PB1220 - DNase-1 overcomes thrombolytic rt-PA resistance of platelet-rich ischemic stroke thrombi

Tuesday, June 27, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Sarah Vandelanotte, MA

Phd student
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
kortrijk, West-Vlaanderen, Belgium

Co-Author(s)

OF

Olivier Francois

MD
Department of Medical Imaging, AZ Groeninge, Kortrijk, Belgium
kortrijk, West-Vlaanderen, Belgium
SS

Senna Staessens

PhD
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk
Kortrijk, West-Vlaanderen, Belgium
LD

Linda Desender

Lab technician
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk
Kortrijk, West-Vlaanderen, Belgium
AV

Alexander Vanhoorne

MD
Department of Medical Imaging, AZ Groeninge, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
CT

Claudia Tersteeg

Prof., Dr.
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
Karen Vanhoorelbeke, PhD

Prof., Dr.
KU Leuven
Kortrijk, West-Vlaanderen, Belgium
PV

Peter Vanacker

MD
Department of Neurology, AZ Groeninge, Kortrijk, Belgium / Neurovascular Center and Stroke Unit Antwerp, Antwerp University Hospital, Antwerp, Belgium. / Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
Kortrijk, West-Vlaanderen, Belgium
TA

Tommy Andersson

MD
Departments of Neuroradiology, Karolinska University Hospital, and Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
Stockholm, Stockholms Lan, Sweden
SD

Simon F. De Meyer

Prof., Dr., Eng.
Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium

Background: The fibrinolytic agent recombinant tissue plasminogen activator (rt-PA) is the only approved drug to lyse the occluding thrombus in ischemic stroke patients. In the majority of patients, recanalization is not successful due to rt-PA resistance of the thrombus. The exact nature of this rt-PA resistance is not fully understood but thrombus composition most likely plays an important role. We previously showed that, besides fibrin, extracellular DNA and neutrophil extracellular traps are a structural feature of RBC-poor (and thus platelet-rich) ischemic stroke thrombi, which could influence thrombolysis.

Aims: To investigate the link between rt-PA resistance and thrombus composition in ischemic stroke thrombi and to explore the potential thrombolytic effect of DNase-1 in combination with rt-PA.

Methods: A total of 63 ischemic stroke patient thrombi were divided into three treatment groups (1µg/mL rt-PA, combination of 1µg/mL rt-PA and 100U/mL Dnase-1 or no treatment). Each thrombus was subjected to lysis for 180 minutes and residual thrombus weight as percentage of original weight was calculated as a measure of lysis efficiency. For each thrombus, one separate part was used for detailed histological analysis.

Results: A strong positive correlation was found between thrombus RBC content and rt-PA lysis. Rt-PA-mediated lysis was significantly less effective in RBC-poor thrombi ( < 50% RBC) than in RBC-rich thrombi (>50% RBC) (residual weight 59.6%±25.1% and 24.9%±18.6% respectively). Interestingly, combination of rt-PA and Dnase-1 significantly improved thrombolysis of RBC-poor thrombi (residual weight of 27.4%±18.8%, p< 0.05), while Dnase-1 had no additional thrombolytic effect on the rt-pa-mediated lysis of RBC-rich thrombi (residual weight of 24.9%±7.7%).

Conclusion(s): Rt-PA-mediated thrombolysis is much more difficult in RBC-poor (platelet-rich) thrombi. The combined use of rt-PA and DNase-1 significantly improves lysis of rt-PA resistant platelet-rich thrombi. These results are important to overcome current limitations of rt-PA and to further improve efficient recanalization in acute ischemic stroke patients.