"Inhibitor" is the term used to refer to alloantibodies to factor (F) VIII or FIX that may develop in patients with haemophilia A (HA) or B (HB) following exposure to the deficient coagulation factor (FVIII or FIX), which are recognised by the immune system as ‘non-self’. Sources may include plasma, cryoprecipitate and plasma-derived or recombinant FVIII/FIX concentrates. Inhibitors to FVIII and FIX are binding immunoglobulins (Ig), usually IgG, which may partially or completely neutralise the clotting activity of factor concentrates and render standard replacement therapy partially or completely ineffective.1 The immunological mechanisms regulating inhibitor development have not been fully elucidated.
There is a large range (4–52%) in the cumulative incidence of inhibitors in patients with haemophilia.1 Inhibitors develop in 20–30% of patients with severe HA and 5–10% of patients with mild or moderate HA.1 However, the reported prevalence of inhibitors is between 5–7%.1 This variation between prevalence and incidence of inhibitors is likely related to the occurrence of transient inhibitors or successful inhibitor eradication with immune tolerance induction therapy.1 There is a lower incidence of inhibitors in patients with HB than for HA (1.5–3%),2 however there is a higher risk of anaphylactic reactions for patients with HB at the time of inhibitor development.3,4
Patients with a severe FVIII or FIX deficiency (FVIII or FIX levels <0.01 IU/mL) are most likely to develop an inhibitor due to previous non-exposure to the endogenous protein.3 Other potential risk factors for inhibitor development have also been identified.5 Patient-related risk factors include severity of haemophilia, family history of inhibitor development, presence of immune-response gene polymorphisms, specific F8 or F9 gene mutations and ethnicity.5 The risk of inhibitor development is significantly higher for siblings and in families with a previous history of inhibitors.6 Gene mutation studies have identified large deletions, missense, nonsense, frameshift and splice mutations in F8 and F9 that are associated with the development of inhibitors.7,8 Patients of Hispanic or African descent are more likely to develop inhibitors, possibly due to the presence of immune haplotypes in this population that differ from the haplotypes corresponding to proteins currently included in recombinant FVIII products.9,10
Treatment-related risk factors that have been described include the number of exposure days (EDs), the intensity of treatment, age at first exposure, type of therapeutic agent used (i.e., plasma-derived or recombinant), the current infection or inflammatory state of the patient and simultaneous vaccination administration with factor replacement therapy.5 The potential influence of the type of therapeutic product (recombinant vs plasma-derived ± von Willebrand factor), constitutes an ongoing debate issue, with non-conclusive results currently available11. Many inhibitors develop after 9–12 EDs and often within 50 EDs, and therefore frequent testing is recommended during those time periods.1,12
The presence of inhibitors should be suspected when a patient fails to respond to FVIII or FIX replacement therapy. Thorough testing is then required to confirm the presence and type (low or high response) of inhibitors, followed by regular monitoring to confirm transience and increasing or decreasing titres.
In patients with HA or HB, the presence of an inhibitor significantly worsens the prognosis and complicates treatment, especially in patients with high-titre inhibitors.13 Patients with mild or moderate HA or HB can also develop inhibitors, which may result in a more severe phenotype as the residual endogenous activity is neutralised by the inhibitor.3 Patients with inhibitors do not appear to have a greater tendency to bleed than untreated patients with severe haemophilia, and a correlation between bleeding severity and the presence of inhibitors has not been reported; however, patients with an inhibitor are more difficult to treat, since traditional factor replacement therapy is partially or completely ineffective. The development of inhibitors therefore complicates treatment and a reliable control of bleeding episodes, in addition to preventing joint disease in these patients, is challenging.13
The development of bypassing agents has greatly improved the treatment of haemophilia patients with inhibitors, ensuring the on-demand treatment of bleeding episodes when they occur. In countries in which patients have access to prophylactic FVIII/FIX replacement therapy, patients with HA or HB with inhibitors have worse outcomes, with a higher burden of orthopaedic complications and a lower quality of life compared to patients without inhibitors.14
1. Astermark J. Overview of inhibitors. Semin Hematol 2006;43:S3-7.
2. DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol 2007;138:305-15.
3. World Federaton of Hemophilia (WFH): Report on the Annual Global Survey 2015; 2016.
4. Warrier I, Lusher JM. Development of anaphylactic shock in haemophilia B patients with inhibitors. Blood Coagul Fibrinolysis 1998;9 Suppl 1:S125-8.
5. Peyvandi F, Ettingshausen CE, Goudemand J, Jimenez-Yuste V, Santagostino E, Makris M. New findings on inhibitor development: from registries to clinical studies. Haemophilia 2017;23 Suppl 1:4-13.
6. Astermark J, Berntorp E, White GC, Kroner BL, Group MS. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia 2001;7:267-72.
7. Payne AB, Miller CH, Kelly FM, Michael Soucie J, Craig Hooper W. The CDC Hemophilia A Mutation Project (CHAMP) mutation list: a new online resource. Hum Mutat 2013;34:E2382-91.
8. Li T, Miller CH, Payne AB, Craig Hooper W. The CDC Hemophilia B mutation project mutation list: a new online resource. Mol Genet Genomic Med 2013;1:238-45.
9. Carpenter SL, Michael Soucie J, Sterner S, Presley R, Hemophilia Treatment Center Network I. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database. Haemophilia 2012;18:e260-5.
10. Viel KR, Ameri A, Abshire TC, et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 2009;360:1618-27.
11. Peyvandi F, Mannucci PM, Garagiola I et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med 2016;374(21):2054-64.
12. World Federation of Hemophilia (WFH): Guidelines for the Management of Hemophilia; 2012.
13. Blanchette VS, Manco-Johnson MJ. Meeting unmet needs in inhibitor patients. Haemophilia 2010;16 Suppl 3:46-51.
14. Morfini M, Haya S, Tagariello G, et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007;13:606-12.