Inherited Disorders of
Haemostasis and
Thrombosis
Dr Cleona Duggan
Consultant Haematologist
How does bleeding start and stop?
•
Blood vessel injury
•
The capillary contracts to help slow the
bleeding.
•
Platelets make a plug to patch the
hole.
•
Clotting factors in plasma
work together to form a clot over the
plug.
How does bleeding start and stop?
•
Blood vessel injury
•
The capillary contracts to help slow the
bleeding.
•
Platelets make a plug to patch the
hole.
•
Clotting factors in plasma
work together to form a clot over the
plug.
Prolonged bleeding in Haemophilia
•
Haemophilia - clotting factor absent or
low. This makes it difficult for the blood
to form a clot, so bleeding continues
longer than usual (not faster).
•
FVIII deficiency
FIX deficiency
Vessel
injury
Platelet
Release rxn
Coagulation
Cascade
Vasoconstriction
Platelet
Aggregation
Stable
Haemostatic Plug
Congenital bleeding disorders
•
•
•
•
•
•
•
•
•
•
Haemophilia A (Factor VIII Deficiency)
Haemophilia B (Factor IX Deficiency)
Von Willebrand Disease
Factor X Deficiency
Factor XI Deficiency
Factor VII Deficiency
Factor V Deficiency
Congenital thrombocytopenia
Platelet function defect
Rare defects
Principal Bleeding Disorders
• Haemophilia A (factor VIII deficiency)
• Haemophilia B (factor IX deficiency)
• von Willebrand Disease (vWD)
• Other
Haemophilia
• Haemophilia A
• VIII deficiency
• X-linked, 1/3rd carriers <50% FVIIIC.
• 1:20,000 births
• Haemophilia B
• IX deficiency
• X-linked, 1/3rd carriers <50% FIXC .
• 1:100,000
• These are clinically indistinguishable
Haemophilia
• 1:10,000 males FVIII > FIX x 6
• X-linked recessive -lyonisation- females can be affected.
• 1/3 no family history / spontaneous mutation in FVIII/FIX
genes of mother.
• Molecular diagnosis possible > 90%
• Carrier status of mother can be accurately predicted (though
germline mosaicism cannot be excluded even if maternal DNA does not
appear to carry the mutation)
Inheritance
What are the chances a baby will
have haemophilia?
•
•
Females XX
Males X Y.
• The haemophilia gene is
carried on the X chromosome
• X-LINKED DISORDER
INHERITANCE OF HAEMOPHILIA
Haemophilia
• Spectrum of severity is wide - clinical phenotype tends to
be similar in all affected members of the same family
• When there is no family history, infants with
moderate/severe disease usually present:
– post-circumcision bleeding
– bad “toddler bruising”
– soft tissue/muscle or joint bleeds at 6-18 months of
age
– RARE, intracranial, ilio-psoas, intra-abdominal,
haematuria
DISEASE SEVERITY
50-200%
5-50%
2-5%
Mild
Moderate
<1%
Severe
Detection of Haemophilia
• Family history
• Symptoms
• Haemostatic challenges
– Surgery
– Dental work
– Trauma, accidents
• Laboratory testing


APTT prolonged in FVIII/FIX deficiency
F VIII, F IX ,vWF
Ankle bleed
Bleeding following a vein puncture using a vacuum system
Femoral arterial puncture
Haemophilia in pregnancy
 Delivery & neonatal period is a high risk time for baby and
carrier mother
 In 1/3 of cases there is no family history
 31% of carriers with +ve family history not aware of their
carrier status at delivery*
 Knowledge of carrier status has an impact on delivery and
management of baby
Mothers unaware of their status were more likely to have instrumental deliveries*
*Maclean Haemophilia 2004; 10: 560-4
CLINICAL PRESENTATION
• Bleeding has a prediliction for joints, particularly weight
bearing.
– Haemarthrosis
– Also bleed intramuscularly
– Bleed post haemostatic challenge – surgery/dental
extraction/injury
– Intracranial haemorrhage
HAEMOPHILIA - HAEMARTHROSIS
CHRONIC JOINT BLEEDING
Which joint bleeds are most common?
• Most common ankles, knees,
and elbows – weight bearing
joints
• Bleeds in other joints can
also happen, including the
toes, shoulders, and hips.
What happens in a joint bleed?
• joint feels tingly and warm.
• Swelling, painful and difficult to
move.
Long-term effects of Joint bleeds?
•
Repeated bleeding causes synovium
(lining) to swell
•
The synovium stops producing the
slippery, oily fluid that helps the joint
move.
•
Damages the cartilage- joint stiff,
painful and unstable.
•
With time, most of the cartilage breaks
down and some bone wears away. The
whole process is called haemophilic
arthropathy.
What Happens in a Muscle bleed?
•
During a bleed, the muscle feels STIFF
and PAINFUL.
•
The bleed causes SWELLING that is
WARM and PAINFUL to touch.
•
In some deeper muscles, the swelling
may press on nerves or arteries,
causing TINGLING and NUMBNESS
•
muscle SPASM.
Common Muscle Bleeds
•
Calf, thigh, and upper arm.
•
Bleeds in the psoas muscle (front of
the hip
•
Can put pressure on nerves and
arteries, causing permanent damage.
(numbness – classic sign)
•
Joints above and below the muscle
can’t move properly. May bleed more
often.
•
Nerve damage.
Serious or Life-threatening bleeds?
• Head injury • Throat /airway bleeds
• Major loss uncommon except after
injury or if related to another
medical condition.
• Other bleeds may be very serious,
but usually not life-threatening, eg
bleeds into the eyes, spine, and
psoas muscle.
Haemophilia
• Mild haemophilia ( 5 - 20 %):
– bleed only with trauma and surgery.
• Severe haemophilia( < 1%) :
–
–
–
–
Haemarthroses 2-8 times/month.
Muscle bleeds.
Intracerebral bleeding
Prolonged bleeding with trauma and surgery.
Treatment of Bleeds
• Bleeds should be treated
quickly to recover more
fully, quickly and prevent
later damage.
• If in doubt, treat. Don’t
wait!
Treatment of bleeding disorders
- general principles
• Avoid IM injections
• Avoid NSAIDs
• Avoid delay in treating the patient. Treat on suspicion
of a bleed
• Listen to the patient - he/she has lifelong experience
• Record any treatment given including batch numbers
to ensure full traceability of factor concentrates
• Contact the haematologist on call if in doubt
Evolution of Clotting Factor Therapy
1. Fresh whole blood
2. Fresh frozen plasma ( FFP )
3. Cryoprecipitate ( “CRYO” )
4. Factor VIII / IX concentrates
5. Ultra high purity plasma derived factor VIII / IX
concentrates
6. Recombinant factor concentrates
Factor Concentrates
CONCENTRATE
INDICATION
HALF - LIFE
Advate
Recombinant
FVIII Deficiency
12 Hours
BeneFIX
Recombinant
FIX Deficiency
18 Hours
Novoseven
Recombinant
Patients with inhibitors to
FVIII or FIX
+/-2.7 Hours
Role of factor concentrate
• Replaces missing factor
• Injected IV
• Bleeding stops when enough factor reaches the bleeding site
• Treat ASAP
• R.I.C.E.
Investigation of bleeding disorders
•
•
•
•
PT, APTT
Von Willebrand Factor
Specific clotting factor assays
Platelet function testing
Von Willebrand Disease





1926
5yr old girl – died at 13yr
during 4th menstrual
period
4 siblings died from
gastrointestinal
haemorrhage
Both parents had
significant bleeding
history
VWF – identified 1950s,
purified 1972, sequenced
1985
Von Willebrand Disease
• Up to 1% of the
population
• 125 / million have a
clinically significant
bleeding disorder
• Autosomal inheritance
Von Willebrand factor
• Large glycoprotein produced by endothelial
cells and megakaryocytes
• Mediates platelet to endothelial adhesion
• Mediates platelet to platelet interaction
• Carrier protein for Factor VIII
Von Willebrand Disease
• MILD/MODERATE BLEEDING TENDANCY
mucocutaneous bleeding
• easy bruising
• epistaxis
• menorrhagia
• recurrent iron deficiency
• family history
VWD Treatment
•
•
•
•
•
Avoid NSAIDs
Avoid IM injections
Vaccinate against Hepatitis A and B
Treat anaemia
Dental hygiene
• Very few patients require treatment with
clotting factor concentrate
VWD TREATMENT
-Specific measures
• Fandhi –plasma derived product
• DDAVP
• Cyclokapron
DDAVP
• Promotes release of VWF and factor VIII from
endothelial cells
• 0.3ug/kg in 100mls N/Saline over 30 mins
• Average response is a threefold rise in VWF and FVIII
• Treatment of choice in responsive patients for
spontaneous bleeding , trauma or minor surgery
• Intra nasal DDAVP
VWD TREATMENT
-Specific measures
• Cyclokapron
– Antifibrinolytic agent
– Stabilises clot
– Given orally
– Provides adequate cover for minor procedures or
dental work
Recognition of Bleeding Disorders
The Bleeding History
• Personal history
– Epistaxis
– Bleeding post surgery
– Bleeding post dental extraction
– Menorrhagia
– History of anaemia
– Easy bruising
• Family history NB
The Bleeding history
• Coag. Deficiencies
• Prolonged bleeding
after trauma and
surgery (>24 hrs).
• Haemarthroses
• Muscle bleeding.
• Platelet defects and
VWD:
• Bruising.
• Petechiae or
purpura.
• Epistaxis.
• Menorrhagia
• Prolonged posttrauma bleeding
Investigations
TISSUE FACTOR
TRIGGER
VII
VII
XI
VIIa
TISSUE FACTOR
COMPLEX
+TF
XIa
IX
IXa
X
VIII
Xa
VIIIa
V
Va
THROMBIN
FIBRINOGEN
PROTHROMBIN
FIBRIN
Investigation of bleeding disorders
• FBC - platelet count
• Prothrombin time (PT) - factors V,
VII, X
• Activated partial thromboplastin
time (APTT)- factors VIII, IX, XI, XII
• Fibrinogen
Tissue factor (Extrinsic) Pathway
Tissue Damage
Tissue Factor Exposure / Thromboplastin
FVIIa
FVII
FX
FV
IIa
FVa
FXa
II
IIa
Fibrinogen
Fibrin
Fibrin Polymer
Fibrin Clot
Contact factor (Intrinsic) Pathway
Kallikrein
Prekallikrein
FXII
FXI
FXIIa
FIX
FVIII
IIa
FXIa
FVIIIa
FX
FV
IIa
FIXa
FVa
FXa
II
IIa
Fibrinogen
Fibrin
Fibrin Polymer
Fibrin Clot
VWD diagnosis
• Coag screen often normal
• VWF - quantiative assays
• VWF Ricof - functional assay
VWD - diagnosis
• Levels increased by menstrual cycle,
OCP, pregnancy, smoking, stress,
inflammatory disorders
• Repeat sampling recommended
equivocal results
minor abnormalities
strong personal or family history