INTRODUCTION TO HAEMOPHILIA

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1 INTRODUCTION TO HAEMOPHILIA Dr Clodagh Ryan, Consultant Paediatric Haematologist, CUH Ms Norma Collins, CNS Bleeding Disorders, CUH 5 th September 2009

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4 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.

5 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 FIX

6 HAEMOPHILIA HAEMOPHILIA A Deficiency of FVIII X-Linked Disorder 1:10,000 live births HAEMOPHILIA B Deficiency of FIX (aka Christmas disease) X-Linked Disorder 1:50,000 live births

7 Classification Factor Level Severe < 1% Moderate 1-5% Mild > 5% Normal %

8 HOSPITAL FOR SICK CHILDREN : COMPREHENSIVE CARE HEMOPHILIA PROGRAM N = 179 Mild 7 % Moderate 8 % Severe 7 % Inhibitors 2 % Severe 34 % VIII 76 % IX 22 % Inhibitors 2 % Mild 28 % Moderate 14 %

9 Pediatric Comprehensive Care Hemophilia Team Medical Specialties Infectious Disease Gastroenterology Community Physician School HIV Clinic Dental Hemophilia MD Nurse Psychosocial Psychiatry Genetics Laboratory Blood Bank Coagulation Musculoskeletal

10 OPTIMAL DAGNOSIS / CARE FOR PERSONS WITH HEMOPHILIA -% optimal Comprehensive care hemophilia model - Unlimited access to safe factor concentrates 50 80% of persons with hemophilia in the world have limited or no access to accurate diagnosis and safe factor concentrates 0 - Diagnosis often not confirmed - No or limited access to safe factor concentrates

11 Inheritance How do people get haemophilia? People are born with haemophilia. (very rarely acquired) Haemophilia is usually inherited, meaning that it is passed on through a parent s genes. Genes carry messages about the way the cells of the body work.

12 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

13 INHERITANCE 2/3 will have family history, remainder spontaneous mutation Obligate carriers - Daughter of patient with haemophilia - mum with two sons with haemophilia - mum with one son with haemophilia and strong family Hx on maternal side. Mum a carrier for the haemophilia mutation and pregnant male fetus : 1:2 chance of having haemophilia female fetus : 1:2 chance of being a carrier

14 INHERITANCE OF HAEMOPHILIA

15 Is Haemophilia lifelong? A person born with haemophilia will have it for life. The level of factor VIII or IX in his blood usually stays the same throughout life. FIX Leiden

16 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

17 CHRONIC JOINT BLEEDING

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19 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.

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

21 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.

22 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.

23 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 t move properly. May bleed more often. Nerve damage.

24 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.

25 Treatment of Bleeds Bleeds should be treated quickly to recover more fully, quickly and prevent later damage. If in doubt, treat. Don t wait!

26 Factor Concentrates CONCENTRATE Advate Recombinant INDICATION FVIII Deficiency HALF - LIFE 12 Hours BeneFIX Recombinant FIX Deficiency 18 Hours Novoseven Recombinant Patients with inhibitors to FVIII or FIX +/-2.7 Hours

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

28 PROPHYLAXIS

29 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

30 Prophylaxis Definition Treatment by intravenous injection of factor concentrate in anticipation of and in order to prevent bleeding Consensus Conference on Prophylaxis ( London, UK 2002 ) Erik Berntorp et al Hemophilia 2003 ; 9 (suppl 1 ) : 1-4

31 HISTORY OF PROPHYLAXIS IN HEMOPHILIA 1958 Prophylaxis in boys with severe hemophilia A initiated in Malmö, Sweden by Prof. Inga Marie Nilsson and her colleagues

32 Twenty-five years experience of prophylactic treatment in severe Haemophilia A and B I. M. Nilsson, E. Berntorp, T. Löfqvist & H. Pettersson From the Department of Coagulation Disorders and the Department of Orthopaedics. University of Lund, Malmö General Hospital, Malmö, and the Department of Radiology, University Hospital, Lund, Sweden SWEDEN Malmö Journal of Internal Medicine 1992 ; 232 : 25-32

33 we therefore reasoned that, if the plasma concentration of factor VIII could be maintained at a level of at least 1% of normal in severe hemophilia A, it might be possible to change the hemophilia from a severe to a milder form Nilsson IM et al J Int Med 1992 ; 232 : 25-32

34 Malmö High-Dose Prophylaxis Regimen Hemophilia A IU FVIII / kg alternate days ( minimum x 3 per week ) Hemophilia B IU FIX / kg x 2 per week

35 Prophylactic Treatment of 60 Patients with Severe Hemophilia AGE ( YEARS ) Number of Cases Age ( yr ) at start of prophylaxis Number of joint bleeds / yr Orthopaedic joint score Radiological joint score Values shown are means

36 Study Group N = Haemophilia A Haemophilia B 13 British Journal of Haematology 1999 ; 105 :

37 HISTORY OF PROPHYLAXIS IN HEMOPHILIA Late 1960 s Prophylaxis introduced in the Netherlands by Professor Van Creveld IU F VIII / kg x 2-3 per week after the occurrence of joint bleeding with therapy escalated to prevent joint bleeding

38 High-Dose ( Malmö ) Intermediate Dose ( Netherlands) Number of Cases 18* 42 Number of Joint Bleeds / Year 0.2** 3.7 Orthopaedic Joint Scores 0 ( 0-0 ) 0 ( 0-2 ) Pettersson X-Ray X Score 0 0 ( 0-5 ) * Patients with severe hemophilia born between ** Values are medians ( interquartile ranges ) Haemophilia 2002 ; 8 :

39 Retrospective cohort study of 76 patients with severe factor VIII / IX deficiency who were born in the period patients who started prophylaxis early ( < 3 joint bleeds ) were e more likely to have normal joints than those who started prophylaxis after 3 or more joint bleeds ( 70% vs 31% ) joint damage increased with each year that prophylaxis was delayed after the first joint bleed [ 8% higher radiologic joint score ( Pettersson score ) per year of delay ] Blood 2002 ; 99 :

40 HISTORY OF PROPHYLAXIS IN HEMOPHILIA Report of USA Joint Outcome Study Manco-Johnson M et al NEJM 2007;357:

41 KEY FINDINGS Correlation between the number of clinically evident hemarthroses and joint failure defined by MRI leading the investigators to suggest that : chronic microhemorrhages into the joints or subchondral bone in young boys with hemophilia causes deterioration of joints without clinical evidence of hemarthroses and that prophylaxis prevents this subclinical process Manco-Johnson MC et al N Engl J Med 2007 ; 357 :

42 HISTORY OF PROPHYLAXIS IN HEMOPHILIA 2006 JTH 2006; 4:

43 Study Protocol STEP 1 STEP 2 50 Units / kg x 1 / week 30 Units / kg x 2 / week Escalatio n STEP 3 25 Units / kg on alternate days ( minimum x 3 / week ) Escalatio n

44 On Demand Therapy Intermediate Dose Prophylaxis ( Netherlands, Canada) Full Dose Prophylaxis ( Malmö Protocol ) Cost $ $$ $$$$ Size of +++ benefit +++ +?

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46 Health-Related Quality of Life Measures in Hemophilia Haemo - QoL ( 1 ) CHO - KLAT ( 2 ) 1. von Mackensen S, Bullinger M and the Haemo-QoL Group Haemophilia 2003 ;10 ( suppl 1 ) : Young NL et al. Development of a health - related quality of life measure for boys with haemophilia : The Canadian Haemophilia Outcomes Kids Life Assessment Tool ( CHO - KLAT) Hemophilia 2004 ; 10 ( suppl 1 ) : 34 43

47 PROPHYLAXIS : NEED FOR INDIVIDUALIZED THERAPY

48 Acknowledgements WFH World Federation of Haemophilia Haemophilia in Pictures Norma Collins, Helen Brown, Brid Booth Fleming and Ann- Marie Ryan CNS, Bleeding disorders, CUH. Professor V Blanchette, The Hospital for Sick Children, Toronto