OC 62.5 - Next-generation, dendrimer-like polyphosphate inhibitor is a safe and effective antithrombotic agent

Tuesday, June 27, 2023

15:45 – 16:00 ET

Room: 710B

Session Available As: On-Demand

Presenting Author(s)

Stephanie A. Smith, DVM (she/her/hers)

Research Assistant Professor
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA
Ann Arbor, Michigan, United States

Co-Author(s)

CL

Chanel La

Researcher
Centre for Blood Research, University of British Columbia
Vancouver, British Columbia, Canada
SV

Sreeparna Vappala, PhD (she/her/hers)

Researcher
University of British Columbia
Winnipeg, Manitoba, Canada
RA

Raymond Adili

Scientist
Bloodworks Research Institute
Seattle, Washington, United States
CL

Catherine Luke

Research Laboratory Specialist
University of Michigan
Ann Arbor, Michigan, United States
SA

Srinivas Abbina

Researcher
Centre for Blood Research, University of British Columbia
Vancouver, British Columbia, Canada
HL

Haiming D. Luo

Scientist
Centre for Blood Research, University of British Columbia
Vancouver, British Columbia, Canada
IC

Irina Chafeeva

Research technician
Centre for Blood Research, University of British Columbia
Vancouver, British Columbia, Canada
MD

Matthew Drayton

Research technician
Centre for Blood Research, University of British Columbia
Vancouver, British Columbia, Canada
LC

Louise A. Creagh

Assoc. Prof
University of British Columbia
Vancouver, British Columbia, Canada
NR

Nicole Rhoads

Technician
Bloodworks Research Institute
Seattle, Washington, United States
MK

Manu Thomas Kalathottukaren

Scientist
University of British Columbia
Vancouver, British Columbia, Canada
PH

Peter Henke

Professor
University of Michigan
Ann Arbor, Michigan, United States
SS

Suzana K. Straus

Professor
University of British Columbia
Vancouver, British Columbia, Canada
CD

Caigan Du

Assoc. Professor
University of British Columbia
Vancouver, British Columbia, Canada
Edward M Conway, MD, PhD

Professor
Centre for Blood Research, University of British Columbia
Vancouver, British Columbia, Canada
Michael Holinstat, PhD

Associate Professor of Pharmacology
University of Michigan
Ann Arbor, Michigan, United States
CH

Charles A Haynes

Professor
Michael Smith Laboratories, Chemical & Biological Engineering, University of British Columbia
Vancouver, British Columbia, Canada
James H. Morrissey, PhD

Professor
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Ann Arbor, Michigan, United States
Jayachandran N. Kizhakkedathu, PhD (he/him/his)

Professor
Centre for Blood Research, University of British Columbia
Vancouver, British Columbia, Canada

Background: Use of current treatments (anticoagulants and platelet antagonists) to prevent thrombosis are complicated by the persistent risk of bleeding. Because polyphosphate (polyP) acts to enhance activity at multiple steps in the coagulation cascade, its inhibition could be useful as an antithrombotic strategy. We have developed a new dendrimer-like compound (MPI-8) as a polyP inhibitor.

Aims: To evaluate polyP inhibition in vitro and in vivo, and adverse effects of MPI-8.

Methods: Plasma coagulation and thrombin generation, and whole blood thromboelastometry was triggered by 20 µM long-chain polyP, or tissue factor with added 5 µM platelet-size polyP in the presence of up to 30 mg/mL of MPI-8. In vivo models included FeCl3 carotid (monitored by doppler), laser-injury cremaster (intravital microscopy with platelet and fibrin accumulation), and caudal vena cava stenosis (post-mortem thrombus weight). Safety was assessed with scanning electron microscopy in clots formed in vitro and platelet aggregometry, and in vivo with the murine tail bleeding model. Potential toxicity was evaluated after administration via mouse observation, serum chemistries, and organ histology.

Results: MPI-8 completely inhibited coagulation triggered by both long-chain polyP (contact activation) and platelet-sized polyP in plasma-based clotting and thrombin-generation assays at 10 µg/mL. PolyP was also inhibited in whole blood thromboelastography. In vivo, MPI-8 delayed or prevented thrombosis in all evaluated murine models when dosed at 100-200 mg/kg. With regard to safety, MPI-8 did not affect coagulation, thrombin-generation, fibrin clot structure or platelet aggregation in vitro when added in the absence of polyP. MPI-8 did not increase bleeding at 300 mg/kg in the tail-bleeding model. Administration of MPI at 500 mg/kg was well-tolerated without evidence of toxicity.

Conclusion(s): MPI-8 has promise as an inhibitor of polyP, and a potential as a non-toxic antithrombotic agent without significant risk of bleeding.

Learning Objectives:

Describe the nature of our novel dendrimer like polyP inhibitor
Discuss the in vitro anti-coagulant properties of the dendrime-like inhibitor
Discuss the in vivo anti-thrombotic effects of the dendrimer-like inhibitor