People with inhibitors are more difficult to manage and treat than people without inhibitors. There are a number of different approaches. Decisions regarding treatment should take into account the person’s inhibitor titer and anamnestic response, the site and severity of the bleed, and whether he/she has started or is planning to start immune tolerance induction therapy. Ideally, a person with inhibitors should be treated at a hemophilia treatment centre with specialized expertise.
High-dose factor concentrates
Administering factor concentrates at higher doses and/or more frequent intervals is the preferred treatment for acute bleeding in low responders. The person’s factor level should be measured right after each infusion to make sure that target levels are reached. Continuous infusion may be useful. High-dose factor concentrate is also the preferred treatment option for acute bleeding in previous high responders with current low titer inhibitors; however, it is vital to take into account that the anamnestic response will get stronger within five to seven days, at which time treatment should be switched to bypassing agents.
Bypassing agents, such as activated prothrombin complex concentrates (APCC) and recombinant factor VIIa (rFVIIa), are used to treat acute bleeding in people with high titer inhibitors. However, these treatment products are expensive and not always available in every country.
The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted marketing authorisation for Hemlibra® (emicizumab), a first-in-class medicine to prevent bleeding or reduce the frequency of bleeding episodes in patients with hemophilia A with factor VIII inhibitors, both children and adults. It is not currently approved for use in people with hemophilia without inhibitors.
Emicizumab is a monoclonal antibody. It works by mimicking the coagulation function of factor VIII rather than replacing it. The treatment is given weekly via a subcutaneous (under the skin) injection. Prophylaxis with emicizumab is not factor replacement therapy, therefore its effectiveness cannot be measured by looking at FVIII levels.
Before starting using emicizumab it is very important to talk to your doctor about using “bypassing agents” (medicines that help blood clot but which work in a different way from FVIII). This is because treatment with bypassing agents may need to change while receiving emicizumab. Monitoring for the development of thrombotic microangiopathy (TMA) and thrombotic events (blood clots in small blood vessels) is recommended if APCC is administered while taking emicizumab. Cases of TMA and thrombotic events have been reported when on average a cumulative amount of >100 U/kg/24 hours of APCCs was administered for 24 hours or more to patients receiving emicizumab. APCCs should be discontinued and emicizumab prophylaxis suspended if symptoms occur.
Tranexamic acid is an antifibrinolytic drug that can be given as an additional therapy in pill form or by injection to help stop blood clots from breaking down. It is particularly useful for bleeding that involves mucous membranes such as those in the nose or mouth. However, it should not be used in combination with APCCs.
Epsilon aminocaproic acid (AMICAR™)
Epsilon aminocaproic acid is an antifibrinolytic drug that can be given as an additional therapy in pill form or by injection to help hold clots in place in certain parts of the body, such as the mouth, bladder, and uterus.
Plasmapheresis is a procedure that removes inhibitors from the person’s bloodstream. It is usually done when the inhibitor titer needs to be brought down quickly (for example, before major surgery or in cases of severe bleeding that are not well controlled with bypassing agents).
Immune tolerance induction therapy
Immune tolerance induction (ITI) therapy involves giving the person with inhibitors frequent doses of factor concentrates over several months, or sometimes years, to train the body to recognize the treatment product without reacting to it. This process is called tolerance induction. If a person plans to undergo ITI therapy, but has not yet started, it is better not to use factor products to treat acute bleeding episodes because they are likely to provoke a rise in inhibitor titer.
Content developed by the WFH Inhibitors Working Group
Updated March 2018