Strategies for the drug treatment of haemophilia and VWD depend on the risk of bleeding.
- For haemophilia, replacement FVIII is the treatment of choice for prophylaxis and acute treatment of bleeding
- Desmopressin may be preferred for patients with mild or moderate haemophilia A when FVIII can be raised to an appropriate therapeutic level; in such cases, this avoids the cost and risks a clotting factor. Desmopressin is of no value in the treatment of haemophilia B because it does not affect FIX levels
- Tranexamic acid is used adjunctively to manage skin and mucosal bleeding and during dental procedures
- For type 1 VWD, desmopressin is the treatment of choice
- For patients with type 3 VWD, and in patients with type 1 or 2 VWD in whom desmopressin fails or is contraindicated, replacement VWF/FVIII or VWF concentrate is the treatment of choice
There are two types of clotting factor products for replacement therapy:
- concentrates produced by fractionating human plasma
- recombinant clotting factors
Recombinant factors accounted for 89% of FVIII units and 83% of FIX units prescribed to treat people with haemophilia in the UK in 2014/15; plasma products accounted for almost all of the remainder [UKHCDO, 2015]. By contrast, virtually all factors used to treat VWD were derived from human plasma. Blood products are more widely used in countries unable to afford recombinant clotting factors.
Human plasma concentrates
Examples of human plasma concentrates are Human Coagulation Factor VIII, Dried (also known as Factor VIII Fraction, Dried) for the treatment of haemophilia A; and Factor IX Fraction, Dried for haemophilia B. It is worth noting that some FVIII products also contain VWF and not all of these are licensed for the treatment of VWD.
Brands containing FVIII and VWF include:
- Haemate P
- Octanate (FVIII only), Octanate LV
Of these, Optivate, Fanhdi, Octanate and Octante LV do not contain sufficient concentrations of VWF and are not licensed to treat VWD.
Brands of Factor IX Fraction include:
Products containing only VWF include:
These products all conform to pharmacopoeial standards for extraneous protein content and FVIII, FIX and VWF activity but variation in manufacturing processes mean they are not identical. They differ in the way the dose is prepared prior to administration and the recommended infusion rate. They also differ in the amount of protein they contain and this is a risk factor for hypersensitivity reactions; products with higher purity carry a lower risk but tend to be more expensive.
As with any product derived from human blood, viral contamination is a major concern. The risk is reduced by obtaining blood from screened donors and incorporating inactivation steps such as exposure to heat and/or detergent into the manufacturing process. Ultrafiltration may also be used to remove small viruses but is not currently considered effective in avoiding the risk of transmission.These approaches are effective for removing enveloped viruses such as human immunodeficiency virus, hepatitis B and C viruses and the non-enveloped hepatitis A virus but not parvovirus or prions. Parvovirus B19 poses a risk to pregnant women and people with immunodeficiency or increased erythropoiesis (for example, as associated with haemolytic anaemia). It is recommended that people who regularly treated with a plasma concentrate are vaccinated against hepatitis A and B [Watson et al, 2013]
During the 1970s and 1980s, the NHS used human plasma products contaminated with HIV and hepatitis C to treat people with haemophilia; 4,670 were infected and over 2,000 subsequently died [Colthart 2011] and it was some time before viral inactivation measures were developed.
Other blood products
Other preparations derived from blood that contain clotting factors are:
- fresh frozen plasma, or FFP (contains all factors)
- cryoprecipitate, which comprises solids obtained by slowly thawing FFP, is preferred to FFP; contains significant quantities of FVIII, VWF, fibrinogen and FXII, but not FIX or FXI
- FFP and cryoprecipitate do not undergo viral inactivation procedures
- cryo-poor plasma is the liquid that remains after removing cryoprecipitate; it contains other coagulation factors such as VII, IX, X, and XI.
- prothrombin complex concentrate contains Factors II, VII, IX and X
Recombinant clotting factors for the prophylaxis and treatment of bleeding in haemophilia A are manufactured using cultures of genetically engineered cells, usually stable lines of Chinese hamster ovary or kidney cells; simoctocog alfa is produced from cultures of human embryonic kidney cells. Recombinant factors have the advantages of a greatly reduced risk of viral contamination and less non-factor protein in the formulation. However, they do appear to reduce the risk of inhibitors that impair efficacy compared with blood products [Peyvandi et al, 2016].
The recombinant FVIII products currently available are:
- octocog alfa (Helixate NexGen, Advate, Kogenate)
- moroctocog alfa (ReFacto AF)
- simoctocog alfa (Nuwiq)
None of these is licensed to treat von Willebrand’s disease.
Two forms of recombinant FIX are available: nonacog alfa (BeneFIX) and nonacog gamma (Rixubis). These molecules are structurally and functionally similar and the products have the same licensed indication (treatment and prophylaxis of bleeding in haemophilia B in all age groups).
Recombinant factors represented a major step forward in safety compared with the blood products they have largely replaced (at least in the treatment of haemophilia) but they are eliminated from the body just as quickly as factors derived from blood products – that is, their elimination half-life is still about 12 – 15 hours (or less in children). For patients, this means the day-to-day impact of treatment is still dominated by the need for infusions every 2 – 3 days.
A new generation of agents with extended half-lives (EHL) is now on the horizon. In these products, the clotting factor is combined with another molecule – polyethylene glycol (PEG), albumin or a portion of IgG – to slow its removal from the body. The new products have half-lives that are 1.5 – 1.7 times longer for FVIII and 3 – 5 times longer for FIX [Laffan, 2016]. For people with haemophilia B, an EHL replacement factor offers the prospect of one dose every 1 – 2 weeks. The impact is more modest in haemophilia A, where the dose interval will probably rise by one day, though this could still benefit individuals who need very frequent doses.
The management of bleeding disorders is about to advance by another significant step with the advent of a new generation of agents that may avoid the risk of developing inhibitors. These agents use different strategies to correct abnormal clotting – examples include emicizumab, a once-weekly monoclonal antibody that mimics the function of FVIII [Shima et al, 2016], and fitusiran, which reduces antithrombin [Alnylam, 2016]. Gene therapy is now undergoing studies in animal models and could transform treatment if its potential is fulfilled; progress is currently better in haemophilia B than A [Peyvandi et al, 2013].
These products have the potential to transform the way patients access heath care and how health professionals deliver it. Accordingly, they are known as ‘disruptive technologies’.
Desmopressin is a synthetic analogue of the hormone vasopressin (but lacks its effect of raising blood pressure). It stimulates the release of FVIII and VWF but not FIX and is therefore not indicated for the treatment of haemophilia B.
Although widely known under the brand DDAVP, desmopressin is licensed for the treatment of haemophilia A and VWD only as the Octim brand of desmopressin acetate and is available as a nasal spray and an injection for subcutaneous or intravenous use. This is important because the other brands deliver a lower dose of desmopressin than is needed to treat bleeding disorders (10 per actuation rather than 150mcg). The effects of the nasal spray are less predictable than those of the injection.
The WFH states [Srivastava et al, 2013]:
- desmopressin may be the treatment of choice for patients with mild or moderate haemophilia A when FVIII can be raised to an appropriate therapeutic level because it avoids the expense and potential hazards of using a clotting factor concentrate
- is particularly useful in the treatment or prevention of bleeding in carriers of haemophilia
- the decision to use desmopressin must be based on both the baseline concentration of FVIII, the increment achieved, and the duration of treatment required.
The UKHCDO states [Laffan et al, 2014]:
- a trial of desmopressin should be carried out in patients with type 1, type 2A, 2M and 2N VWD
- when shown to be effective, desmopressin should be used in preference to blood-derived products where possible.
The adverse effects of desmopressin include flushing and hypotension; fluid intake should be adjusted to avoid fluid overload. It should be used with caution in young children and is contraindicated in children <2 years who are at particular risk of seizures secondary to cerebral oedema due to water retention. Desmopressin has been associated with thrombosis and should be used with caution in patients with or who are at risk of cardiovascular disease.
Tranexamic acid is an antifibrinolytic agent that inhibits the activation of plasminogen to plasmin and promotes clot stability. It is a useful adjunct in the management of bleeding disorders but regular use is not effective in reducing haemarthrosis. Applications include controlling bleeding from skin and mucosal surfaces (e.g. epistaxis, menorrhagia) and to control bleeding associated with eruption or shedding of teeth. A course of treatment lasts for 7 days.
Tranexamic acid should not be given to patients with FIX deficiency who are being treated with a prothrombin complex concentrate because this will exacerbate the risk of thromboembolism. If both agents are necessary, at least 12 hours should elapse between the last dose of the prothrombin complex and tranexamic acid.
Available commercially as tablets and an injection, tranexamic acid can also be prescribed as a mouthwash (as a ‘special’ order product). Adverse gastrointestinal effects may occur after oral use; rapid parenteral administration may cause hypotension and dizziness.
People with moderate haemophilia whose level of clotting factor is maintained above 0.01 IU/ml (1.0%) experience less bleeding and have better preserved joint function than those with lower levels. Prophylaxis – the regular administration of clotting factor with the aim of preventing (rather than treating) bleeding and joint damage – is ‘the goal of therapy to preserve musculoskeletal function’ [Srivastava et al, 2013].
Prophylaxis is strongly recommended for children and young people with haemophilia [WFH, 2013]. It is not routine for VWD, which in most cases is a mild bleeding disorder, but exceptions include patients with type 3 VWD plus haemarthroses, severe epistaxis, women with menorrhagia and individuals who also have ongoing risk factor for bleeding such as angiodysplasia [Laffan et al, 2014].
- Primary prophylaxis is the initiation of prophylaxis before the onset of joint disease – this means starting at age 1 – 2 years but it presents challenges with venous access
- Secondary prophylaxis is initiation after joint disease has developed.
Prophylaxis protocols vary widely, reflecting the absence of definitive evidence that one regimen is superior to others
- the protocol should be individualized according to age, venous access, bleeding phenotype, activity and availability of clotting factor concentrates
- regimens of 15 – 30 or 25 – 40 IU/kg 3 times per week for haemophilia A and twice weekly for haemophilia B are typical
- prophylaxis may begin weekly in young children and adjusted according to bleeding frequency and venous access
- prophylaxis is best given in the morning to cover periods of activity and is advisable prior to engaging in activities with higher risk of injury
Prophylaxis is expensive and may not be feasible where resources are constrained (even though it is cost effective because it prevents long term complications); low-dose prophylaxis is an option in such cases (e.g. 10–20 IU/kg twice per week)
It is uncertain whether prophylaxis should continue into young adulthood because some individuals appear to do well after discontinuing it. The alternative to continuing prophylaxis is on-demand therapy, in which a clotting factor is administered in response to an acute bleeding episode or to cover periods of increased risk (e.g. elective surgery). In patients with repeated bleeding, particularly into target joints, another option is prophylaxis for 4 – 8 weeks combined with intensive physiotherapy or synoviorthesis.