Mechanisms of thrombocytopenia in platelet-type von Willebrand disease

Loredana Bury, Alessandro Malara, Stefania Momi, Eleonora Petito, Alessandra Balduini, Paolo Gresele

Research output: Contribution to journalArticle

Abstract

Platelet-type von Willebrand disease is an inherited platelet disorder characterized by thrombocytopenia with large platelets caused by gain-of-function variants in GP1BA leading to enhanced GPIbα-von Willebrand factor (vWF) interaction. GPIbα and vWF play a role in megakaryocytopoiesis, thus we aimed to investigate megakaryocyte differentiation and proplatelet-formation in platelet-type von Willebrand disease using megakaryocytes from a patient carrying the Met239Val variant and from mice carrying the Gly233Val variant. Platelet-type von Willebrand disease megakaryocytes bound vWF at an early differentiation stage and generated proplatelets with a decreased number of enlarged tips compared to control megakaryocytes. Moreover, they formed proplatelets upon contact with collagen, differently from normal megakaryocytes. Similarly, collagen triggered megakaryocytes showed defective activation of the RhoA-MLC2 axis, which prevents proplatelet formation, and increased phosphorylation of Lyn, which acts as a negative regulator of GPVI signaling, thus preventing ectopic proplatelet-formation on collagen. Consistently, human and murine bone marrow contained an increased number of extravascular platelets compared to controls. In addition, platelet survival of mutant mice was shortened compared to control mice, and the administration of desmopressin, raising circulating vWF, caused a marked drop in platelet count. Taken together, these results show for the first time that thrombocytopenia in platelet-type von Willebrand disease is due to the combination of different pathogenic mechanisms, i.e. the formation of a reduced number of platelets by megakaryocytes, the ectopic release of platelets in the bone marrow, and the increased clearance of platelet/vWF complexes.

Original languageEnglish
Pages (from-to)1473-1481
Number of pages9
JournalHaematologica
Volume104
Issue number7
DOIs
Publication statusPublished - Jul 1 2019

Fingerprint

Megakaryocytes
Thrombocytopenia
von Willebrand Factor
Blood Platelets
Platelet Count
Collagen
Bone Marrow
Thrombopoiesis
Deamino Arginine Vasopressin
Platelet type Von Willebrand disease
Phosphorylation

ASJC Scopus subject areas

  • Hematology

Cite this

Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. / Bury, Loredana; Malara, Alessandro; Momi, Stefania; Petito, Eleonora; Balduini, Alessandra; Gresele, Paolo.

In: Haematologica, Vol. 104, No. 7, 01.07.2019, p. 1473-1481.

Research output: Contribution to journalArticle

Bury, L, Malara, A, Momi, S, Petito, E, Balduini, A & Gresele, P 2019, 'Mechanisms of thrombocytopenia in platelet-type von Willebrand disease', Haematologica, vol. 104, no. 7, pp. 1473-1481. https://doi.org/10.3324/haematol.2018.200378
Bury, Loredana ; Malara, Alessandro ; Momi, Stefania ; Petito, Eleonora ; Balduini, Alessandra ; Gresele, Paolo. / Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. In: Haematologica. 2019 ; Vol. 104, No. 7. pp. 1473-1481.
@article{d8dfb15183b6420b822b6088ae5fcde6,
title = "Mechanisms of thrombocytopenia in platelet-type von Willebrand disease",
abstract = "Platelet-type von Willebrand disease is an inherited platelet disorder characterized by thrombocytopenia with large platelets caused by gain-of-function variants in GP1BA leading to enhanced GPIbα-von Willebrand factor (vWF) interaction. GPIbα and vWF play a role in megakaryocytopoiesis, thus we aimed to investigate megakaryocyte differentiation and proplatelet-formation in platelet-type von Willebrand disease using megakaryocytes from a patient carrying the Met239Val variant and from mice carrying the Gly233Val variant. Platelet-type von Willebrand disease megakaryocytes bound vWF at an early differentiation stage and generated proplatelets with a decreased number of enlarged tips compared to control megakaryocytes. Moreover, they formed proplatelets upon contact with collagen, differently from normal megakaryocytes. Similarly, collagen triggered megakaryocytes showed defective activation of the RhoA-MLC2 axis, which prevents proplatelet formation, and increased phosphorylation of Lyn, which acts as a negative regulator of GPVI signaling, thus preventing ectopic proplatelet-formation on collagen. Consistently, human and murine bone marrow contained an increased number of extravascular platelets compared to controls. In addition, platelet survival of mutant mice was shortened compared to control mice, and the administration of desmopressin, raising circulating vWF, caused a marked drop in platelet count. Taken together, these results show for the first time that thrombocytopenia in platelet-type von Willebrand disease is due to the combination of different pathogenic mechanisms, i.e. the formation of a reduced number of platelets by megakaryocytes, the ectopic release of platelets in the bone marrow, and the increased clearance of platelet/vWF complexes.",
author = "Loredana Bury and Alessandro Malara and Stefania Momi and Eleonora Petito and Alessandra Balduini and Paolo Gresele",
year = "2019",
month = "7",
day = "1",
doi = "10.3324/haematol.2018.200378",
language = "English",
volume = "104",
pages = "1473--1481",
journal = "Haematologica",
issn = "0390-6078",
publisher = "NLM (Medline)",
number = "7",

}

TY - JOUR

T1 - Mechanisms of thrombocytopenia in platelet-type von Willebrand disease

AU - Bury, Loredana

AU - Malara, Alessandro

AU - Momi, Stefania

AU - Petito, Eleonora

AU - Balduini, Alessandra

AU - Gresele, Paolo

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Platelet-type von Willebrand disease is an inherited platelet disorder characterized by thrombocytopenia with large platelets caused by gain-of-function variants in GP1BA leading to enhanced GPIbα-von Willebrand factor (vWF) interaction. GPIbα and vWF play a role in megakaryocytopoiesis, thus we aimed to investigate megakaryocyte differentiation and proplatelet-formation in platelet-type von Willebrand disease using megakaryocytes from a patient carrying the Met239Val variant and from mice carrying the Gly233Val variant. Platelet-type von Willebrand disease megakaryocytes bound vWF at an early differentiation stage and generated proplatelets with a decreased number of enlarged tips compared to control megakaryocytes. Moreover, they formed proplatelets upon contact with collagen, differently from normal megakaryocytes. Similarly, collagen triggered megakaryocytes showed defective activation of the RhoA-MLC2 axis, which prevents proplatelet formation, and increased phosphorylation of Lyn, which acts as a negative regulator of GPVI signaling, thus preventing ectopic proplatelet-formation on collagen. Consistently, human and murine bone marrow contained an increased number of extravascular platelets compared to controls. In addition, platelet survival of mutant mice was shortened compared to control mice, and the administration of desmopressin, raising circulating vWF, caused a marked drop in platelet count. Taken together, these results show for the first time that thrombocytopenia in platelet-type von Willebrand disease is due to the combination of different pathogenic mechanisms, i.e. the formation of a reduced number of platelets by megakaryocytes, the ectopic release of platelets in the bone marrow, and the increased clearance of platelet/vWF complexes.

AB - Platelet-type von Willebrand disease is an inherited platelet disorder characterized by thrombocytopenia with large platelets caused by gain-of-function variants in GP1BA leading to enhanced GPIbα-von Willebrand factor (vWF) interaction. GPIbα and vWF play a role in megakaryocytopoiesis, thus we aimed to investigate megakaryocyte differentiation and proplatelet-formation in platelet-type von Willebrand disease using megakaryocytes from a patient carrying the Met239Val variant and from mice carrying the Gly233Val variant. Platelet-type von Willebrand disease megakaryocytes bound vWF at an early differentiation stage and generated proplatelets with a decreased number of enlarged tips compared to control megakaryocytes. Moreover, they formed proplatelets upon contact with collagen, differently from normal megakaryocytes. Similarly, collagen triggered megakaryocytes showed defective activation of the RhoA-MLC2 axis, which prevents proplatelet formation, and increased phosphorylation of Lyn, which acts as a negative regulator of GPVI signaling, thus preventing ectopic proplatelet-formation on collagen. Consistently, human and murine bone marrow contained an increased number of extravascular platelets compared to controls. In addition, platelet survival of mutant mice was shortened compared to control mice, and the administration of desmopressin, raising circulating vWF, caused a marked drop in platelet count. Taken together, these results show for the first time that thrombocytopenia in platelet-type von Willebrand disease is due to the combination of different pathogenic mechanisms, i.e. the formation of a reduced number of platelets by megakaryocytes, the ectopic release of platelets in the bone marrow, and the increased clearance of platelet/vWF complexes.

UR - http://www.scopus.com/inward/record.url?scp=85069230401&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069230401&partnerID=8YFLogxK

U2 - 10.3324/haematol.2018.200378

DO - 10.3324/haematol.2018.200378

M3 - Article

C2 - 30655369

AN - SCOPUS:85069230401

VL - 104

SP - 1473

EP - 1481

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 7

ER -