The Risk of Factor VIII Inhibitors in Hemophilia A Treatment

Approximately 30% of patients with severe hemophilia who have treated with factor replacement therapies develop inhibitors, compared to about 5% of patients with mild to moderate hemophilia. Both previously treated patients and those newly exposed to factor replacement therapies are at risk of inhibitor development.

When treating patients with hemophilia A, it’s important to understand the causes and risk factors for inhibitors, as well as current diagnostic methods and treatment strategies.

Understanding FVIII Inhibitor Formation 

When people with severe hemophilia A are given FVIII replacement therapy, their immune system may see the introduced protein as foreign and in response, develop neutralizing alloantibodies, or “inhibitors,” against it. These inhibitors can block FVIII’s participation in the clotting process, making the replacement therapy ineffective.

Because inhibitors retain the ability to recognize FVIII, they can swiftly reactivate the immune response during future treatments.

While inhibitors do not affect the frequency, severity, or location of bleeds, they do make it challenging to control bleeding episodes. Inhibitors can reduce both how a patient responds to an infusion (factor recovery) and how quickly the factor degrades (factor half-life).

Detecting Inhibitors in Patients 

While inhibitors mostly develop during childhood or in a patient’s first 20 or 50 exposure days to FVIII, they can develop at any time. Not all patients, especially those with low-titer inhibitors, will show symptoms of reduced treatment efficacy. Recent research found that in some patients over 40 years old, an inhibitor was only detected after over 150 exposures.

Inhibitors may be suspected when patients experience frequent bleeds despite prophylactic care, do not seem to respond well to factor replacement therapy, or have bleeds that take longer to resolve. It is preferable to detect inhibitors via a diagnostic blood test before a patient shows poor response to treatment, particularly if they are at high risk of developing inhibitors.

Risk Factors of FVIII Inhibitors in Hemophilia A Treatment 

The exact reason why some patients with hemophilia A develop inhibitors and others don’t remains unclear, but multiple genetic and environmental risk factors have been identified.

Genetic Risk Factors of Inhibitor Formation 

Genetic factors associated with inhibitor development include ethnicity, a family history of inhibitors, and certain gene mutations.

Ethnicity: Hemophilia patients of Latin American or African descent have a higher risk of developing an inhibitor. In a case-control study of almost 1000 hemophilia A patients spread across 16 treatment centers in the United States, 25% of African Americans in the study were found to have inhibitors in comparison to 3.5% of non-African Americans.

Family history: A known family history of inhibitors is one of the strongest independent risk factors among previously untreated hemophilia patients developing inhibitors after FVIII treatment.

Type of gene mutation: Hemophilia A has a very high percentage of gross genetic abnormalities, with large insertions and/or deletions, as well as complex rearrangements seen in about 50% of severe cases. Large genetic changes can result in null alleles, mutations that result in a complete lack of FVIII protein production. This absence prevents the immune system from recognizing and tolerating FVIII, which increases the risk of inhibitor development.

Environmental Risk Factors of Inhibitor Formation 

The Diagnosis of FVIII Inhibitors 

The Centers for Disease Control and Prevention (CDC) recommends that all patients with hemophilia are tested for inhibitors at least once a year.

The National Bleeding Disorders Foundation’s Medical and Scientific Advisory Council (MASAC) further recommends that inhibitor testing is carried out before elective surgery, if a response to a FVIII therapy is inadequate, before and after a change in factor products, and 2 to 3 weeks following an intensive treatment. They also outline an ongoing schedule of inhibitor testing for those with severe hemophilia A exposed to FVIII, starting with at least every third exposure day (ED) until 20 ED have been reached, followed by every 3 to 6 months until 150 ED.

The Bethesda and Nijmegen-Bethesda Assays

The amount of FVIII inhibitors (inhibitor titer) in patient plasma are measured by the Bethesda assay blood test and its modified version, the Nijmegen-Bethesda assay. False positives are possible with these tests, so a second test is sometimes needed for an accurate diagnosis of inhibitors.

A Nijmegen-Bethesda Unit (NBU) or Bethesda Unit (BU) quantifies the amount of inhibitor required to neutralize 50% of a single unit of factor during the given incubation period. Test results of more than 5 NBU/BU indicate a high-titer inhibitor and results of less than 5 units are considered low-titer.

Treatment Challenges for Hemophilia Patients With Inhibitors 

Low-titer blood test results of less than 5 BU indicate a low immune response against factor, allowing continued use of FVIII therapies at higher or more frequent doses to overcome inhibitors and promote hemostasis.

However, high-titer results of more than 5 BU prevent the safe administration of FVIII therapies in sufficient quantities to overcome neutralizing activity, meaning these patients require alternative treatment approaches.

Treatment Strategies for Patients With Inhibitors 

Treatment strategies used to manage hemophilia A with FVIII inhibitors include bypassing agents and non-factor therapies.

Bypassing Agents

Instead of replacing the deficient factor, bypassing agents circumvent the inhibited factors, enabling the formation of a normal clot. The 2 types of bypassing agents available are recombinant FVIIa (rFVIIa) and plasma-derived activated prothrombin complex concentrates (aPCC). The latter are virally inactivated, containing inactive precursors of clotting proteins and their activated forms.

Both of these bypassing agents can be used for prophylaxis during major and minor surgery and have been shown to be an effective treatment for 90% of musculoskeletal bleeds.

Non-Factor Therapies 

FVIII mimetics are bispecific monoclonal antibodies that are designed to mimic the function of FVIII in the blood-clotting process. They work by bringing together factor IXa (FIXa) and factor X (FX), leading to the activation of FX, which then allows the coagulation cascade to continue toward the production of a clot. In contrast to factor replacement therapies that are given intravenously, factor mimetics can be administered via a subcutaneous injection.

One disadvantage of non-factor therapies is that they can only be used to prevent bleeding episodes. For perioperative management or acute breakthrough bleeds, another form of treatment is required.

Conclusion 

By understanding the risks and underlying mechanisms of FVIII inhibitors and creating a personalized treatment plan from available treatment options, the challenge that inhibitors present for hemophilia A patients can be mitigated.