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

2. Introduction:HAEMOPHILIA Commonest inherited bleedingdisorder Bleeding due to deficiency of FVIII /IX / XI coagulant activity Severity of bleeding is related toFVIII / 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 affectedFemales carriers 5. INHERITANCE 6. INHERITANCE 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 7. FEMALES AFFECTED ONLY WHEN: 1) TURNERS SYNDROME 2) MOSAICISM/LYONISATION3) MOTHER TO DAUGHTERTRANSMISSION (POSSIBLETHEORETICALLY BUT EXTREMLYRARE) 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 infactor2. Dysfunctional protein 5-10 % Haemophilia A 40-50 % B 10. Severity of haemophilia 1 ml of normal plasma contains 1 unit (U) of eachfactor 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. Severity of haemophilia Haemostatic level of factor VIII: 30-40 U/dl of factor IX: 25-30 U/dl 12. Severity of HaemophiliaSeverity Factor Type of presentation leveliu/dl (%)Severe coma May be seen in neonates 17. SUBDURAL HEMORRHAGE 18. CLINICAL FEATURES - FRANKHEMARTHROSIS (joint bleed) hallmark ofhemophilia Joints affected: in toddlers - ankle (most common) earliest jtinvolved due to lack of stability as they assumeupright posture Older child knee, elbow (most common)** Target joint recurrent bleeding at a samejoint LL > UL 19. CLINICAL FEATURES - FRANK Later : all joints Contact sports can provoke Recurrent may be unprovoked,spontaneousLARGE HEMATOMAS & EXTENSIVEECCHYMOSES 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 HaemophiliaBLEEDING 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 - especiallyflexion Tenderness and heat in the jointAcute symptoms last 3-4 days; full recoverytakes 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 RadiologicalChanges 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-periostealhaemorrhage Pseudo tumours in bone Gross destruction of normal architectureof bone Large bone cysts Pathological fracture 28. Complications : Pain Anaemia (proportionate to bleeding) Constitutional disturbances:fever < 24 hrsanorexia, 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 toa factor deficiency or an inhibitor Normal plasma : all Clotting factors-V,VIII,IX,X,XI,XII Method: add patient plasma to equal volumeof normal plasma and repeat PT & PTT Correction of PT & PTT suggests- deficiencyof clotting factors Assays for factors 31. MIXING STUDIES Remains prolonged after mixing study:indicates inhibitor - most common islupus 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- decient Aged plasma - FVIII- decient Mix patients plasma with normal /aged/adsorbed plasma Correction of APTT with normal & agedplasma/ not with adsorbed plasma F IXdeficiency 33. Correction of APTT with normal /adsorbed plasma & not with agedplasma F VIII deficiency If correction does not occur suspectinhibitor 34. Inhibitors: Antibodies against factors blocks clottingactivity 14-25 % patients who receive factors (VIII/ IX) Failure of a bleeding episode to respond toappropriate replacement therapy 1st sign ofinhibitor 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 replacementtherapy 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 = 8 hrs FIX 1u/kg Increase plasma factor IX by 1%(1iu/dl) - t = 18-20 hrs Risk of HIV, HBV, HCV, CMV transmission 39. FACTOR CONCENTRATES Prothrombin complex concentrates(PCC) - Contain F IX & Vitamin Kdependent factors I.e. II, VII, IX, X highcost Pure factor IX concentrates available Currently high cost 40. THERAPY FOR HAEMOPHILIA FACTOR RECOVERY AFTER I.V.INFUSION Factor VIII100% Factor IX30-50% Raise factor levels to: 100 U/dl life threatening bleeds35- 40 U/dl other bleeds 41. DOSAGE CALCULATION Dose of F VIII (U): desired rise in plasma F VIII (U/dl) X body wt (kg) X0.5 Dose of F IX (U): desired rise in plasma F IX (U/dl) X body wt (kg) X1.4 42. Factor FVIIIlevel FIX DoseIndication or Site of Bleeding Dose,Desired,IU/kg IU/kg*%Severe epistaxis; mouth, lip,20-5010-2520-50tongue, or dental workJoint (hip or groin) - Repeat in 24-48 h 4020 40Soft tissue or muscle 20-4010-2040Muscle (calf and forearm) 30-4015-2040Muscle deep (thigh, hip, iliopsoas)40-6020-3040-60Transfuse, repeat at 24 hNeck or throat50-8025-4050-80 43. Hematuria40 2040Laceration 40 2040GI or retroperitoneal 60-8030-40 60-80bleedingHead trauma (no evidence of502550CNS bleeding)Head trauma (probable ordefinite CNS bleeding, eg, 10050100headache, vomiting,neurologic signs)Trauma with bleeding, 80-100 50100surgery 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 withcaution- may induce GI bleed Paracetamol, pethidine, diazepam can beused Home infusions : train for early administration 46. PROPHYLAXIS Mild/moderate hemophilia 10-20 units/kg 2-3 times/week Can have normal life andparticipate in sports 47. PREVENTION Immunisation : SC not IM Avoid IM injections- apply pressure 5 minutes Avoid contact sports 48. PREVENTION Orthopaedic care- traction, splinting,reconstructive surgery Regular dental exam and hygiene Prophylactic immunization- hep B Counselling 49. DRUGS EACA - aminocaproic acid Tranexemic acid: 25mg/kg/day C/I in hematuria- ppt renal failure Desmopressin acetate: increases levels forfirst 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 Willebrands disease Not effective in Haemophilia B 52. Danazol:AndrogenElevates levels of protein in factorsIncreases levels of F VIII & F IX PrednisoloneAcute 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:1) porcine FVIII2) activated prothrombin complex3) activated FVII4) plasmapheresis5) immunosuppresants6) recombinant FVIII/IX 56. THERAPY FOR HAEMOPHILIA DEMAND THERAPYHospitalHomeLong standing approach to haemophilia Patient treats when bleeds Arrest acute bleed No arrest, long term sequelae PROPHYLACTIC THERAPY 57. PROPHYLACTIC THERAPY Initiated with the 1st bleed Home - self or patient infused Small dose FVIII (FIX) 2-3 X /week ( 20%-30%)Prevents bleedsPrevents long term sequelaeTHERAPY FOR SURGERY/ DENTISTRY Prophylactic Enables major procedures - 10 days cover 58. Thank youDownload more documents and slide shows on TheMedical Post [ www.themedicalpost.net ]