Amy Dunn , MD

Guy Young , MD

Disclaimer : The following positions were assigned to the participants and do not necessarily reflect ASH opinions , the participants ’ opinions , or what they do in daily practice .

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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 – plasmaderived 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 the new infectious agents we don ’ t yet know about are 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 a mother 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 .

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