Plasmin Generation Potential and Recanalization in Acute Ischaemic Stroke; an Observational Cohort Study of Stroke Biobank Samples.

Thomas Lillicrap,Prajwal Gyawali,John Attia,Timothy Kleinig,Bradford B Worrall,Simon Koblar,Geoffrey Cloud,Joan Montaner,Andrew Bivard,Heidi Ho,Jilly Chan,Robert L Medcalf,Philip Choi,Charithani B Keragala,Neil Spratt,Alejandro Bustamante,Stevi Harman,Dominik F Draxler,Carlos García-Esperón ,Lisa F Lincz ,Jane Maguire ,Elizabeth G Holliday ,Israel Fernández Cadenas ,Monica Anne Hamilton‐Bruce ,Be׳Eri Niego ,Christopher Levi ,Mark Parsons

doi:10.3389/fneur.2020.589628

Abstract

Rationale: More than half of patients who receive thrombolysis for acute ischaemic stroke fail to recanalize. Elucidating biological factors which predict recanalization could identify therapeutic targets for increasing thrombolysis success.Hypothesis: We hypothesize that individual patient plasmin potential, as measured by in vitro response to recombinant tissue-type plasminogen activator (rt-PA), is a biomarker of rt-PA response, and that patients with greater plasmin response are more likely to recanalize early.Methods: This study will use historical samples from the Barcelona Stroke Thrombolysis Biobank, comprised of 350 pre-thrombolysis plasma samples from ischaemic stroke patients who received serial transcranial-Doppler (TCD) measurements before and after thrombolysis. The plasmin potential of each patient will be measured using the level of plasmin-antiplasmin complex (PAP) generated after in-vitro addition of rt-PA. Levels of antiplasmin, plasminogen, t-PA activity, and PAI-1 activity will also be determined. Association between plasmin potential variables and time to recanalization [assessed on serial TCD using the thrombolysis in brain ischemia (TIBI) score] will be assessed using Cox proportional hazards models, adjusted for potential confounders.Outcomes: The primary outcome will be time to recanalization detected by TCD (defined as TIBI ≥4). Secondary outcomes will be recanalization within 6-h and recanalization and/or haemorrhagic transformation at 24-h. This analysis will utilize an expanded cohort including ~120 patients from the Targeting Optimal Thrombolysis Outcomes (TOTO) study.Discussion: If association between proteolytic response to rt-PA and recanalization is confirmed, future clinical treatment may customize thrombolytic therapy to maximize outcomes and minimize adverse effects for individual patients.

Highlights

Despite the increasing use of mechanical thrombectomy (MT), thrombolysis with recombinant tissue-type plasminogen activator remains a cornerstone of acute ischaemic stroke treatment
Samples from patients who received thrombolysis and underwent transcranial doppler (TCD) before thrombolysis, and at least once within 6 h after thrombolysis will be included in the primary analysis
Samples from patients who received thrombolysis and underwent angiography, either computed tomography (CT) or magnetic resonance imaging (MRI), before and 24-h post-thrombolysis will be included in secondary analyses

Summary

Introduction

Despite the increasing use of mechanical thrombectomy (MT), thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) remains a cornerstone of acute ischaemic stroke treatment. While great strides have been made with regard to selecting patients who are likely to have a favorable clinical outcome after thrombolysis [4,5,6], the reasons some patients fail to recanalize remain largely unknown. Previous studies have examined baseline levels of individual fibrinolysis markers in acute ischemic stroke patients [7] but this approach is limited as the potency of thrombolysis depends on the net capacity of a patient’s plasma to generate plasmin from plasminogen in response to rt-PA and this may not necessarily correlate with baseline levels of individual fibrinolysis markers. We aim to examine association between net plasmin generation in the presence of rt-PA and clinical outcomes, time to recanalization

Objectives

Methods

Conclusion