Haemophilia is a hereditary bleeding disorder that can vary in severity. The two main types are haemophilia A, due to clotting factor VIII deficiency, and haemophilia B (Christmas disease) due to factor IX deficiency. This deficiency can be quantitative or qualitative, with the normal range between 50 and 150%. Usually, half of haemophilia patients have severe disease (factor levels below 1%) and the other half have mild to moderate disease (factor levels 1 to 50%). The UK prevalence for haemophilia A is approximately 1 in 8000 and the prevalence for haemophilia B is approximately 1 in 35000.1
Haemophilia A is caused by genetic mutations in the factor VIII gene, and haemophilia B is caused by mutations in the factor IX gene. Both genes are located on the X chromosome and are passed on recessively. Females, with two X chromosomes, are carriers for the disease, and a homozygous mutated factor gene inherited from an affected father and a carrier mother can cause female haemophilia.2 Occasionally, haemophilia may be acquired due to autoantibody formation or malignancy.3
Haemostasis is the process of stopping bleeding and preventing further blood loss from a damaged blood vessel. It starts with the blood vessel constricting to decrease pressure downstream, followed by circulating platelets becoming activated and plugging the hole. This unstable plug is known as the primary plug. When clotting factors contact the sub-endothelium or extravascular components, the clotting cascade is initiated. The clotting cascade is a series of reactions activating factor zymogens which in turn activate the next zymogen in the chain. The cascade has two arms, the intrinsic and extrinsic cascades, which both lead to activation of factor X, turning prothrombin to thrombin and activating fibrin which accumulates around and stabilises the primary plug, known as the secondary plug. Both factor VIII and IX are involved in the intrinsic cascade which is triggered by platelets around the vascular injury.
When both components - factors VIII and IX - of the coagulation cascade are present, clot formation is effective and the chance of blood loss is minimized. If either one of these components is deficient, the cascade works inefficiently, resulting in decreased formation of secondary plug and risking blood loss through the primary plug.
Haemophilia can vary in presentation depending on the patient's age and the severity of the disease. Hereditary cases commonly appear at younger ages and acquired cases in older individuals. Severe cases, with lower factor levels, often have an earlier presentation, possibly even at birth.
Mild haemophilia may go undetected until a bleed occurs after trauma, surgery, or with the use of certain drugs such as NSAIDs or aspirin.
Severe haemophilia usually presents with spontaneous or extended bleeding. Common symptoms include: severe nosebleeds, bleeding gums, haematuria, intra-articular and intramuscular bleeds, bruises and haemorrhages, and long-lasting bleeding from surgeries or blood tests.
Less common symptoms are intracranial haemorrhage, haematemesis, melaena, and frank rectal bleeding, haemoptysis, and compartment syndrome.
When taking a history, other important aspects to consider are secondary symptoms such as fatigue or infections, drug history, social history, and family history as most haemophilia is inherited.
Clinical examination may reveal signs of haemophilia such as bruising, haematomas, active bleeding, and joint swelling (haemarthrosis).
The body's haemostatic and fibrinolytic systems normally counterbalance each other to maintain equilibrium. If this balance is lost, excessive bleeding can occur.
Common differential diagnoses for haemophilia include:
Platelet disorders can also present similarly to haemophilia, though platelet deficiencies generally cause petechial haemorrhages and ecchymoses (bruising) rather than the haematomas and haemarthroses associated with clotting factor deficiencies.
Iatrogenic causes of spontaneous or prolonged bleeding can also occur in patients taking anticoagulants or antiplatelets.
It is essential to run a full blood count (FBC) and extended clotting screen in anyone with unexplained spontaneous or prolonged bleeding symptoms, as this can detect haemophilia and exclude many of the differential diagnoses.
Findings associated with haemophilia include:
PT measures the extrinsic and common pathways. APTT measures the intrinsic and common pathways. Both factor VIII and IX form part of the intrinsic clotting pathway, so deficiencies can affect the APTT reading.
A mixing study can also be used to investigate haemophilia. By blending a haemophilia patient's blood plasma in a 1:1 ratio with normal plasma, a prolonged APTT should normalise because normal plasma contains functional clotting factor, bypassing the deficiency.
Imaging can be used in emergency situations to identify bleeds, or in the chronic setting to spot signs of degenerative joint disease. Suitable modalities to diagnose bleeds include CT, MRI, and Doppler ultrasound.
Prophylactic treatment is needed to prevent illness, in this case bleeding events. Prophylaxis also helps retain long-term joint function by reducing episodes of haemarthrosis.
Severe forms of haemophilia can require prophylactic factor infusions, adding the missing or non-functional clotting factor, to forestall frequent haemarthroses or other bleeding episodes. Factor infusions should be administered until the child reaches physical maturity, although they are frequently continued long-term, with the continual review of a haematologist.
The genetically engineered factor injections are usually given as a slow intravenous bolus and may need to be provided up to three times a week.
Dose amounts of prophylaxis should be tailored to each patient, for example a child's physical education lessons.
Patients with severe haemophilia are at high risk of bleeding during and after surgery. To increase safety, activity levels of their factor should stay between 50-100% for 2-7 days before the surgery and closer to 100% if the procedure is on the brain or prostate. Consider taking tranexamic acid which inhibits fibrinolysis in healthy people without increasing thrombosis risk.
Monitor factor and factor inhibitor levels regularly during prophylaxis, and assess the Haemophilia Joint Health Score (HJHS) frequently. Patients should also have a medical alert bracelet stating their disease, factor level and other necessary info.
Patients should stay away from contact sports and manual labor as they increase risks of haemarthroses and head injuries. They should instead engage in racquet sports or swimming.
To protect against illnesses, all patients and their caretakers should get hepatitis A and B immunizations. For haemophilia patients, these immunizations should be administered subcutaneously instead of intramuscularly as to reduce the risk of bleeding and haematoma formation.
Stop bleeding using normal physical methods. Depending on severity, treatments may include factor infusions, fresh frozen plasma or cryoprecipitate.
For major haemorrhages such as those involving the central nervous, gastrointestinal and genitourinary systems increase factor levels to 100%. For minor haemorrhages such as haemarthrosis, oral mucosal and intramuscular bleeds, aim to increase factor levels to 30-50% and maintain those levels for several days with further infusions.
If possible, take coagulation tests and a group and save sample before treatment, but don't delay treatment for those.
Haemarthroses and haematomas can be very painful and require analgesic treatment. Preferably give treatment through oral route, however NSAIDs should be avoided as they increase risk of gastrointestinal bleeding. Intramuscular opiates should also be avoided to prevent intramuscular bleeding and haematoma formation.
Mild haemophilia A patients can be treated with desmopressin (DDAVP) which increases von Willebrand factor (vWF) and thus factor VIII activity.
Formulas have been published to calculate the dose needed for haemophilia A and B patients. Doses should be rounded up to the nearest vial size, and slight overtreatment does not have a large negative effect. The formulas are:
Note: Always double check factor product literature as this may vary.
As haemophilia has an X-linked recessive inheritance pattern, a daughter of a male haemophilia patient will be a carrier whilst a son will be unaffected, as they inherit their father's normal Y chromosome.
There is a 50% chance that a daughter of a female carrier will be a carrier and a 50% chance that a son will be affected. This information should be discussed with haemophilia patients or carriers who want to have children.
Genetic testing and counselling should be offered to potential parents. During pregnancy, the fetus can be tested for haemophilia mutations through:
Both procedures carry a low risk of premature labour or miscarriage, which should be discussed by the family beforehand. The obstetrics haematology team should be involved in the management of the pregnancy and birth.
A haemophilia diagnosis should be made as soon as possible after delivery, through testing of uncontaminated cord blood. Recombinant factor should be administered right away after a positive haemophilia diagnosis.
If left untreated, severe disease can lead to arthropathy (pain and reduced movement), joint deformities, soft tissue haemorrhages, retroperitoneal bleeds or haematoma formation. These may require surgical action as an emergency.
Prior to 1985, factor concentrate was plasma-derived and generated from multiple blood donations. Due to this, many haemophilia patients were infected with bloodborne viruses such as HIV, hepatitis B and hepatitis C. The prevalence of these infections is higher in those with haemophilia A due to the condition being more common, often being severe and requiring factor treatment, as well as needing more plasma from multiple donors for concentrate.
One survey conducted in the UK in 1988 showed that 59% of severe haemophilia A patients and 11% of severe haemophilia B patients tested positive for HIV antibodies.8
Many haemophilia patients are still infected with HIV and hepatitis viruses, which together give an worse prognosis and lead to other conditions such as liver failure and hepatocellular carcinoma. This is not a concern for those newly diagnosed with the condition, as this risk has been virtually eliminated with the advent of safer and more effective recombinant factor products.
Antibody inhibitor formation affects almost a third of haemophilia A patients and a smaller proportion of haemophilia B patients which diminishes the effectiveness of factor therapy. Inhibitors, or factor antibodies, form as the patient's immune system identifies therapeutic factor as foreign and mounts an immune response against them.
Haemophilia is a bleeding disorder, most often inherited in an X-linked recessive fashion. Factor VIII or IX deficiency is responsible for a phenotype involving spontaneous and prolonged bleeding. APTT is often prolonged, and reduced factor activity levels can be used to diagnose haemophilia.
Recombinant factor infusions can be given prophylactically to prevent bleeds and joint deformity or therapeutically to treat acute bleeds. But, the immune response can result in anaphylaxis on exposure to any factor product, so first exposure should always take place in a specialist centre. It is more common for inhibitors to diminish the effect of factor treatment, a state that worsens over time and so should be monitored.
One method of treatment is immune toleration induction (ITI), which involves administering small quantities of factor regularly over a period of time until inhibitor antibody levels decrease. This treatment is usually offered to severe haemophilia A patients but is avoided in severe haemophilia B patients, as it is often less effective and carries a risk of anaphylaxis. Immunosuppressants can also be offered to haemophilia patients with mild disease to avoid inhibitor formation.
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