An 8-year-old boy, Carlos, presents to ED with right ankle pain and swelling, with decreased range of motion. He is unsure of the mechanism of injury and thinks he may have rolled over his ankle. His mother tells you he has haemophilia…what do you do next?
Haemophilia is a clotting factor deficiency
Clotting factors are proteins in the blood that help control bleeding. When you bleed, your clotting factors form a blood clot. Haemophilia is a bleeding disorder due to low levels of a specific clotting factor. In Australia, haemophilia affects more males at 1 in 6000 to 10,000 than females at less than 1 in 300,000.
There are three main types of haemophilia: Haemophilia A (“Classic Haemophilia”), a clotting Factor VIII (8) deficiency; Haemophilia B (“Christmas Disease”), a clotting Factor IX (9) deficiency; and Haemophilia C, a clotting Factor XI (11) deficiency.
Haemophilia A and B are X-linked disorders, while Haemophilia C is a rare autosomal recessive disorder associated with variable bleeding phenotypes. Haemophilia A is the most common, accounting for roughly 85% of haemophilia cases; Haemophilia B accounts for 15% of cases; and Haemophilia C is the rarest, comprising less than 1% of cases. In this article, we’ll concentrate on the most common, Haemophilia A and B.
Children with moderate to severe haemophilia receive prophylaxis
Children with moderate to severe haemophilia are usually on prophylactic treatment, whereas children with mild haemophilia are treated as required for bleeding or surgery.
The severity of haemophilia is determined by the percentage of clotting factor remaining in the bloodstream, the baseline factor level.
Mild cases are defined by factor levels of 5-40%, moderate cases as 1-4%, and severe <1%. Children with moderate to severe haemophilia usually receive prophylactic treatment to prevent bleeds.
Historically, prophylaxis was with regular IV factor VIII or IX. However, many children with haemophilia A are starting or being transitioned to non-factor prophylaxis with emicizumab (more on that later). Available factor products include Biostate (Factor VIII and von Willebrand factor), Factor VIII (standard half-life, extended half-life) and Factor IX (standard half-life, extended half-life).
Studies have shown that children on regular extended half-life treatments have an improved health-related quality of life, as infusion frequency is reduced and plasma trough levels are higher, allowing a more active lifestyle while preventing spontaneous bleeds.
Earlier prophylaxis started before the age of two, has been associated with reduced bleeding rates and better long-term joint health. Modern practice is to begin prophylaxis as soon as a child shows signs of mobility or sooner if they experience spontaneous bleeding. Immunisations are generally administered subcutaneously rather than intramuscularly to reduce the risk of a haematoma at the injection site.
Factor inhibitors can develop, reducing the effectiveness of treatment
During treatment, some patients develop antibodies against Factor VIII/IX. These antibodies are called inhibitors and develop in approximately 25% of haemophilia A patients (half transient and half persistent) and 3% of haemophilia B patients (associated with significant morbidity and the unique occurrence of anaphylactic reactions and nephrotic syndrome).
Clues that a child has developed a factor inhibitor include a worsening bleeding phenotype without explanation or bleeding episodes that are difficult to treat. It is becoming increasingly common to treat children with haemophilia A who have inhibitors with emicizumab. Suppose a child has a high titre inhibitor over 5 Bethesda Units. In that case, they may require an inhibitor elimination treatment plan – desensitisation with high dose daily factor exposure or immunomodulation such as steroids, sirolimus, mycophenolate mofetil, or rituximab.
How do we treat Carlos and other patients with haemophilia?
Ask for a detailed description of the type and mechanism of injury, as significant internal and joint injuries are often missed. Don’t forget to assess the site and extent of bleeding and the impact on function. If you suspect a life-threatening bleed such as an intracranial, neck, chest, genitourinary, psoas or gastrointestinal bleed, contact the haematologist urgently and immediately treat with clotting factor replacement!
If no potentially life-threatening bleed is suspected, Carlos will need imaging (usually an ultrasound) to check for any joint effusion/bleed. Blood tests are generally not required, but you may want to consider screening for factor inhibitors as we are uncertain whether Carlos has a provoked (e.g., trauma-induced) or unprovoked bleed.
Minor soft tissue injuries or bruises do not require factor replacement
Remember to always put firm pressure on cuts and scrapes and pressure on nostrils in epistaxis.
Antifibrinolytic agents such as oral/IV tranexamic acid are effective for treating and preventing mouth bleeds and epistaxis in all severities of haemophilia. Gauze can also be soaked in tranexamic acid and applied topically for oral mucosal and dental bleeds.
IV or subcutaneous desmopressin (DDAVP) is a preferred treatment alternative for patients with mild haemophilia A and minor bleeding. DDAVP temporarily releases stored Factor VIII and von Willebrand factor into blood circulation. Note this is not advised for children under two years of age as it may cause hyponatraemia and seizures. Patients with mild haemophilia A with severe injuries or significant bleeding still require factor replacement therapy.
Major and internal bleeds require clotting factor replacement
Doses of IV clotting factor replacement should be administered and rounded to the nearest 250 units, with the required amount determined by the haematologist on call. Clotting factor replacement can be standard half-life or extended half-life, recombinant (made in a laboratory) or plasma-derived (made from blood donated by healthy humans).
If you are situated in a regional or remote area, and no factor replacement is readily available, use Fresh Frozen Plasma. If the child has factor inhibitors, contact the haematologist urgently – they might prescribe bypassing agents to bypass the inhibitor and initiate clotting, such as activated Factor VIIa (NovoSeven) or activated prothrombin complex concentrates (aPCCs, e.g. Factor Eight Inhibitor Bypassing Agent aka FEIBA).
Due to a potential thrombosis risk, FEIBA must not be used in patients on emicizumab. If the child fails to respond clinically to adequate factor replacement, suspect the presence of a new factor inhibitor. Invasive procedures should only be performed after clotting factor replacement.
Joint and muscle bleed require pain management and strategies to limit bleeding
Protection, Rest, Ice, Compression bandage and Elevation (P-RICE) should be followed. Certain areas may also require joint washouts or steroid administration. Paracetamol is sufficient analgesia, and children should avoid aspirin or NSAIDs as they may worsen bleeding.
Children with haemophilia can develop joint complications such as worsening pain/disability, arthropathy (secondary to chronic synovial inflammation) and “target joint,” subject to recurrent bleeds. Therefore, clinical surveillance such as Haemophilia Joint Health Score (HJHS), physiotherapy reviews and/or imaging for arthropathy surveillance can benefit these children in the long term.
Haemophilia management is an evolving space and there are multiple new treatments
Emicizumab (or Hemlibra) is a modern treatment for haemophilia A. Emicizumab is a humanised bispecific antibody that does Factor VIII’s job by binding activated Factor IX to inactive Factor X, thus activating it. It is administered through a subcutaneous injection and is given regularly (weekly, fortnightly or monthly). Many children with moderate to severe haemophilia A are started on emicizumab or are being transitioned from IV factor to subcutaneous emicizumab injections. However, Emicizumab cannot be used for major acute bleeding as it is only for prophylaxis. This new transition means parental IV access skills are being lost, and more children may present with bleeds to the emergency department, where they might have self-treated at home. Unfortunately, those with haemophilia B only have IV factor treatment as an option.
Access to treatment remains an issue, particularly in rural or regional areas. Although children can be given advanced care plans, they often do not have ready access to clotting factor concentrate as they are not routinely available in all hospitals. Haemophilia Treatment Centres are trying to organise for families to keep their own “emergency factor” doses at home, given that factors are not universally stocked at every hospital they might present to.
The good news is that gene therapy is on the horizon and has been conducted in clinical trials recently. The goal is to increase Factor VIII/IX production to “mild” or higher, not necessarily normalising it. However, a common side effect is raised alanine transaminase levels in the liver. So as we continue to research and make advancements in this space, gene therapy will hopefully become a treatment option, making haemophilia much more manageable.
Practical aspects of extended half-life products for the treatment of haemophilia – Thierry Lambert, Gary Benson, Gerry Dolan, Cedric Hermans, Victor Jiménez-Yuste, Rolf Ljung, Massimo Morfini, Silva Zupančić-Šalek, Elena Santagostino, 2018 (sagepub.com)