Research ArticleCardiovascular Disease

A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk

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Science Translational Medicine  05 Feb 2014:
Vol. 6, Issue 222, pp. 222ra17
DOI: 10.1126/scitranslmed.3006804

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When Life-Saving Is Life-Threatening

We all need a vacation sometimes. For the heart and lungs, that time can come during surgery (such as cardiopulmonary bypass procedures), in instances of organ failure (for example, in septic patients), or while awaiting a replacement organ for transplantation. When the heart and lungs take time off, oxygenation of the blood needs to occur outside of the body by circulation through a cardiopulmonary bypass system (also called a heart-lung machine). In order to prevent blood clot formation in the extracorporeal circuit, an anticoagulant is added to the system. Anticoagulants block thrombus formation that would occlude the circulation; however, the drugs also interfere with the body’s ability to stop bleeding at the site of injury. Thus, an ideal anticoagulant would only block blood clotting in thrombosis without causing excess bleeding. Now, Larsson et al. describe a new antibody that prevents thrombosis and facilitates blood flow in a specific heart-lung machine without causing bleeding in large animal models.

The anticoagulant heparin is used most often during extracorporeal oxygenation and targets multiple components of the blood coagulation cascade that are necessary formation of fibrin—a clotting protein essential for stemming injury-related blood loss. The authors used phage display to identify an antibody that binds to and inhibits the protease activity of factor XIIa (FXIIa), a protein that controls fibrin formation in vitro but does not appear to be required for cessation of bleeding from injury sites. A fully humanized version of the antibody, called 3F7, protected against pathological thrombosis in the extracorporeal bypass system without increasing bleeding from injuries in rabbits. 3F7 had the added benefits of a broad therapeutic range and easy monitoring at the point of care. And because 3F7 doesn’t cause bleeding, it should not require neutralization after surgery and can simply be cleared from the patient’s circulation naturally.

Even with optimal heparin treatment, bleeding remains the most common complication of anticoagulation therapy. Additional mechanistic and clinical studies will show whether 3F7—or an optimized version—will be able to give heparin a vacation from facilitating extracorporeal circulation and possibly other scenarios that require safe anticoagulation.