VPB0647 - DNase 1 unveils the presence and unlocks the thrombolytic potential of intraveneously administered t-PA in large vessel occlusion acute ischemic stroke

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: Virtual

Presenting Author(s)

LD

Lucas Di Meglio, MD PhD

INSERM Unit 1148
PARIS, Ile-de-France, France

Co-Author(s)

MS

Mialitiana Solo Nomenjanahary

engineer
INSERM UNIT 1148
PARIS, Ile-de-France, France
Marie-Charlotte BOURRIENNE, PharmD

Assistant
Laboratoire d'Hématologie, AP-HP, Hôpital Bichat Claude-Bernard, Paris, France.
PARIS, Ile-de-France, France
Véronique Ollivier, PhD

Dr
INSERM UMRS-1148
Paris cedex 18, Ile-de-France, France
MM

Mikael Mazighi

Professor
ROTHSCHILD FOUNDATION HOSPITAL PARIS
paris, Ile-de-France, France
Benoît Ho-Tin-Noé, PhD

Research Director
Université de Paris Descartes, INSERM, Hôpital Bichat, UMR-S1148, F-75000 Paris, France
Paris, Ile-de-France, France
JD

Jean-Philippe Desilles

MD Assistant Professor
Rothschild Foundation Hospital
paris, Ile-de-France, France

Background: DNase 1 has been shown to potentiate the thrombolytic activity of t-PA added ex vivo to AIS thrombi. Nevertheless, it remains unknown whether extracellular DNA in AIS thrombi is responsible for intravenous thrombolysis (IVT) failure in AIS due to large vessel occlusion (LVO).

Aims: We investigated whether biologically relevant intrathrombus concentrations of t-PA were achieved following IVT in patients with LVO-related AIS, and whether extracellular DNA contributed to IVT failure.

Methods: In this cohort study, a total of 103 thrombi from AIS patients with LVO having received (n=50) or not (n=53) IVT prior to MT were analyzed. While 83 thrombi were compared for t-PA content, a subset of 10 thrombi per patient group was subjected to ex vivo thrombolysis by addition of plasminogen, in the presence or absence of DNase 1.

Results: AIS thrombi from the IVT group contained more tPA than those from the non-IVT group (0.093 vs 0.209 µg/mg of thrombus, p< 0.0001). Thrombus Glu-plasminogen content was similar in both groups. There were no correlations between thrombus t-PA content of IVT-treated patients and thrombus cell composition or site of occlusion. A highly significant negative correlation was found between thrombus t-PA content and IVT to thrombectomy delay (p=1.2x10-5). Ex vivo thrombolysis assays revealed that, whereas addition of plasminogen alone did not induce lysis of AIS thrombi from either group of patients, it caused a significant decrease in thrombus weight in the IVT group in the presence of DNase 1.

Conclusion(s): These results indicate that intrathrombus t-PA concentrations reached after IVT bear a therapeutic potential that is however impaired by DNA presence. Our results stress the interest of using DNase 1 as an adjuvant thrombolytic therapy to current IVT t-PA regimens.