Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions (2024)

Nagy, M., Perrella, G., Dalby, A., Becerra, M. F., Quintanilla, L. G., Pike, J. A., Morgan, N. V., Gardiner, E. E., Heemskerk, J. W. M., Ocar, L. A., Miquel, J. F., Mezzano, D., & Watson, S. P. (2020). Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions. Blood advances, 4(13), 2953-2961. https://doi.org/10.1182/bloodadvances.2020001761

Nagy, Magdolna ; Perrella, Gina ; Dalby, Amanda et al. / Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions. In: Blood advances. 2020 ; Vol. 4, No. 13. pp. 2953-2961.

@article{b85d625a2bd64241b2828cfe484bccb2,

title = "Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions",

abstract = "The role of glycoprotein VI (GPVI) in platelets was investigated in 3 families bearing an insertion within the GP6 gene that introduces a premature stop codon prior to the transmembrane domain, leading to expression of a truncated protein in the cytoplasm devoid of the transmembrane region. Western blotting and flow cytometry of GP6hom (hom*ozygous) platelets confirmed loss of the full protein. The level of the Fc receptor g-chain, which associates with GPVI in the membrane, was partially reduced, but expression of other receptors and signaling proteins was not altered. Spreading of platelets on collagen and von Willebrand factor (which supports partial spreading) was abolished in GP6hom platelets, and spreading on uncoated glass was reduced. Anticoagulated whole blood flowed over immobilized collagen or a mixture of von Willebrand factor, laminin, and rhodocytin (noncollagen surface) generated stable platelet aggregates that express phosphatidylserine (PS). Both responses were blocked on the 2 surfaces in GP6hom individuals, but adhesion was not altered. Thrombin generation was partially reduced in GP6hom blood. The frequency of the GP6het (heterozygous) variant in a representative sample of the Chilean population (1212 donors) is 2.9%, indicating that there are ;4000 GP6hom individuals in Chile. These results demonstrate that GPVI supports aggregation and PS exposure under flow on collagen and noncollagen surfaces, but not adhesion. The retention of adhesion may contribute to the mild bleeding diathesis of GP6hom patients and account for why so few of the estimated 4000 GP6hom individuals in Chile have been identified.",

author = "Magdolna Nagy and Gina Perrella and Amanda Dalby and Becerra, {M. Francisca} and Quintanilla, {Lourdes Garcia} and Pike, {Jeremy A.} and Morgan, {Neil V.} and Gardiner, {Elizabeth E.} and Heemskerk, {Johan W.M.} and Ocar, {Lorena Az{\^a}´} and Miquel, {Juan Francisco} and Diego Mezzano and Watson, {Steve P.}",

note = "Publisher Copyright: {\textcopyright} 2020 American Society of Hematology. All rights reserved.",

year = "2020",

month = jul,

day = "14",

doi = "10.1182/bloodadvances.2020001761",

language = "English",

volume = "4",

pages = "2953--2961",

journal = "Blood advances",

issn = "2473-9529",

publisher = "Elsevier B.V.",

number = "13",

}

Nagy, M, Perrella, G, Dalby, A, Becerra, MF, Quintanilla, LG, Pike, JA, Morgan, NV, Gardiner, EE, Heemskerk, JWM, Ocar, LA, Miquel, JF, Mezzano, D & Watson, SP 2020, 'Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions', Blood advances, vol. 4, no. 13, pp. 2953-2961. https://doi.org/10.1182/bloodadvances.2020001761

Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions. / Nagy, Magdolna; Perrella, Gina; Dalby, Amanda et al.
In: Blood advances, Vol. 4, No. 13, 14.07.2020, p. 2953-2961.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions

AU - Nagy, Magdolna

AU - Perrella, Gina

AU - Dalby, Amanda

AU - Becerra, M. Francisca

AU - Quintanilla, Lourdes Garcia

AU - Pike, Jeremy A.

AU - Morgan, Neil V.

AU - Gardiner, Elizabeth E.

AU - Heemskerk, Johan W.M.

AU - Ocar, Lorena Azâ´

AU - Miquel, Juan Francisco

AU - Mezzano, Diego

AU - Watson, Steve P.

N1 - Publisher Copyright:© 2020 American Society of Hematology. All rights reserved.

PY - 2020/7/14

Y1 - 2020/7/14

N2 - The role of glycoprotein VI (GPVI) in platelets was investigated in 3 families bearing an insertion within the GP6 gene that introduces a premature stop codon prior to the transmembrane domain, leading to expression of a truncated protein in the cytoplasm devoid of the transmembrane region. Western blotting and flow cytometry of GP6hom (hom*ozygous) platelets confirmed loss of the full protein. The level of the Fc receptor g-chain, which associates with GPVI in the membrane, was partially reduced, but expression of other receptors and signaling proteins was not altered. Spreading of platelets on collagen and von Willebrand factor (which supports partial spreading) was abolished in GP6hom platelets, and spreading on uncoated glass was reduced. Anticoagulated whole blood flowed over immobilized collagen or a mixture of von Willebrand factor, laminin, and rhodocytin (noncollagen surface) generated stable platelet aggregates that express phosphatidylserine (PS). Both responses were blocked on the 2 surfaces in GP6hom individuals, but adhesion was not altered. Thrombin generation was partially reduced in GP6hom blood. The frequency of the GP6het (heterozygous) variant in a representative sample of the Chilean population (1212 donors) is 2.9%, indicating that there are ;4000 GP6hom individuals in Chile. These results demonstrate that GPVI supports aggregation and PS exposure under flow on collagen and noncollagen surfaces, but not adhesion. The retention of adhesion may contribute to the mild bleeding diathesis of GP6hom patients and account for why so few of the estimated 4000 GP6hom individuals in Chile have been identified.

AB - The role of glycoprotein VI (GPVI) in platelets was investigated in 3 families bearing an insertion within the GP6 gene that introduces a premature stop codon prior to the transmembrane domain, leading to expression of a truncated protein in the cytoplasm devoid of the transmembrane region. Western blotting and flow cytometry of GP6hom (hom*ozygous) platelets confirmed loss of the full protein. The level of the Fc receptor g-chain, which associates with GPVI in the membrane, was partially reduced, but expression of other receptors and signaling proteins was not altered. Spreading of platelets on collagen and von Willebrand factor (which supports partial spreading) was abolished in GP6hom platelets, and spreading on uncoated glass was reduced. Anticoagulated whole blood flowed over immobilized collagen or a mixture of von Willebrand factor, laminin, and rhodocytin (noncollagen surface) generated stable platelet aggregates that express phosphatidylserine (PS). Both responses were blocked on the 2 surfaces in GP6hom individuals, but adhesion was not altered. Thrombin generation was partially reduced in GP6hom blood. The frequency of the GP6het (heterozygous) variant in a representative sample of the Chilean population (1212 donors) is 2.9%, indicating that there are ;4000 GP6hom individuals in Chile. These results demonstrate that GPVI supports aggregation and PS exposure under flow on collagen and noncollagen surfaces, but not adhesion. The retention of adhesion may contribute to the mild bleeding diathesis of GP6hom patients and account for why so few of the estimated 4000 GP6hom individuals in Chile have been identified.

UR - http://www.scopus.com/inward/record.url?scp=85088376946&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2020001761

DO - 10.1182/bloodadvances.2020001761

M3 - Article

SN - 2473-9529

VL - 4

SP - 2953

EP - 2961

JO - Blood advances

JF - Blood advances

IS - 13

ER -

Nagy M, Perrella G, Dalby A, Becerra MF, Quintanilla LG, Pike JA et al. Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions. Blood advances. 2020 Jul 14;4(13):2953-2961. doi: 10.1182/bloodadvances.2020001761