A modified in vitro clot lysis assay predicts outcomes and safety in acute ischemic stroke patients undergoing intravenous thrombolysis

Rita Orbán-Kálmándi,Ervin Berényi,Zsuzsa Bagoly,Nikolett Vasas,László Csiba,Ferenc Sarkady,Klára Fekete,István Szegedi,István Fekete

doi:10.1038/s41598-021-92041-1

Rita Orbán-Kálmándi, Ervin Berényi + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-92041-1

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Journal: Scientific Reports	Publication Date: Jun 16, 2021
Citations: 8	License type: open-access

Affiliation: University of Debrecen

Abstract

The outcome of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is only favorable in ≈ 40% of acute ischemic stroke (AIS) patients. Moreover, in ≈ 6–8% of cases, intracerebral hemorrhage (ICH) develops. We tested whether a modification of clot lysis assay (CLA), might predict therapy outcomes and safety. In this prospective observational study, blood samples of 231 AIS patients, all receiving intravenous rt-PA, were taken before thrombolysis. Cell-free DNA (cfDNA), CLA and CLA supplemented with cfDNA and histones (mCLA) were determined from the blood samples. Stroke severity was determined by NIHSS on admission. ICH was classified according to ECASSII. Short- and long-term outcomes were defined at 7 and 90 days post-event according to ΔNIHSS and by the modified Rankin Scale, respectively. Stroke severity demonstrated a step-wise positive association with cfDNA levels, while a negative association was found with the time to reach 50% lysis (50%CLT) parameter of CLA and mCLA. ROC analysis showed improved diagnostic performance of the mCLA. Logistic regression analysis proved that 50%CLT is a predictor of short-term therapy failure, while the AUC parameter predicts ICH occurrence. A modified CLA, supplemented with cfDNA and histones, might be a promising tool to predict short-term AIS outcomes and post-lysis ICH.

Highlights

The outcome of intravenous thrombolysis using recombinant tissue plasminogen activator is only favorable in ≈ 40% of acute ischemic stroke (AIS) patients
Recent studies indicated a new model of stroke thrombus evolution, where, as the last step in the process of thrombi ageing, neutrophils infiltrate the thrombus by forming neutrophil extracellular traps (NETs) and stabilize the thrombus with much smaller pores[23]
Clot dissolution by recombinant tissue plasminogen activator (rt-PA) is the easiest in the early stages of thrombus formation, when the cross-linking of fibrin and fibrinolysis inhibitors to fibrin by activated factor XIII has not yet taken place, and the clot is less compact with larger pores

Summary

Introduction

The outcome of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is only favorable in ≈ 40% of acute ischemic stroke (AIS) patients. We tested whether a modification of clot lysis assay (CLA), might predict therapy outcomes and safety In this prospective observational study, blood samples of 231 AIS patients, all receiving intravenous rt-PA, were taken before thrombolysis. A modified CLA, supplemented with cfDNA and histones, might be a promising tool to predict short-term AIS outcomes and post-lysis ICH. It has been shown that increased thrombus cell free DNA (cfDNA) content decreases the efficacy of rt-PA treatment, and a strategy involving the administration of deoxyribonuclease 1 (DNAse 1) in addition to thrombolysis has been p roposed[11] Before implementing such approaches in the clinical practice, further research is warranted. We aimed to find out whether a modified in vitro CLA, that incorporates the effect of cfDNA and histones, potentially present within the thrombus, might better predict therapy outcomes and safety as compared to the conventional assay

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