Plasma or Recombinant Products for Hemophilia?

Amy Dunn, MD
Pediatric hematology/oncology specialist at Nationwide Children’s Hospital in Ohio
Guy Young, MD
Professor of Pediatrics at the Keck School of Medicine at the University of Southern California

For the past half-century, plasma products have been the mainstay for the treatment of patients with hemophilia. In the 1950s, hematologists used large volumes of fresh frozen plasma to stop minor bleeds, and though the development of plasma-derived clotting factor concentrates allowed for more accurate dosing in the 1960s, the hemophilia community was devastated by HIV and hepatitis virus transmission through plasma infusions in the 1980s.

With a better understanding of these viruses and better screening methods, the safety of plasma products dramatically improved. Another development in the 1980s and 1990s further reduced the risk of infection: recombinant human factor VIII (FVIII). While these products can overcome some of the limitations of plasma-derived products, are they safer or more effective?

In this edition of Drawing First Blood, ASH Clinical News invited Amy Dunn, MD, and Guy Young, MD, to debate the question, “What is the optimal treatment for patients with hemophilia – plasma-derived or recombinant clotting factors?” Dr. Dunn, of Nationwide Children’s Hospital in Ohio, will argue on the “recombinant” side, and Dr. Young, of the Keck School of Medicine at the University of Southern California, will argue on the “plasma” side.


Amy Dunn, MD: If there is a group that is at risk for an infectious complication, it is the hemophilia patient population. In the 1980s and 1990s, the hemophilia population was hit hard by transmission of infectious agents like HIV and hepatitis through plasma. It’s easy to see why people became wary of plasma concentrates. How could we be sure scientists were making a concentrate safe from infectious agents when the infectious agents had never even been described?

Of the numerous arguments in favor of recombinant factor products for hemophilia, the perceived safety benefit is the first that pops into most minds. Making even one vial of plasma concentrate for someone with hemophilia requires thousands of blood donors. If a patient is routinely taking plasma concentrates, he or she is exposed to thousands of blood donors over months, years, and potentially an entire lifetime. Recombinant products prevent exposure to infectious agents.

Guy Young, MD: The HIV epidemic was a horrible disaster for the hemophilia community, but improved viral inactivation and screening methods have made transmission of HIV or hepatitis through plasma transfusion improbable.

Dr. Dunn: Right, but I think new infectious agents we don’t yet know about is what concern people. Again, we can’t make sure that plasma products will be safe from every infectious agent. When you deal with a community with a history like that of the hemophilia population – who lost an entire generation of patients – it’s a sensitized group.

As a pediatrician, I’m often dealing with the children of men who died from these infectious complications. The thought of treating a child with a plasma concentrate is too big a burden for parents to bear. Also, to this day, we do not know if the safety precautions used to collect and treat plasma will eliminate agents like prions.

Dr. Young: When I treat patients newly diagnosed with hemophilia who may have concerns about the infectious risk, I tell them, “These days, plasma products are perfectly safe. It has been more than 30 years since a transmission of HIV and more than 20 years since a transmission of hepatitis through plasma-derived FVIII products.”1 Today, I think most people who are having kids who might inherit hemophilia either don’t have a family history, or don’t know of any family member who’s been affected by viral transmission through plasma.

The other point I make when explaining plasma-derived products to new patients is that plasma products could reduce their risk for developing inhibitors – an extremely serious complication of hemophilia.

The patient population that I would recommend plasma-derived products to are what we call PUPs, or “previously untreated patients.” That recommendation is based on data from the Survey of Inhibitors in Plasma-Product Exposed Toddlers, or SIPPET trial, that was presented as a plenary abstract at the 2015 American Society of Hematology Annual Meeting and later published in The New England Journal of Medicine.2,3 In SIPPET, we investigated whether the development of inhibitors was related to the type of concentrate used for factor replacement therapy. Of 251 PUPs with hemophilia A enrolled, 125 were assigned to receive plasma-derived FVIII–containing von Willebrand factor (vWF), and 126 were assigned to receive recombinant FVIII with no vWF.

We found that PUPs treated with plasma-derived products had about a 50 percent lower rate of developing inhibitors, compared with those treated with recombinant factors.3 Based on these data, I think the target population for plasma-derived products would be pediatric PUPs, because we want to do whatever we can to limit or prevent the number of inhibitors that occur in patients with hemophilia.

Dr. Dunn: However, treating patients with plasma-derived products requires much higher volumes of products for infusion, compared with recombinant products, which only require a couple milliliters of concentrate. So, if I’m treating pediatric patients, who have tiny blood vessels, with plasma products, I might need to use central venous access devices to deliver the higher volumes of plasma necessary. Implanting a central venous access device, though, means major surgery, which introduces risks associated with anesthesia, infection, and the device itself. If I can ever avoid surgical procedures in patients with hemophilia, I certainly want to do that. I can infuse smaller-volume recombinant products more easily through peripheral veins in pediatric patients.

Dr. Young: The other instance when I would prefer plasma-derived products is in patients who have already developed inhibitors. We also use plasma concentrates when we perform immune tolerance induction therapy, in which we give repeated doses of FVIII to try to eradicate inhibitors.

Dr. Dunn: We have to be concerned about the high concentrations of vWF present in some plasma products. As the von Willebrand protein accumulates over time in patients who receive these products, it can put patients with bleeding disorders at increased risk of thrombosis – particularly if these agents are being used in high doses or before surgical procedures.

Also, the risk of thrombosis is particularly high in pediatric patients because children have lower volumes of blood than adults. On the other end of the spectrum, older patients with hemophilia who might have cardiovascular disease already have an elevated risk of thrombosis; that risk will be even higher if the patients are being treated with plasma FVIII concentrates that have greater vWF levels.

Still, the big problem with the SIPPET study is that plasma-derived concentrates did not eliminate inhibitors in patients receiving plasma concentrates. Those patients still developed inhibitors, so there is clearly something about inhibitor development that we don’t understand.

Dr. Young: SIPPET was a randomized, controlled trial, and it provided pretty good evidence that the plasma-derived FVIII reduces the risk for inhibitors. Without strong evidence to the contrary, hematologists can argue that using plasma-derived FVIII with vWF may be more effective at eliminating inhibitors than recombinant products.

There also are published case series suggesting that the success rates for immune tolerance therapy are higher than for recombinant FVIII, but again, this hasn’t been studied in a head-to-head comparison. Conducting these types of trials is difficult because inhibitors are rare: In the U.S., only 400 PUPs develop inhibitors each year, and only 30 percent of the entire population of patients with hemophilia develop inhibitors. Assessing therapies in both PUPs and patients with inhibitors is incredibly challenging.

Dr. Dunn: What we really need to figure out is why inhibitors develop in the first place. Then, we could decide if there is something about plasma-derived factor concentrates that have a protective effect against inhibitor development. The lack of knowledge about this complication is one of my biggest concerns. If we don’t understand the mechanism of inhibitor formation or who is at risk, how can we choose the best treatment option for a given patient?

Hemophilia is not a single condition: It’s one of the most varied genetic conditions. Inhibitor discordance between monozygotic twins is well documented and indicates that a genetic mutation in and of itself does not predict inhibitor risk. There’s more to the story than just a patient’s genetic makeup. Learning more about inhibitor development will help us understand who is and isn’t at risk for inhibitors.

Of course, another question we can’t yet answer is how newer agents for hemophilia will affect these questions. With the recent U.S. Food and Drug Administration approval of emicizumab, the world of hemophilia care is poised to change dramatically. It may render the entire plasma-versus-recombinant debate moot; we may be able to start patients on emicizumab when they’re young and don’t have bleeding complications. In the future, the vast majority of patients with hemophilia might never be exposed to FVIII concentrates.

Dr. Young: I agree and I would predict that, over the coming years, we’re going to see factor replacement therapy slowly go away as we transition to subcutaneous therapies. These treatments are much easier to administer than factor replacement products – regardless of the type of concentrate. If we can administer a subcutaneous therapy that requires less frequent dosing, patients will want that option – and families are going to want that for their children.

We’re seeing the beginning of the end, so to speak. Factor replacement therapy is not going to disappear next year, but I think over the next five to 10 years, subcutaneous therapies and gene therapies might replace it.


References

  1. Franchini M. Plasma-derived versus recombinant factor VIII concentrates for the treatment of haemophilia A: recombinant is better. Blood Transfus. 2010;8:292-6.
  2. Peyvandi F, Mannucci PM, Garagiola I, et al. Source of factor VIII replacement (PLASMATIC OR RECOMBINANT) and incidence of inhibitory alloantibodies in previously untreated patients with severe hemophilia A: the multicenter randomized Sippet study. Abstract #5. Presented at the 2015 ASH Annual Meeting; December 6, 2015; Orlando, FL.
  3. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374:2054-64.

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