Two Birds, One Stone: Anti-β3 Integrin PSI Domain Antibodies Inhibit Both Platelet Aggregation and Blood Coagulation
ISTH Academy. Neves M. Jul 10, 2019; 273921; OC 78.4
Miguel Neves
Miguel Neves
Access to Reserved content is available to attendees of the Congress until the end of the year and always available for full ISTH members.

Click here to join ISTH or renew your membership.

Discussion Forum (0)
Rate & Comment (0)

OC 78.4

Two Birds, One Stone: Anti-β3 Integrin PSI Domain Antibodies Inhibit Both Platelet Aggregation and Blood Coagulation

T.W. Stratton1, M. Neves1,2, G. Zhu1, Y. Wang1,2, P. Chen1,2, R.C. Gallant1, P.A.A. Norris1, J. Freedman1, H. Ni1,2
1St. Michael's Hospital / University of Toronto, Toronto, Canada, 2Canadian Blood Services Centre for Innovation, Toronto, Canada

Main Topic: Platelets and Megakaryocytes
Category: Platelet Antagonists & Novel Therapeutics

Background: Integrin αIIbβ3 plays key roles in thrombosis and hemostasis through mediating platelet adhesion and aggregation. We recently reported the active site of thiol-isomerases, CXXC, is expressed twice within the plexin-semaphorin-integrin (PSI) domain across all integrins (Blood, 2017). We developed anti-β3 integrin PSI domain monoclonal antibodies (mAbs) that inhibit the thiol-isomerase activity of β3 PSI domain and decrease platelet adhesion, aggregation, and thrombosis without increasing bleeding. Interestingly, the mAbs inhibition of thrombosis in vivo was 10-20x greater than on in vitro platelet aggregation.
Aims: Mechanistically explore how the PSI domain contributes to blood coagulation.
Methods: Utilize our proprietary anti-β3 PSI domain mAbs in in vitro / ex vivo coagulation assays.
Results: Clot retraction assays performed with human and mouse blood showed less clot retraction and a significantly lower dry clot weight in whole blood treated with anti-PSI mAbs compared to controls. Laser scanning confocal microscopy of platelet-rich plasma (PRP) samples with labelled fibrin(ogen) showed that fibrin network formation of anti-PSI mAb treated clots was significantly decreased. To measure blood coagulation, thromboelastography (TEG) was performed. Blinded TEG showed that coagulation decreased in anti-PSI mAb-treated whole blood (human and mouse) and PRP. We further compared our anti-PSI mAbs with other anti-β3 integrin mAbs. TEG analysis uncovered that the anti-PSI mAbs significantly decreased coagulation parameters, much more than M1, JAN D1, and the Abciximab precursor 7E3, which more potently inhibit αIIbβ3-fibrinogen binding and platelet aggregation. This suggests the decreased coagulation may result from the anti-thiol-isomerase activity of the anti-PSI mAbs and its impact on coagulation factors. The mechanistic features of this inhibitory effect are under investigation.
Conclusions: This is the first evidence of an allosteric therapeutic target of β3 integrin and suggests that targeting the PSI domain partially blocks platelet aggregation and coagulation, resulting in less bleeding while maintaining strong anti-thrombotic effects.

Code of conduct/disclaimer available in General Terms & Conditions
Anonymous User Privacy Preferences

Strictly Necessary Cookies (Always Active)

MULTILEARNING platforms and tools hereinafter referred as “MLG SOFTWARE” are provided to you as pure educational platforms/services requiring cookies to operate. In the case of the MLG SOFTWARE, cookies are essential for the Platform to function properly for the provision of education. If these cookies are disabled, a large subset of the functionality provided by the Platform will either be unavailable or cease to work as expected. The MLG SOFTWARE do not capture non-essential activities such as menu items and listings you click on or pages viewed.

Performance Cookies

Performance cookies are used to analyse how visitors use a website in order to provide a better user experience.

Google Analytics is used for user behavior tracking/reporting. Google Analytics works in parallel and independently from MLG’s features. Google Analytics relies on cookies and these cookies can be used by Google to track users across different platforms/services.

Save Settings