The hemostatic balance is a fine balance between too much clotting (thrombosis) and not enough clotting (bleeding). In hemophilia, an essential clotting factor is lacking, and the hemostatic balance is tipped toward too much bleeding. The goal of non-factor replacement products is to prevent bleeds by raising hemostatic potential (how likely the blood is to clot if a blood vessel is injured), rather than by raising factor levels.
Figure adapted, with permission, from Novel approaches to haemophilia therapy: successes and challenges. Arruda VR, Doshi BS, and Samelson-Jones BJ, Blood 2017;130(21):2251-2256.
The goal of non-factor replacement products is different to the goal of gene therapy, which attempts to achieve stable factor levels by getting the body to produce the clotting factor that is missing. Ideally, non-factor replacement therapies are administered at a dose that gives rise to a very stable hemostatic level (to prevent bleeds), even though it does not involve a change in factor level.
The non-factor replacement product, emicizumab, has been approved for people with hemophilia A with and without inhibitors, and other products in this class are currently in clinical trials for similar indications. The treatment of people with hemophilia and inhibitors has been the greatest unmet need in hemophilia treatment products, with bypassing agents constituting the mainstay of this treatment. This new class of products that rebalance hemostasis in people with inhibitors provides a promising alternative. While emicizumab is the only non-factor replacement product that has been approved at this time, others currently in clinical trials include anti-TFPI antibodies and fitusiran, a small inhibitory RNA that can block anti-thrombin.
Factor VIII substitution therapy
Factor VIII substitution therapy is a type of non-factor replacement hemophilia product that takes the place of factor VIII in the series of reactions that leads to clotting (coagulation cascade). Emicizumab is a bispecific monoclonal antibody, which means it has been manufactured in a laboratory and designed to recognise and bind to 2 different targets.
Emicizumab is a bispecific antibody that binds to activated factor IX (FIXa) on one arm and to factor X (FX) on the other arm. By doing so it carries out the natural function of activated factor VIII (FVIIIa, missing or defective in hemophilia A) that is needed for effective clotting. Since it does not replace the function of missing factor IX it cannot be used to treat hemophilia B.
Factor VIII substitution therapy with emicizumab is the first non-factor replacement product to be approved in a number of countries for the prophylactic treatment of people of all ages with hemophilia A with or without inhibitors. Some countries have not approved the use of emicizumab while other countries have not approved this entire indication. Consult your local regulatory agency for the latest details in your region.
Although emicizumab is highly effective at preventing bleeds, it cannot be used to treat bleeds. Healthcare professionals experienced in the treatment of hemophilia must determine the appropriate dosing of agents, such as bypassing agents and factor VIII, to treat different kinds of bleeds in someone who is taking emicizumab. People with hemophilia should carefully follow the urgent action plan they establish with their hemophilia specialist to treat breakthrough bleeds. A few people using specific combinations of high doses of activated prothrombin complex concentrates (aPCCs) and emicizumab have experienced serious and potentially life-threatening side effects including thrombotic microangiopathy and thromboembolism. Hemophilia specialists should avoid using aPCCs and emicizumab at the same time unless no other treatment options, such as factor VIIa, are available.
Emicizumab interferes with certain laboratory tests that measure how well a person’s blood clots, leading to false readings. Before undergoing laboratory tests that measure blood clotting, people with hemophilia should inform any healthcare professionals that they are taking emicizumab. It is important for them to know so that they do not misinterpret the results of the tests, which could affect management decisions.
To learn more about the specific tests that are impacted, please consult the Non-factor Replacement Hemophilia Therapies eLearning module.
Releasing the brakes on hemostasis
The body has several processes in place to prevent coagulation running longer than necessary or starting when it should not, to avoid too much blood clotting. One of these mechanisms includes natural anticoagulants that act as brakes to limit clotting.
Research is ongoing into innovative non-factor replacement products that target a number of natural anticoagulants, including antithrombin (AT) and tissue factor pathway inhibitor (TFPI), and release the brakes on hemostasis, which could tip the balance back towards more clotting. Research is exploring the impact of reducing or blocking these, and other, anticoagulants to restore hemostatic balance.
Removing the brakes on coagulation, by using non-factor replacement products that block or remove anticoagulants, has shown potential for rebalancing hemostasis in hemophilia without replacing the missing clotting factor.
Impact on people with hemophilia
The potential of non-factor replacement products is to rebalance hemostasis, in people with hemophilia A or B, without the need for infusions of clotting factor concentrates (CFCs). While non-factor replacement products reduce the severity of hemophilia, these products do not provide a cure and occasional on-demand treatment for breakthrough bleeds may be required.
People with hemophilia who are taking a non-factor replacement product should:
- Work closely with their primary hematologist or hemophilia specialist to develop an urgent action plan that describes what to do in the event of a breakthrough bleed or in anticipation of a medical procedure or surgery
- Update their emergency medical information to state the type of hemophilia they have, whether they have inhibitors, the non-factor replacement product they are taking, and that these products interfere with certain laboratory tests that measure how well blood clots, leading to false results
- Educate other healthcare providers, close friends, and family about the differences between factor and non-factor replacement products, and how these differences impact the management of their hemophilia, particularly emergency care
Non-factor replacement hemophilia therapies are used strictly prophylactically to prevent bleeds, making them fundamentally different from clotting factor concentrates (CFCs) that can also be used to treat a suspected bleed. The “if in doubt, treat” approach must not be applied to these products. The products are administered subcutaneously and may not act quickly enough to promote blood clotting, and the efficacy and safety of taking high doses of these products is unknown. They are not to be administered intravenously. Combining them with different products that promote coagulation may, in some cases, even tip the balance in their body too far towards more clotting (thrombosis).
Non-factor replacement products are very new hemophilia treatment options and their full safety profile is not yet known. They do not have decades of safety history like factor replacement products and it will be important to continue to gather information about potential safety issues as non-factor replacement products gain widespread use. Only one non-factor replacement product has been approved for use in people with hemophilia A, emicizumab. Others are in clinical trials.
Updated August 2020