Repeated Altuviiio dosing doesn’t boost risk of blood clots in mice

Repeated dosing of the long-lasting factor replacement therapy Altuviiio (efanesoctocog alfa) over a short timeframe may not increase the risk of dangerous clotting events, according to studies in a mouse model of hemophilia A.

Blood analysis showed an increase in global coagulation function, which measures the formation and breakdown of blood clots. However, this increase was comparable to repeat dosing of Adynovate (rurioctocog alfa pegol), a therapy that doesn’t last as long in the bloodstream. Thrombotic markers, which help assess the risk of clotting and stroke, were also present at similar levels for both medications.

“While our data did not indicate increased global coagulation function or early thrombotic markers with short-interval repeated dosing, clinical risk assessment should continue to consider individual patient conditions,” the researchers wrote.

The study, ”Repeated short-interval administration of efanesoctocog alfa is not associated with increased global coagulation potential in hemophilia A mice,” was published in the International Journal of Hematology.

Hemophilia is a genetic condition that reduces the function of clotting factors, proteins that help blood form clots. Different types of hemophilia involve different clotting factors; hemophilia A specifically affects factor VIII (FVIII).

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A common strategy for treating hemophilia is factor replacement therapy. This provides the body with a working version of the missing factor. Altuviiio is an FVIII replacement that lasts for three to four times longer in the bloodstream than other replacement products, which can support less frequent dosing. For routine bleed prevention, people with hemophilia A typically receive Altuviiio infusions once weekly.

For major surgery or severe bleeding, doctors may recommend more frequent dosing, with infusions every two to three days. “However, the potential thrombotic risk and global coagulation function associated with frequent administration of efanesoctocog alfa over a short period remains unknown,” the researchers wrote.

The team aimed to assess this risk using mouse models of hemophilia A. For comparison, they also measured the effects of Adynovate, a FVIII replacement therapy typically administered more frequently than Altuviiio.

First, the researchers exposed FVIII-deficient human blood samples to different concentrations of both treatments. They then measured changes in the levels of thrombin, a crucial clotting protein, over time. Peak thrombin levels were comparable for the two medications, regardless of the concentration.

The mouse experiments followed, with mice receiving Altuviiio doses every 24 hours. Because of differences in how mice and humans break down the medication, the researchers expected this to be similar to dosing a human every 48 hours.

Activated partial thromboplastin time, which measures the time it takes for blood to clot, decreased notably after one dose of either Altuviiio or Adynovate. This measure was similar across the two therapies and did not decrease further with repeat dosing. However, levels of FVIII activity increased more in mice that received Altuviiio.

Using a different blood analysis technique, the team then measured global coagulation in the animals. “Coagulation potential after repeated doses of [Altuviiio] in a short period of time was comparable to that of [Adynovate],” they wrote.

Likewise, thrombotic markers didn’t differ significantly between the medications, regardless of the number of doses.

These results do not suggest a substantial increase in clot risk with repeated dosing of Altuviiio in a short timeframe. Although Altuviiio persists longer in the bloodstream, its effects on clotting metrics were similar to those of Adynovate, which has a well-established safety profile for short-term repeat dosing. Higher levels of FVIII activity may correspond to a higher risk of clots, but similarities in global coagulation potential and thrombotic markers suggest this may not be the case.

Using animal models of disease has inherent limitations that affect the generalizability of the results. “Therefore, these findings are specific to the experimental conditions in the present study and further investigation in patients under real-world dosing conditions is warranted,” the researchers noted.