Coagulation biomarkers for ischemic stroke

Abstract

A State of the Art lecture titled "coagulation biomarkers for ischemic stroke" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Ischemic stroke (IS) is a common disease with major morbidity and mortality. It is a challenge to determine which patients are at risk for IS or have poor clinical outcome after IS. An imbalance of coagulation markers may contribute to the progression and prognosis of IS. Therefore, we now discuss studies on the association of selected coagulation biomarkers from the hemostasis, inflammation, and immunothrombosis systems with the risk of IS, stroke severity at the acute phase, and clinical outcome after treatment. We report on coagulation biomarker-induced risk of IS, stroke severity, and outcomes following IS derived from prospective population studies, case-control studies, and acute-phase IS studies. We found indications that many coagulation and inflammation biomarkers are associated with IS, but it is early to conclude that any of these biomarkers can be applied in a therapeutic setting to predict patients at risk of IS, stroke severity at the acute phase, and clinical outcome after treatment. The strongest evidence for a role in IS was found for beta-thromboglobulin, von Willebrand factor, factor VIII, fibrinogen, thrombin-activatable fibrinolysis inhibitor, D-dimer, and neutrophil extracellular traps, and therefore, they are promising candidates. Further research and validation in large-size populations using well-defined study designs are warranted. Finally, we provide a selection of recent data relevant to this subject that was presented at the 2022 ISTH Congress.

Keywords: coagulation biomarkers; immunothrombosis; inflammation; ischemic stroke; prognosis; therapy.

Figure 1

An overview of the potential biomarkers (also nonhemostasis-related) associated with an ischemic stroke that may predict the risk of stroke, stroke severity, and clinical outcome after treatment. In this review, we only discussed biomarkers of the hemostasis, inflammation, and immunothrombosis due to a close link between them. Hemostasis biomarkers: ßTG, GPVI, VWF, ADAMTS-13, FVIII, FBG, TG, TTP, PAI-1, TAFI, DD, AT III, TAT, Aß2GP1, AAFA, TM, tPA, FVII, FIX, FXI, FXII, FXIII, α-2AP, and PTF. Inflammation biomarkers: CRP, MCP-1, EM-PAF, IL-6, IL-1, beta IL-4, IL-8, IL-33, MP-1/2/9/10, TIMP, sRAGE, CD-40L, SVCAM-1, and PTX3e. Immunothrombosis biomarker: NETs. Neuronal/glial injury/cell damage biomarkers: S100B/ß, PRG, PKP, NSP, BG-DNA, GFAP, MBP, and NSE. (Growth) hormones: I-like GF-1 and GDF 15. Cardiac biomarkers: ANP, BNP/NT-proBNP, TI, and TT. Endothelial function biomarkers: HC, LAPA2, and EDT-1. Physiologic stress biomarkers: CP and TRD-P/A. Others: μRNA, NMP, UA, NSE, and E/Pμ. Abbreviations: AAFA, anticardiolipin antibodies fibrinopeptide A; ADAMTS-13, a disintegrin and metalloprotease with thrombospondin motif repeats 13; ANP, atrial natriuretic peptide; Aß2GP1, anti–beta-2 glycoprotein 1; AT III, antithrombine III; beta, IL-4=interleukin-6; BG-DNA, beta-globin DNA; BNP/NT-proBNP, brain natriuretic peptide; CD-40L, cluster of differentiation 40 ligand; CP, copeptin; CRP, C-reactive protein; DD, D-dimer; E/Pμ, endothelial/platelet microparticles; EDT-1, endothelin-1; EM-PAF, enhanced monocyte-platelet aggregate formation; FBG, fibrinogen; FIX, factor IX; FVII, factor VII; FVIII, factor VIII; FXI, factor XI; FXII, factor XII; FXIII, factor XIII; GDF 15, growth differentiation factor 15; GFAP, glial fibrillary acidic protein; GPVI, glycoprotein VI; HC, homocysteine; IL-1, interleukin-1; IL-33, interleukin-33; IL-6, interleukin-6; IL-8, interleukin-8; I-like GF-1, insulin-like growth factor-1; LAPA2, lipoprotein associated phospholipase A2; MBP, myelin basic protein; MCP-1, monocyte chemoattractant protein 1; MP-1/2/9/10, matrix metalloproteinase-1/2/9/10; NET, neutrophil extracellular trap; NMP, normetanephrine; NSE, neurone specific enolase; NSE, neurone specific enolase; NSP, neuroserpin; PAI-1, plasminogen activator inhibitor-1; PKP, proenkephalin; PRG, progranulin; PTF, prothrombin fragments; PTX3e, pentraxin-related protein expression; S100B/ß, S100 calcium-binding protein B; sRAGE; secretory receptor for advanced glycation end-products; ßTG, beta-thromboglobulin; SVCAM-1, selectin vascular cell adhesion molecule-1; TAFI, thrombin-activatable fibrinolysis inhibitor; TAT, thrombine-antitrombine complex; TG, thrombin generation; TI, troponin I; TIMP, tissue inhibitor of matrix metalloproteinase; TM, thrombomodulin; tPA, tissue-type plasminogen activator; TRD-P/A, thioredoxin paraoxonase/arylesterase; TT, troponin T; TTP, tissue-type plasminogen; UA, uric acid; VWF, von Willebrand factor; α-2AP, alpha-2 antiplasmin; μRNA, microRNA.

Figure 2

Future directions. Studies at the stable moment will help identify biomarkers that are associated with stroke risk [[6], [7], [8]], whereas studies at the acute moment of stroke will help identify biomarkers that can predict treatment effect and thereby clinical outcome, including clinical trials MR CLEAN NOIV, MR CLEAN MED, and MR CLEAN LATE [[95], [96], [97]].