Cargando…

A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction

INTRODUCTION: Advancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an acute Myocardial Infarction (MI). While fibrin...

Descripción completa

Detalles Bibliográficos
Autores principales: Dunster, Joanne L., Wright, Joy R., Samani, Nilesh J., Goodall, Alison H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281867/
https://www.ncbi.nlm.nih.gov/pubmed/35845083
http://dx.doi.org/10.3389/fcvm.2022.919394
_version_ 1784746981068898304
author Dunster, Joanne L.
Wright, Joy R.
Samani, Nilesh J.
Goodall, Alison H.
author_facet Dunster, Joanne L.
Wright, Joy R.
Samani, Nilesh J.
Goodall, Alison H.
author_sort Dunster, Joanne L.
collection PubMed
description INTRODUCTION: Advancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an acute Myocardial Infarction (MI). While fibrinogen levels are a recognized risk factor for MI, the association of thrombotic risk with other coagulation proteins is inconsistent. This is likely due to the complex balance of pro- and anticoagulant factors in any individual. METHODS: We compared measured levels of pro- and anticoagulant proteins in plasma from 162 patients who suffered an MI at an early age (MI <50 y) and 186 age- and gender-matched healthy controls with no history of CAD. We then used the measurements from these individuals as inputs for an established mathematical model to investigate how small variations in hemostatic factors affect the overall amplitude of the hemostatic response and to identify differential key drivers of the hemostatic response in male and female patients and controls. RESULTS: Plasma from the MI patients contained significantly higher levels of Tissue Factor (P = 0.007), the components of the tenase (FIX and FVIII; P < 0.0001 for both) and the prothrombinase complexes (FX; P = 0.003), and lower levels of Tissue Factor Pathway Inhibitor (TFPI; P = 0.033) than controls. The mathematical model, which generates time-dependent predictions describing the depletion, activation, and interaction of the main procoagulant factors and inhibitors, identified different patterns of hemostatic response between MI patients and controls, and additionally, between males and females. Whereas, in males, TF, FVIII, FIX, and the inhibitor TFPI contribute to the differences seen between case and controls, and in females, FII, FVIII, and FIX had the greatest influence on the generation of thrombin. We additionally show that further donor stratification may be possible according to the predicted donor response to anticoagulant therapy. CONCLUSIONS: We suggest that modeling could be of value in enhancing our prediction of risk of premature MI, recurrent risk, and therapeutic efficacy.
format Online
Article
Text
id pubmed-9281867
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-92818672022-07-15 A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction Dunster, Joanne L. Wright, Joy R. Samani, Nilesh J. Goodall, Alison H. Front Cardiovasc Med Cardiovascular Medicine INTRODUCTION: Advancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an acute Myocardial Infarction (MI). While fibrinogen levels are a recognized risk factor for MI, the association of thrombotic risk with other coagulation proteins is inconsistent. This is likely due to the complex balance of pro- and anticoagulant factors in any individual. METHODS: We compared measured levels of pro- and anticoagulant proteins in plasma from 162 patients who suffered an MI at an early age (MI <50 y) and 186 age- and gender-matched healthy controls with no history of CAD. We then used the measurements from these individuals as inputs for an established mathematical model to investigate how small variations in hemostatic factors affect the overall amplitude of the hemostatic response and to identify differential key drivers of the hemostatic response in male and female patients and controls. RESULTS: Plasma from the MI patients contained significantly higher levels of Tissue Factor (P = 0.007), the components of the tenase (FIX and FVIII; P < 0.0001 for both) and the prothrombinase complexes (FX; P = 0.003), and lower levels of Tissue Factor Pathway Inhibitor (TFPI; P = 0.033) than controls. The mathematical model, which generates time-dependent predictions describing the depletion, activation, and interaction of the main procoagulant factors and inhibitors, identified different patterns of hemostatic response between MI patients and controls, and additionally, between males and females. Whereas, in males, TF, FVIII, FIX, and the inhibitor TFPI contribute to the differences seen between case and controls, and in females, FII, FVIII, and FIX had the greatest influence on the generation of thrombin. We additionally show that further donor stratification may be possible according to the predicted donor response to anticoagulant therapy. CONCLUSIONS: We suggest that modeling could be of value in enhancing our prediction of risk of premature MI, recurrent risk, and therapeutic efficacy. Frontiers Media S.A. 2022-06-30 /pmc/articles/PMC9281867/ /pubmed/35845083 http://dx.doi.org/10.3389/fcvm.2022.919394 Text en Copyright © 2022 Dunster, Wright, Samani and Goodall. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Dunster, Joanne L.
Wright, Joy R.
Samani, Nilesh J.
Goodall, Alison H.
A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction
title A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction
title_full A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction
title_fullStr A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction
title_full_unstemmed A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction
title_short A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction
title_sort system-wide investigation and stratification of the hemostatic proteome in premature myocardial infarction
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281867/
https://www.ncbi.nlm.nih.gov/pubmed/35845083
http://dx.doi.org/10.3389/fcvm.2022.919394
work_keys_str_mv AT dunsterjoannel asystemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction
AT wrightjoyr asystemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction
AT samaninileshj asystemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction
AT goodallalisonh asystemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction
AT dunsterjoannel systemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction
AT wrightjoyr systemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction
AT samaninileshj systemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction
AT goodallalisonh systemwideinvestigationandstratificationofthehemostaticproteomeinprematuremyocardialinfarction