An acquired Bernard‐Soulier‐like platelet defect associated with juvenile myelodysplastic syndrome

Berndt, Michael C.; Kabral, Arnold; Grimsley, P.G.; Watson, Neville; Robertson, T. I.; Bradstock, Kenneth F.

doi:10.1111/j.1365-2141.1988.tb04185.x

Cited by 36 publications

(14 citation statements)

References 18 publications

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“…Acquired deficiency of platelet GP in patients with hematologic neoplasms has sometimes been reported. Berndt et al 37 reported a case of juvenile MDS with loss of CD42a on platelets (similar to what is seen in patients with Bernard-Soulier's syndrome). Also, acquired Glanzmann thrombasthenia due to anti-GPIIb/IIIa auto-antibodies is usually associated with autoimmune conditions 38 and has been reported in both non-Hodgkin's 38 (NHL) and Hodgkin's lymphomas.…”

Section: Discussionmentioning

confidence: 81%

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Sandes¹,

Yamamoto²,

Matarraz³

et al. 2012

Haematologica

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BackgroundMultiparameter flow cytometric analysis of bone marrow and peripheral blood cells has proven to be of help in the diagnostic workup of myelodysplastic syndromes. However, the usefulness of flow cytometry for the detection of megakaryocytic and platelet dysplasia has not yet been investigated. The aim of this pilot study was to evaluate by flow cytometry the diagnostic and prognostic value of platelet dysplasia in myelodysplastic syndromes. Design and MethodsWe investigated the pattern of expression of distinct surface glycoproteins on peripheral blood platelets from a series of 44 myelodysplastic syndrome patients, 20 healthy subjects and 19 patients with platelet alterations associated to disease conditions other than myelodysplastic syndromes. Quantitative expression of CD31, CD34, CD36, CD41a, CD41b, CD42a, CD42b and CD61 glycoproteins together with the PAC-1, CD62-P, fibrinogen and CD63 platelet activation-associated markers and platelet light scatter properties were systematically evaluated. ResultsOverall, flow cytometry identified multiple immunophenotypic abnormalities on platelets of myelodysplastic syndrome patients, including altered light scatter characteristics, over-and under expression of specific platelet glycoproteins and asynchronous expression of CD34; decreased expression of CD36 (n=5), CD42a (n=1) and CD61 (n=2), together with reactivity for CD34 (n=1) were only observed among myelodysplastic syndrome cases, while other alterations were also found in other platelet disorders. Based on the overall platelet alterations detected for each patient, an immunophenotypic score was built which identified a subgroup of myelodysplastic syndrome patients with a high rate of moderate to severe alterations (score>1.5; n=16) who more frequently showed thrombocytopenia, megakaryocytic dysplasia and high-risk disease, together with a shorter overall survival. ConclusionsOur results show the presence of altered phenotypes by flow cytometry on platelets from around half of the myelodysplastic syndrome patients studied. If confirmed in larger series of patients, these findings may help refine the diagnostic and prognostic assessment of this group of disorders.

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Section: Discussionmentioning

confidence: 81%

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Sandes¹,

Yamamoto²,

Matarraz³

et al. 2012

Haematologica

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“…Intriguingly, BSS-like hematologic indicators such as giant platelets and reduction of surface GPIb␣ expression have been reported in subsets of patients with myelodysplasia. 40,41 In conclusion, our study has established gp96/grp94 as a molecular chaperone for gpIX and the gpIb complex. We have provided yet another striking example of the defect of protein quality control in causing a unique genetic disorder.…”

Section: Discussionmentioning

confidence: 99%

Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex

Staron

Hong

et al. 2011

Blood

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The platelet glycoprotein Ib-IX-V complex (GPIb-IX-IV) is the receptor for VWF and is responsible for VWF-mediated platelet activation and aggregation. Loss of the GPIb-IX-V complex is pathogenic for Bernard-soulier Syndrome (BSS), which is characterized by macrothrombocytopenia and impaired platelet function. It remains unclear how the GPIb-IX-V complex is assembled and whether there is a role for a specific molecular chaperone in the process. In the present study, we report that the assembly of the GPIb-IX-V complex depends critically on a molecular chaperone in the endoplasmic reticulum (ER): gp96 (also known as grp94 and HSP90b1). gp96/grp94 deletion in the murine hematopoietic system results in thrombocytopenia, prolonged bleeding time, and giant platelets that are clinically indistinguishable from human BSS. Loss of gp96/grp94 in vivo and in vitro leads to the concomitant reduction in GPIb-IX complex expression due to ER-associated degradation. We further demonstrate that gp96/grp94 binds selectively to the GPIX subunit, but not to gpIb␣ or gpIb␤. Therefore, we identify the platelet GPIX subunit of the GPIb-IX-V complex as an obligate and novel client of gp96/grp94. (Blood. 2011;117(26):7136-7144) IntroductionThe molecular chaperone gp96, 1 which is also known as grp94 2 or HSP90b1, is the paralog of heat-shock protein 90 (HSP90) in the endoplasmic reticulum (ER). Like other HSPs, gp96/grp94 is induced by the accumulation of misfolded proteins. 3 gp96/grp94 binds and hydrolyzes ATP, 4-6 is the most abundant protein in the ER lumen, and is ubiquitously expressed in all nucleated cells. Genetic studies have begun to clarify and expand the role of gp96/grp94 as the critical chaperone for multiple TLRs and integrins [7][8][9][10][11] and in the unfolded protein response (UPR). 12 Without gp96/grp94, the majority of integrins and TLRs are unable to fold properly and thus fail to exit the ER to traffic to the proper post-ER compartment. Using a Cre/loxP-mediated conditional deletion of gp96/grp94 in mice, we recently discovered that gp96/grp94 selectively regulates lymphopoiesis but not myelopoiesis. 10 However, it remains unclear whether gp96/grp94 chaperones other, as-yet-unidentified client proteins in the hematopoietic system.The platelet glycoprotein Ib-IX-V (GPIb-IX-V) complex consists of 4 transmembrane proteins: GPIb␣, GPIb␤, GPIX, and GPV 13 and functions as a receptor for VWF for platelet activation. 14 Defects in the biogenesis of this complex result in BSS. At the molecular and structural level, GPIb␣ and GPIb␤ are covalently linked by a disulfide bond; these proteins are noncovalently associated with GPIX and GPV. 13,15 The GPIb-IX complex belongs to proteins of the leucine-rich repeat (LRR) family. 16 Like other LRR-motif-containing proteins, GPIb␣ adopts a "horseshoe-like" shape that is thought to be involved in intermolecular interactions and ligand binding. 14 In support of this notion, several mutations in the LRR domain of GPIb␣, GPIb␤, and GPIX result in loss of GPIb function and the developm...

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“…An aquired von Willebrand disease [17,18], a reduction of platelet procoagulant activity and an aquired form of Bernard-Soulier syndrome were also reported in these disorders [19].…”

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confidence: 99%

Abnormalities of platelet aggregation in chronic myeloproliferative disorders

Avram

Lupu

Angelescu

et al. 2001

J Cellular Molecular Medi

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A large variety of platelet dysfunctions has been described in chronic myeloproliferative disorders. These abnormalities may be due to deficiency of platelet granules, arahidonic acid metabolism defects or platelet membrane glycoproteins abnormalities. In this study we intend to detect the incidence of platelet function defects in 76 patients with various types of chronic myeloproliferative disorders. The platelet activity was studied in vitro by measuring platelet aggregation in response to ADP, epinephrine, collagen, arachidonic acid and ristocetin. These results were subsequently correlated with bleeding time and clinical aspects (bleeding or thrombosis). We found complex changes in platelet response with all agonists, in varied proportions. These abnormalities include absent, decreased or abnormal platelet aggregation response. In a few cases we found a markedly decreased, almost absent platelet response to all agonists while in some patients a normal platelet aggregation was noted. The correlation between these results and template bleeding time, thrombotic or hemorrhagic events and the type of diseases was difficult to establish and sometimes conflictual. Despite this fact, we consider that investigating platelet aggregation may be useful not only for the assesment of the hemostatic balance in chronic myeloproliferative disorders but also for a better insight into cell abnormalities occuring in these pathologic conditions.

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An acquired Bernard‐Soulier‐like platelet defect associated with juvenile myelodysplastic syndrome

Cited by 36 publications

References 18 publications

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex

Abnormalities of platelet aggregation in chronic myeloproliferative disorders

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