Program Genealogies: Adult Hemophilia Treatment Center at the University of Toronto, St. Michael’s Hospital Free

In the early 1980s, care for hemophilia patients in Toronto (Canada’s largest city) was decentralized and haphazard. In the two preceding decades, the development of cryoprecipitate and lyophilized plasma-derived factor VIII and IX concentrates had revolutionized hemophilia care,^1-3  providing effective control and prevention of bleeding and making it practical for patients to self-infuse replacement therapy at home. By the 1970s, these developments led to the comprehensive hemophilia treatment center (HTC) model for the delivery of multidisciplinary care.^4,5  In Canada, this management model was pioneered in Montreal.⁶ 

In 1982, the Toronto and Central Ontario Region (TCOR) of the Canadian Hemophilia Society (CHS) issued a request for proposal (RFP) for the creation of an adult HTC. Leading the RFP was the late Frank Terpstra, a hemophilia patient and clinical biochemist. He established an adjudication committee chaired by Lou Aledort, MD, an eminent clinician-investigator in hemophilia from Mount Sinai Hospital in New York City. TCOR would provide start-up funding for the HTC, including two years’ salary for a nurse-coordinator, and would encourage its members to seek care there. The host hospital would be responsible for ongoing operational costs. Those costs would be relatively modest, as the Canadian Red Cross Blood Transfusion Service (CRC BTS) supplied all liquid and lyophilized replacement products for hemophilia and other bleeding disorders throughout Canada, without any cost to hospitals or patients.

Bernadette Garvey, MD, director of the Division of Hematology at St. Michael’s Hospital (SMH), a fully affiliated University of Toronto teaching hospital, took the lead as principal investigator in responding to the RFP. Dr. Garvey had established the Special Coagulation Laboratory at SMH after pursuing postgraduate training in coagulation at the U.S. National Institutes of Health. Her co-applicants were John Freedman, MD, a transfusion medicine specialist trained at St. Mary’s Hospital in London and director of the hospital’s Blood Transfusion Laboratory, and Jerry Teitel, MD, a hematologist recently recruited to the division after completing a research fellowship in hemostasis and thrombosis under Robert Rosenberg, MD, PhD, at Harvard Medical School.

The SMH proposal won the RFP competition, and the successful team proceeded to establish the adult HTC. They secured a small space in which to hold weekly clinics, hired full-time hemophilia nurse-coordinator Ann Harrington, and held their first hemophilia clinic in the spring of 1983. Frank Terpstra, who later succumbed to HIV infection, was one of their first patients. Drs. Garvey and Teitel were designated as codirectors of the HTC, with Dr. Freedman as a key team member in his role as director of transfusion medicine. That same year, a dedicated pediatric HTC opened at the Hospital for Sick Children in Toronto under the direction of Victor Blanchette, MD.

The early years of the HTC were tumultuous. As it was inaugurated, the epidemic of infection with what came to be called HIV was unfolding. The first case of AIDS in Canada had been diagnosed in March 1982, and the first diagnosis of AIDS in a Canadian hemophilia patient (a 29-year-old man in British Columbia) was reported in June 1983.⁷ 

It quickly became apparent that the source of HIV infection in hemophilia patients was replacement therapy, primarily the lyophilized factor VIII and IX concentrates that had revolutionized their care and liberated them from total dependence on hospitals. Although techniques for inactivating viruses had been known as early as the 1940s,^8,9  they had not been applied to these hemophilia treatment products, which were pooled from thousands of donors. During these times of uncertainty and anxiety, our HTC switched primarily to single-donor products for inpatient treatment — cryoprecipitate for patients with hemophilia A and fresh frozen plasma for those with hemophilia B. However, we continued to issue plasma-derived clotting factor concentrates for patients who already self-infused at home.

The first freeze-dried factor VIII concentrate heated to inactivate viruses was approved by the U.S. Food and Drug Administration in March 1983 and marketed by the Hyland Therapeutics Division of Travenol Laboratories. The ability of retroviruses to withstand the procedures to concentrate factor VIII from plasma, and their susceptibility to inactivation by heating the lyophilized powder at 68 degrees Celsius, was published in September 1984,¹⁰  shortly after the definitive identification of HIV (as it was later named) as the causative agent of AIDS by Luc Montagnier, MD, in France¹¹  and Robert Gallo, MD, in the U.S.¹² 

The first heat-treated factor concentrates were not approved in Canada until November 1984. In an attempt to protect patients felt most likely to have remained uninfected with HIV, CHS’ Medical and Scientific Advisory Committee recommended criteria for priority distribution of what were initially limited supplies. Sufficient inventory of viral inactivated products to treat all hemophilia patients became available by July 1985. We were able to perform HIV antibody testing on our patients, first as part of a clinical research project and later using blood tests approved for clinical use. By November 1985, all donations to CRC BTS were tested for HIV antibodies.

A large number of patients at our HTC had been infected with HIV. Our therapeutic tools were pitifully insufficient to prevent the tragic toll of illness and death from pneumocystis pneumonia and other opportunistic infections early in the epidemic. We treated HIV-positive hemophilia patients in our program with azidothymidine when it became available in Canada in 1990, with the backup of consultants from the SMH Division of Infectious Disease. Those colleagues assumed the primary role in our patients’ HIV management when effective combination therapies with other classes of drugs such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors were introduced. They remain important partners with us in hemophilia care.

It is both gratifying and important to acknowledge that despite the unfolding epidemic, CHS and its provincial chapters maintained positive collaborative relationships with our HTC and others across Canada, working together on educational and support programs for the community and on lobbying efforts with the blood system and the political establishment. In this respect, the Canadian experience differed from that of some other countries, where recrimination and anger led to the fracturing of relationships between the lay and professional hemophilia communities.

The unfolding epidemic led to changes in the blood system. The recommendations of the Commission of Inquiry on the Blood System in Canada (the Krever Commission of 1993 to 1997) led to the formation in 1998 of two new agencies replacing the role of CRC BTS in managing the blood system — Canadian Blood Services (CBS) and Héma-Québec. To formalize the independent input of HTC directors, Drs. Teitel and Blanchette led the effort to form the Association of Hemophilia Clinic Directors of Canada (AHCDC), a professional organization of doctors in hemophilia care. AHCDC was incorporated as a nonprofit in 1994 with Dr. Blanchette as its interim president and Dr. Teitel succeeding him as its first elected president. CBS and Héma-Québec continue to be responsible for supplying hemophilia treatment products, including recombinant concentrates and emicizumab. However, it is anticipated that they are unlikely to be involved in the provision of the gene-based and new non-replacement treatment products in development.

In 1989, hepatitis C was identified as the causative agent of non-A, non-B hepatitis. Serological testing to identify it became available the following year, with the seroprevalence of the hepatitis C virus (HCV) in hemophilia patients in Canada found to be 69%.¹³  Our HTC initially referred HCV-positive patients to hepatologists at other University of Toronto hospitals. In the early years, many of them had liver biopsies, generally via the transjugular route. The first treatment regimens for HCV, based on interferon and ribavirin, had limited efficacy and considerable adverse effects. Since 2014, highly effective and well-tolerated direct-acting oral antiviral regimens have replaced interferon and ribavirin, and biopsies are now done rarely, usually on suspicion of hepatocellular carcinoma.

Our HTC census grew steadily despite attrition due to HIV-related deaths. With time, the role of hemophilia nurse-coordinator was upgraded to nurse practitioner, and our core team grew with additional part-time nursing and physiotherapy support, a data manager, and a full-time pharmacist. With Dr. Garvey’s retirement as codirector of the HTC and director of the coagulation laboratory, we recruited Michelle Sholzberg, MDCM, MSc, to fill both roles. Dr. Sholzberg has greatly enhanced our academic capacity by establishing a divisional pool of research coordinators. Clinically, the HTC has close collaboration with many medical and surgical divisions in our hospital, notably infectious disease, orthopedics, general surgery, and rheumatology. We also collaborate closely with an off-site dentistry practice that has become skilled at managing patients with bleeding disorders.

Our HTC census now includes 543 patients with hemophilia A, 113 with hemophilia B, 539 with von Willebrand disease (of whom 139 have a type 2 or 3 variant), and 628 with other rare inherited bleeding disorders. This makes us the largest HTC in Canada. We work very closely with our sister pediatric HTC located at the Hospital for Sick Children and its core medical team, which has been led by Manuel Carcao, MD, MSc, following the death of Dr. Blanchette. Patients seamlessly transition from the pediatric to the adult clinic at age 17 or 18. Our HTC is the major regional referral center for patients with congenital bleeding disorders and for acquired hemophilia, of which we typically see eight to 12 new cases per year.

The academic productivity of our HTC, focused on clinical, epidemiological, and quality improvement in bleeding disorders, is catalyzed by the strong collaborations with HTCs across the country, including those located at four other research universities in Ontario. These linkages are formalized through our joint membership in AHCDC, which promotes collaborative research and maintains robust national databases such as the Canadian Bleeding Disorders Registry.

Our HTC is also engaged in developmental and educational activities in the international hemophilia community. We participated in an organizational twinning project between the Jordanian Thalassemia and Hemophilia Society and the Toronto and Central Ontario Region of Hemophilia Ontario, the medical component of which was led by Dr. Garvey. We also recently completed an HTC twinning project between Toronto (both the adult and pediatric HTCs) and Barbados, led jointly on the Toronto side by Dr. Teitel and the late Dr. Blanchette. Our HTC is designated as an International Hemophilia Training Centre (IHTC). After pandemic restrictions were lifted, our first IHTC fellow, a Tanzanian hematologist, joined us in 2024.

The members of our HTC have taken prominent leadership roles in professional organizations related to hemophilia care in Canada, including AHCDC, the Canadian Association of Nurses in Hemophilia Care, and the Canadian Physiotherapists in Hemophilia Care. Through these professional associations and CHS, the hemophilia community in Canada is closely integrated, collegial, and collaborative.

With emerging technologies such as subcutaneous non-replacement drugs and in vivo and ex vivo gene therapies to complement traditional replacement therapy, the focus of HTCs has evolved from managing complications of bleeding disorders to preventing those complications and preserving health and quality of life. We anticipate a future in which definitive management of these once deadly diseases becomes so effective and easily accessible that perhaps the role of HTC can be consigned to medical history.