Hemophilia A, B

Von Willebrand
disease

• Theo Audi Yanto

Hemophilia on @slideshare http://www.slideshare.net/theoaudi/hemophilia-16206610

Hemophilia A
Hemophilia B
 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
 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)
 Russian House

British House
Spanish
House
 Hemophilia A
Factor VIII deficiency
1 in 5000-10000 males
 Hemophilia B
Factor IX deficiency
1 in 25000-35000 males
Christmas disease (1952)
•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
 Bleeds in Hemophilia
• Minor Bleeds
– Oral mucosa
– Intra-articular
– GI/GU
– Intramuscular

• Major Bleeds
– Retroperitoneal
– Retropharyngeal
– Intracranial
 ACUTE COMPLICATIONS OF HEMOPHILIA

Hemarthrosis
Muscle hematoma (pseudotumor) (joint bleeding)
2
0
Clinical Manifestations:
Hemarthrosis
 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
 If treated early it can subside in 6 to 8 hs and
disappear in 12 to 24 hs.
 Complications: Chronic involvement with joint
deformity complicated by muscle atrophy and
soft tissue contractures
 LONG-TERM COMPLICATIONS
OF HEMOPHILIA

Joint destruction Nerve damage

Clinical Manifestations
Hemarthrosis-Images

• Stage III- early  Stage IV- narrowing of

subchondral cyst intraarticular space
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
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
• As they increase in size
they erode contiguous
A pseudotumor is deforming the cortex of the femur (arrow). structures.
Other ossified masses in the soft tissues (arrowheads) are
probably soft-tissue pseudotumors.
• May require radical
surgeries or amputation,
and surgery is often
complicated with infection
 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%
 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

•MildFrequency and
>5% severity of bleeding
Hemorrhageare related
sec to to
trauma or F VIII
surgery
levels Rare sp bleeding

 Coinheritance of prothrombotic mutations (i.e. Factor V Leiden)

can decrease the risk of bleeding
 History taking
• Sign of Hemorrhage
• Family history
• infection related transfusion:
–HIV, hepatitis related symptom
Physical examination
• Sign of bleeding
• Vital sign: tachycardia, tachypnea,
hypotension, orthostasis
• Organ system-specific sign of
hemorrhage:
–MSK, CNS, GI, GUT
 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
3
2
 Normal PT
Abnormal PTT
50:50 mix is
Repeat abnormal
with Test for inhibitor activity:
50:50 Specific factors: VIII,IX, XI
Non-specific (anti-phospholipid
mix
Ab)

50:50 mix is normal

Test for factor deficiency:

Isolated deficiency in intrinsic pathway
(factors VIII, IX, XI)
Multiple factor deficiencies (rare)
3
4
•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
 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%)
 Cryoprecipitate AHF
(Antihemophilic Factor)

• Contain Factor VIII

• Factor XIII
• Von Willebrand Factor and fibrinogen
• keep in temperature ≤30°C)
• contain: 70 IU/unit F VIII dan > 140mg/unit
fibrinogen

3
7
Replacement Therapy

 Plasma-derived Recombinent
Heating 1990s
Solvent- Cost
detergent 2-3 x
mixture Persistent inhibitors
10-15%
Hep A
Parvovirus B19
CJD
 Factor VIII containing
products
• Factor VIII, human plasma derived :
–Monarc M, Monoclonat, hemofil M, Koate-
DVI, recombinate, kogenate, helixate,
advate, xyntha

3
9
 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
 A little about cost
Product Cost/dose

Recombinant FVIII $4400

Monoclonal FVIII $3300

BeneFIX $8800

Mononine $8300

FEIBA $5000

NovoSeven $6500 x 2
 Other meds
• Amicar (epsilon aminocaproic acid)
(antifibrinolytic)
• DDAVP (antihemophilic)
 Von Willebrand Disease
• Inherited
• Deficiency or dysfunction of vWF
–vWF, a large, multimeric glycoprotein
–mediate adhesion of platelet
–bind and stabilized procoagulant FVIII
 vWF
• 125/1.000.000
–severe disease only 0.5-5/million
• Male and female equaly
• mild and manageable bleeding
 vWD
• 1) partial quantitative deficiency (type I)
• (2) qualitative deficiency (type II)
• (3) total deficiency (type III)
 Work Up
• Bleeding time
• PT and aPTT
• vWD Factor Antigen
• Ristocetin activity
• vWD multimeric Panel
• Genetic Testing
 Presentation
• Easily bruising
• prolonged bleeding
• severe hemorrhage after surgery
• menorrhagia
• Physical finding: usually normal, only sign
of bleeding or bruises
 Treament
• Desmopressin DDAVP
–150 mcg intra nasal 2 h prior to
procedure
• Transfusion: Cryoprecipitate
• Plasma derived: Humate-P (intermediate)
Disorder BT Plt PT aPTT TT Fib

Vasculop
athies,
connectiv
e tissue Normal
diseases, or
Long Normal Normal Normal Normal
or increased
collagen *
disorders
affecting
skin

Thrombo
Long Low Normal Normal Normal Normal
cytopenia

Qualitativ
e platelet Normal
Long Normal Normal Normal Normal
abnormal or low•
ities
Hemophil
ia A