inherited disorders of haemostasis and thrombosis dr cleona duggan consultant haematologist
TRANSCRIPT
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Inherited Disorders of Haemostasis and
Thrombosis
Dr Cleona DugganConsultant Haematologist
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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 plasmawork together to form a clot over the plug.
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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 plasmawork together to form a clot over the plug.
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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
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Vesselinjury
PlateletRelease rxn
PlateletAggregation
Vasoconstriction CoagulationCascade
StableHaemostatic Plug
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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
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Principal Bleeding Disorders
• Haemophilia A (factor VIII deficiency)
• Haemophilia B (factor IX deficiency)
• von Willebrand Disease (vWD)
• Other
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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
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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)
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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
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INHERITANCE OF HAEMOPHILIA
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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
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DISEASE SEVERITY
50-200% 5-50% 2-5% <1%
Mild Moderate Severe
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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
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Ankle bleed
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Bleeding following a vein puncture using a vacuum system
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Femoral arterial puncture
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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
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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
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HAEMOPHILIA - HAEMARTHROSIS
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CHRONIC JOINT BLEEDING
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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.
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What happens in a joint bleed?
• joint feels tingly and warm.
• Swelling, painful and difficult to move.
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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.
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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.
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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.
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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.
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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.
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Treatment of Bleeds
• Bleeds should be treated quickly to recover more fully, quickly and prevent later damage.
• If in doubt, treat. Don’t wait!
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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
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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
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Factor Concentrates
CONCENTRATE INDICATION HALF - LIFE
Advate Recombinant
FVIII Deficiency 12 Hours
BeneFIXRecombinant
FIX Deficiency 18 Hours
NovosevenRecombinant
Patients with inhibitors to FVIII or FIX
+/-2.7 Hours
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Role of factor concentrate
• Replaces missing factor
• Injected IV
• Bleeding stops when enough factor reaches the bleeding site
• Treat ASAP
• R.I.C.E.
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Investigation of bleeding disorders
• PT, APTT• Von Willebrand Factor• Specific clotting factor assays• Platelet function testing
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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
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Von Willebrand Disease
• Up to 1% of the population
• 125 / million have a clinically significant bleeding disorder
• Autosomal inheritance
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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
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Von Willebrand Disease
• MILD/MODERATE BLEEDING TENDANCY mucocutaneous bleeding
• easy bruising• epistaxis• menorrhagia• recurrent iron deficiency• family history
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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
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VWD TREATMENT -Specific measures
• Fandhi –plasma derived product
• DDAVP
• Cyclokapron
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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
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VWD TREATMENT -Specific measures
• Cyclokapron– Antifibrinolytic agent– Stabilises clot– Given orally– Provides adequate cover for minor procedures or
dental work
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Recognition of Bleeding Disorders
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The Bleeding History
• Personal history– Epistaxis– Bleeding post surgery– Bleeding post dental extraction– Menorrhagia– History of anaemia– Easy bruising
• Family history NB
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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 post-
trauma bleeding
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Investigations
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TISSUE FACTOR
+TFVIITISSUE FACTOR
COMPLEXXI
IXX
VIII
V
PROTHROMBINTHROMBIN
VII VIIa
FIBRINOGEN
Va
VIIIa
XIa
IXaXa
TRIGGER
FIBRIN
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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
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Tissue Damage
Tissue Factor Exposure / Thromboplastin
FVIIFVIIa
FX
FXa
II IIa
Fibrinogen Fibrin
Fibrin Polymer
Fibrin Clot
FV FVa
Tissue factor (Extrinsic) Pathway
IIa
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Kallikrein Prekallikrein
FXII
FXIIaFXI
FXIaFIX
FIXaFX
FXa
II IIa
Fibrinogen Fibrin
Fibrin Polymer
Fibrin Clot
FVIII FVIIIa
FV FVa
Contact factor (Intrinsic) Pathway
IIa
IIa
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VWD diagnosis
• Coag screen often normal
• VWF - quantiative assays
• VWF Ricof - functional assay
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VWD - diagnosis
• Levels increased by menstrual cycle, OCP, pregnancy, smoking, stress,
inflammatory disorders
• Repeat sampling recommendedequivocal resultsminor abnormalitiesstrong personal or family history