Advances in transfusion medicine improve life expectancy for someone with severe hemophilia to 20 years

The use of fresh frozen plasma, which often required hospitalization, is the mainstay of treatment for hemophilia

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 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.

Mary M. Gooley assembles one of the first comprehensive care centers in Rochester, NY

Mary M. Gooley serves as the center’s president from 1959 until her retirement in 1986, when the clinic is renamed the Mary M. Gooley Hemophilia Center.

Judith Pool discovers a simple way to make cryoprecipitates (cold insoluble precipitates that contain factor VIII) for the treatment of hemophilia

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. This is the first successful treatment for hemophilia beyond whole blood. After cryoprecipitate is developed, life expectancy grows to 24 years old.

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Working with Hyland Labs, Dr. Kenneth Brinkhous discovers a method to distill cryoprecipitate into clotting factor, an even more potent therapy for controlling bleeding

Health Disparities

As factor concentrate becomes available, patients are given instructions on how to access it. Availability of factor concentrate varies by center and region. Women, people of color, and those living in rural areas are rarely mentioned in media descriptions of people with bleeding disorders.

Dr. Shelby Dietrich leads Orthopedic Hospital in Los Angeles, California, in becoming a well-respected center for hemophilia care

The availability of lyophilized (dried) factor VIII or factor IX concentrates allows home infusion therapy to become a common treatment practice

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, factor concentrate usage continues to vary. Some doctors are still prescribing and instructing patients to use cryoprecipitate in the early 1970s.

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Advancements in Care

Treatment at home is becoming more prevalent and some patients no longer feel tethered to the hospital. For decades, hemophilia families have organized blood drives to replace the donations needed for transfusions. These remain common, despite the increasing availability of cryoprecipitate and clotting factor concentrates.

The Hemophilia Act of 1973 allows federally funded comprehensive hemophilia treatment centers to be established

The act provided funding for hemophilia treatment centers, which were established to provide specialized medical care and education for individuals with hemophilia and their families.

In addition, the Hemophilia Act of 1973 established a federal program to provide financial assistance for the purchase of clotting factor therapies. This program was intended to ensure that individuals with hemophilia had access to the costly clotting factor treatments they needed to manage their condition.

The Hemophilia Act of 1973 was significant because it was one of the first federal laws to provide specific support for individuals with a genetic disorder. It recognized the unique challenges faced by individuals with hemophilia and provided resources to help them manage their condition and improve their quality of life. The law has been amended several times over the years to reflect changing medical and financial circumstances.

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NHF

In 1973, NHF launched a two-year campaign to establish the creation of a nationwide network of hemophilia diagnostic and treatment centers. The goal was to provide a range of comprehensive services for patients and families within one treatment facility. Today, there are about 141 federally funded treatment centers and programs across the country.

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An article in the Journal of the American Medical Association notes it is possible to heat treat albumin, a blood product, to effectively kill some of the hepatitis viruses

While this process was industry standard in Germany, another major producer of antihemophilic factor concentrates, it did not become mainstream in the U.S. until the mid-1980s.

The hepatitis viruses and HIV threaten the worldwide blood supply

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.

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Using gene sequencing techniques, researchers clone factor IX

Cloning of factor IX was first reported in 1982, and a licensed r factor IX product became available for people with hemophilia B in 1997.

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Using gene sequencing techniques, researchers clone factor VIII

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.

By 1992, two pharmaceutical companies had licensed r factor VIII products for use in hemophilia A.

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Hepatitis C Virus (HCV) is isolated

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.

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After only a few years of successful clinical trials, recombinant human factor products become licensed and are available to hemophilia patients

The first recombinant factor VIII concentrate becomes commercially available. It is 1997 before a recombinant factor IX concentrate becomes commercially available. Recombinant products are not made from human plasma and so do not carry the same risk for transmitting diseases such as HIV/AIDS and hepatitis.

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Recombinant factor IX becomes commercially available

Scientists have also developed innovative treatment products for “bypassing” an 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.

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Recent advances include a better understanding of the cause, detection, and elimination of inhibitor antibodies found in many hemophilia patients

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). 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.
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First subcutaneous Hemophilia A treatment is approved for people with or without inhibitors

On October 4, 2018, the Food and Drug Administration approved emicizumab-kxwh injection for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients (ages newborn and older) with hemophilia A (congenital factor VIII deficiency) with or without factor VIII (FVIII) inhibitors.

This treatment was first approved in 2017, but only for people with inhibitors.

Unlike previous treatments, this treatment does not contain factor VIII. Instead, it relies on a synthetic enzyme that replicates the function of factor VIII.

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First gene therapy treatment is approved

On November 22nd, 2022, the FDA approved the first gene therapy treatment for adults with hemophilia B.

This drug is an adeno-associated virus vector-based gene therapy for the treatment of adults with Hemophilia B who currently use Factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.

The introduction of gene therapy treatments is raising many new questions about the future of treatments and the role of Hemophilia Treatment Centers (HTCs).

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