Overview and Treatment Goals of Hemophilia

Meera B. Chitlur, MD: Hemophilia A and B are X chromosomal recessive bleeding disorders that are characterized by deficiency of factor VIII or factor IX, and the severity of the deficiency defines the severity of the disease. Due to X-linked chromosomal inheritance, males are usually affected by the disorder and females are carriers. However, females can be affected by deficiency of the clotting protein itself due to extreme lyonization. The incidence of hemophilia A is about 1 in 8000 males and hemophilia B is about 1 in 30,000 males. About 400,000 patients with hemophilia have been identified in the United States so far. A third of these patients have new mutations and no family history.

Severe hemophilia refers to deficiency of the clotting protein, where you have less than 1% of clotting factor ability; moderate hemophilia refers to factor levels between 1% and 5%; and mild hemophilia refers to factor levels between 5% and 40%.

The severity of bleeding symptoms correlates or corresponds with the factor levels, although the genotype and phenotype do not necessarily always correspond. However, children with severe hemophilia are usually diagnosed during infancy or during the toddler stage, when they begin to walk and develop hematomas or bleeding symptoms with minor trauma. That’s usually how they end up being diagnosed. Moderate and mild hemophilia, on the other hand, are usually diagnosed following trauma resulting in bleeding or hematoma formation, sometimes after procedures or surgeries that result in excessive bleeding.

Lifelong increased risk of bleeding is the most significant complication that you see in patients with hemophilia. There is a risk for life-threatening hemorrhage in these patients. In the era of replacement products and easy availability of replacement products, the development of inhibitors is actually considered to be the most serious complication in these patients. Bleeding in these patients can occur in joints, as well as intracranially. The major sites of bleeding are defined as intracranial, neck, chest, and abdomen because these are sites where you can’t really see the bleeding occur. Inhibitor development is a major risk factor in these patients and management is extremely difficult in this population, which makes it the most relevant complication in this day and age.

The primary aim of treatment in hemophilia is to prevent bleeding and take care of bleeding complications once they occur. Hemophilia is a really rare bleeding disorder and the management of these patients is extremely complicated. The primary aim of our treatment in this population is to replace the product and the factor that are missing. The aims of replacing factor are to ensure a level that will prevent spontaneous bleeding and to manage any activity-related bleeding complications.

The goal of treatment, or the treatment plan, typically includes establishing a good diagnosis, which means that you need to have a laboratory that is able to assess factor level accurately in a patient. Once the severity of hemophilia has been determined, the next step is to ensure treatment appropriately. Most patients who have mild and moderate disease are placed on prophylaxis with replacement factor product. The frequency of a replacement will depend on the need of the patient. Previously, our aim was to keep factor levels above 1% to prevent spontaneous bleeding because it has been determined through studies that if you can maintain a level above 1%, you can prevent spontaneous joint bleeding.

But now, patients expect that they should be able to participate in and expect a better quality of life, which means we have to ensure levels that are not necessarily just aimed at preventing spontaneous bleeding but also aimed at preventing activity-related bleeding. Depending on the needs of the patient, we have to increase the frequency of factor administration, which typically is about 2 to 3 times a week depending on whether you have a deficiency of factor VIII or factor IX. In addition to replacing factor, it’s also important for us to ensure that there’s no breakthrough bleeding. We monitor for breakthrough bleeding and reassess our treatment plan to ensure that there isn’t excessive breakthrough bleeding. Monitoring for inhibitor formation should be part of our treatment plan in these patients.

The primary driver for choosing a therapeutic regimen is the factor activity level. The more severe the deficiency, the greater frequency at which I would administer the replacement. Patients with severe and moderate hemophilia, as I mentioned before, would probably have factor replacement that is targeted to be given 2 to 3 times a week to prevent spontaneous bleeding.

In the developed world, in this day and age, the aim is also to cater to the quality of life of our patients and ensure normalization of their life. In this situation, we would want them to participate in sports, play activities, and go to gym class in school, in which case I need to ensure that their factor levels are appropriate at times when it’s most needed.

Many of these patients may choose to have a plan where they administer factor prior to every sports-related activity. If they play basketball 3 times a week, they’re treated 3 times a week. And if there’s an additional game over the weekend, they would get an additional dose prior to that event. Our treatment plan is truly catered to patients’ needs. It’s very difficult to identify a proper treatment plan. It is individualized to the needs of the patient.

The major complication related to treatment of patients with hemophilia with replacement product is the development of inhibitors. Inhibitors are antibodies that develop to the protein that is being replaced, and the development of inhibitors is associated with excessive bleeding and major morbidity and mortality. Looking at this as a complication related to treatment, one of the things that I have to do is monitor for the development of inhibitors.

We know that the inhibitor risk is highest in the first 100 days of treatment, or the first 30 exposures, usually. That is for severe hemophilia A. The incidence of inhibitor development for severe hemophilia A is about 30%, whereas for hemophilia B, it’s a lower incidence somewhere between 1% and 5%. However, both of these patient populations have to be monitored for the development of inhibitors.

Periodically, we monitor patients who are on replacement therapy—every 3 to 4 doses—and check for the development of inhibitors. If development is noted, then we have to stop the replacement of factor and consider alternative therapies in these patients.

Transcript edited for clarity.