Blocking anticoagulant protein S may boost replacement therapy

Quicker clotting seen for hem B children when antibody added to FIX therapy

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Adding an antibody targeting the anticoagulant protein S to factor IX (FIX) replacement therapy accelerated blood clotting in samples from children with hemophilia B, including those with severe disease, a study showed.

Greater production of the blood clotting protein thrombin also was seen in these samples, while blocking protein S facilitated clotting in a FIX-treated mouse model of the bleeding disorder.

“Our findings imply that a PS [protein S] antibody would be a valuable adjunct [add-on] to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe [hemophilia B],” the researchers wrote.

The study, “Protein S Antibody as an Adjunct Therapy for Hemophilia B,” was published in blood advances.

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Normal blood clotting, or coagulation, requires a balance between procoagulant and anticoagulant molecules. Excessive activation of clotting cascades can lead to harmful clots in the blood vessels (thrombosis), whereas deficient clotting results in bleeding disorders like hemophilia.

A lack of FIX, an important blood clotting protein, in hemophilia B patients leads to episodes of prolonged or spontaneous bleeding. FIX replacement therapy provides them with a lab-made version of FIX via intravenous (into-the-vein) infusions that help restore blood clotting and prevent bleeds.

This currently lifelong therapy comes in standard half-life versions, with infusions that may be required at least once a week for bleed prevention, or extended half-life versions, which are modified to prolong their presence in the bloodstream, requiring fewer infusions.

“A valuable enhancement to current [hemophilia B] therapy would be an adjunct treatment that increases the effectiveness of a given concentration of FIXa, thereby reducing the frequency of FIX injections or increasing the time interval between FIX injections,” the researchers, all at institutions in the U.S., wrote.

“The burden and inconvenience of frequent intravenous FIX infusions are major barriers to patient compliance, especially in the pediatric population,” they added.

Protein S is a naturally occurring anticoagulant known to also suppress the activated form of FIX, or FIXa, ultimately limiting the production of thrombin, an important blood clotting enzyme, “and contributing to prevention of thrombosis,” the researchers wrote.

As such, blocking protein S may be one way to prolong the presence of infused FIX in the bloodstream.

To investigate, the scientists evaluated the effects of adding an anti-protein S antibody to FIX replacement therapy in blood samples from 11 children with hemophilia B (six white and five African American).

They tested this approach in a pediatric population because hemophilia B is more severe in children relative to adults, the study noted.

Anti-protein S antibody sped blood clotting, even with severe FIX deficiency

Patients’ median age was 10 years (range, 2 months to 17 years), and most (54.5%) had a severe FIX deficiency, meaning less than 1% of normal protein levels. One had a moderate deficiency (1%-5% of normal), and four had mild deficiencies (5%-40% of normal).

All had been treated on-demand or preventively with standard or extended half-life FIX replacement therapy. Commercial blood samples deficient in FIX and then supplemented with FIX therapy also were evaluated.

Results indicated quicker blood clotting in the presence of an anti-protein S antibody, even in blood samples from children with severe disease. “In the presence of varying concentrations of FIXa, clotting times were consistently shortened with the addition of PS antibody,” the team wrote.

The type of FIX replacement given to patients did not influence the antibody’s effects. Similar results were obtained with FIX-deficient commercial blood samples and with different commercial anti-protein S antibodies.

Blocking the protein also associated with increased generation of thrombin, which was greatest in blood samples from children with severe hemophilia B — rising by about 60%-70% in these patients compared with about 20% in those with mild disease.

Higher fibrin levels found in treated mouse model of hemophilia B

The approach then was tested in a mouse model of hemophilia B after a vein injury. Combining the anti-PS antibody with FIX replacement therapy was associated with a 4.5 times higher accumulation of fibrin relative to FIX therapy alone at 30 and 60 minutes after the injury.

Fibrin, the result of thrombin’s enzymatic activity, is the protein that ultimately forms a clot and impedes blood flow.

Accumulation of platelets, blood cell fragments involved in clotting, also rose significantly with the antibody’s addition.

“Our … data clearly indicates that PS antibody prevented PS from inhibiting FIXa, thereby enhancing fibrin formation in Hemophilia B mice,” the researchers wrote.

But “antibodies are not without shortcomings,” the scientists added, noting that antibody-based therapies can contribute to a risk of blood clots or allergic reactions. As such, other approaches for blocking protein S may warrant exploration.

“In sum, current treatment of [hemophilia B] involves infusion of purified FIX. Although this replacement therapy provides some benefits, it is expensive. Thus, PS antibody’s ability to extend FIX’s functional lifetime is a valuable enhancement to current [hemophilia B] therapy,” the researchers concluded.

“We showed that such a novel adjunct is attainable and effective,” they added.