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Updated: Apr 4, 2026
Ferric Chloride-induced Murine Thrombosis Models
Published on: September 5, 2016
Activated-platelet targeting of CD39 as a potential way forward. The quest for efficient antithrombotic therapy
1Prof. Karlheinz Peter, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia, Karlheinz.Peter@bakeridi.edu.au.
Insights
A novel recombinant antibody protein combines CD39 and an anti-GPIIb/IIIa antibody fragment to create a potent antiplatelet therapy. This approach targets activated platelets, reducing thrombosis without increasing bleeding risk.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Antiplatelet therapy is crucial but linked to increased bleeding risk.
- Existing drugs face a trade-off between anti-thrombotic potency and bleeding complications.
- A need exists for antiplatelet agents that decouple efficacy from bleeding risk.
Purpose of the Study:
- To develop a novel antiplatelet agent combining enzymatic degradation of platelet activators with targeted delivery.
- To create a recombinant fusion protein for enhanced antiplatelet effects with reduced systemic impact.
Main Methods:
- Genetically engineered a fusion protein incorporating ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) CD39 and a single-chain variable fragment (scFv) targeting the activated GPIIb/IIIa receptor.
- Evaluated the fusion protein's ability to degrade adenosine diphosphate (ADP) and inhibit platelet activation, adhesion, and aggregation in vitro and in vivo models (mice).
Main Results:
- The fusion protein effectively degrades platelet-activating ADP and produces platelet-inhibiting adenosine.
- Targeting activated platelets with the scFv component allowed for low systemic concentrations.
- Demonstrated potent inhibition of platelet aggregation and thrombosis in mice without prolonging bleeding time.
Conclusions:
- A novel recombinant antiplatelet protein effectively targets activated platelets.
- This approach localizes antiplatelet effects, mitigating bleeding complications.
- The developed fusion protein offers a promising strategy for antithrombotic therapy with an improved safety profile.
Unlabelled:
Antiplatelet therapy is given to millions of patients and has saved numerous lives. However, it is also associated with complications including fatal bleedings. Clinically used antiplatelet drugs seem to follow the rule of an inherent link of improved anti-thrombotic potency with increased risk of bleeding complications. Therefore, there is an ongoing quest to develop drugs that are able to break this link that has prevented many patients from receiving antiplatelet protection and has resulted in substantial mortality and morbidity. We describe a new antiplatelet approach that is based on an recombinant antibody protein, a drug format that has recently attracted major interest. Two unique components are genetically combined in this molecule: 1) The ecto-nucleoside triphosphate diphosphohydrolase NTPDase CD39, which enzymatically degrades ATP and ADP to AMP, which is then further degraded to adenosine by the endothelially expressed CD73. Thereby, the platelet activating ADP is reduced and replaced by the platelet inhibiting adenosine resulting in a strong antiplatelet effect. 2) A single-chain antibody (scFv) that specifically binds to the activated GPIIb/IIIa receptor and thus allows targeting to activated platelets. The described fusion protein results in strong enrichment of CD39's antiplatelet effect, resulting in potent inhibition of platelet adhesion and aggregation and thrombosis in mice. The activated platelet targeting allows using a low systemic concentration that does not interfere with normal haemostasis and thus does not cause bleeding time prolongation in mice.
Conclusion:
We describe a new antiplatelet approach that promises to deliver strong localized antithrombotic effects without associated bleeding problems.
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