Giant platelet disorder in a patient with type 2B von Willebrand's disease

Moll, Stephan; Lazarowski, Alicia Rico; White, Gilbert

doi:10.1002/(sici)1096-8652(199801)57:1<62::aid-ajh11>3.0.co;2-b

Cited by 12 publications

(16 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…14,[18][19][20] As anticipated, the mutant VWF displays a high affinity to platelets, 19 and many patients have persistent or transient thrombocytopenia, [21][22][23] large platelets, and spontaneous platelet aggregation. 4,6 One illustrative example is a 5-year-old boy with the heterozygous V1316M VWF mutation who presented with macrothrombocytopenia (platelet count ϳ 20 ϫ 10 9 /L), platelet clumping on blood film, and loss of plasma high and intermediate molecular weight VWF multimers. 4 This boy had severe epistaxis that was successfully treated with VWF/FVIII concentrates, although concomitant platelet transfusions were occasionally required.…”

Section: Resultsmentioning

confidence: 99%

“…The disorder was named Montreal platelet syndrome (MPS). 2 Several studies have now shown that some patients with type 2B von Willebrand disease (VWD) present with macrothrombocytopenia [4][5][6][7][8] and spontaneous platelet aggregation in vitro, [4][5][6][7]9 features found in MPS. 10 A diagnosis of type 2 VWD is suggested by a discrepantly low ristocetin cofactor activity (VWF:RCo) compared with the VWF antigen (VWF:Ag; [VWF:RCo/VWF:Ag ratio Ͻ 0.7]).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation

Jackson

Sinclair

Cloutier

et al. 2009

Blood

View full text Add to dashboard Cite

Montreal platelet syndrome (MPS), hitherto described in only one kindred, is a hereditary thrombocytopenia associated with mucocutaneous bleeding, giant platelets, and spontaneous platelet aggregation in vitro. These are features shared with some forms of type 2B von Willebrand disease (VWD); however, the MPS kindred had not been investigated for VWD. We found that all affected MPS family members had borderline to normal von Willebrand factor antigen (VWF:Ag; 0.43-0.75 U/mL), discrepantly low ristocetin cofactor activity (VWF:RCo; 0.16-0.29 U/mL), and normal factor VIII coagulant activity (FVIII:C; 0.57-1.04 U/mL). Unaffected family members all had normal VWF:Ag, VWF:RCo, and FVIII:C levels. In addition, persons with MPS, but not unaffected family members, had loss of plasma (but not platelet) high molecular weight VWF multimers, and were heterozygous for the previously reported V1316M type 2B VWD mutation. Thus, in reevaluating this kindred, we determined that patients with MPS have type 2B VWD with the V1316M VWF mutation. (Blood. 2009;113:3348-3351)

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation

Jackson

Sinclair

Cloutier

et al. 2009

Blood

View full text Add to dashboard Cite

show abstract

“…37,38 While the presence of agglutinates and severe thrombocytopenia is one variable in type 2B VWD, the presence of giant platelets is another. [17][18][19] Yet, 3 patients with thrombocytopenia and giant platelets possessed different mutations in the VWF gene (1304insMet, V1316M, P1337L), showing that such morphologic changes are not linked to a recurrent mutation. 19 Although thrombocytopenia can be greater during pregnancy or after DDAVP infusion in type 2B VWD, when plasma levels of VWF are increased, 1,39 in our family the severe thrombocytopenia was constant.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the degree of reported thrombocytopenia is highly variable, with sometimes giant and morphologically abnormal platelets being observed. 17,18 We ourselves have previously reported giant platelets in 3 unrelated patients with type 2B VWD. 19 Here, we describe a previously unreported family with an autosomal dominant trait and where severe thrombocytopenia is associated with the presence of agglutinates of morphologically abnormal platelets.…”

Section: Introductionmentioning

confidence: 91%

Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia

Nurden

Debili

Vainchenker

et al. 2006

Blood

View full text Add to dashboard Cite

In type 2B von Willebrand disease, there is spontaneous binding of mutated von Willebrand factor (VWF) multimers to platelets. Here we report a family in which severe thrombocytopenia may also be linked to abnormal megakaryocytopoiesis. A heterozygous mutation in the VWF A1 domain gave a R1308P substitution in an interactive site for glycoprotein Ib␣ (GPIb␣). Electron microscopy showed clusters of platelets in close contact. Binding of antibodies to the GPIb␣ N-terminal domain was decreased, whereas GPIX and GPV were normally detected. In Western blotting (WB), GPIb␣, ␣IIb, and ␤3 were normally present. Proteins involved in Ca 2؉ homeostasis were analyzed by quantitating platelet mRNA or by WB. Plasma membrane Ca 2؉ ATPase (PMCA)-4b and type III inositol trisphosphate receptor (InsP 3 -R3) were selectively increased. The presence of degradation products of polyadenosine diphosphate (ADP)-ribose polymerase protein (PARP) suggested ongoing caspase-3 activity. These were findings typical of immature normal megakaryocytes cultured from peripheral blood CD34 ؉ cells with TPO. Significantly, megakaryocytes from the patients in culture produced self-associated and interwoven proplatelets. Immunolocalization showed VWF not only associated with platelets, but already on the megakaryocyte surface and within internal channels. In this family, type 2B VWD is clearly associated with abnormal platelet production. IntroductionVon Willebrand disease (VWD) is the most common inherited disorder of the platelet-vessel wall interaction and involves both quantitative and qualitative defects of von Willebrand factor (VWF), a crucial mediator of platelet function and carrier of the FVIII protein. In type 1 and type 3 VWD, deficiencies or absence of VWF protein are responsible for the bleeding syndrome, but in type 2 disease a functionally abnormal protein or the specific lack of large multimers account for the VWD phenotype. 1,2 In hemostasis, glycoprotein Ib␣ (GPIb␣) mediates platelet attachment to exposed subendothelium by binding through its N-terminus to the A1 domain of VWF exposed within the subendothelial matrix. 3,4 In healthy subjects, soluble VWF multimers in plasma fail to gain access to their binding site on GPIb␣, accessibility being controlled by a disulfide-linked double-loop region just below the leucine-rich repeats of GPIb␣. 5 In type 2B VWD, mutations giving rise to a selective number of amino acid substitutions in the A1 domain provide gain of function to the VWF multimers which then spontaneously bind to platelets in suspension through a direct interaction with GPIb␣. [6][7][8] This often results in the loss of the largest multimers from plasma, although these may be at least partially preserved in some cases. 9 Bleeding results from platelets having blocked GPIb function despite a heightened ristocetininduced platelet agglutination in platelet function testing, and perhaps through the relative hemostatic inefficiency of the remaining small multimers. The thrombocytopenia that accompanies this disorder in some, a...

show abstract

“…Thrombocytopenia is often present in VWD2B, and the presence of giant platelets has been reported in isolated cases. [9][10][11][12] Circulating platelet agglutinates have been found in rare families. [12][13][14] Studies using a nanobody recognizing soluble VWF in its gain-of-function state confirmed that soluble VWF in its GPIb␣-binding conformation was present in greater amounts in most patients with VWD2B with thrombocytopenia.…”

mentioning

confidence: 99%

Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B

Nurden

Gobbi

Enouf

et al. 2010

Blood

View full text Add to dashboard Cite

Giant platelet disorder in a patient with type 2B von Willebrand's disease

Cited by 12 publications

References 17 publications

The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation

The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation

Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia

Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B

Contact Info

Product

Resources

About