Haemophilia

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Key points ⚡
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Haemophilia\: inherited bleeding disorder; haemophilia A (factor VIII de
Severity\: depends on factor VIII or IX levels; severe (\<1%), moderate (1-5%), mild (5-50%).
Aetiology\: X-linked recessive mutations in factor VIII (haemophilia A) or factor IX (haemophilia B) genes; can also be
acquired through autoantibodies or malignancy.
Pathophysiology\: involves intrinsic clotting cascade; de
Symptoms\: severe epistaxis, bleeding gums, haematuria, intra-articular/intramuscular bleeds, excessive bruising,
prolonged post-surgical bleeding, spontaneous haemorrhage.
Diagnosis\: FBC (reduced haemoglobin and haematocrit) can indicate a recent or chronic bleed, clotting screen (normal PT,
prolonged APTT), factor activity levels (reduced), mixing studies, imaging for bleeds.
Management\:
Prophylaxis\: regular factor infusions, avoiding contact sports, vaccinations for hepatitis A/B, monitoring factor levels.
Acute bleeds\: factor infusions, FFP, cryoprecipitate, analgesics for haemarthroses, desmopressin for mild haemophilia A.
Genetic counselling\: essential for prospective parents; prenatal testing via chorionic villus sampling or amniocentesis.
Complications\: arthropathy, joint deformity, soft tissue haemorrhages, bloodborne viruses (pre-1985 plasma-derived
factor), antibody inhibitor formation.
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A comprehensive topic overview

Introduction

Haemophilia is a largely inherited bleeding disorder of variable severity.
There are two main types\: haemophilia A, caused by a clotting factor VIII de
Christmas disease) which is caused by a factor IX de
factor can be inadequate in terms of quantity or function.
The severity of both diseases is generally dependent on the levels of factor VIII or IX. Laboratory factor levels are reported
as a percentage of normal factor activity, with the normal range between 50 and 150%. This can also be converted into
international units, where 100% factor activity is equal to 1.00 U/ml.
Roughly half of haemophilia patients are classed as having severe disease, with factor levels below 1%. The remaining
haemophilia patients are classed as either moderate, with factor levels of 1-5%, or mild, with levels from 5 to 50%.
In 2019, the UK prevalence for haemophilia A was approximately 1 in 8000, whilst the prevalence for haemophilia B was
roughly 1 in 35000.
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Aetiology

Haemophilia A is caused by mutations in the factor VIII gene, whilst haemophilia B is caused by mutations in the factor IX
gene. Both genes are mapped to the X chromosome and are passed down in a recessive fashion, so males with a single
mutation will have the disease, whilst females, with two X chromosomes, will be carriers for the disease.In the rare case of a female having a homozygous mutated factor gene, inherited from an a
mother, it has been observed that they can present with haemophilia symptoms.
2
Occasionally, haemophilia can be acquired due to the formation of autoantibodies targeting factor VIII or IX, or as a result
of malignancy.
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Haemostasis physiology
Haemostasis is the process of stopping bleeding and preventing further blood loss from a damaged blood vessel. It is a
three-step process, triggered by damage to the blood vessel endothelium\:
Blood vessel vasoconstriction
Primary haemostasis
Secondary haemostasis
After the blood vessel constricts, which decreases pressure downstream, circulating platelets come into contact with the
collagen of the broken vessel and become activated. Activated platelets start to plug the hole, and also release ADP and
thromboxane A2, two chemicals that can activate other platelets in a positive feedback mechanism. This unstable and
fragile platelet plug is named the primary plug.
When clotting factors make contact with the sub-endothelium or extravascular components, the clotting cascade is
triggered. The clotting cascade is a series of reactions whereby factor zymogens become activated and, in turn, activate
the next zymogen in the chain.
There are two arms of this amplifying factor cascade, the intrinsic and extrinsic cascades, which both lead to activation of
factor X. Activated factor X turns prothrombin into thrombin, which activates
stimulating the coagulation cascade). Fibrin
the secondary plug.
Both factor VIII and IX are involved in the intrinsic cascade, which is initially triggered by the activation of thrombin and
factor XII by platelets surrounding the vascular injury. If either one of these factors is de
ine
Figure 1.Coagulation cascade pathway, highlighting the position of factors VIII and IX in the intrinsic pathway.
4

Clinical features

Haemophilia can present di
characterised by lower factor levels, often presents earlier in life (even as early as during delivery).
On the other hand, mild haemophilia patients often do not realise they have the disease, and only present after a bleed
following major trauma or surgery, or precipitated by drugs such as non-steroidal anti-in
History
Severe haemophilia will typically present early with spontaneous or prolonged bleeding.
5
Typical symptoms of haemophilia may include\:
Severe epistaxis
Bleeding gums
Haematuria\: gross or microscopic (i.e. detected on dipstick).
Intra-articular or intramuscular bleeds\: commonly a
Excessive bruising/ecchymoses, contusions or spontaneous haemorrhage during childhood play.
Prolonged bleeding after a surgical or dental procedure, or post-venepuncture.
Other less common bleeding presentations include\:
Intracranial haemorrhage\: presenting with neurological symptoms.
Haematemesis, melaena and frank rectal bleeding (from gastrointestinal bleeding).
Haemoptysis
Compartment syndrome
When taking a history, other important areas to cover include\:
Secondary symptoms such as fatigue or frequent infections, as they may indicate alternative diagnoses (e.g.
haematological malignancy).
Drug history\: several di
warfarin, aspirin, NOACs).
Social history\: consider the possibility of violence as the cause of excessive bruising or bleeding (e.g. domestic violence).
Family history\: given that most haemophilia is inherited, it's essential that you take a comprehensive family history.
Clinical examination
Clinical examination may reveal signs suggestive of haemophilia such as bruising, haematoma, active bleeding and joint
swelling (haemarthrosis).

Di

The haemostatic and
medical conditions can result in loss of this balance, resulting in excessive bleeding.
Common di
von Willebrand’s disease (VWD)\: especially subtype 2N
vitamin K de
disorders of the
hepatic disease (many clotting factors, as well as several anticoagulative proteins, are synthesised in the liver)
de
Platelet disorders can also present similarly to haemophilia, although platelet de
haemorrhages and ecchymoses (bruising) rather than the haematomas and haemarthroses which are more characteristic
of clotting factor de
Iatrogenic causes of spontaneous or prolonged bleeding are also a possibility in patients being treated with anticoagulants
or antiplatelets.Investigations
Full blood count and extended clotting screen
It is important to carry out a full blood count (FBC) and extended clotting screen in any patient presenting with
unexplained spontaneous or prolonged bleeding symptoms. This can help diagnose haemophilia and rule out many of the
di
Findings associated with haemophilia include\:
Reduced haemoglobin and low haematocrit on FBC\: can indicate a recent or chronic bleed.
Normal platelet count on FBC
Normal prothrombin time (PT), bleeding time (BT),
Prolonged activated partial thromboplastin time (APTT)\: although this can be normal in mild disease.
Reduced factor VIII or factor IX activity level\: for haemophilia A or B respectively.
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 de
For more information, see the Geeky Medics guide on interpreting a coagulation screen.
Mixing study
A mixing study is another useful investigation of haemophilia. By mixing a haemophilia patient’s blood plasma in a 1\:1 ratio
with normal plasma, a prolonged APTT should normalise. This is because the normal plasma contains functional clotting
factor, so the de
Imaging
Imaging can be carried out in emergency situations to detect bleeds or in the chronic setting to identify signs of
degenerative joint disease. Suitable modalities used to diagnose bleeds include CT, MRI and Doppler ultrasound.

Management

Prophylaxis
Prophylactic treatment is given in order to prevent disease, in this case bleeding events. Prophylaxis also helps to
preserve long-term joint function by reducing episodes of haemarthrosis.
Severe forms of haemophilia can require prophylactic factor infusions, replacing the missing or non-functional clotting
factor, in order to prevent frequent haemarthroses or other bleeding episodes. Factor infusions should ideally be
administered until the child reaches physical maturity, but are often continued long-term, under the continuous review of a
haematologist.
The genetically engineered factor injections are given as a slow intravenous bolus and in some cases may be required up
to three times a week. These doses should be tailored to the patient, such as administration just prior to a child’s physical
education lessons.
Patients with severe haemophilia are at high risk of bleeding during and after surgery. For this reason, their factor activity
should be increased to 50-100% for 2-7 days before surgery, and closer to 100% for surgery on the brain or prostate.
Tranexamic acid can be considered as this inhibits
Monitoring of factor and factor inhibitor levels (see complications) should occur regularly during prophylaxis, and the
Haemophilia Joint Health Score (HJHS) should be calculated frequently. Additionally, patients should wear a medical
emergency identi
Patients should also avoid competitive contact sports and unnecessary manual labour, as these increase the risk of
haemarthroses and head injuries. Other exercises, including racquet sports or swimming, should be encouraged.
To protect against bloodborne diseases, all patients and carers that may inject blood products should be vaccinated
against hepatitis A and hepatitis B. In haemophilia patients, these immunisations should be given subcutaneously rather
than intramuscularly to avoid bleeding and haematoma formation.Acute bleeds
For any bleeding episodes, normal physical methods of bleeding cessation should be advised. Depending on the severity
of bleeding, patients may need factor infusions, fresh frozen plasma or cryoprecipitate.
For major haemorrhage, including those involving the central nervous, gastrointestinal and genitourinary systems the aim
is to correct factor levels to 100%.
For minor haemorrhages, such as haemarthrosis, oral mucosal and intramuscular bleeds, the aim is to increase factor
levels to 30-50%. These raised factor levels should be maintained through further infusions for several days.
If possible, coagulation tests and a group and save sample should be taken prior to treatment, however, these
investigations should not delay treatment.
Haematomas and haemarthroses can be very painful and require analgesic treatment. The oral route is preferred,
although NSAIDs should be avoided as they increase the risk of gastrointestinal bleeding. Intramuscular opiates should
also be avoided as this mode of delivery can result in intramuscular bleeding and haematoma formation.
It is possible to treat acute bleeds in mild haemophilia A patients with desmopressin (DDAVP), which stimulates von
Willebrand factor (vWF), which in turn promotes factor VIII activity.
Calculating factor dose
There are formulas published to calculate the dose required to treat a bleed in a haemophilia A or B patient.
6
Doses are rounded up to the nearest vial size, as slight overtreatment has minimal detrimental e
follows\:
Haemophilia A dose formula\: weight (kg) * factor level increase desired (%) * 0.5 = number of factor VIII units needed
Haemophilia B dose formula\: weight (kg) * factor level increase desired (%) = number of factor IX units needed
NB\: Always check factor product literature as this may vary.
Genetic counselling and pregnancy
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 una
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 a
information should be discussed with any haemophilia patients or carriers looking to have a child.Figure 2.X-linked recessive inheritance pattern, as observed with haemophilia.
7
Genetic testing and counselling should be made available to prospective parents. During pregnancy, the fetus can be
tested for a haemophilia mutation via\:
Chorionic villus sampling at 11-14 weeks\: removing a small portion of the placenta for testing.
Amniocentesis at 15-20 weeks\: sampling the amniotic
Both procedures carry small risks of premature labour and miscarriage, which should be assessed by the family prior to the
procedure. The obstetric haematology team should be involved in the management of pregnancy and birth.
A haemophilia diagnosis should be made as soon as possible after delivery, by testing of uncontaminated cord blood.
Recombinant factor should be administered immediately after a positive haemophilia diagnosis.

Complications

If untreated, severe disease, and repeated bleeding into joints, can lead to arthropathy (painful and reduced range of
movement), joint deformity, soft tissue haemorrhages, retroperitoneal bleeds or haematoma formation. These can present
as surgical emergencies and may require operative intervention.
Bloodborne viruses
Before 1985, factor concentrate was plasma-derived and created from multiple blood donations. As a result, many
haemophilia patients were infected with bloodborne viruses, including HIV, hepatitis B and hepatitis C. The prevalence of
plasma-derived factor viral infection is higher in haemophilia A patients, as the condition is more common, was more often
severe (requiring factor treatment) and more plasma from multiple donors was needed for their concentrate.
One UK-based survey carried out in 1988 recorded 59% of severe haemophilia A and 11% of severe haemophilia B patients
tested positive for HIV antibody.
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Many haemophilia patients to this day are currently infected with HIV and hepatitis viruses, which together produce a worse
prognosis, and lead to other disease states, including liver failure and hepatocellular carcinoma. This is not a concern for
newly diagnosed patients, as this risk has been virtually eliminated with the invention of safer and more e
recombinant factor products.
Antibody inhibitor formationAntibody inhibitor formation a
B patients, reducing the e
recognises therapeutic factor as non-self and forms an immune response against these proteins.The immune response can result in anaphylaxis on exposure to any factor product, so
place in a specialist centre.
5
It is more common for inhibitors to diminish the e
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 o
often less e
mild disease to avoid inhibitor formation.

References

Acute Myeloid Leukaemia
United Kingdom Haemophilia Centre Doctors’ Organisation. U K H C D O A n n u a l R e p o r t 2 0 1 9 i n c l u d i n g B l e e d i n g D i s o r d e r
Anaemia Overview
S t a t i s t i c s f o r 2 0 1 8 / 2 0 1 9 . Published in 2019. Available from\: [LINK]
Chronic Myeloid Leukaemia
Nair P.S., Shetty S. and Ghosh K.. A H o m o z y g o u s F e m a l e H e m o p h i l i a A . Published in 2012. Available from\: [LINK]
Disseminated Intravascular Coagulation (DIC)
Franchini M., Lippi G.. A c q u i r e d F a c t o r V I I I I n h i b i t o r s . Published in 2008. Available from\: [LINK]
Haemolytic anaemia
Joe D. Coagulation w i t h a r r o w s f o r n e g a t i v e a n d p o s i t i v e f e e d b a c k . Licence\: [CC-BY-SA]. Available from\: [LINK]
NHS.uk. H a e m o p h i l i a . Published in 2020. Available from\: [LINK]
Hemophilia of Georgia. C a l c u l a t i n g t h e D o s e . Available from\: [LINK]

Test yourself

SUM1. X -l i n k e d r e c e s s i v e i n h e r i t a n c e s c e n a r i o s f o r e i t h e r t h e m o t h e r b e i n g a c a r r i e r o r t h e f a t h e r b e i n g a
[CC-BY-SA]. Available from\: [LINK]
AIDS Group of the United Kingdom Haemophilia Centre Directors. P r e v a l e n c e o f a n t i b o d y t o H I V i n h a e m o p h i l i a c s i n t h e

Reviewer

Aetiology
Clinical features
Dr Richard Gooding
Consultant haematologist
Di
Investigations
Management
Complications
Source\: geekymedics.com