Haemophilia is an X-linked genetic disorder characterised by a deficiency or absence of coagulation factors VIII or IX, resulting in a life-long bleeding disorder.1–7 Haemophilia is also called the ‘Royal disease’ because Queen Victoria was a carrier of haemophilia and her descendants spread the disease among Royal houses throughout Europe.1
Types of haemophilia
The most common types of haemophilia are:
- Haemophilia A, or classic haemophilia, caused by a lack or shortage of coagulation factor VIII (FVIII) (affects 1 in 5000 live male births)1–5
- Haemophilia B, or Christmas disease, caused by a lack or shortage of coagulation factor IX (FIX) (affects 1 in 30,000 live male births).1,3–5
There is currently no cure for haemophilia. Goals of treatment are prevention, early recognition of bleeding disorders and appropriate intervention to prevent complications.1–7
Prophylactic therapy involves regular infusion of factor concentrates (often two to three-times per week) to increase the factor level to a moderate range (> 1%) to prevent spontaneous bleeding or bleeding after minor injury. It is highly effective in reducing bleeding and long-term complications of bleeding (for example, chronic arthropathy). Prophylaxisis recommended for children with severe haemophilia. Prophylaxis can be primary or secondary.
- Primary prophylaxis is usually started in young children to reduce or prevent joint disease and is continued indefinitely
- Secondary prophylaxis is usually short term and is started when a bleed has occurred and continued on a regular schedule for a defined period of time.
Advantages of prophylaxis include reduced risk of joint damage, ability to participate in sports and other physical activities, reduced risk of spontaneous bleeding, reduced hospitalisations and reduced absenteeism from school or work. Disadvantages include the frequency of injections and the cost.
Prophylactic administration of factors to prevent bleeding in patients with severe haemophilia has been recommended as standard of care by the Medical and Scientific Advisory Council (MASAC) of the National Haemophilia Foundation, the World Federation of Haemophilia, and the World Health Organization.8–10
Treatment on an ‘as needed basis’ (episodic) is considered conventional therapy for patients with mild to moderate haemophilia. The factor is injected after an injury has occurred. Advantages (fewer injections, lower cost) and disadvantages (increased risk of joint damage and spontaneous bleedings) need to be outlined when determining the best treatment for an individual.
The preferred treatment for bleeding in haemophilia focuses on replacing the deficient coagulation factor (replacement therapy) with coagulation factor concentrates. The missing factor protein is injected, which makes the factor immediately available in the bloodstream, thereby enabling activation to continue the clotting cascade and stop the bleeding.1–6
Plasma-derived products and recombinant factor concentrates are used in treatment. Plasma-derived products have been available for many years, but viral safety concerns have led to subsequent development of recombinant factors. The products differ in their composition, purity, and potential contaminants.5 The plasma-derived products are stratified based on ‘purity’, whereas recombinant factor concentrates are characterised by ‘generation’.
These are factor concentrates obtained from carefully screened donated blood plasma. During manufacturing processes, the proteins are extracted from the plasma through a series of extensive sterilisation procedures to eliminate viruses and other contaminants. Nowadays, plasma-derived products have been shown to be as safe as recombinant products for known transmittable pathogens.
- Plasma-derived factor VIII products include Hemofil-M® (Shire), Monoclate-P® (CSL Behring), and Koate DVI® (Kedrion Biopharma); these are monoclonal antibody-purified (ultrahigh purity). Haemate P® (CSL Behring) is an intermediate purity product that contains factor VIII and von Willebrand factor and is mainly used for the treatment of von Willebrand disease.
- Plasma-derivedfactor IX productsincludeAlphaNine® (Grifols) and Mononine® (CSL Behring).
Recombinant factor concentrates
These are ultra-pure products derived from animal or human cell lines that have been transvected with a human factor gene. Although these cell lines are considered to be free of viruses, the concentrates are subjected to viral clearance and inactivation steps to ensure safety and purity.Some factor concentrates are stabilised using human albumin, while others are stabilised using sucrose.
Different generations of products are available, reflecting the species of cell line (animal/human) in which they are produced and the addition of or exposure to human and/or animal protein in the final product.5 In principle, the human cell line could make the protein more similar to endogenous factor VIII.
Factor VIII products
- First generation:products produced in cellculture supernatant of transfected animal cell lines. Albumin was used as a stabiliser (theoretical risk of viral exposure)
- Second generation: products produced in cell culture supernatant of transfected animal cell lines (no albumin in final preparation). For example, Kogenate (Bayer), ReFacto® (Pfizer).
- Third generation:products are produced in animal cell lines without added human/animal protein. For example, Advate® (Baxter), Kovaltry® (Bayer), Novoeight® (Novo Nordisk), Xyntha®/ReFacto AF® (Pfizer).
- Fourth generation:products produced in human cell lines without added human/animal protein. For example, Elocta® (Sobi/Biogen), Nuwiq® (Octapharma)
Factor IX products
Recombinant human factor IX is genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line (for example, BeneFIX® (Pfizer), Ixinity® (Aptevo), Rixubis® (Baxalta)). All have been demonstrated to be safe and effective in the treatment.
An overview of products is available on the website of the Medical and Scientific Advisory Council (MASAC) of the National Haemophilia Foundation (NHF) (www.haemophilia.org).
Alternative therapy includes desmopressin, used to manage minor bleeding in patients with mild haemophilia A. Desmopressin can be administered intravenously or intranasally. For mucocutaneous bleeding in haemophilia A and B, tranexamic acid is effective.
Longer lasting recombinant factors
To prolong exogenous factor half-life, different strategies are emploted, including sustained delivery mechanisms, chemical modification to decrease clearance (for example, conjugation with a hydrophilic polymer such as polyethylene glycol (PEG) or PEGylated liposomes to encapsulate the drug), formation of inactivation-resistant fusion proteins, and manufactured genetic mutations that decrease exogenous factor metabolism by preventing spontaneous dissociation.11
Increasing the half-life allows alonger dosing interval, thereby enhancing the ease of administration for some patients, reducing the cost of factor concentrates and reducing immunogenicity of the products.
Factor VIII products
Factor VIII-Fc fusion
- Recombinant product composed of FVIII fused with a human immunoglobulin Fc domain12
- Binds to neonatal Fc receptor, hence protecting the factor from degradation. Half-life is extended 1.5–1.7-fold
- Example: Elocta® (Sobi/Biogen)
- Recombinant product composed of FVIII covalently fused to one or more (PEG) molecules
- PEG molecules extend the half-life 1.4–1.5-fold
- Example: Adynovate® (Shire)
Factor IX products
Recombinant factor IX-Fc fusion
- Recombinant product composed of FIX fused with a human immunoglobulin Fc domain
- Binds to the neonatal Fc receptor hence protecting rFIX-Fc from degradation, extending the half-life 3–5-fold compared with unmodified factor IX (for example, half-life of 54–90 hours, compared with 18 hours for native factor IX)12
- Example: Alprolix®(Sobi/Biogen)
Recombinant factor IX–albumin fusion
- Recombinant FIX product comprising factor IX gene fused to gene for albumin via a cleavable linker sequence. The linker is cleaved upon factor IX activation, releasing activated factor IX13
- Half-life is approximately 102 hours (approximately 5.6-fold prolongation)
- Potential for higher trough levels, which may provide increased protection
- Example: Idelvion® (CSL Behring)
Glyco-PEGylated recombinant factor IX
- Recombinant FIX product composed of FIX with PEG to activation sequence of the FIX protein
- PEG moiety is removed during factor IX activation
- Half-life of this product is approximately 93 hours (approximately five-fold prolongation)
- Products are under investigation.11,14
Prophylatic treatments under development
In addition to available products, a number of approaches are under investigation, including subcutaneous therapy, which would avoid the need for intravenous access of central venous catheter placement, and also the use of antibodies.
Emicizumab is arecombinant antibody that binds to factors IXa and X simultaneously, bringing these two molecules together and essentially substituting for the role of factor VIIIa as a cofactor for factor IXa in activating factor X, with a long half-life of 4-5 weeks in healthy volunteers. Data from a phase II study were recently published.5,11,15,16
Concizumab is a monoclonal antibody directed against tissue factor pathway inhibitor, which inhibits the coagulation cascade by blocking the function of factor Xa and the activity of the tissue factor–factor VIIa complex. Concizumab can be administered subcutaneously or intravenously.5,15
Other approaches includegene therapy,which can lead to endogenous production of the deficient coagulation factor without the need for regular infusions of factor or other products, and cellular therapy, whichinvolves the introduction of intact cells into the patient rather than manipulation of coagulation factor genes.
Coagulation factors are generally well-tolerated. Side-effects vary by products and include headache, pruritus, skin rash, nausea, vomiting, catheter infection, arthralgia and hypersensitivity reactions. Factor replacement therapy can be complicated by transfusion-related infections, inhibitor development and occasionally thrombotic events. A complete overview of adverse reactions is available from the individual Summaries of Product Characteristics.
The most feared and challenging complication of coagulation factors is the formation of inhibiting antibodies (inhibitors) against exogenously administered FVIII or FIX. Between 20% and 30% of patients with severe haemophilia A and 2–5% of patients with haemophilia B develop inhibitors against infused products.
Patients may develop antibodies when the immune system identifies the infused coagulation factor as a foreign protein. When inhibitors are formed directed against active parts of the FVIII or FIX protein, the clotting factor is inactivated and unable to effectively perform stopping bleeding. Inhibitors do not affect the location, frequency, or severity of bleeds, but they do make them more difficult to control.In addition, it is not easy to eradicate them. They usually occur within the first 50 days of exposure to treatment.1–7,16
Patients developing inhibitors are usually described as high responders or low responders.
In high responders, the amount of inhibitor in the blood increases quickly after the factor is administered and treatment with standard clotting factor is difficult. For this group of patients, a valuable treatment option is the use of a bypassing agent. These agents bypass the inhibitor instead of replacing the missing factor VIII or IX. They contain an activated form of a downstream clotting factor in the coagulation cascade. Activated factor VII (factor VIIa) can directly activate factor X, bypassing the need for factors VIII and IX.1,5,6
Available products are recombinant activated factor VII (NovoSeven®, NovoSeven RT®; NovoNordisk) and activated prothrombin complex concentrates such as FEIBA® (Factor Eight Inhibitor Bypassing Agent; Baxalta).
Another option is immune tolerance induction (ITI) by which large amounts of clotting factor are given every day for many weeks or months. ITI therapy requires specialised medical expertise, is costly, and may take a long time to work.
Low respondersare patients for whom the amount of inhibitor does not increase after factor is administered. They are usually able to use standard clotting factor treatment and may need to receive higher doses than standard doses or repeated doses.
Data suggest that recombinant FVIII factor products might be more immunogenic than plasma-derived products. However, no consensus has been reached so far.17
A large number of replacement factors, including plasma-derived proteins, recombinant proteins, and recombinant proteins with modifications to extend the half-life are now available. New molecules and approaches are under development to enhance the treatment and the quality of life of patients with haemophilia.
1.National Haemophilia Foundation. www.hemophilia.org/. (accessed July 2017).
2.Konkle BAet al (eds). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2000 Sep 21 [updated 2017 Jun 22].
3.Konkle BAet al (eds). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2000 Oct 2 [updated 2017 Jun 15].
4. Coppola A et al. Treatment of haemophilia: a review of current advances and ongoing issues. J Blood Med 2010;1:183–95.
5. Hoots K, Shapiro A. Haemophilia A and B: Routine management including prophylaxis.In: UpToDate, UpToDate, Waltham, MA, 2017. www.uptodate.com/home/index.html. (accessed July, 2017).
6. Hoots K, Shapiro A. Treatment of bleeding and perioperative management in hemophilia A and B Treatment of bleeding and perioperative management in hemophilia A and B Treatment of bleeding and perioperative management in hemophilia A and B Treatment of bleeding and perioperative management in hemophilia A and BTreatment of bleeding and perioperative management in haemophilia A and B. In: UpToDate, UpToDate, Waltham, MA, 2017. www.uptodate.com/home/index.html. (accessed July 2017).
7. Branchford B, Monahan P, Di Paola J. New developments in the treatment of pediatric haemophilia and bleeding disorders. Curr Opin Pediatr 2013;25:23–30.
8. Medical and Scientific Advisory Council (MASAC) of the National Haemophilia Foundation. www.haemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scienti… (accessed July, 2017).
9. World Federation of Haemophilia (WFH) 2012 guideline. https://www1.wfh.org/publication/files/pdf-1472.pdf (accessed July 2017).
10. World Health Organization. www.who.int/en/ (accessed July 2017).
11. Morfini M. A new era in the haemophilia treatment: Lights and shadows! J Hematol Transfus 2016;4(3):1051.
12. Mancuso ME, Mannucci PM. Fc-fusion technology and recombinant FVIII and FIX in the management of the haemophilias. Drug Des Devel Ther 2014;8:365–71.
13. Lyseng-Williamson KA. Coagulation factor IX (recombinant), albumin fusion protein (Albutrepenonacog Alfa; Idelvion®): A review of its use in haemophilia B.Drugs 2017;77(1):97–106.
14. Tiede A et al. Pharmacokinetics of a novel extended half-life glycoPEGylated factor IX, nonacog beta pegol (N9-GP) in previously treated patients with haemophilia B: results from two phase 3 clinical trials. Haemophilia 2017;23(4):547–55.
15. https://clinicaltrials.gov/. (accessed July 2017).
16. Oldenburg J et al. Emicizumabprophylaxis in haemophilia A with inhibitors. N Engl J Med 2017; Jul 10. www.nejm.org/doi/full/10.1056/NEJMoa1703068#t=article(accessed August 2017).
17. Lai J et al. Biological considerations of plasma-derived and recombinant factor VIII immunogenicity. Blood 2017;129(24):3147–54.