1183–1535) domains. We conclude that the IgM autoantibody inhibits the vWF:CBA activity by reacting with an epitope present on both the glycoprotein Ib and A3 domains of vWF.

scholarly journals THE ROLE OF BLEEDING HISTORY AND CLINICAL MARKERS FOR THE CORRECT DIAGNOSIS OF VWD

2013 ◽  
Vol 5 (1) ◽  
pp. e2013051 ◽  
Author(s):  
Alberto Tosetto
Keyword(s):  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Assessment Tools ◽  
Bleeding Tendency ◽  
Clinical Markers ◽  
Web Based ◽  
Bleeding Score ◽  
Bleeding History ◽  
Von Willebrand ◽  
Willebrand Factor

Quantification of the bleeding severity by use of bleeding assessment tools (BAT) and bleeding score (BS) has been consistently shown to improve the clinical diagnosis of von Willebrand disease (VWD) while helping researchers establish phenotype/genotype correlations.  Subjects with a BS equal or higher than 3 may be consider having a bleeding tendency, and should be referred for a laboratory investigation, particularly for VWD. In the diagnosis of type 1 VWD, the use of the BS has been shown to be highly specific (>95%) with reported sensitivities ranging from 40 to 100%. The BS is related to all available measurements of von Willebrand factor activity, including the PFA-100 closure time. Therefore, in clinical practice the use of BAT should always be the first step to standardize the assessment of patients with suspected VWD. The use of the recent ISTH consensus BAT is suggested to harmonize the collection of bleeding symptoms in patients with a suspected or confirmed hemostatic disorder, particularly VWD. The ISTH BAT is also coupled with a Web-based repository of bleeding symptoms, therefore providing an integrated framework for collaboration in the field of clinical evaluation of VWD and mild bleeding disorders.

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 congenital platelet abnormality characterized by spontaneous platelet aggregation, enhanced von Willebrand factor platelet interaction, and the presence of all von Willebrand factor multimers in plasma

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2028-2033
Author(s):  
A Casonato ◽  
L De Marco ◽  
M Mazzucato ◽  
V De Angelis ◽  
D De Roia ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Platelet Rich Plasma ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Binding Studies ◽  
Spontaneous Platelet Aggregation ◽  
Von Willebrand ◽  
Willebrand Factor

A case is reported of a 49-year-old woman with a mild bleeding tendency. Her bleeding time, platelet count and size, plasma ristocetin cofactor activity, von Willebrand factor (vWF) antigen, and vWF multimeric pattern are all within normal limits. Spontaneous platelet aggregation is observed when citrated platelet-rich plasma (PRP) is stirred in an aggregometer cuvette. This aggregation is completely is only slightly diminished by an antiglycoprotein (GP) IIb/IIIa or by an anti GPIb monoclonal antibody. The patient's PRP shows increased sensitivity to ristocetin. The distinct feature of this patient, also present in two family members studied, is that platelet aggregation is initiated by purified vWF in the absence of any other agonist. The vWF- induced platelet aggregation is abolished by anti-GPIb and anti- GPIIb/IIIa monoclonal antibodies and by EDTA (5 mmol/L). Apyrase inhibits the second wave of aggregation. Patient's platelets in PRP are four to six times more reactive to asialo vWF-induced platelet aggregation than normal platelets. The amount of radiolabeled vWF bound to platelets in the presence of either low concentration of ristocetin or asialo vWF was increased 30% compared with normal. The patient's platelet GPIb was analyzed by SDS page and immunoblotting and by binding studies with anti-GPIb monoclonal antibodies showed one band with slightly increased migration pattern and a normal number of GPIb molecules. Unlike the previously reported patients with pseudo or platelet-type von Willebrand disease, this patient has normal vWF parameters.

scholarly journals A p.Arg127Gln variant in GPIbα LRR5 allosterically enhances affinity for VWF: a novel form of platelet-type VWD

2021 ◽  
Author(s):  
Loredana Bury ◽  
Emanuela Falcinelli ◽  
Haripriya Kuchi Bhotla ◽  
Anna Maria Mezzasoma ◽  
Giuseppe Guglielmini ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Conformational Dynamics ◽  
Von Willebrand Disease ◽  
High Affinity ◽  
Laboratory Test Results ◽  
Hydrogen Deuterium ◽  
Von Willebrand ◽  
The Impact ◽  
First Time ◽  
Willebrand Factor

Gain-of-function (GoF) variants in GP1BA cause platelet-type von Willebrand disease (PT-VWD), a rare inherited autosomal dominant bleeding disorder characterized by enhanced platelet GPIbα-von Willebrand factor (VWF) interaction and thrombocytopenia. To date, only 6 variants causing PT-VWD have been described, 5 in the C-terminal disulfide loop of the VWF-binding domain of GPIbα and 1 in the macroglycopeptide. GoF GP1BA variants generate a high affinity conformation of the C-terminal disulfide loop with a consequent allosteric conformational change on another region of GPIbα, the leucine-rich-repeat (LRR) domain. We identified a novel GP1BA variant (p.Arg127Gln) affecting the LRR5 domain of GPIbα in a boy with easy bruising and laboratory test results suggestive of PT-VWD. We thus aimed to investigate the impact of the p.Arg127Gln variant on GPIbα affinity for VWF and on GPIbα structure. CHO cells expressing p.Arg127Gln GPIbα showed increased binding of VWF induced by ristocetin and enhanced tethering on immobilized VWF as compared with cells expressing wild-type (WT) GPIbα. Surface plasmon resonance confirmed that p.Arg127Gln enhances the binding affinity of GPIbα for VWF. Hydrogen-deuterium exchange mass spectrometryshowed that p.Arg127Gln of LRR, while having little effect on the dynamics of the LRR locally, enhances the conformational dynamics of the GPIbα C-terminal disulfide loop structure. Our data demonstrate for the first time that GoF variants outside the GPIbα C-terminal disulfide loop may be pathogenic and that aminoacidic changes in the LRR may cause allosterically conformational changes in the C-terminal disulfide loop of GPIbα inducing a conformation with high affinity for VWF.

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.

Interactions of von Willebrand factor and ADAMTS13 in von Willebrand disease and thrombotic thrombocytopenic purpura

2014 ◽  
Vol 34 (03) ◽  
pp. 215-225 ◽  
Author(s):  
R. Schneppenheim ◽  
U. Budde
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Active Phase ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Thrombocytopenic Purpura ◽  
Acquired Von Willebrand Syndrome ◽  
Key Factor ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe function of von Willebrand factor (VWF), a huge multimeric protein and a key factor in platelet dependent primary haemostasis, is regulated by its specific protease ADAMTS13. The ADAMTS13 dependent degradation of VWF to its proteolytic fragments can be visualized as a characteristic so-called triplet structure of individual VWF oligomers by multimer analysis. Lack of VWF high molecular weight multimers (VWF-HMWM) or their pathologically enhanced degradation under - lies a particular type of von Willebrand disease, VWD type 2A with a significant bleeding tendency, and may also be observed in acquired von Willebrand syndrome due to cardiovascular disease. In these conditions multimer analysis is an obligatory and powerful tool for diagnosis of VWD. The opposite condition, the persistence of ultralarge VWF (UL-VWF) multimers may cause the microangiopathic life-threatening disorder thrombotic thrombocytopenic purpura (TTP). During the course of active TTP, UL-VWF is consumed in the hyaline thrombi formed in the microvasculature which will ultimately result in the loss of UL-VWF and VWF-HMWM. Therefore, VWF multimer analysis is not a valid tool to diagnose TTP in the active phase of disease but may be helpful for the diagnosis of TTP patients in remission.

scholarly journals How I treat type 2 variant forms of von Willebrand disease

Blood ◽  
2015 ◽  
Vol 125 (6) ◽  
pp. 907-914 ◽  
Author(s):  
Alberto Tosetto ◽  
Giancarlo Castaman
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Risk ◽  
Von Willebrand Disease ◽  
Major Surgery ◽  
Bleeding Tendency ◽  
Wide Range ◽  
Deficiency Type ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractType 2 von Willebrand disease (VWD) includes a wide range of qualitative abnormalities of von Willebrand factor structure and function resulting in a variable bleeding tendency. According to the current classification, 4 different subtypes can be identified, each with distinctive phenotypic and therapeutic characteristics. Current available laboratory methods allow a straightforward approach to VWD subtyping, and although the precise molecular characterization remains complex, it is not required for appropriate treatment of the vast majority of cases. Desmopressin can be useful only in a few type 2 cases compared with patients with actual quantitative deficiency (type 1), most often in variants with a nearly normal multimeric pattern (type 2M). However, since no laboratory test accurately predicts response to desmopressin, a trial test should always be performed in all type 2 VWD patients, with the exception of type 2B ones. Replacement therapy with plasma-derived von Willebrand factor-factor VIII concentrates represents the safe mainstay of treatment of all patients, particularly those not responding to desmopressin or requiring a sustained hemostatic correction because of major surgery or bleeding. A significant patient bleeding history correlates with increased bleeding risk and should be considered in tailoring the optimal antihemorrhagic prophylaxis in the individual patient.

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