Inherited Disorders of Haemostasis and

Thrombosis

Dr Cleona DugganConsultant 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 plasmawork 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 plasmawork 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

Vesselinjury

PlateletRelease rxn

PlateletAggregation

Vasoconstriction CoagulationCascade

StableHaemostatic 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% <1%

Mild Moderate 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

BeneFIXRecombinant

FIX Deficiency 18 Hours

NovosevenRecombinant

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 post-

trauma bleeding

Investigations

TISSUE FACTOR

+TFVIITISSUE FACTOR

COMPLEXXI

IXX

VIII

V

PROTHROMBINTHROMBIN

VII VIIa

FIBRINOGEN

Va

VIIIa

XIa

IXaXa

TRIGGER

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 Damage

Tissue Factor Exposure / Thromboplastin

FVIIFVIIa

FX

FXa

II IIa

Fibrinogen Fibrin

Fibrin Polymer

Fibrin Clot

FV FVa

Tissue factor (Extrinsic) Pathway

IIa

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

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 recommendedequivocal resultsminor abnormalitiesstrong personal or family history