Successes in Rare Bleeding Disorders: Hemophilia and Others

Successes in Rare Bleeding Disorders: Hemophilia and Others

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Dr. Manuel Carcao
Clinician Investigator, Division of Haematology/Oncology (Department of Paediatrics)
Senior Associate Scientist, Child Health Evaluative Sciences, SickKids
Professor of Paediatrics, University of Toronto

By: Erika Opingari

A cure for hemophilia is in the near future. A seemingly surreal statement to write and read, but a welcomed prospect nonetheless.

Hemophilia A and B are rare X-linked bleeding disorders caused by genetic mutations leading to respective deficiencies in the blood-clotting proteins, factor VIII (FVIII) and factor IX (FIX).
As an X-linked disorder, hemophilia is mainly a disease affecting males with a prevalence of one in 5,000 and one in 1,0000 females, respectively. Yet there are estimated to be two or three times as many women who are carriers of a hemophilia mutation–20-30% of these women also suffer from excessive bleeding. A life-long condition usually recognized in childhood, the severity of hemophilia reflects the degree of factor deficiency. Fortunately, over the years, therapy for hemophilia has decreased mortality rates and improved patient outcomes.

To provide an expert review and discuss the trajectory of hemophilia treatment and care practices is Dr. Manuel Carcao, a Clinician Investigator in the Division of Haematology/Oncology at The Hospital for Sick Children. Dr. Carcao completed his medical training at the University of Toronto, after which he completed fellowships in pediatric hematology/ oncology and hemostasis before joining both institutes as faculty. Alongside his clinical practice, Dr. Carcao conducts both basic science and clinical research into congenital bleeding disorders, including hemophilia, von Willebrand disease, as well as rare inherited coagulation and platelet disorders, such as Glanzmann thrombasthenia.

Bleeding disorders typically occur due to a deficiency of a certain protein in the coagulation cascade. For a clot to form, there are a series of interconnected steps involving platelets and coagulation factors (factors I to XIII) which result in the formation of strong fibrin-platelet matrices. When one of the coagulation factors is absent (i.e. severe hemophilia) or reduced (i.e. mild/ moderate hemophilia), the process is disrupted, thereby preventing proper clot formation and increasing the risk of bleeding. Conventional management of bleeding disorders has been the replacement of the missing factor through intravenous injection. In the 1960s, when factor replacement therapy began for hemophilia, the products that existed were all plasma-derived factor concentrates prepared by obtaining and pooling blood from thousands or tens of thousands of donors. While this was effective, the potential for contamination was not fully appreciated at the time. Unfortunately, in the 1980s a disaster occurred when virtually all plasma-derived factor concentrates were contaminated with HIV. As a result, thousands of individuals with hemophilia and other bleeding disorders contracted HIV. “This tragedy resulted in a tremendous drive to shift hemophilia therapies towards genetically engineered recombinant factors,” says Dr. Carcao, “and by the 1990s, this was successfully translated into practice.”

While recombinant factors have drastically changed outcomes for patients with hemophilia, there remain many challenges with the administration of these products, particularly in children. Factor products must be given intravenously and, due to short half-lives in the bloodstream, must be given frequently–sometimes several times a week. To address these issues, extended half-life recombinant factor products have been developed and implemented to reduce the frequency of injections and to improve quality of life. However, many patients with hemophilia may also develop inhibitors (neutralizing antibodies) against the infused factor during treatment. The development of inhibitors diminishes the benefits of the treatment and complicates the management of these patients, as the immune system will destroy the factor upon its infusion. Consequently, such patients have traditionally had the worst outcomes.

Still, hemophilia research continues to push the boundaries and improve treatment options. Dr. Carcao explains that the next wave of change in hemophilia involves non-factor therapies, which will replace the function of certain factors, in particular FVIII. Non-factor therapies have the advantage of being able to be administered subcutaneously and infrequently–weekly or even monthly, thus facilitating the administration and accessibility of treatment for patients. Non-factor therapies can also be used in patients with inhibitors and can provide these patients with comparable treatment efficacy to that of patients without inhibitors.

Almost unbelievably, Dr. Carcao says we are close to the point of curing hemophilia. He predicts that in just ten years from now, hemophilia patients will no longer require regular therapies with either intravenous factor infusions or non-factor therapies. Instead, they will be treated, or even cured with gene editing and gene therapy. Many studies are investigating the role of gene therapy in fixing factor deficiencies, which will allow patients to endogenously produce all the necessary factors. Evidently, hemophilia management has dramatically changed over the decades and is expected to keep changing. “We’ve generally in the past, never talked about curing a genetic disorder,” says Dr. Carcao, “and now many clinical trials are doing just that.”

While hemophilia has taken great strides in research and treatment, other rare congenital bleeding disorders require further attention. Although the development of recombinant factors to treat other, rarer bleeding disorders would be greatly beneficial, there has been much less fervor to pursue this research. Dr. Carcao explains that because the market for very rare diseases is much smaller, pharmaceutical companies do not invest as many resources towards the costly development of products for these rare conditions.

Alongside his clinical work, Dr. Carcao is also involved with his colleagues Drs. Walter Kahr, Victor Blanchette and Margaret Rand, in basic laboratory research of congenital and acquired coagulation (e.g. von Willebrand disease, Factor XIII deficiency, anti-plasmin deficiency) and platelet disorders (e.g. Glanzmann thrombasthenia (GT), MYH9 macrothrombocytopenia, and gray platelet syndrome). Being in such a multicultural city such as Toronto, Dr. Carcao and his colleagues encounter a much larger prevalence of patients with these extremely rare bleeding disorders compared to other centers. Consequently, The Hospital for Sick Children sees a larger number of patients with disorders such as type 3 Von Willebrand disease, GT and Factor XIII deficiency than any other North American center.

GT is a severe, autosomal recessive bleeding disorder caused by a quantitative or qualitative defect of platelet membrane glycoprotein IIb-IIIa, a fibrinogen receptor required for platelet aggregation. It is estimated to affect one in one million individuals worldwide, making it much rarer than hemophilia. Consequently, GT has not seen the same trajectory in medical advancement as has hemophilia. While patients with GT have normal platelet counts, their platelets are dysfunctional, resulting in uncontrolled bleeding. Therefore, they often require platelet transfusions to prevent or stop bleeding. Transfusing patients with GT is unique in that it is the only situation where patients with normal platelet counts are routinely transfused with platelets. The uniqueness and the ramifications of this situation was not fully appreciated prior to the work completed by Dr. Carcao and his colleagues.

Dr. Carcao and colleagues showed that in patients with GT, the healthy transfused platelets are completely overpowered by the native dysfunctional platelets, which remain in the majority. Competition between the native malfunctioning platelets and the healthy transfused platelets reduces the expected benefits of a platelet transfusion. Therefore, patients with GT require higher levels of transfused platelets than normal in order to achieve therapeutic goals. This important finding will modify practice, thereby improving the treatment of patients with GT. It is due to the dedicated work of investigators, like Dr. Carcao and his colleagues, that
we continue to make advancements in medicine and change the story of patients with rare diseases. Curing hemophilia is hopefully just the beginning of this story.