Hemophilia

1. Hemophilia Download more documents and slide shows on The Medical Post [ www.themedicalpost.net ] Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital

2. Introduction: HAEMOPHILIA Commonest inherited bleeding disorder Bleeding due to deficiency of FVIII / IX / XI coagulant activity Severity of bleeding is related to FVIII / IX /XI concentration in blood

3. INCIDENCE 1 per 5,000 male births 1 per 10,000 population 85 % - F VIII deficiency 10- 15 % - F IX deficiency Haemophilia A: B= 7:1

4. Mode of Inheritance : X- linked recessive Males affected Females carriers

5. INHERITANCE

6. Father with Haemophilia: Daughters are carriers Sons normal Mother with haemophilia gene (carrier) Sons 50:50 normal or affected Daughters 50:50 normal or carriers INHERITANCE

7. FEMALES AFFECTED ONLY WHEN: TURNERS SYNDROME MOSAICISM/LYONISATION MOTHER TO DAUGHTER TRANSMISSION (POSSIBLE THEORETICALLY BUT EXTREMLY RARE)

8. Types: Haemophilia A – deficiency of Factor VIII Haemophilia B – deficiency of Factor IX Haemophilia C – deficiency of Factor XI

9. HAEMOPHILIA A & B: Basic abnormality : 1. Reduction in amount of protein in factor 2. Dysfunctional protein 5-10 % Haemophilia A 40-50 % ” ” B

10. Severity of haemophilia 1 ml of normal plasma contains 1 unit (U) of each factor 100 ml plasma contains 100 U/dl (100 % activity) Severity depends on factor level in blood: Severe haemophilia: < 1 U/dl (%) Moderate haemophilia: 1-5 U/dl (%) Mild haemophilia: 5-30 U/dl (%)

11. Haemostatic level of factor VIII: 30-40 U/dl ” ” of factor IX: 25-30 U/dl Severity of haemophilia

12. Severity of Haemophilia Severity Factor level iu /dl (%) Type of presentation Severe < 1 Spontaneous bleeds, Severe bleeding Moderate 1-5 Few bleeds, Haemathrosis - traumatic Mild 5-30 Few bleeds, Post-traumatic Post-dental surgery

13. Pathophysiology: tissue injury platelet plug delayed (Haemophilia A & B) fibrin clot prolonged bleeding

14. CLINICAL FEATURES – SUBTLE Bleeding as a baby rare Prolonged bleed from umbilical cord Muscle hematoma during immunisation Bleeding during circumcision

15. CLINICAL FEATURES – SUBTLE Toddlers - Large and prolonged bleed to trivial injury/cuts/abrasions Lip bleeds (hematomas) First bleeding in childhood Tooth extraction Trauma with walking G um bleeds while brushing teeth

16. SIGNIFICANT HEMORRHAGES RETROPERITONEAL H’GE: severe abd pain, anemia and shock HEMATURIA GI BLEED : difficult to control, severe INTRACRANIAL: extradural, subdural, intracerebral - Headache, vomiting, altered sensorium -> coma May be seen in neonates

17. SUBDURAL HEMORRHAGE

18. CLINICAL FEATURES - FRANK HEMARTHROSIS ( joint bleed) – hallmark of hemophilia Joints affected: in toddlers - ankle (most common) – earliest jt involved due to lack of stability as they assume upright posture Older child – knee, elbow (most common) ** Target joint – recurrent bleeding at a same joint LL > UL

19. CLINICAL FEATURES - FRANK Later : all joints Contact sports can provoke Recurrent – may be unprovoked, spontaneous LARGE HEMATOMAS & EXTENSIVE ECCHYMOSES

20. BLEEDING INTO JOINTS First haemorrhage : Swelling >> Pain Subsequent haemorrhages: Pain >> Swelling

21. Bleeding in Haemophilia Acute Haemarthrosis Chronic haemophilic arthropathy Bleeding into muscles Haemophilic pseudo tumour - cysts Haematuria Gastrointestinal bleeding Intracranial bleeding

22. Bleeding in Haemophilia BLEEDING IN CARRIERS Reduced FVIII (IX) levels Mild bleeding tendency Childbirth

23. C/F OF ACUTE HAEMARTHROSIS Abnormal sensation Pain and swelling of joint Limitation of movement - especially flexion Tenderness and heat in the joint Acute symptoms last 3-4 days; full recovery takes weeks

24. STAGES Initial bleed into joint - haemarthrosis Inflammatory stage affecting Synovium (synovial hypertrophy) Cartilage - Bone Final Stage Permanent joint changes Erosion & destruction Cartilage, Bone - Knees** ,Ankles** , Elbows* Wrists Shoulders less common Hips

25. Chronic Haemophilic Arthropathy Repeated bleeds - many years  Chronic degenerative changes Chronic haemophilic arthritis → Loss of joint movement → Fixed flexion contractures → Severe muscle wasting → Muscle action imbalance → Valgus deformities → Crippling deformities → Wheel chair-bound

26. Chronic Haemophilic Arthropathy – Radiological Changes Epiphyseal overgrowth Enlargement of bone ends Loss of cartilage (joint space) Gross irregularity articular surface Subchondral collapse Subchondral cysts Osteophyte formation Osteoporosis Changes in joint alignment

27. HAEMOPHILIC PSEUDO TUMOURS (BLOOD CYSTS) Cysts within the fascial muscle envelope Cysts arising in muscles Cysts arising from sub- periosteal haemorrhage Pseudo tumours in bone Gross destruction of normal architecture of bone Large bone cysts Pathological fracture

28. Complications : Pain Anaemia (proportionate to bleeding) Constitutional disturbances: fever < 24 hrs anorexia, malaise Chronic arthritis Pressure effects of large haematomas Transfusion acquired infections Inhibitors

29. Lab findings: Hb low – proportional to blood loss Platelets- normal Bleeding time -normal PT normal APTT prolonged > 2-3 times ULN CT prolonged Low levels of F VIII / IX Factor VIII and IX assay : mixing studies Genetic analysis

30. MIXING STUDIES To determine if prolonged PT or PTT is due to a factor deficiency or an inhibitor Normal plasma : all Clotting factors-V,VIII, IX,X,XI,XII Method: add patient plasma to equal volume of normal plasma and repeat PT & PTT Correction of PT & PTT – suggests- deficiency of clotting factors Assays for factors

31. MIXING STUDIES Remains prolonged after mixing study: indicates inhibitor - most common is lupus anticoagulant - therapeutic anticoagulant - rarely ,inhibitors to factors VIII, IX, XI

32. MIXING STUDIES With normal /adsorbed plasma/aged plasma Normal plasma : all factor present Adsorbed plasma : FIX- deficient Aged plasma - FVIII- deficient Mix patient’s plasma with normal /aged/ adsorbed plasma – Correction of APTT with normal & aged plasma/ not with adsorbed plasma  F IX deficiency

33. Correction of APTT with normal / adsorbed plasma & not with aged plasma  F VIII deficiency If correction does not occur  suspect inhibitor

34. Inhibitors: Antibodies against factors  blocks clotting activity 14-25 % patients who receive factors (VIII/ IX) Failure of a bleeding episode to respond to appropriate replacement therapy  1 st sign of inhibitor Others develop higher titres  desensitisation- higher doses of factors given

35. RADIOLOGICAL INVESTIGATIONS Radiographs of joints USG joints for effusions MRI joints/ abdomen CT head

36. MANAGEMENT -PRINICIPLES Control bleeding episodes – replacement therapy Prophylaxis and prevention Life style modifications Treatment of complications Rehabilitation Antenatal diagnosis and counselling Team effort : pediatrician, hematologist, orthopedician, physiotherapist, dentist

37. REPLACEMENT THERAPY Fresh whole blood FFP Cryoprecipitate Factor concentrates Recombinant/ porcine factor VIII FIX : inhibitors of natural F-VIII/IX Prothrombin complex concentrates (PCC)

38. FFP AND CRYOPPT FFP contains F VIII and IX CRYOPPT contains F-VIII, fibrinogen, VWF 1 unit FFP = 200 units factor VIII/IX 1 unit cryoppt = 100 units factor VIII FVIII 1u/kg Increase plasma factor VIII by 2% ( 2 iu/dl) - t ½ = 8 hrs FIX 1u/kg Increase plasma factor IX by 1% (1iu/dl) - t ½ = 18-20 hrs Risk of HIV, HBV, HCV, CMV transmission

39. FACTOR CONCENTRATES Prothrombin complex concentrates (PCC) - Contain F IX & Vitamin K dependent factors I.e. II, VII, IX, X – high cost Pure factor IX concentrates available Currently high cost

40. THERAPY FOR HAEMOPHILIA FACTOR RECOVERY AFTER I.V. INFUSION Factor VIII 100% Factor IX 30-50% Raise factor levels to: 100 U/dl – life threatening bleeds 35- 40 U/dl – other bleeds

41. Dose of F VIII (U): desired rise in plasma F VIII (U/dl) X body wt (kg) X 0.5 Dose of F IX (U): desired rise in plasma F IX (U/dl) X body wt (kg) X 1.4 DOSAGE CALCULATION

42. Indication or Site of Bleeding Factor level Desired, % FVIII Dose, IU/kg * FIX Dose IU/kg Severe epistaxis ; mouth, lip, tongue, or dental work 20-50 10-25 20-50 Joint (hip or groin) - Repeat in 24-48 h 40 20 40 Soft tissue or muscle 20-40 10-20 40 Muscle (calf and forearm) 30-40 15-20 40 Muscle deep (thigh, hip, iliopsoas ) Transfuse, repeat at 24 h 40-60 20-30 40-60 Neck or throat 50-80 25-40 50-80

43. Hematuria 40 20 40 Laceration 40 20 40 GI or retroperitoneal bleeding 60-80 30-40 60-80 Head trauma (no evidence of CNS bleeding) 50 25 50 Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) 100 50 100 Trauma with bleeding, surgery † 80-100 50 100

44. Other measures: General supportive measures: bed rest hospitalize for severe bleeds analgesics Local haemostasis Immobilisation Physiotherapy

45. HEMARTHOSIS MANAGEMENT 25 U F-VIII/kg q12h Prompt rx : prevent early sequalae Check APTT Joint immobilisation - 48hrs Early ambulation and physio NSAIDS : Aspirin, indomethacin – with caution- may induce GI bleed Paracetamol, pethidine, diazepam – can be used Home infusions : train for early administration

46. PROPHYLAXIS Mild/moderate hemophilia 10-20 units/kg 2-3 times/week Can have normal life and participate in sports

47. PREVENTION Immunisation : SC not IM Avoid IM injections- apply pressure 5 minutes Avoid contact sports

48. Orthopaedic care- traction, splinting, reconstructive surgery Regular dental exam and hygiene Prophylactic immunization- hep B Counselling P REVENTION

49. DRUGS EACA - aminocaproic acid Tranexemic acid : 25mg/kg/day C/I in hematuria- ppt renal failure Desmopressin acetate : increases levels for first 2 days from body stores Danazol Fibrin glue : tooth extraction

50. Other agents used: Tranexamic acid Used for external bleeding eg. teeth extraction Not for internal bleedings Inhibits fibrinolysis decreases F VIII requirement

51. DDAVP D-amino D-arginine Vasopressin Found to raise FVIII levels Mild haemophilia- releases F VIII from storage sites Moderate to severe cases- no endogenous stores  treatment ineffective Mild von Willebrand’s disease Not effective in Haemophilia B

52. Danazol: Androgen Elevates levels of protein in factors Increases levels of F VIII & F IX Prednisolone Acute synovitis

53. ANTENATAL DIAGNOSIS 18-20 weeks Male fetuses Fetal blood : Amniotic fluid fibroblasts : DNA probe Chorionic villous sampling : PCR

54. CARRIER DETECTION FVIII-C: FVIIIAg = 1:1 normally In carriers FVIII-C is low Hence ratio: 0.6:1

55. ACQUIRED HEMOPHILIA 5-20% of hemophiliacs develop antibodies against factor VIII/IX with time - alloantibodies Hemophilia A > Hemophilia B Suspect when failure of therapy Manage: porcine FVIII activated prothrombin complex activated FVII plasmapheresis immunosuppresants recombinant FVIII/IX

56. DEMAND THERAPY  Hospital  Home Long standing approach to haemophilia Patient treats when bleeds Arrest acute bleed No arrest, long term sequelae PROPHYLACTIC THERAPY THERAPY FOR HAEMOPHILIA

57. PROPHYLACTIC THERAPY Initiated with the 1 st bleed Home - self or patient infused Small dose FVIII (FIX) 2-3 X /week (  20%-30%) Prevents bleeds Prevents long term sequelae THERAPY FOR SURGERY/ DENTISTRY Prophylactic Enables major procedures - 10 days cover

58. Thank you Download more documents and slide shows on The Medical Post [ www.themedicalpost.net ]