Effect of platelet-derived beta-thromboglobulins on coagulation

Karl Egan; Johanna P. van Geffen; Hui ma; Barry Kevane; Aine Lennon; Seamus Allen; Elaine Neary; Martin Parsons; Patricia Maguire; Kieran Wynne; Richard O' Kennedy; JohanW. M. Heemskerk; Fionnuala Ni Ainle

doi:10.1016/j.thromres.2017.03.023

Effect of platelet-derived beta-thromboglobulins on coagulation

Karl Egan
, Johanna P. van Geffen
, Hui ma
, Barry Kevane
, Aine Lennon
, Seamus Allen
, Elaine Neary
, Martin Parsons
, Patricia Maguire
, Kieran Wynne
, Richard O' Kennedy
, JohanW. M. Heemskerk
, Fionnuala Ni Ainle^*

^*Corresponding author for this work

Biochemie

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

Abstract

Background: beta-thromboglobulins are derived from the cleavage of the CXC chemokine platelet basic protein and are released in high concentrations by activated platelets. Platelet-derived beta-thromboglobulins (beta TG) share 70% homology with platelet factor 4 (PF4), another CXC chemokine released by activated platelets. PF4 modulates coagulation by inhibiting heparin-antithrombin interactions, promoting protein C activation, and attenuating the activity of activated protein C. In contrast, the effect of beta TG on coagulation is unknown.

Aim/Methods: Clotting times, thrombin generation, chromogenic clotting factor assays, and surface plasmon resonance (SPR) were used to assess the effect of purified beta TG on coagulation.

Results: In normal pooled plasma, beta TG shortened the lagtime and time to peak thrombin generation of tissue factor (TF)-dependent and TF-independent thrombin generation. In factor VIII and factor IX-deficient plasmas, beta TG induced thrombin generation in the absence of a TF stimulus and in the presence of anti-TF and factor VIIa inhibitory antibodies. The procoagulant effect was not observed when thrombin generation was independent of factor X activation (supplementation of factor X-deficient plasma with factor Xa). Cleavage of a factor Xa-specific chromogenic substrate was observed when beta TG was incubated with factor X, suggesting a direct interaction between beta TG and factor X. Using SPR, beta TG were found to bind to immobilised factor X in a dose dependent manner.

Original language	English
Pages (from-to)	7-15
Number of pages	9
Journal	Thrombosis Research
Volume	154
DOIs	https://doi.org/10.1016/j.thromres.2017.03.023
Publication status	Published - Jun 2017

Keywords

Platelet-derived beta-thromboglobulins
Coagulation
Thrombin generation
Factor X
PEPTIDE CTAP-III
ACTIVATED PROTEIN-C
THROMBIN GENERATION
CXC CHEMOKINES
HEMOPHILIA-A
FACTOR-XA
TISSUE
PLATELET-FACTOR-4
LOCALIZATION
INACTIVATION

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10.1016/j.thromres.2017.03.023

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@article{08cfa9eabc93461d8c9963a20b59b60f,

title = "Effect of platelet-derived beta-thromboglobulins on coagulation",

abstract = "Background: beta-thromboglobulins are derived from the cleavage of the CXC chemokine platelet basic protein and are released in high concentrations by activated platelets. Platelet-derived beta-thromboglobulins (beta TG) share 70\% homology with platelet factor 4 (PF4), another CXC chemokine released by activated platelets. PF4 modulates coagulation by inhibiting heparin-antithrombin interactions, promoting protein C activation, and attenuating the activity of activated protein C. In contrast, the effect of beta TG on coagulation is unknown.Aim/Methods: Clotting times, thrombin generation, chromogenic clotting factor assays, and surface plasmon resonance (SPR) were used to assess the effect of purified beta TG on coagulation.Results: In normal pooled plasma, beta TG shortened the lagtime and time to peak thrombin generation of tissue factor (TF)-dependent and TF-independent thrombin generation. In factor VIII and factor IX-deficient plasmas, beta TG induced thrombin generation in the absence of a TF stimulus and in the presence of anti-TF and factor VIIa inhibitory antibodies. The procoagulant effect was not observed when thrombin generation was independent of factor X activation (supplementation of factor X-deficient plasma with factor Xa). Cleavage of a factor Xa-specific chromogenic substrate was observed when beta TG was incubated with factor X, suggesting a direct interaction between beta TG and factor X. Using SPR, beta TG were found to bind to immobilised factor X in a dose dependent manner.Conclusion: beta TG modulate coagulation in vitro via an interaction with factor X. (C) 2017 Elsevier Ltd. All rights reserved.",

keywords = "Platelet-derived beta-thromboglobulins, Coagulation, Thrombin generation, Factor X, PEPTIDE CTAP-III, ACTIVATED PROTEIN-C, THROMBIN GENERATION, CXC CHEMOKINES, HEMOPHILIA-A, FACTOR-XA, TISSUE, PLATELET-FACTOR-4, LOCALIZATION, INACTIVATION",

author = "Karl Egan and \{van Geffen\}, \{Johanna P.\} and Hui ma and Barry Kevane and Aine Lennon and Seamus Allen and Elaine Neary and Martin Parsons and Patricia Maguire and Kieran Wynne and Kennedy, \{Richard O'\} and Heemskerk, \{JohanW. M.\} and Ainle, \{Fionnuala Ni\}",

year = "2017",

month = jun,

doi = "10.1016/j.thromres.2017.03.023",

language = "English",

volume = "154",

pages = "7--15",

journal = "Thrombosis Research",

issn = "0049-3848",

publisher = "Elsevier Ltd",

}

TY - JOUR

T1 - Effect of platelet-derived beta-thromboglobulins on coagulation

AU - Egan, Karl

AU - van Geffen, Johanna P.

AU - ma, Hui

AU - Kevane, Barry

AU - Lennon, Aine

AU - Allen, Seamus

AU - Neary, Elaine

AU - Parsons, Martin

AU - Maguire, Patricia

AU - Wynne, Kieran

AU - Kennedy, Richard O'

AU - Heemskerk, JohanW. M.

AU - Ainle, Fionnuala Ni

PY - 2017/6

Y1 - 2017/6

N2 - Background: beta-thromboglobulins are derived from the cleavage of the CXC chemokine platelet basic protein and are released in high concentrations by activated platelets. Platelet-derived beta-thromboglobulins (beta TG) share 70% homology with platelet factor 4 (PF4), another CXC chemokine released by activated platelets. PF4 modulates coagulation by inhibiting heparin-antithrombin interactions, promoting protein C activation, and attenuating the activity of activated protein C. In contrast, the effect of beta TG on coagulation is unknown.Aim/Methods: Clotting times, thrombin generation, chromogenic clotting factor assays, and surface plasmon resonance (SPR) were used to assess the effect of purified beta TG on coagulation.Results: In normal pooled plasma, beta TG shortened the lagtime and time to peak thrombin generation of tissue factor (TF)-dependent and TF-independent thrombin generation. In factor VIII and factor IX-deficient plasmas, beta TG induced thrombin generation in the absence of a TF stimulus and in the presence of anti-TF and factor VIIa inhibitory antibodies. The procoagulant effect was not observed when thrombin generation was independent of factor X activation (supplementation of factor X-deficient plasma with factor Xa). Cleavage of a factor Xa-specific chromogenic substrate was observed when beta TG was incubated with factor X, suggesting a direct interaction between beta TG and factor X. Using SPR, beta TG were found to bind to immobilised factor X in a dose dependent manner.Conclusion: beta TG modulate coagulation in vitro via an interaction with factor X. (C) 2017 Elsevier Ltd. All rights reserved.

AB - Background: beta-thromboglobulins are derived from the cleavage of the CXC chemokine platelet basic protein and are released in high concentrations by activated platelets. Platelet-derived beta-thromboglobulins (beta TG) share 70% homology with platelet factor 4 (PF4), another CXC chemokine released by activated platelets. PF4 modulates coagulation by inhibiting heparin-antithrombin interactions, promoting protein C activation, and attenuating the activity of activated protein C. In contrast, the effect of beta TG on coagulation is unknown.Aim/Methods: Clotting times, thrombin generation, chromogenic clotting factor assays, and surface plasmon resonance (SPR) were used to assess the effect of purified beta TG on coagulation.Results: In normal pooled plasma, beta TG shortened the lagtime and time to peak thrombin generation of tissue factor (TF)-dependent and TF-independent thrombin generation. In factor VIII and factor IX-deficient plasmas, beta TG induced thrombin generation in the absence of a TF stimulus and in the presence of anti-TF and factor VIIa inhibitory antibodies. The procoagulant effect was not observed when thrombin generation was independent of factor X activation (supplementation of factor X-deficient plasma with factor Xa). Cleavage of a factor Xa-specific chromogenic substrate was observed when beta TG was incubated with factor X, suggesting a direct interaction between beta TG and factor X. Using SPR, beta TG were found to bind to immobilised factor X in a dose dependent manner.Conclusion: beta TG modulate coagulation in vitro via an interaction with factor X. (C) 2017 Elsevier Ltd. All rights reserved.

KW - Platelet-derived beta-thromboglobulins

KW - Coagulation

KW - Thrombin generation

KW - Factor X

KW - PEPTIDE CTAP-III

KW - ACTIVATED PROTEIN-C

KW - THROMBIN GENERATION

KW - CXC CHEMOKINES

KW - HEMOPHILIA-A

KW - FACTOR-XA

KW - TISSUE

KW - PLATELET-FACTOR-4

KW - LOCALIZATION

KW - INACTIVATION

U2 - 10.1016/j.thromres.2017.03.023

DO - 10.1016/j.thromres.2017.03.023

M3 - Article

SN - 0049-3848

VL - 154

SP - 7

EP - 15

JO - Thrombosis Research

JF - Thrombosis Research

ER -

Effect of platelet-derived beta-thromboglobulins on coagulation

Abstract

Keywords

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