1. Hemophilia
Dr. Kalpana Malla
MD Pediatrics
Manipal Teaching Hospital
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2. Introduction:HAEMOPHILIA
• Commonest inherited bleeding
disorder
• Bleeding due to deficiency of FVIII /
IX / XI coagulant activity
• Severity of bleeding is related to
FVIII / IX /XI concentration in blood

3. INCIDENCE
• 1 per 5,000 male births
• 1 per 10,000 population
• 85 % - F VIII deficiency
• 10- 15 % - F IX deficiency
• Haemophilia A: B= 7:1

4. Mode of Inheritance :
– X- linked recessive
Males affected
Females carriers

5. INHERITANCE

6. INHERITANCE
• Father with Haemophilia:
Daughters are carriers Sons normal
• Mother with haemophilia gene (carrier)
Sons 50:50 normal or affected
Daughters 50:50 normal or carriers

7. FEMALES AFFECTED ONLY WHEN:
1) TURNERS SYNDROME
2) MOSAICISM/LYONISATION
3) MOTHER TO DAUGHTER
TRANSMISSION (POSSIBLE
THEORETICALLY BUT EXTREMLY
RARE)

8. Types:
• Haemophilia A – deficiency of Factor VIII
• Haemophilia B – deficiency of Factor IX
• Haemophilia C – deficiency of Factor XI

9. HAEMOPHILIA A & B:
• Basic abnormality :
1. Reduction in amount of protein in
factor
2. Dysfunctional protein
5-10 % Haemophilia A
40-50 % ” ” B

10. Severity of haemophilia
• 1 ml of normal plasma contains 1 unit (U) of each
factor
100 ml plasma contains 100 U/dl (100 % activity)
Severity depends on factor level in blood:
● Severe haemophilia: < 1 U/dl (%)
● Moderate haemophilia: 1-5 U/dl (%)
● Mild haemophilia: 5-30 U/dl (%)

11. Severity of haemophilia
• Haemostatic level of factor VIII: 30-40 U/dl
• ” ” of factor IX: 25-30 U/dl

12. Severity of Haemophilia
Severity Factor Type of presentation
level
iu/dl (%)
Severe <1 Spontaneous bleeds, Severe bleeding
Moderate 1-5 Few bleeds, Haemathrosis - traumatic
Mild 5-30 Few bleeds, Post-traumatic
Post-dental surgery

13. Pathophysiology:
tissue injury
platelet plug
delayed (Haemophilia A & B)
fibrin clot
prolonged bleeding

14. CLINICAL FEATURES – SUBTLE
• Bleeding as a baby rare
• Prolonged bleed from umbilical cord
• Muscle hematoma during immunisation
• Bleeding during circumcision

15. CLINICAL FEATURES – SUBTLE
• Toddlers - Large and prolonged bleed to
trivial injury/cuts/abrasions
• Lip bleeds (hematomas)
• First bleeding in childhood
Tooth extraction
Trauma with walking
Gum bleeds while brushing teeth

16. SIGNIFICANT HEMORRHAGES
• RETROPERITONEAL H’GE: severe abd
pain, anemia and shock
• HEMATURIA
• GI BLEED : difficult to control, severe
• INTRACRANIAL:
extradural, subdural, intracerebral
- Headache, vomiting, altered sensorium ->
coma
• May be seen in neonates

17. SUBDURAL HEMORRHAGE

18. CLINICAL FEATURES - FRANK
HEMARTHROSIS (joint bleed) – hallmark of
hemophilia
• Joints affected:
• in toddlers - ankle (most common) – earliest jt
involved due to lack of stability as they assume
upright posture
• Older child – knee, elbow (most common)
** Target joint – recurrent bleeding at a same
joint
• LL > UL

19. CLINICAL FEATURES - FRANK
• Later : all joints
• Contact sports can provoke
• Recurrent – may be unprovoked,
spontaneous
LARGE HEMATOMAS & EXTENSIVE
ECCHYMOSES

20. BLEEDING INTO JOINTS
• First haemorrhage : Swelling >> Pain
• Subsequent haemorrhages: Pain >>
Swelling

21. Bleeding in Haemophilia
• Acute Haemarthrosis
• Chronic haemophilic arthropathy
• Bleeding into muscles
• Haemophilic pseudo tumour - cysts
• Haematuria
• Gastrointestinal bleeding
• Intracranial bleeding

22. Bleeding in Haemophilia
BLEEDING IN CARRIERS
• Reduced FVIII (IX) levels
• Mild bleeding tendency
• Childbirth

23. C/F OF ACUTE HAEMARTHROSIS
• Abnormal sensation
• Pain and swelling of joint
• Limitation of movement - especially
flexion
• Tenderness and heat in the joint
Acute symptoms last 3-4 days; full recovery
takes weeks

24. STAGES
• Initial bleed into joint - haemarthrosis
• Inflammatory stage affecting
Synovium (synovial hypertrophy)
Cartilage - Bone
• Final Stage
Permanent joint changes
Erosion & destruction Cartilage, Bone -
Knees** ,Ankles** , Elbows*
Wrists
Shoulders less common
Hips

25. Chronic Haemophilic Arthropathy
• Repeated bleeds - many years 
Chronic degenerative changes
• Chronic haemophilic arthritis → Loss
of joint movement → Fixed flexion
contractures → Severe muscle wasting
→ Muscle action imbalance →Valgus
deformities → Crippling deformities →
Wheel chair-bound

26. Chronic Haemophilic Arthropathy – Radiological
Changes
• Epiphyseal overgrowth
• Enlargement of bone ends
• Loss of cartilage (joint space)
• Gross irregularity articular surface
–Subchondral collapse
–Subchondral cysts
–Osteophyte formation
–Osteoporosis
–Changes in joint alignment

27. HAEMOPHILIC PSEUDO TUMOURS (BLOOD
CYSTS)
• Cysts within the fascial muscle envelope
• Cysts arising in muscles
• Cysts arising from sub-periosteal
haemorrhage
• Pseudo tumours in bone
• Gross destruction of normal architecture
of bone
• Large bone cysts
• Pathological fracture

28. Complications :
• Pain
• Anaemia (proportionate to bleeding)
• Constitutional disturbances:
fever < 24 hrs
anorexia, malaise
• Chronic arthritis
• Pressure effects of large haematomas
• Transfusion acquired infections
• Inhibitors

29. Lab findings:
• Hb low – proportional to blood loss
• Platelets- normal
• Bleeding time -normal
• PT normal
• APTT prolonged > 2-3 times ULN
• CT prolonged
• Low levels of F VIII / IX
• Factor VIII and IX assay : mixing studies
• Genetic analysis

30. MIXING STUDIES
• To determine if prolonged PT or PTT is due to
a factor deficiency or an inhibitor
• Normal plasma : all Clotting factors-V,VIII,
IX,X,XI,XII
• Method: add patient plasma to equal volume
of normal plasma and repeat PT & PTT
• Correction of PT & PTT – suggests- deficiency
of clotting factors
• Assays for factors

31. MIXING STUDIES
• Remains prolonged after mixing study:
indicates inhibitor - most common is
lupus anticoagulant
- therapeutic anticoagulant
- rarely ,inhibitors to factors VIII, IX, XI

32. MIXING STUDIES
• With normal /adsorbed plasma/aged plasma
• Normal plasma : all factor present
• Adsorbed plasma : FIX- deficient
• Aged plasma - FVIII- deficient
• Mix patient’s plasma with normal /aged/
adsorbed plasma –
• Correction of APTT with normal & aged
plasma/ not with adsorbed plasma  F IX
deficiency

33. • Correction of APTT with normal /
adsorbed plasma & not with aged
plasma  F VIII deficiency
• If correction does not occur suspect
inhibitor

34. Inhibitors:
• Antibodies against factors blocks clotting
activity
• 14-25 % patients who receive factors (VIII/ IX)
• Failure of a bleeding episode to respond to
appropriate replacement therapy 1st sign of
inhibitor
• Others develop higher titres 
desensitisation- higher doses of factors given

35. RADIOLOGICAL INVESTIGATIONS
• Radiographs of joints
• USG joints for effusions
• MRI joints/ abdomen
• CT head

37. MANAGEMENT -PRINICIPLES
• Control bleeding episodes – replacement
therapy
• Prophylaxis and prevention
• Life style modifications
• Treatment of complications
• Rehabilitation
• Antenatal diagnosis and counselling
• Team effort : pediatrician, hematologist,
orthopedician, physiotherapist, dentist

38. REPLACEMENT THERAPY
• Fresh whole blood
• FFP
• Cryoprecipitate
• Factor concentrates
• Recombinant/ porcine factor VIII FIX :
inhibitors of natural F-VIII/IX
• Prothrombin complex concentrates
(PCC)

39. FFP AND CRYOPPT
• FFP contains F VIII and IX
• CRYOPPT contains F-VIII, fibrinogen, VWF
• 1 unit FFP = 200 units factor VIII/IX
• 1 unit cryoppt = 100 units factor VIII
• FVIII 1u/kg Increase plasma factor VIII by 2% (
2 iu/dl) - t ½ = 8 hrs
• FIX 1u/kg Increase plasma factor IX by 1%
(1iu/dl) - t ½ = 18-20 hrs
• Risk of HIV, HBV, HCV, CMV transmission

40. FACTOR CONCENTRATES
• Prothrombin complex concentrates
(PCC) - Contain F IX & Vitamin K
dependent factors I.e. II, VII, IX, X – high
cost
• Pure factor IX concentrates available
– Currently high cost

41. THERAPY FOR HAEMOPHILIA
• FACTOR RECOVERY AFTER I.V.
INFUSION
Factor VIII 100%
Factor IX30-50%
• Raise factor levels to:
100 U/dl – life threatening bleeds
35- 40 U/dl – other bleeds

42. DOSAGE CALCULATION
• Dose of F VIII (U):
desired rise in plasma F VIII (U/dl) X body wt (kg) X
0.5
• Dose of F IX (U):
desired rise in plasma F IX (U/dl) X body wt (kg) X
1.4

43. Factor
FVIII
level FIX Dose
Indication or Site of Bleeding Dose,
Desired, IU/kg
IU/kg*
%
Severe epistaxis; mouth, lip,
20-50 10-25 20-50
tongue, or dental work
Joint (hip or groin) - Repeat in 24-
48 h 40 20 40
Soft tissue or muscle 20-40 10-20 40
Muscle (calf and forearm) 30-40 15-20 40
Muscle deep (thigh, hip, iliopsoas)
40-60 20-30 40-60
Transfuse, repeat at 24 h
Neck or throat 50-80 25-40 50-80

44. Hematuria 40 20 40
Laceration 40 20 40
GI or retroperitoneal
60-80 30-40 60-80
bleeding
Head trauma (no evidence of
50 25 50
CNS bleeding)
Head trauma (probable or
definite CNS bleeding, eg,
100 50 100
headache, vomiting,
neurologic signs)
Trauma with bleeding,
80-100 50 100
surgery†

45. Other measures:
• General supportive measures:
bed rest
hospitalize for severe bleeds
analgesics
Local haemostasis
Immobilisation
Physiotherapy

46. HEMARTHOSIS MANAGEMENT
• 25 U F-VIII/kg q12h
• Prompt rx : prevent early sequalae
• Check APTT
• Joint immobilisation - 48hrs
• Early ambulation and physio
• NSAIDS : Aspirin, indomethacin – with
caution- may induce GI bleed
• Paracetamol, pethidine, diazepam – can be
used
• Home infusions : train for early administration

47. PROPHYLAXIS
• Mild/moderate hemophilia
• 10-20 units/kg 2-3 times/week
• Can have normal life and
participate in sports

48. PREVENTION
• Immunisation : SC not IM
• Avoid IM injections-
apply pressure 5 minutes
• Avoid contact sports

49. PREVENTION
• Orthopaedic care- traction, splinting,
reconstructive surgery
• Regular dental exam and hygiene
• Prophylactic immunization- hep B
• Counselling

50. DRUGS
• EACA - aminocaproic acid
• Tranexemic acid: 25mg/kg/day
• C/I in hematuria- ppt renal failure
• Desmopressin acetate: increases levels for
first 2 days from body stores
• Danazol
• Fibrin glue : tooth extraction

51. Other agents used:
• Tranexamic acid
Used for external bleeding
eg. teeth extraction
Not for internal bleedings
Inhibits fibrinolysis
decreases F VIII requirement

52. • DDAVP D-amino D-arginine Vasopressin
Found to raise FVIII levels
Mild haemophilia- releases F VIII from storage
sites
Moderate to severe cases- no endogenous
stores treatment ineffective
Mild von Willebrand’s disease
Not effective in Haemophilia B

53. • Danazol:
Androgen
Elevates levels of protein in factors
Increases levels of F VIII & F IX
• Prednisolone
Acute synovitis

54. ANTENATAL DIAGNOSIS
• 18-20 weeks
• Male fetuses
• Fetal blood :
• Amniotic fluid fibroblasts :DNA probe
• Chorionic villous sampling :PCR

55. CARRIER DETECTION
• FVIII-C: FVIIIAg = 1:1 normally
• In carriers FVIII-C is low
• Hence ratio: 0.6:1

56. ACQUIRED HEMOPHILIA
• 5-20% of hemophiliacs develop antibodies against
factor VIII/IX with time - alloantibodies
• Hemophilia A > Hemophilia B
• Suspect when failure of therapy
• Manage:
1) porcine FVIII
2) activated prothrombin complex
3) activated FVII
4) plasmapheresis
5) immunosuppresants
6) recombinant FVIII/IX

57. THERAPY FOR HAEMOPHILIA
• DEMAND THERAPY Hospital
Home
Long standing approach to haemophilia
Patient treats when bleeds
Arrest acute bleed
No arrest, long term sequelae
• PROPHYLACTIC THERAPY

58. PROPHYLACTIC THERAPY
• Initiated with the 1st bleed
• Home - self or patient infused
• Small dose FVIII (FIX) 2-3 X /week ( 20%-
30%)
Prevents bleeds
Prevents long term sequelae
THERAPY FOR SURGERY/ DENTISTRY
• Prophylactic
• Enables major procedures - 10 days cover

59. Thank you
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Medical Post [ www.themedicalpost.net ]