Haemophilia A is due to defective or low levels of factor 8 (F8). Before the 1950s there was no therapy and patients often died before 30 years old, but by the 1950s patients could be treated with plasma or whole blood and from the 1960s by cryoprecipitate.
Freeze dried F8 became available from 1960–70s but carried with it the possibility of blood-bourne disease, a disaster for haemophiliacs some of whom are now entering older age. In the early 1980s outbreaks of AIDS were identified and not long after Hepatitis C (HCV) was discovered.
By 1985 blood was screened for HIV and by 1991 for HCV virus. Virus inactivated plasma derived clotting factor concentrates and recombinant products are now used by haemophiliacs in prosperous nations. There are a number of haemophiliacs in the UK over the age of 50 years and this article explores the highs and lows of medical progress in therapy and current care.
Haemophilia A affects one in 5,000–10,000 male live births but can occur in women. The genetic information for F8 is found on the sex linked X chromosome on the long (q) arm at position 28: Xq28.1 There are over 1300 mutations, which can cause variable defects and deficiencies in F8 levels and so prevent coagulation. Haemophilia A is divided into mild (5–50% normal F8), moderate (1–5% normal F8) and severe (<1% normal F8 levels).2 60% of patients with Haemophilia A are severe.3 Usually women are carriers but if two X sex chromosomes are inherited because a male haemophiliac and a female carrier or female haemophiliac have children then the female offspring may also have haemophilia. It is about five times more common than Haemophilia B (F9 deficiency or Christmas disease). Other congenital factor haemophilias have been discovered and also acquired haemophilia.
F8 is a protein formed by the liver and haemophilia A can be cured by liver transplantation. F8 is essential to fibrin plug formation as it activates F10, amplifying its effect and causing cleavage of prothrombin to form thrombin and this in turn cleaves fibrinogen to produce insoluble fibrin in large amounts and so converts the soft platelet aggregate to a hard clot. Patients with haemophilia A have normal platelet function, normal platelet count, normal prothrombin time (PT or expressed as INR) but prolonged activated partial thromboplastin time, aPTT, and low F8 levels compared to normal people.
Without therapy patients can bleed to death after minor trauma. It is thought that Queen Victoria was a new mutation carrier of Haemophilia B (F9 deficiency) and her eighth child, Leopold, died at 31 years old of intracranial haemorrhage (ICH). Two of her daughters, Alice and Beatrice, were carriers and through marriage had offspring with haemophilia affecting the German, Spanish and Russian royal families. Our Queen is descended from great grandfather King Edward V11 (Albert Edward Saxe-Coburg-and Gotha) who was the oldest and unaffected son of Queen Victoria, then via George V and then George V1 (George Windsor) so our current royal family has not been affected.
Symptoms and joints
Patients with mild haemophilia have prolonged bleeding at venesection and may develop bruising, bleeding gums or epistaxis. Prior to blood product availability patients with severe haemophilia A were likely to die early from bleeding. This may have been internal, particularly ICH, or external and either spontaneous or after minor trauma. Haemophilia patients frequently bleed into soft tissues and can get compartment syndrome or compression neuropathy and bleed into joints causing haemarthrosis leading to early onset OA, known as haemophilic arthropathy—subsequently requiring joint replacement.
Joint pain and swelling can be attributed by the patient to an injury and haemarthrosis is under-recognised. The advent of prophylactic F8 self-dosing will hopefully prevent joint damage but the older haemophiliacs on practice lists will not have had prophylactic therapy as children and will be at increased risk of joint failure and orthopaedic intervention. Unfortunately some patients will not adhere to medical management for a number of reasons and will bleed into joints. Some milder haemophiliacs may bleed into a joint even though considered a mild haemophiliac and therefore not requiring prophylaxis. Lastly some haemophiliacs develop antibodies which neutralise the effect of F8 so that therapy is suboptimal. This last group is a major cause of arthropathy.3
ICH occurs in 3% of patients with haemophilia and head injury in the haemophiliac needs to be carefully assessed and managed.3
The advent of F8 products revolutionised the outlook for haemophiliac patients in the 1960s–80s until it became apparent that a number of them were contracting hepatitis A, B, C and HIV. Haemophiliacs born before 1985 are at risk of HIV and those born before 1990 are at risk of hepatitis C (HCV).
Most haemophiliacs got HCV prior to 1985 with viraemia, raised liver enzymes, hepatitis and fibrosis. Up to 60% of haemophiliacs over 65 years old who are still infected with HCV will have cirrhosis and develop liver failure or hepatocellular cancer.4 HCV can be treated with antiviral therapy successfully but not in all patients and some will also have HIV. HCV, hepatitis B and D transmission via F8 has stopped since 1997 when new processes of manufacture were introduced using recombinant technology. Haemophiliac patients should receive vaccination for hepatitis A and B. Other viruses like hepatitis G have been discovered but the risk to patients is not yet known.
HIV causing AIDS became epidemic amongst haemophiliacs due to the blood products used in the 1970s–mid 1980s. It is thought to have affected 50% of the haemophiliac population and at present 10–15% of haemophiliacs have HIV. In Britain over 4,000 haemophiliacs developed hepatitis C and 1,200 HIV prior to heat treatment of F8.5
HIV can induce cancers and particularly non-Hodgkin’s lymphoma, although the use of highly active antiretrovirals (HAART) has reduced this. Blood is currently screened in the UK for Hepatitis B and C, Human T-cell Lymphotrophic virus, syphilis and HIV.6 There remains a short window in which a patient may be incubating disease and yet donate blood.
In the UK haemophiliacs given UK-sourced plasma infusion products between 1980 and 2001 may be at increased risk for vCJD (Variant Creutzfeldt-Jakob disease). Some of these products were also exported to Brazil, Brunei, India, Jordan, Oman, Singapore, Turkey, and United Arab Emirates. Currently UK-sourced plasma is not used in any product worldwide and clotting factors from plasma are not derived from UK sources to minimise transmission problems. There have been cases of transfusion transmitted vCJD but only one possibly linked to a haemophiliac patient.
Patients with haemophilia do not appear to be protected from coronary heart disease (CHD) and may develop metabolic syndrome if they restrict their activity to minimise trauma. Those with HIV have an increased risk of CHD due to highly active retroviral therapy (HAART) induced hyperlipidaemia.4
In general anticoagulants should be avoided in haemophiliac patients but in some cases aspirin has been used and statins are well tolerated unless there is liver damage due to hepatitis. Patients have undergone percutaneous coronary intervention and stenting for acute coronary syndrome and undergone coronary artery bypass grafting. The coagulation of these patients is measured carefully and adjusted by their specialist haematologist. Patients needing heart valve replacement will be selected for a bioprosthetic valve to prevent the need for anticoagulation.
Patients may be slow to report episodes of blood loss from the bowel and urine and require education about presenting with “red flag cancer” symptoms as they age. The use of cancer chemotherapy with its bone marrow suppression and mucositis raises the bleeding risk in the haemophiliac and requires careful management. Haemophiliac patients are also at increased risk of renal disease through recurrent bleeds and renal effects of antiviral or anticancer therapies. Renal disease raises the risk of hypertension which the GP should control.7 Patients with haemophilia also have an increased risk of osteoporosis for unclear reasons.8
Specialist centres set up comprehensive care networks for haemophiliacs to optimise outcomes. Therapy includes the acute treatment of bleeding or ongoing or planned prophylaxis. Therapy for haemophilia has changed over the years so that a number of haemophiliacs now self-administer F8 prophylaxis. Older haemophiliacs will not have had this as young people and the aim is to reduce the incidence of complications. Preventive therapy is often required less as the patient ages and becomes less active than in childhood but can be restarted if required.
Some older patients are however starting this when clinically indicated eg. for continuing joint damage. In scheduled surgical procedures levels of F8 can be raised to 100% and maintained for a number of days until bleeding risk is reduced and healing has occurred. F8 is also given for acute bleeds. After a severe bleed the specialist can discuss with the patient whether to start F8 prophylaxis.
Desmopressin (DDAVP) is also given to increase F8 levels9 and tranexamic acid as an antifibrinolytic agent.
Around 20–30% of haemophiliacs will develop inhibitor antibodies to F8 and are registered with specialist comprehensive care haemophilia centres. Detection of inhibitors prevents optimal therapy and requires therapy to develop immune tolerance.10 Usual F8 therapy is not as effective and these patients may need prothrombin complex concentrate or activated F7 to stop bleeding.
It is advised to detect inhibitors before routine surgery and after intensive therapy with F8. Immune tolerance therapy (ITT) involves daily injections of F8 (octocog alfa) and therapy continues over 6–24 months. It has an 80% success rate in clearing inhibitors.10
This is a rare condition with an incidence of one in a million. It has two age peaks: 20–30 years old and increased in postpartum women and those aged 68–80 years old. The patient has no family history of bleeding and 50% of cases are idiopathic but others are associated with autoimmune disease, drugs or are paraneoplastic.
Patients present with spontaneous bleeding and the mortality rate is 8–22%. Treatment is to correct the bleeding problem and then the patient is given immunosuppression, including corticosteroids.7 There has recently been a MHRA report sent to GPs advising of a small number of acquired haemophilia cases occurring in patients on clopidogrel (an antiplatelet drug)11 and suggesting that an isolated prolonged aPPT should raise the suspicion of acquired haemophilia.
Haemophiliac patients without HIV and HCV can expect to live a normal life span. Barriers to keeping fit and adhering to medication may revolve around expert specialist care and patient education. In addition, patient adherence reduces with length of time of illness and for the haemophiliac patient there may be an element of becoming blasé and in addition problems with IV access, pain, frequency of infusions and time to prepare and administer them may mitigate against perfect outcomes for some individuals.
Patients are likely to have newer products in the future which allow longer dosing intervals for prevention and gene therapy that offers a potential cure. Patients can have an active working life but should be advised not to undertake extreme or contact sports like rugby. They should be encouraged to wear a Medicalert bracelet.
The older haemophiliacs will have experienced changes in therapy, possibly the introduction of prophylactic therapy and lived through the problems of HIV and Hepatitis. A number of them will have complications of their bleeding disorder. Younger haemophiliac patients should have a normal life expectancy8 and so be present in greater numbers due to the lack of life-threatening infections and bleeds and this present cohort of general practice specialists will be the first to support them through their health issues.
Conflict of interest: none declared
1. Genetic Home Reference factor 8. accessed at http://ghr.nlm.nih.gov/gene/F8 Accessed 10/04/14
2. http://www.patient.co.uk/doctor/haemophilia-a-factor-viii-deficiency Accessed 10/04/14
3. http://www.nhs.uk/Conditions/Haemophilia/Pages/Complications.aspx Accessed 10/04/14
4. Konkle BA, Kessler C, Aledort L, et al. Emerging clinical concerns in the ageing haemophilia patient. Haemophilia (2009); 15: 1197–1209
5. Terence Higgins Trust. http://www.tht.org.uk/ Accessed 10/04/14
6. UK Blood Services joint statement on blood safety - June 2012. http://www.nhsbt.nhs.uk/current_issues/joint_statement_on_blood_safety.html Accessed 10/04/14
7. Franchini M, Tagliaferri A, Mannucci PM. The management of hemophilia in elderly patients. Clinical Interventions in Aging 2007: 2(3)
8. Young G. New challenges in hemophilia: long-term outcomes and complications. ASH Education Book2012; 1: 362–68
9. Leissinger C, Carcao C, Gill JC, et al. Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. Haemophilia 2013-01-01. ISSN: 1351–8216.
10. Collins PW, Chalmers E, Hart DP, et al. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th Ed.) published online: 15 NOV 2012. British Journal of Haematology 2013; 160 (32): 153–70
11. Direct Healthcare Professional Communication on the association of clopidogrel with acquired haemophilia. Dec 2013. http://www.mhra.gov.uk/Safetyinformation/ Accessed 10/04/14 DrugSafetyUpdate/CON350671