kuliah Hemofilia UPH

1. Hemophilia A, B
Von Willebrand disease
disease
Theo Audi Yanto

2. Hemophilia A
Hemophilia B
Hemophilia B

3. Definition
• Hemophilia- “love of bleeding”
• 2 types: A and B
• Hemophilia A:
• X linked recessive hereditary
disorder that is due to defective or
deficient factor VIII

4. Incidence
• It is the second most common inherited
clotting factor abnormality (after von
Willebrand disease)
• 1 in 5000-10000 live male births
• No difference between racial groups

6. Genetics
• Transmitted by females, suffered by males
• The female carrier transmits the disorder to half their sons
and the carrier state to half her dtrs
• The affected male does not transmit the disease to his
sons (Y is nl) but all his dtrs are all carriers (transmission
of defected X)

7. Russian House
British House
Spanish
House

8. Hemophilia A
Factor VIII deficiency
1 in 5000-10000 males
60% with severe disease
Actvitiy < 1%

9. Hemophilia B
Factor IX deficiency
1 in 25000-35000 males
30% spontaneous mutation
50% with mild to moderate
disease
Activity > 1%
Christmas disease (1952)

13. •Deficiency of factor VIII or IX affects the propagation phase
of coagulation
•Most likely to cause bleeding in situations where tissue
factor exposure is relatively low

14. Bleeds in Hemophilia
• Minor Bleeds
– Oral mucosa
– Intra-articular
– GI/GU
– Intramuscular
• Major Bleeds

15. ACUTE COMPLICATIONS OF HEMOPHILIA
Hemarthrosis
Muscle hematoma (pseudotumor) (joint bleeding)

16. 16

17. Clinical Manifestations:
•
Hemarthrosis
The most common, painful and most physically,
economically and psychologically debilitating
manifestation.
• Clinically:
 Aura: tingling warm sensation
 Excruciating pain
 Generally affects one joint at the time
 Most commonly: knee; but there are others as elbows,
wrists and ankles.
 Edema, erythema, warmth and LOM
 If treated early it can subside in 6 to 8 hs and
disappear in 12 to 24 hs.
 Ddx: DJD
 Complications: Chronic involvement with joint
deformity complicated by muscle atrophy and soft

18. Nerve destruction
Joint damage
LONG-TERM COMPLICATIONS
OF HEMOPHILIA

19. Clinical Manifestations
Hemarthrosis-Images
• Stage III- early  Stage IV- narrowing of
intraarticular space
subchondral cyst

20. Clinical Manifestations
Hematomas
• Subcutaneous and muscular hematomas spread within
fascial spaces, dissecting deeper structures
• Subcutaneous bleeding spreads in characteristic manner- in
the site of origin the tissue is indurated purplish black and
when it extends the origin starts to fade
• May compress vital structures: such as the airway if it is
bleeding into the tongue throat or neck; it can compromise
arteries causing gangrene and ischemic contractures are
common sequelae, especially of calves and forearms
• Muscle hematomas: 1)calf,2)thigh,3)buttocks,4)forearms
• Psoas hematoma- if right sided may mimic acute
appendicitis
• Retroperitoneal hematoma: can dissect through the
diaphragm into the chest compromising the airway. It can
also compromise the renal function if it compresses the
ureter

21. Clinical manifestations
Pseudotumors
• Dangerous and rare
complication
• Blood filled cysts that are
gradually expanding
• Occur in soft tissues or
bones.
• Most commonly in the thigh
A pseudotumor is deforming the cortex of the femur (arrow). • As they increase in size they
Other ossified masses in the soft tissues (arrowheads) are
probably soft-tissue pseudotumors. erode contiguous structures.
• May require radical surgeries
or amputation, and surgery is
often complicated with
infection

22. Clinical manifestations
Intracranial
hemorrhage
• Leading cause of death of
hemophiliacs
• Spontaneous or following
trauma
• May be subdural, epidural or
intracerebral
• Suspect always in hemophilic
patient that presents with
unusual headache
• If suspected- FIRST TREAT,
then pursue diagnostic
workup
• LP only when fVIII has been
replaced to more than 50%

23. Clinical manifestations
Severity F VIII activity Clinical manifestations
Spontaneous hemorrhage from early infancy
Severe <1%
Freq sp hemarthrosis
Hemorrhage sec to trauma or surgery
Moderate 2-5%
Occ sp hemarthrosis
Hemorrhage sec to trauma or surgery
Mild >5%
Rare sp bleeding
• Frequency and severity of bleeding are related to F VIII levels
 Coinheritance of prothrombotic mutations (i.e. Factor V Leiden) can
decrease the risk of bleeding

24. History taking
• sign of Hemorrhage
• Family history
• infection related transfusion:
• HIV, hepatitis realated symptom

25. Physical examination
• Sign of bleeding
• Vital sign: tachycardia, tachypnea, hypotension,
orthostasis
• Organ system-specific sign of hemorrhage:
• MSK, CNS, GI, GUT

26. Hemophilia: Work-up
Hgb/Hct nml/low
PT nml
aPTT high/nml
Platelets nml
Factor levels (50-150%)
Mild > 5%
Moderate 1-5%
Severe < 1%
Inhibitor levels
Low titer 0-10 Bethesda U
High titer > 10 Bethesda U

28. 28

29. Normal PT
Abnormal PTT
50:50 mix is
Repeat abnormal
with Test for inhibitor activity:
50:50 Specific factors: VIII,IX, XI
mix Non-specific (anti-phospholipid Ab)
50:50 mix is normal
Test for factor deficiency:
Isolated deficiency in intrinsic pathway
(factors VIII, IX, XI)
Multiple factor deficiencies (rare)

30. 30

31. •Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 days
•Trough factor levels with q 12 h dosing after major surgery should be at least 50-75%
•Most joint and muscle bleeds can be treated with “minor” (50%) doses for 1-3 days without
monitoring

32. Treatment: The Old Days
Factor replacement
 Units = (wt[kg]) x (50mL plasma/kg) x (1 U factor/mL plasma) x
(desired factor level – native factor level)
FFP: 10-20 mL/kg BB will increase factor level 20-30%
Number of unit : desire dose (mL)/200 mL/unit
Plasma concentrates
Thousands of donors
Hepatitis B, C
HIV (60-70%)

33. Cryoprecipitate AHF
(Antihemophilic Factor)
(Antihemophilic Factor)
Berisi Faktor VIII
Faktor XIII
Von Willebrand Factor dan
fibrinogen
(suhu simpan ≤30°C)
Kandungan: 70 IU/unit F VIII dan >
140mg/unit fibrinogen
33

34. Replacement Therapy
Plasma-derived Recombinent
Heating  1990s
Solvent-  Cost
detergent  2-3 x
mixture  Persistent inhibitors
Hep A  10-15%
Parvovirus B19
CJD

35. Factor VIII containing
products
Factor VIII, human plasma
derived :
Monarc M, Monoclonat, hemofil
M, Koate-DVI, recombinate,
kogenate, helixate, advate,
xyntha
35

36. Factor VIII concentrates differ in purity and
manufacturing processes
Plasma-derived Recombinant
Intermediate High Ultrapure Standard Human albumin-
free
Humate-P Koate-HP Hemofil-M Recombinate Advate
Alphanate Monoclate Kogenate ReFacto-AF
Monarc-M Helixate
ReFacto

37. A little about cost
Product Cost/dose
Recombinant FVIII $4400
Monoclonal FVIII $3300
BeneFIX $8800
Mononine $8300
FEIBA $5000
NovoSeven $6500 x 2

38. Other meds
•Amicar (epsilon aminocaproic
acid) (antifibrinolytic)
•DDAVP (antihemophilic)

39. Von Willebrand
Disease
• Inherited
• Deficiency or dysfunction of vWF
• vWF, a large, multimeric glycoprotein
• mediate adhesion of platelet
• bind and stabilized procoagulant FVIII

40. vWF
• 125/1.000.000
• severe disease only 0.5-5/million
• Male and female equaly
• mild and manageable bleeding

41. vWD
• 1) partial quantitative deficiency (type I)
• (2) qualitative deficiency (type II)
• (3) total deficiency (type III)

42. Work Up
• Bleeding time
• PT and aPTT
• vWD Factor Antigen
• Ristocetin activity
• vWD multimeric Panel
• Genetic Testing

43. Presentation
• Easily bruising
• prolonged bleeding
• severe hemorrhage after surgery
• menorrhagia
• Physical finding: usually normal, only sign of
bleeding or bruises

44. Treament
• Desmopressin DDAVP
• 150 mcg intra nasal 2 h prior to
procedure
• Transfusion: Cryoprecipitate
• Plasma derived: Humate-P (intermediate)

45. Disorder BT Plt PT aPTT TT Fib
Vasculopathie
s, connective
tissue
Normal or
diseases, or Long Normal Normal Normal Normal
increased*
collagen
disorders
affecting skin
Thrombocyto
Long Low Normal Normal Normal Normal
penia
Qualitative
Normal or
platelet Long Normal Normal Normal Normal
low•
abnormalities
Hemophilia A
(factor VIII Normal Normal Normal Long Normal Normal
deficiency)
von
Willebrand Long Normal** Normal LongΔ Normal Normal
disease
Disseminated
intravascular Long Low Long Long Long Low
coagulation