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kuliah Hemofilia UPH

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  1. 1. Hemophilia A, BVon Willebrand disease disease Theo Audi Yanto
  2. 2. Hemophilia AHemophilia BHemophilia B
  3. 3. Definition• Hemophilia- “love of bleeding”• 2 types: A and B• Hemophilia A: • X linked recessive hereditary disorder that is due to defective or deficient factor VIII
  4. 4. Incidence• It is the second most common inherited clotting factor abnormality (after von Willebrand disease)• 1 in 5000-10000 live male births• No difference between racial groups
  5. 5. Genetics• Transmitted by females, suffered by males• The female carrier transmits the disorder to half their sons and the carrier state to half her dtrs• The affected male does not transmit the disease to his sons (Y is nl) but all his dtrs are all carriers (transmission of defected X)
  6. 6. Russian HouseBritish House Spanish House
  7. 7. Hemophilia A Factor VIII deficiency 1 in 5000-10000 males 60% with severe disease Actvitiy < 1%
  8. 8. Hemophilia B Factor IX deficiency 1 in 25000-35000 males 30% spontaneous mutation 50% with mild to moderate disease Activity > 1% Christmas disease (1952)
  9. 9. •Deficiency of factor VIII or IX affects the propagation phaseof coagulation•Most likely to cause bleeding in situations where tissuefactor exposure is relatively low
  10. 10. Bleeds in Hemophilia• Minor Bleeds – Oral mucosa – Intra-articular – GI/GU – Intramuscular• Major Bleeds
  11. 11. ACUTE COMPLICATIONS OF HEMOPHILIA HemarthrosisMuscle hematoma (pseudotumor) (joint bleeding)
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  13. 13. Clinical Manifestations: • Hemarthrosis The most common, painful and most physically, economically and psychologically debilitating manifestation. • Clinically:  Aura: tingling warm sensation  Excruciating pain  Generally affects one joint at the time  Most commonly: knee; but there are others as elbows, wrists and ankles.  Edema, erythema, warmth and LOM  If treated early it can subside in 6 to 8 hs and disappear in 12 to 24 hs.  Ddx: DJD  Complications: Chronic involvement with joint deformity complicated by muscle atrophy and soft
  14. 14. Nerve destructionJoint damage LONG-TERM COMPLICATIONS OF HEMOPHILIA
  15. 15. Clinical ManifestationsHemarthrosis-Images • Stage III- early  Stage IV- narrowing of intraarticular space subchondral cyst
  16. 16. Clinical Manifestations Hematomas • Subcutaneous and muscular hematomas spread within fascial spaces, dissecting deeper structures • Subcutaneous bleeding spreads in characteristic manner- in the site of origin the tissue is indurated purplish black and when it extends the origin starts to fade • May compress vital structures: such as the airway if it is bleeding into the tongue throat or neck; it can compromise arteries causing gangrene and ischemic contractures are common sequelae, especially of calves and forearms • Muscle hematomas: 1)calf,2)thigh,3)buttocks,4)forearms • Psoas hematoma- if right sided may mimic acute appendicitis • Retroperitoneal hematoma: can dissect through the diaphragm into the chest compromising the airway. It can also compromise the renal function if it compresses the ureter
  17. 17. Clinical manifestations Pseudotumors • Dangerous and rare complication • Blood filled cysts that are gradually expanding • Occur in soft tissues or bones. • Most commonly in the thigh A pseudotumor is deforming the cortex of the femur (arrow). • As they increase in size they Other ossified masses in the soft tissues (arrowheads) are probably soft-tissue pseudotumors. erode contiguous structures. • May require radical surgeries or amputation, and surgery is often complicated with infection
  18. 18. Clinical manifestations Intracranial hemorrhage • Leading cause of death of hemophiliacs • Spontaneous or following trauma • May be subdural, epidural or intracerebral • Suspect always in hemophilic patient that presents with unusual headache • If suspected- FIRST TREAT, then pursue diagnostic workup • LP only when fVIII has been replaced to more than 50%
  19. 19. Clinical manifestations Severity F VIII activity Clinical manifestations Spontaneous hemorrhage from early infancy Severe <1% Freq sp hemarthrosis Hemorrhage sec to trauma or surgery Moderate 2-5% Occ sp hemarthrosis Hemorrhage sec to trauma or surgery Mild >5% Rare sp bleeding • Frequency and severity of bleeding are related to F VIII levels Coinheritance of prothrombotic mutations (i.e. Factor V Leiden) can decrease the risk of bleeding
  20. 20. History taking• sign of Hemorrhage• Family history• infection related transfusion: • HIV, hepatitis realated symptom
  21. 21. Physical examination• Sign of bleeding• Vital sign: tachycardia, tachypnea, hypotension, orthostasis• Organ system-specific sign of hemorrhage: • MSK, CNS, GI, GUT
  22. 22. Hemophilia: Work-up Hgb/Hct nml/low PT nml aPTT high/nml Platelets nml Factor levels (50-150%) Mild > 5% Moderate 1-5% Severe < 1% Inhibitor levels Low titer 0-10 Bethesda U High titer > 10 Bethesda U
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  24. 24. Normal PT Abnormal PTT 50:50 mix is Repeat abnormal with Test for inhibitor activity: 50:50 Specific factors: VIII,IX, XI mix Non-specific (anti-phospholipid Ab)50:50 mix is normal Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)
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  26. 26. •Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 days •Trough factor levels with q 12 h dosing after major surgery should be at least 50-75% •Most joint and muscle bleeds can be treated with “minor” (50%) doses for 1-3 days without monitoring
  27. 27. Treatment: The Old Days Factor replacement  Units = (wt[kg]) x (50mL plasma/kg) x (1 U factor/mL plasma) x (desired factor level – native factor level) FFP: 10-20 mL/kg BB will increase factor level 20-30% Number of unit : desire dose (mL)/200 mL/unit Plasma concentrates Thousands of donors Hepatitis B, C HIV (60-70%)
  28. 28. Cryoprecipitate AHF(Antihemophilic Factor)(Antihemophilic Factor) Berisi Faktor VIII Faktor XIII Von Willebrand Factor dan fibrinogen (suhu simpan ≤30°C) Kandungan: 70 IU/unit F VIII dan > 140mg/unit fibrinogen 33
  29. 29. Replacement Therapy Plasma-derived Recombinent Heating  1990s Solvent-  Cost detergent  2-3 x mixture  Persistent inhibitors Hep A  10-15% Parvovirus B19 CJD
  30. 30. Factor VIII containingproducts Factor VIII, human plasma derived : Monarc M, Monoclonat, hemofil M, Koate-DVI, recombinate, kogenate, helixate, advate, xyntha 35
  31. 31. Factor VIII concentrates differ in purity and manufacturing processes Plasma-derived RecombinantIntermediate High Ultrapure Standard Human albumin- freeHumate-P Koate-HP Hemofil-M Recombinate AdvateAlphanate Monoclate Kogenate ReFacto-AF Monarc-M Helixate ReFacto
  32. 32. A little about cost Product Cost/doseRecombinant FVIII $4400Monoclonal FVIII $3300 BeneFIX $8800 Mononine $8300 FEIBA $5000 NovoSeven $6500 x 2
  33. 33. Other meds •Amicar (epsilon aminocaproic acid) (antifibrinolytic) •DDAVP (antihemophilic)
  34. 34. Von Willebrand Disease• Inherited• Deficiency or dysfunction of vWF • vWF, a large, multimeric glycoprotein • mediate adhesion of platelet • bind and stabilized procoagulant FVIII
  35. 35. vWF• 125/1.000.000 • severe disease only 0.5-5/million• Male and female equaly• mild and manageable bleeding
  36. 36. vWD• 1) partial quantitative deficiency (type I)• (2) qualitative deficiency (type II)• (3) total deficiency (type III)
  37. 37. Work Up• Bleeding time• PT and aPTT• vWD Factor Antigen• Ristocetin activity• vWD multimeric Panel• Genetic Testing
  38. 38. Presentation• Easily bruising• prolonged bleeding• severe hemorrhage after surgery• menorrhagia• Physical finding: usually normal, only sign of bleeding or bruises
  39. 39. Treament• Desmopressin DDAVP • 150 mcg intra nasal 2 h prior to procedure• Transfusion: Cryoprecipitate• Plasma derived: Humate-P (intermediate)
  40. 40. Disorder BT Plt PT aPTT TT FibVasculopathies, connectivetissue Normal ordiseases, or Long Normal Normal Normal Normal increased*collagendisordersaffecting skinThrombocyto Long Low Normal Normal Normal NormalpeniaQualitative Normal orplatelet Long Normal Normal Normal Normal low•abnormalitiesHemophilia A(factor VIII Normal Normal Normal Long Normal Normaldeficiency)vonWillebrand Long Normal** Normal LongΔ Normal NormaldiseaseDisseminatedintravascular Long Low Long Long Long Lowcoagulation