Inherited Disorders of Haemostasis and Thrombosis

1. Inherited Disorders of Haemostasis and Thrombosis Dr Cleona Duggan Consultant Haematologist

2. 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.

3. 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.

4. 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

5. Vessel injury Platelet Release rxn Coagulation Cascade Vasoconstriction Platelet Aggregation Stable Haemostatic Plug

6. 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

7. Principal Bleeding Disorders • Haemophilia A (factor VIII deficiency) • Haemophilia B (factor IX deficiency) • von Willebrand Disease (vWD) • Other

8. 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

10. 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 germlinemosaicism cannot be excluded even if maternal DNA does not appear to carry the mutation)

11. 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

12. INHERITANCE OF HAEMOPHILIA

14. 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

15. DISEASE SEVERITY 50-200% 5-50% 2-5% <1% Mild Moderate Severe

16. 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

18. Ankle bleed

19. Bleeding following a vein puncture using a vacuum system

20. Femoral arterial puncture

21. 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

22. 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

23. HAEMOPHILIA - HAEMARTHROSIS

24. CHRONIC JOINT BLEEDING

26. 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.

27. What happens in a joint bleed? • joint feels tingly and warm. • Swelling, painful and difficult to move.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. Treatment of Bleeds • Bleeds should be treated quickly to recover more fully, quickly and prevent later damage. • If in doubt, treat. Don’t wait!

34. 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

35. 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

36. Factor Concentrates

37. Role of factor concentrate • Replaces missing factor • Injected IV • Bleeding stops when enough factor reaches the bleeding site • Treat ASAP • R.I.C.E.

38. Investigation of bleeding disorders • PT, APTT • Von Willebrand Factor • Specific clotting factor assays • Platelet function testing

39. 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

40. Von Willebrand Disease • Up to 1% of the population • 125 / million have a clinically significant bleeding disorder • Autosomal inheritance

45. 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

46. Von Willebrand Disease • MILD/MODERATE BLEEDING TENDANCY mucocutaneousbleeding • easy bruising • epistaxis • menorrhagia • recurrent iron deficiency • family history

47. 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

48. VWD TREATMENT -Specific measures • Fandhi –plasma derived product • DDAVP • Cyclokapron

49. 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

50. VWD TREATMENT -Specific measures • Cyclokapron • Antifibrinolytic agent • Stabilises clot • Given orally • Provides adequate cover for minor procedures or dental work