Hemophilia: From Plasma to Recombinant Factors
This article was published in December 2008 as part of the special ASH anniversary brochure, 50 Years in Hematology: Research That Revolutionized Patient Care.
Hemophilia is caused by the failure to produce certain proteins required for blood clotting: factor VIII (hemophilia A) or factor IX (hemophilia B). Because the genes encoding these factors are on the X chromosome, these diseases (termed "X-linked") usually affect only men, who carry only one X chromosome. Women carrying the disease gene are "carriers" and can transmit the disease to their sons, but women are rarely affected because they also carry a normal X chromosome. Patients with severe hemophilia produce less than 1 percent of the normal amount of the affected clotting factor and are dependent on factor from intravenous infusions to treat or prevent bleeding episodes.
In the late 1950s and much of the 1960s, fresh frozen plasma (FFP) was the mainstay of treatment for hemophilia A and hemophilia B. Each bag of FFP contained only miniscule amounts of factor VIII and factor IX, thus large volumes of intravenously administered FFP were needed to stop bleeding episodes. Children were usually hospitalized for treatment of bleeding into a knee, an elbow, or other joint. Many adolescents were reluctant to tell their parents that they were bleeding, delaying treatment and gradually leading to chronic joint disease with crippling deformities.
A great advancement came in the mid-1960s with the discovery of a method for preparing factor VIII from FFP by allowing it to thaw in the cold (cryoprecipitated plasma). This preparation could be stored in frozen form as "cryoprecipitate." This allowed intravenous administration of more factor VIII in a smaller volume, allowing outpatient treatment for bleeds and even elective surgery in persons with hemophilia A. This more concentrated form of clotting factor VIII rapidly became the preferred treatment for acute bleeding episodes in patients with hemophilia A.
By the late 1960s, scientists and manufacturers developed methods for separating factor VIII and factor IX from pooled plasma, resulting in neatly packaged bottles of freezedried (lyophilized) factor VIII or factor IX concentrates. Each bottle had a label indicating the amount of factor VIII or factor IX it contained, allowing more accurate dosing. By the early 1970s, the availability of these concentrates led to home treatment, greatly changing the lives of people with hemophilia.
However, there was a price to be paid for this newfound independence. Thousands of plasma donations were combined as starting material for one batch of plasma-derived factor VIII or factor IX concentrate, and by the early 1980s, human blood, plasma, and plasma-derived products were discovered to be transmitting potentially deadly blood-borne viruses, including hepatitis viruses and HIV. Manufacturers of plasma-derived clotting factor concentrates attempted to kill these viruses with dry heat, solvent-detergent treatment, and pasteurization, with varying degrees of success. By 1985, most patients with hemophilia in the U.S. had been switched to heat-treated concentrates, but many had already been infected with HIV and a large percentage of them succumbed to it. Great concern about the safety of plasma-derived products continued in the hemophilia community.
Eventually better screening methods for blood donors were developed, improving the safety of donated plasma. Screening of donors for the hepatitis B virus was already in place, and in 1989 the hepatitis C virus (HCV) was isolated, allowing HCV antibody testing of donors to begin in 1990. HIV was identified in 1984, and by 1985 a blood test for HIV antibodies was instituted in blood and plasma collection facilities.
The successful cloning of the factor VIII gene in 1984 was a major breakthrough, allowing production of recombinant human factor VIII (r factor VIII). Clinical trials in humans began three years later, and this was truly an exciting time, especially for families who had lost loved ones to AIDS. The boys and young men participating in the studies of r factor VIII were overheard saying, "This is so exciting, being on the cutting edge of science!" By 1992, two pharmaceutical companies had licensed r factor VIII products for use in hemophilia A. Cloning of factor IX was first reported in 1982, and a licensed r factor IX product (BeneFIX) became available for people with hemophilia B in 1997.
Other significant advances that have been made in recent years include treatment for patients with inhibitors (antibodies that inhibit or interfere with the function of factor VIII or factor IX) and prophylaxis (treatment to prevent disease). Inhibitor antibodies develop in approximately 30-35 percent of people with hemophilia A and 1-3 percent with hemophilia B. We now have a much better understanding of the causes (genetic, racial/ethnic, etc.) and natural history of these inhibitors, how to detect and measure them with greater certainty, and how best to eliminate them by manipulating the immune system. Scientists have also developed innovative treatment products for "bypassing" the inhibitor, such as recombinant activated factor VII (r factor VIIa), which was first licensed for use in hemophilia in 1997. Newer second-generation products to treat inhibitors are actively being developed, and while much progress has been made in treating inhibitors, this complication remains the greatest problem in the management of hemophilia today.
Now that we have safer clotting factor replacement products, preventive (prophylactic) treatment has gained acceptance as a means to preserve normal joint and musculoskeletal function in boys and young men with hemophilia. First described by Swedish physicians 40 years ago, then recommended by the (U.S.) National Hemophilia Foundation's Medical and Scientific Advisory Council in 1994, and recently documented as effective in a multicenter controlled trial, increasing numbers of young boys with severe hemophilia A or B are being started on prophylaxis with r factor VIII or r factor IX. Because of these developments, the future for those with hemophilia looks much brighter than it was only a few decades ago.