Haemophilia

Question 1

What is haemophilia?

Answer 1

This is a bleeding disorder usually inherited with X-linked recessive inheritance pattern.
It is characterised by the deficiency of coagulation factor VIII or IX.

Question 2

What is haemophilia A?

Answer 2

This results from the deficiency of clotting factor VIII

Question 3

What is haemophilia B?

Answer 3

This results from the deficiency of clotting factor IX

Question 4

Who is the typical patient for haemophilia?

Answer 4

Occurs almost exclusively in males due to an X-linked pattern of inheritance.

Question 5

Aetiology of haemophilia

Answer 5

Genetic mutations in the factor VIII and IX results in decreased circulating levels of coagulation factor VIII and IX.
Factor VIII and IX genes are located on the long arm of chromosome X.

Question 6

What is the common type of mutation in haemophilia?

Answer 6

About 50% of severe haemophilia A cases are due to intrachromosomal inversions involving regions in introns 1 and 22 of the factor VIII gene.
Most cases of haemophilia B are due to point mutations and deletions.

Question 7

Pathophysiology of haemophilia

Answer 7

Both factors VIII and IX are crucial for thrombin generation via the intrinsic pathway of coagulation.
In patients with haemophilia, there is delayed clot formation due to reduced thrombin generation.
This leads to the formation of an unstable clot that is easily dislodged causing excessive bleeding.

Question 8

Classification of haemophilia

Answer 8

Types of haemophilia according to inheritance- congenital and acquired.
Types of haemophilia according to the type of factor deficit- haemophilia A or B

Question 9

Classification of severity of haemophilia

Answer 9

Mild (>5-40% clotting factor level (CFL))- severe bleeding with trauma and injury.
Moderate (1-5% CFL)- Occasional spontaneous bleeding.
Severe (<1% CFL)- frequent spontaneous bleeding, particularly into joints and muscles, severe bleeding with trauma.

Question 10

Signs and symptoms of haemophilia

Answer 10

Haemophilia A and B are clinically indistinguishable.
Recurrent or severe bleeding.
Bleeding in unusual sites (joints or muscle).
Minor mucocutaneous bleeding (epistaxis, bleeding from gums following minor dental procedures, easy bruising).
Severe bleeding following trauma and surgery.
GI bleeding and haematuria.
Extremity pain/swelling.
Decreased range of motion of an extremity.
Distended and painful abdomen.
Pallor

Question 11

Do women have haemophilia?

Answer 11

Women and girls are normally carriers of congenital haemophilia.
Most commonly present with menorrhagia and bleeding following surgical procedures or childbirth.

Question 12

What is the hallmark sign of congenital haemophilia?

Answer 12

Haemorthosis (musculoskeletal bleeding).

Common bleeding sites include knee, ankle and elbow joints.

Question 13

Investigations in haemophilia

Answer 13

-APTT-usually prolonged; may not be prolonged in mild cases (factor levels >30%)
-Factor VIII and/or factor IX should be requested to confirm the diagnosis if the aPTT is prolonged.
-Mixing study (incubating patient’s plasma with normal plasma for 2 hours at 37 degrees)
-Blood tests:
FBC to rule out thrombocytopenia as a cause of bleeding and to diagnose anaemia.
PT is used to evaluate the extrinsic and common pathways of coagulation.
Von Willebrand factor studies to rule out VW disease
LFTs

Question 14

Imaging studies in haemophilia

Answer 14

Head CT and/or MRI (for evaluation of intracranial haemorrhage)
Neck CT and/or MRI
Abdominal ultrasound or abdominopelvic CT scan for evaluation of GI bleeding.
Upper and/or lower endoscopy.
Plain X-rays- as necessary for bone evaluation.

Question 15

Mutation analysis in haemophilia

Answer 15

Factor VIII or IX mutation analysis to identify the specific genetic mutation.
Women who are known carriers may seek antenatal diagnosis.

Question 16

Differentials of haemophilia

Answer 16

Von Willebrand disease (VWD) 
Platelet dysfunction 
Deficiency of other coagulation factors (factor V, VII, X, XI or fibrinogen) 
Ehlers-Danlos syndrome 
Scurvy 
Fabry's disease 
Child abuse
Disseminated intravascular coagulation

Question 17

Management of haemophilia

Answer 17

Treatment and prevention of bleeding
Long-term management of joint and muscle damage, and of other sequelae of bleeding.
Management and prevention of complications from treatment
Education and promotion of self-guided care
Home therapy
Physiotherapy and joint status- appropriate exercises for muscle strengthening

Question 18

How do you determine the management of an acute bleeding episode?

Answer 18

Disease severity and type.
Inhibitor status
Anatomical site of bleed
History of previous bleeding and type of products used in the past.
Contact information of treating physician/clinic

Question 19

What is a life-threatening bleed in haemophilia?

Answer 19

Life-threatening bleeds include those occurring in the central nervous system, gastrointestinal tract, or airway, or into the iliopsoas.

Urgent treatment is necessary even before full assessment.

Factor levels need to be monitored to adjust dose and frequency. Monitoring is usually done by measuring a trough blood factor level before the first dose in the morning.

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction due to safety concerns regarding the increased risk of thrombosis.

Question 20

Management of life-threatening bleed in haemophilia

Answer 20

-No factor inhibitor:
1)The factor for the relevant disorder (factor VIII for haemophilia A, factor IX for haemophilia B) should be administered urgently.
2)Resuscitation and basic life supportive measures (ABC) are required.
3) Antifibrinolytic agents such as tranexamic acid or aminocaproic acid work by inhibiting plasmin, a critical enzyme involved in fibrinolysis.
These agents may be used as adjunctive therapy to factor replacement to control mucosal bleeding (oral, nasal, gastrointestinal, uterine) but are contraindicated in the presence of haematuria. The use of antifibrinolytic agents should be avoided in patients with bleeding into the pleural space
-Factor inhibitor:
Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working.
Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction.
Factor VIII inhibitor bypassing fraction contains variable amounts of activated and precursor vitamin K-dependent clotting factors (factors II, VII, IX, and X), which generate thrombin by bypassing the coagulation cascade.

Question 21

Management of non-life-threatening bleed into joint or muscle in haemophilia

Answer 21

-No factor inhibitor:
1)The factor for the relevant disorder (factor VIII for haemophilia A, factor IX for haemophilia B) should be administered urgently.
2) Adjunctive measures include rest, ice, compression, and elevation (RICE), analgesia, and physiotherapy evaluation.
Immobilisation and joint paracentesis are not routinely necessary.
-Factor inhibitor:
Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working.
Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction.
Factor VIII inhibitor bypassing fraction contains variable amounts of activated and precursor vitamin K-dependent clotting factors (factors II, VII, IX, and X), which generate thrombin by bypassing the coagulation cascade.

Question 22

Management of non-life-threatening bleed into the urinary tract in haemophilia

Answer 22

-No factor inhibitor:
1) The relevant factor for haemophilia A or B (factor VIII for haemophilia A, factor IX for haemophilia B) is required.
Infusion of a factor in these cases can be done at home by patient/family or set up through home health care.
2) Fluid replacement is with intravenous or oral fluid at a rate of 1.5 times maintenance levels.
-Factor inhibitor:
Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working.
Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction.
Factor VIII inhibitor bypassing fraction contains variable amounts of activated and precursor vitamin K-dependent clotting factors (factors II, VII, IX, and X), which generate thrombin by bypassing the coagulation cascade.

Question 23

Management of non-life-threatening nasal or oral bleed in haemophilia

Answer 23

• No factor inhibitor: mild haemophilia A:
  1) Desmopressin (A desmopressin test dose should be given in the doctor’s office or clinic, which should produce a 2- to 4-fold rise in the levels of factor VIII)
  2) Antifibrinolytic agents such as tranexamic acid or aminocaproic acid work by inhibiting plasmin, a critical enzyme involved in fibrinolysis.
• No factor inhibitor: haemophilia B or moderate-severe haemophilia A:
  1) The appropriate factor concentrate (either factor VIII or factor IX) is given on demand every 12 to 24 hours until symptoms have resolved. On-demand treatment is treatment on an as-needed basis for bleeding and can be administered as an outpatient. Desmopressin is not effective for the treatment of patients with haemophilia B, as factor IX levels are not influenced by desmopressin.
  2) Antifibrinolytic agents such as tranexamic acid or aminocaproic acid work by inhibiting plasmin, a critical enzyme involved in fibrinolysis.
• Factor inhibitor:
  1) Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction.
  2) Antifibrinolytic agents such as tranexamic acid or aminocaproic acid work by inhibiting plasmin, a critical enzyme involved in fibrinolysis.

Question 24

Ongoing management of haemophilia

Answer 24

-Factor inhibitors:
1)The ultimate goal in inhibitor patients is to eliminate the inhibitor with the use of immune tolerance induction (ITI).
Patients receive high doses of factor VIII or IX concentrate for months to years, usually given once a day, although some patients may be treated 3 times/week.
2)Prophylaxis with a bypassing agent may be used to decrease bleeding rates in patients with factor inhibitors. This may be done during ITI (although bleeding rates tend to decrease once ITI is initiated), if unable to initiate ITI, or if ITI fails to clear the inhibitor.
3) Radioactive synovectomy (synoviorthesis) is often recommended when there are recurrent bleeds into a single specific (target) joint.
-No factor inhibitors: severe haemophilia:
1) Prophylaxis is indicated in most patients with severe haemophilia A or B. It is defined as regular, continuous intravenous factor replacement given for at least 45 weeks/year in anticipation of, and to prevent, bleeding.
2) Radioactive synovectomy (synoviorthesis) is often recommended when there are recurrent bleeds into a single specific (target) joint.