Hemophilia

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Hemophilia

  1. 1. Hemophilia Dr. Kalpana Malla MD Pediatrics Manipal Teaching HospitalDownload more documents and slide shows on The Medical Post [ www.themedicalpost.net ]
  2. 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. 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. 4. Mode of Inheritance :– X- linked recessive Males affected Females carriers
  5. 5. INHERITANCE
  6. 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. 7. FEMALES AFFECTED ONLY WHEN: 1) TURNERS SYNDROME 2) MOSAICISM/LYONISATION 3) MOTHER TO DAUGHTER TRANSMISSION (POSSIBLE THEORETICALLY BUT EXTREMLY RARE)
  8. 8. Types:• Haemophilia A – deficiency of Factor VIII• Haemophilia B – deficiency of Factor IX• Haemophilia C – deficiency of Factor XI
  9. 9. HAEMOPHILIA A & B:• Basic abnormality :1. Reduction in amount of protein in factor2. Dysfunctional protein 5-10 % Haemophilia A 40-50 % ” ” B
  10. 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. 11. Severity of haemophilia • Haemostatic level of factor VIII: 30-40 U/dl • ” ” of factor IX: 25-30 U/dl
  12. 12. Severity of HaemophiliaSeverity Factor Type of presentation level iu/dl (%)Severe <1 Spontaneous bleeds, Severe bleedingModerate 1-5 Few bleeds, Haemathrosis - traumaticMild 5-30 Few bleeds, Post-traumatic Post-dental surgery
  13. 13. Pathophysiology:tissue injuryplatelet plug delayed (Haemophilia A & B)fibrin clotprolonged bleeding
  14. 14. CLINICAL FEATURES – SUBTLE• Bleeding as a baby rare• Prolonged bleed from umbilical cord• Muscle hematoma during immunisation• Bleeding during circumcision
  15. 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 walkingGum bleeds while brushing teeth
  16. 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. 17. SUBDURAL HEMORRHAGE
  18. 18. CLINICAL FEATURES - FRANKHEMARTHROSIS (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. 19. CLINICAL FEATURES - FRANK• Later : all joints• Contact sports can provoke• Recurrent – may be unprovoked, spontaneousLARGE HEMATOMAS & EXTENSIVE ECCHYMOSES
  20. 20. BLEEDING INTO JOINTS• First haemorrhage : Swelling >> Pain• Subsequent haemorrhages: Pain >> Swelling
  21. 21. Bleeding in Haemophilia• Acute Haemarthrosis• Chronic haemophilic arthropathy• Bleeding into muscles• Haemophilic pseudo tumour - cysts• Haematuria• Gastrointestinal bleeding• Intracranial bleeding
  22. 22. Bleeding in HaemophiliaBLEEDING IN CARRIERS• Reduced FVIII (IX) levels• Mild bleeding tendency• Childbirth
  23. 23. C/F OF ACUTE HAEMARTHROSIS• Abnormal sensation• Pain and swelling of joint• Limitation of movement - especially flexion• Tenderness and heat in the jointAcute symptoms last 3-4 days; full recovery takes weeks
  24. 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. 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. 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. 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. 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. 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. 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. 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. 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. 33. • Correction of APTT with normal / adsorbed plasma & not with aged plasma  F VIII deficiency• If correction does not occur suspect inhibitor
  34. 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 1st sign of inhibitor• Others develop higher titres  desensitisation- higher doses of factors given
  35. 35. RADIOLOGICAL INVESTIGATIONS• Radiographs of joints• USG joints for effusions• MRI joints/ abdomen• CT head
  36. 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. 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. 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. 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. 40. THERAPY FOR HAEMOPHILIA• FACTOR RECOVERY AFTER I.V. INFUSION Factor VIII 100% Factor IX30-50%• Raise factor levels to: 100 U/dl – life threatening bleeds 35- 40 U/dl – other bleeds
  41. 41. DOSAGE CALCULATION• 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
  42. 42. Factor FVIII level FIX DoseIndication or Site of Bleeding Dose, Desired, IU/kg IU/kg* %Severe epistaxis; mouth, lip, 20-50 10-25 20-50tongue, or dental workJoint (hip or groin) - Repeat in 24-48 h 40 20 40Soft tissue or muscle 20-40 10-20 40Muscle (calf and forearm) 30-40 15-20 40Muscle deep (thigh, hip, iliopsoas) 40-60 20-30 40-60Transfuse, repeat at 24 hNeck or throat 50-80 25-40 50-80
  43. 43. Hematuria 40 20 40Laceration 40 20 40GI or retroperitoneal 60-80 30-40 60-80bleedingHead trauma (no evidence of 50 25 50CNS bleeding)Head trauma (probable ordefinite CNS bleeding, eg, 100 50 100headache, vomiting,neurologic signs)Trauma with bleeding, 80-100 50 100surgery†
  44. 44. Other measures:• General supportive measures: bed rest hospitalize for severe bleeds analgesics Local haemostasis Immobilisation Physiotherapy
  45. 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. 46. PROPHYLAXIS• Mild/moderate hemophilia• 10-20 units/kg 2-3 times/week• Can have normal life and participate in sports
  47. 47. PREVENTION• Immunisation : SC not IM• Avoid IM injections- apply pressure 5 minutes• Avoid contact sports
  48. 48. PREVENTION• Orthopaedic care- traction, splinting, reconstructive surgery• Regular dental exam and hygiene• Prophylactic immunization- hep B• Counselling
  49. 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. 50. Other agents used:• Tranexamic acid Used for external bleeding eg. teeth extraction Not for internal bleedings Inhibits fibrinolysis decreases F VIII requirement
  51. 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. 52. • Danazol: Androgen Elevates levels of protein in factors Increases levels of F VIII & F IX• Prednisolone Acute synovitis
  53. 53. ANTENATAL DIAGNOSIS• 18-20 weeks• Male fetuses• Fetal blood :• Amniotic fluid fibroblasts :DNA probe• Chorionic villous sampling :PCR
  54. 54. CARRIER DETECTION• FVIII-C: FVIIIAg = 1:1 normally• In carriers FVIII-C is low• Hence ratio: 0.6:1
  55. 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. 56. THERAPY FOR HAEMOPHILIA• DEMAND THERAPY Hospital Home Long standing approach to haemophilia Patient treats when bleeds Arrest acute bleed No arrest, long term sequelae• PROPHYLACTIC THERAPY
  57. 57. PROPHYLACTIC THERAPY• Initiated with the 1st bleed• Home - self or patient infused• Small dose FVIII (FIX) 2-3 X /week ( 20%- 30%) Prevents bleeds Prevents long term sequelaeTHERAPY FOR SURGERY/ DENTISTRY• Prophylactic• Enables major procedures - 10 days cover
  58. 58. Thank youDownload more documents and slide shows on The Medical Post [ www.themedicalpost.net ]

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