Unexpected results from a University of North Carolina study suggest that Pradaxa may increase the risk and severity of viral infections, including the flu and myocarditis — a heart infection linked to death in kids and young adults.
Pradaxa is one of several next-generation anticoagulant drugs approved by the U.S. Food and Drug Administration (FDA) in recent years for the treatment of an increasingly common type of irregular heartbeat called non-valvular atrial fibrillation. The condition is associated with a higher risk for potentially deadly blood clots, which the drugs stave off by thinning the blood.
The higher susceptibility to viral infection is an unintended consequence of Pradaxa’s mechanism of action, according to researchers involved in the study. The drug works by blocking the activity of thrombin, an enzyme that plays a central role in the formation of blood clots.
“Our findings show that blocking thrombin reduces the innate immune response to viral infection,” says Nigel Mackman, PhD, senior author of the study.
A report on the study was published in the March 2013 issue of the Journal of Clinical Investigation.
Clotting Helps Combat Infection
Several teams collaborated on the study, including the Mackman group at the University of North Carolina and researchers from the Charité – Universitätsmedizin in Berlin, Germany. The researchers didn’t anticipate the discovery that Pradaxa may increase the risk for viral infections; it was discovered as they attempted to shed light on our understanding of how the body responds to viruses on a cellular level.
According to Mackman, viral infections like mosquito-borne dengue fever trigger coagulation, the process through which the blood forms clots. At first researchers thought this response was problematic, but later discovered that it gives a favorable boost to the immune system.
Subsequent studies on bacterial infections suggested that fibrin, an important clotting protein formed by thrombin, activates special immune cells that attack and digest viruses, bacteria and other harmful pathogens. This too wasn’t entirely accurate.
“It seems that the antiviral mechanism of the clotting system is not via fibrin but rather via thrombin,” says Mackman. He explains that it is actually thrombin that triggers the immune response by activating a type of cell receptor called PAR-1.
Mackman and his team investigated the question by deactivating PAR-1 in mice. When researchers infected the mice with a virus that causes myocarditis, they found increased viral buildup in the heart and increased impairment of heart function. Further, the lack of PAR-1 was associated with a slower immune response after infection.
Similar Problems with Pradaxa
After discovering that the positive immune response to viral infection depends upon thrombin — which Pradaxa blocks — the researchers treated normal mice with the drug to study the effects. They showed that just like in the mice with deactivated PAR-1, Pradaxa led to increased cardiac virus load and cardiac injury after viral infection.
“Pradaxa might not only facilitate significant lifesaving effects in reducing cardiac death, but may also interfere with other processes in the body,” said Mackman.
This finding represents yet another potential risk for patients taking Pradaxa. In 2011, the FDA received approximately 4,000 reports of serious adverse events and 550 reported deaths associated with the drug, according to FDA officials. More than 250 Pradaxa lawsuits have been consolidated in the U.S. District Court for the Southern District of Illinois and are currently pending.
Next, the research team plans to repeat the study using warfarin, which has been the most widely prescribed blood thinner for decades.