Commentary

Will a novel antibody fix the anticoagulant-bleeding problem?


 

It seems inescapable: If patients are made less able to form blood clots, they bleed more.

Bleeding is the perennial problem for anticoagulants. Whether it’s the traditional anticoagulants (heparin, warfarin, and the low-molecular-weight heparins) or new drugs (fondaparinux, dabigatran, rivaroxaban, and apixaban), as the anticoagulant’s potency or dosage increases to stop blood clots from forming, the inevitable downside is increased bleeding.

Maybe not.

A newly developed, synthetic human IgG antibody appears, in animal and in vitro models, to allow normal clotting to occur and stop bleeding at vessel tears and cuts, while short-circuiting pathologic clotting in intravascular spaces – the sorts of clots that cause venous thromboembolisms, myocardial infarctions, and strokes.

Courtesy Yale Rosen/Wikimedia Commons

Ichorcumab, a newly developed, synthetic human IgG antibody, appears to allow normal clotting to occur and stop bleeding at vessel tears and cuts, while short-circuiting pathologic clotting in intravascular spaces.

"It seems too good to be true. It’s beyond comprehension," said Dr. Trevor Baglin, the University of Cambridge, England, hematologist who discovered the first identified, naturally occurring example of this antibody, in IgA form, in a patient he initially saw in 2008. "All we can do is go forward and see if it genuinely is as good as it seems," he said while presenting his group’s initial animal findings with the antibody at the Congress of the International Society on Thrombosis and Haemostasis in Amsterdam earlier this month.

The antibody – which has been patented, synthesized, and is in extensive preclinical testing – has been named ichorcumab. In Greek mythology, "ichor" was the blood factor in gods that made them immortal.

The secret behind ichorcumab is that it binds to and inactivates exosite 1, the part of the thrombin molecule that cleaves fibrinogen into fibrin, an effective brake on clotting. Study results suggest that whether the exosite 1 portion of thrombin is exposed or hidden at various body sites accounts for ichorcumab’s varied effects.

"Our hypothesis is that exosite 1 is protected from the antibody [when a thrombin molecule sits] on a cell or clot surface, so hemostasis is unaffected, but thrombosis occurs in the luminal space, where exosite 1 is exposed an available to the antibody," Dr. Baglin explained.

"While before we thought of just one type of clot, [the work with ichorcumab so far] suggests there is not one clotting mechanism but two," he noted, one that leads to clot formation that stops bleeding, and a second mechanism that produces clots that cause thrombosis. Ichorcumab blocks the bad clots but not the good ones, because the clots form at different locations that affect the way that exosite 1 on thrombin is exposed.

It may sound farfetched, but it’s a way for the researchers to explain the curious patient whom Dr. Baglin first met in 2008, a 53-year old woman who spontaneously makes and carries the IgA prototype of ichorcumab in her blood.

Dr. Baglin said that he consulted on her case after a preprocedural clotting screen revealed that her blood was unclottable by standard tests, yet she had no history of any bleeding disorder. In fact, her history showed that she had undergone knee surgery (when no clotting screen had been done) 5 months before Dr. Baglin first saw her without any hint of a bleeding incident. She subsequently cut the tip of a finger while slicing with a mandolin, but her bleeding stopped spontaneously.

The patient goes through life with this antibody in her blood at a level of about 3 g/L with no bleeding problems whatsoever; yet in a mouse model, a substantially lower level of the mimic antibody, ichorcumab, effectively blocked thrombosis. In the mouse model, this effective dose of ichorcumab does not cause bleeding if the mouse’s tail is cut.

Dr. Baglin and his associates started a company in Cambridge, XO1, to fund the preclinical work and eventually commercialize ichorcumab. They believe it will be another 2 years before any person receives a dose of the antibody.

–BY MITCHEL L. ZOLER

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

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