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Approach to bleeding disorders and acute anemia

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Approach to bleeding disorders and acute anemia

  1. 1. Approach to Bleeding Disorders and Acute Anemia Bundarika Suwanawiboon, M.D. May 10, 2006
  2. 3. Outline <ul><li>Review of Coagulation Pathway </li></ul><ul><li>Approach to bleeding patients </li></ul><ul><li>Laboratory evaluation </li></ul><ul><li>Approach to Acute anemia </li></ul><ul><li>Clinical scenarios </li></ul>
  3. 4. FVIIa/TF FXa/FVa FIXa/FVIIIa FVIIa/TF FVIIa FVII FVIIa FIX FIXa FX FXa Prothrombin T FV FVa T FVIII FVIIIa T FXI FXIa T FBG Fibrin (soluble) FXIIIa FXIII T Fibrin (Insoluble)
  4. 5. Approach to Bleeding Patient (1) <ul><li>Detailed history and physical examination is critical </li></ul><ul><li>First step: Distinguish between </li></ul><ul><ul><li>Local defect </li></ul></ul><ul><ul><li>Systemic defect </li></ul></ul><ul><li>Second: Decide if the defect is caused by </li></ul><ul><ul><li>Primary hemostasis </li></ul></ul><ul><ul><li>Secondary hemostasis </li></ul></ul><ul><ul><li>Combinded defect </li></ul></ul>
  5. 6. Approach to Bleeding Patients (2) <ul><li>Clues: </li></ul><ul><ul><li>Single vs. multiple </li></ul></ul><ul><ul><li>Location : mucosal vs. intramuscular/ </li></ul></ul><ul><ul><li>hemarthrosis </li></ul></ul><ul><ul><li>Onset: inherited vs. acquired </li></ul></ul><ul><ul><li>Severity: spontaneous vs. trauma-induced </li></ul></ul><ul><ul><li>Type of bleeding: constant ooze vs. delayed bleeding </li></ul></ul>
  6. 7. Approach to Bleeding Patients (3) <ul><li>Other important histories: </li></ul><ul><ul><li>Prior blood transfusions </li></ul></ul><ul><ul><li>Family history </li></ul></ul><ul><ul><li>Underlying disease: liver/renal diseases, lymphoproliferative diseases, myeloproliferative disorders, sepsis </li></ul></ul><ul><ul><li>Medication: ASA, NSAIDs, anticoagulants, antibiotics </li></ul></ul>
  7. 8. Potential Conclusions From Patient History <ul><li>Normal hemostatic function </li></ul><ul><li>Possibility of hemostatic defect </li></ul><ul><li>Although negative, bleeding diathesis cannot be excluded </li></ul>
  8. 9. Primary Hemostasis <ul><li>Platelet plug requires </li></ul><ul><ul><li>Functional vessel walls </li></ul></ul><ul><ul><li>Good Platelets (number and function) </li></ul></ul><ul><ul><li>von Willebrand factor </li></ul></ul>
  9. 10. Secondary Hemostasis <ul><li>Initiation </li></ul><ul><li>Propagation </li></ul><ul><li>Fibrin clot formation </li></ul>
  10. 11. History: Identify if the problem is due to… <ul><li>Local vs. systemic defect </li></ul><ul><li>Hereditary vs. acquired disorder </li></ul><ul><li>Primary vs. secondary hemostatic disorder </li></ul>
  11. 12. Clues <ul><li>Location: single vs. multiple sites </li></ul><ul><li>Severity: Spontaneous? Appropriate to </li></ul><ul><li>trauma? </li></ul><ul><li>Onset </li></ul><ul><li>Family history </li></ul><ul><li>Underlying disease </li></ul><ul><li>Medication </li></ul>
  12. 13. <ul><li>Deep </li></ul><ul><li>Deep ecchymosis, </li></ul><ul><li>hematoma </li></ul><ul><li>Rare </li></ul><ul><li>Retroperitoneal </li></ul><ul><li>Hematoma,hemarthrosis </li></ul><ul><li>Superficial </li></ul><ul><li>Petechiae, superficial </li></ul><ul><li>ecchymosis </li></ul><ul><li>Common </li></ul><ul><li>Rare </li></ul><ul><li>Sites </li></ul><ul><li>Skin </li></ul><ul><li>Mucosal </li></ul><ul><li>Others </li></ul>Delayed Immediate Onset Secondary Hemostasis Primary Hemostasis
  13. 14. Major Primary Hemostatic Disorders <ul><li>Inherited </li></ul><ul><li>von Willebrand disease </li></ul><ul><li>Glanzmann’s Thrombasthenia </li></ul><ul><li>Bernard-Soulier syndrome </li></ul><ul><li>Storage Pool disease </li></ul><ul><li>Hereditary hemorrhagic telangiectasia </li></ul><ul><li>Acquired </li></ul><ul><li>Aspirin-like drugs </li></ul><ul><li>Uremia </li></ul><ul><li>Thrombocytopenia </li></ul><ul><ul><li>ITP </li></ul></ul><ul><ul><li>TTP/HUS </li></ul></ul><ul><ul><li>Bone marrow disorders e.g. AA </li></ul></ul>
  14. 15. Common Secondary Hemostatic Disorders <ul><li>Inherited </li></ul><ul><li>Hemophilia A </li></ul><ul><li>Hemophilia B </li></ul><ul><li>Acquired </li></ul><ul><li>Liver disease </li></ul><ul><li>Vitamin K deficiency </li></ul><ul><li>DIC </li></ul><ul><li>Anticoagulant drugs </li></ul><ul><ul><li>Heparin </li></ul></ul><ul><ul><li>Warfarin </li></ul></ul><ul><li>Acquired coagulation factor inhibitor (FVIII) </li></ul>
  15. 16. Primary Hemostasis: Lab studies <ul><li>CBC </li></ul><ul><li>Bleeding time </li></ul><ul><li>vWF panel </li></ul><ul><ul><li>vWF antigen </li></ul></ul><ul><ul><li>vWF Ristocetin Cofactor Assay </li></ul></ul><ul><ul><li>vWF multimer </li></ul></ul><ul><ul><li>FVIII level </li></ul></ul><ul><li>Platelet aggregation study </li></ul>
  16. 17. Lab Interpretation: Primary Hemostasis <ul><li>CBC: examine both numbers and morphologies </li></ul><ul><li>Bleeding time: not very sensitive nor specific* </li></ul><ul><ul><ul><li>↓ Plt (< 100,000), Plt. Dysfunction, vWD, afibrinogenemia, severe hypofibrinogenemia </li></ul></ul></ul><ul><li>NL Plt. count but abnormal Bleeding time: </li></ul><ul><ul><ul><li>Qualitative plt. Dysfunction, vWD or abn. Vessel </li></ul></ul></ul><ul><ul><ul><li>ASA, uremic pts </li></ul></ul></ul>
  17. 18. CBC: Interpretation <ul><li>Normal platelet count: 150,000 – 400,000 </li></ul><ul><ul><li>> 100,000/mm 3 Bleeding unlikely </li></ul></ul><ul><ul><li>< 20,000/mm 3 ↑ risk for spontaneous </li></ul></ul><ul><ul><li>bleeding </li></ul></ul><ul><li>Pitfalls: </li></ul><ul><ul><li>must exclude pseudothrombocytopenia </li></ul></ul>
  18. 19. Pseudothrombocytopenia Must be Excluded
  19. 20. Immune Thrombocytopenic Purpura
  20. 21. Emergency Treatment <ul><li>Indicated for internal or widespread mucocutaeous bleeding </li></ul><ul><li>Admit if Plt.<10,000 or if clinical bleeding is present </li></ul><ul><li>IVIG (1g/kg/D x 2 days) </li></ul><ul><li>IV methylprednisolone/ dexamethasone </li></ul><ul><li>Plt. Transfusion in life-threatening bleeding </li></ul><ul><li>Emergency splenectomy </li></ul>
  21. 22. Thrombotic Thrombocytopenic Purpura (TTP)
  22. 23. Bleeding Time
  23. 24. Bleeding Time <ul><li>Screening test for platelet function </li></ul><ul><ul><li>Increased yield in patient suspected of bleeding disorder </li></ul></ul><ul><li>Limitation </li></ul><ul><ul><li>Operator dependent </li></ul></ul><ul><ul><li>Not very sensitive nor specific in general population </li></ul></ul><ul><ul><li>Poor predictor of surgical bleeding </li></ul></ul>
  24. 25. Bleeding Time: Interpretation <ul><li>Normal value* : < 8 min </li></ul><ul><li>Prolonged bleeding time: </li></ul><ul><ul><li>Thrombocytopenia/ anemia (Hct < 20%) </li></ul></ul><ul><ul><li>Hereditary platelet dysfunction </li></ul></ul><ul><ul><li>von Willebrand disease </li></ul></ul><ul><ul><li>Severe hypofibrinogenemia </li></ul></ul><ul><ul><li>Blood vessels disorders </li></ul></ul><ul><ul><li>Uremia </li></ul></ul><ul><ul><li>Myeloproliferative disorders </li></ul></ul><ul><ul><li>Medication: Aspirin, other antiplatelet drugs </li></ul></ul>
  25. 26. Platelet Aggregation Study
  26. 27. Assessment of Secondary Hemostasis <ul><li>Screening tests: </li></ul><ul><ul><li>PT </li></ul></ul><ul><ul><li>aPTT </li></ul></ul><ul><ul><li>Mixing study </li></ul></ul><ul><li>Additional Tests </li></ul><ul><ul><li>Fibrinogen </li></ul></ul><ul><ul><li>Thrombin Time </li></ul></ul><ul><ul><li>Reptilase time </li></ul></ul><ul><ul><li>Coagulation factor assays </li></ul></ul><ul><ul><li>D-dimer </li></ul></ul><ul><ul><li>Fibrin Degradation Product </li></ul></ul><ul><ul><li>Euglobulin lysis time </li></ul></ul>
  27. 28. Accurate Sample Collection is the Key <ul><li>Always use sodium citrate tube for coag. </li></ul><ul><li>Immediately sent to lab </li></ul><ul><li>Fill tube to the proper level </li></ul><ul><li>(anticoagulant to plasma ratio = 1:9) </li></ul><ul><li>Modification may be required based on Hct </li></ul><ul><ul><li>Sodium citrate (ml) = (100 – Hct pt) x 0.5 / 55* </li></ul></ul><ul><ul><li>* normal plasma vol. </li></ul></ul>
  28. 29. Intrinsic Pathway Extrinsic Pathway Common Pathway XII XIIa XI HK/PK IXa/ IX VIIIa XIa XII XIIa XI XIa HMWK IXa IX VIIIa/PL Tenase Ca ++ X Xa II IIa Va/PL Ca ++ Fibrinogen Fibrin X-linkedFibrin XIIIa Prothrombinase VIIa/TF VII VIIa TF Ca ++ X Xa II IIa Va/PL Ca ++ Fibrinogen Fibrin
  29. 30. Prothrombin Time (PT) PT : test extrinsic and common pathway
  30. 31. Activated Partial Thromboplastin Time (aPTT) aPTT : test intrinsic and common pathway
  31. 32. Mixing Study + 0% 100% 50% <30% Correctable Normal coagulation time Uncorrectable prolonged coagulation time Deficiency Inhibitor
  32. 33. Isolated prolonged PT Mixing study Correctable Uncorrectable Deficiency Inhibitor Hereditary: FVII FVII Acquired: early liver impairment vitamin K antagonist vitamin K deficiency
  33. 34. Isolated prolonged aPTT Bleeding No bleeding Mixing study Mixing study Correctable Uncorrectable Correctable Uncorrectable Deficiency Inhibitor Deficiency Inhibitor Factor VIII / vWD Factor VIII Factor XII Factor XII Factor IX Factor IX HMWK HMWK Factor XI Factor XI Prekallekrein Prekallekrein Lupus anticoagulant
  34. 35. Prolonged aPTTand PT Correctable Uncorrectable Deficiency Inhibitor Hereditary:single factor FII, V, or X Hypofibrinogenemia Afibrinogenemia Dysfibrinogenemia Acquired:multiple factors Acquired: early liver impairment Heparin vitamin K antagonist Lupus anticoagulant vitamin K deficiency DIC
  35. 36. Bleeding Disorders with Normal PT and aPTT <ul><li>Factor XIII deficiency </li></ul><ul><li>Mild hemophilia </li></ul><ul><li>Platelet dysfunction </li></ul><ul><li>Vascular defect </li></ul><ul><li>Paraproteinemia </li></ul>
  36. 37. Further Diagnostic Tests <ul><li>Specific coagulation factor assay </li></ul><ul><li>Coagulation factor inhibitor assay </li></ul><ul><li>Lupus anticoagulant panel </li></ul><ul><li>Thrombin Time (TT) </li></ul><ul><ul><li>Prolonged TT: heparin contamination, dysfibrinogenemia, hypofibrinogenemia, DIC </li></ul></ul>
  37. 38. Etiology of Thrombocytopenia <ul><li>Decreased Production </li></ul><ul><li>Hypoproliferation </li></ul><ul><li>Ineffective Thrombopoiesis </li></ul><ul><li>Aplastic Anemia, Amegakaryocytic </li></ul><ul><li>thrombocytopenia, infection, toxins, drugs </li></ul><ul><li>Infiltrative marrow disease, TAR </li></ul><ul><li>Megaloblastic anemia </li></ul><ul><li>Increased Destruction </li></ul><ul><li>Immune </li></ul><ul><li>Non-immune </li></ul><ul><li>Alloimmune, Autoimmune: ITP, SLE </li></ul><ul><li>DIC, TTP, HUS </li></ul><ul><li>Others </li></ul><ul><li>Splenic sequestration </li></ul><ul><li>Dilutional </li></ul><ul><li>Hypersplenism </li></ul><ul><li>Massive blood transfusion </li></ul>
  38. 39. Thrombocytopenia <ul><li>Immune </li></ul><ul><li>Autoimmune </li></ul><ul><ul><li>ITP </li></ul></ul><ul><ul><li>SLE </li></ul></ul><ul><ul><li>Evan’syndrome </li></ul></ul><ul><li>Alloimmune </li></ul><ul><ul><li>Multiple Blood transfusion </li></ul></ul>Increased destruction <ul><li>Non-immune </li></ul><ul><li>DIC </li></ul><ul><li>Hypersplenism </li></ul><ul><li>TTP, HUS </li></ul>Decreased production <ul><li>Stem cell defects </li></ul><ul><li>Aplastic anemia </li></ul><ul><li>Amegakaryocytic </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>Infiltrative marrow </li></ul><ul><li>disease </li></ul><ul><li>Myelophthisis </li></ul><ul><li>Acute leukemia </li></ul><ul><li>Ineffective thrombopoiesis </li></ul><ul><li>Megaloblastic anemia </li></ul><ul><li>Alcohol </li></ul>
  39. 40. Immune Thrombocytopenic Purpura (ITP) <ul><li>Thrombocytopenia caused by autoantibodies-mediated platelet destruction by reticuloendothelial cell clearance. </li></ul><ul><li>Classification </li></ul><ul><ul><li>Acute vs. chronic (>12 weeks) </li></ul></ul><ul><ul><li>Primary (idiopathic) vs. secondary </li></ul></ul>
  40. 41. Classification <ul><li>Acute </li></ul><ul><ul><li>Commonly seen in children </li></ul></ul><ul><ul><li>Usually following viral infections </li></ul></ul><ul><ul><li>Self-limited </li></ul></ul><ul><li>Chronic </li></ul><ul><ul><li>More common in adults </li></ul></ul><ul><ul><li>Spontaneous remission is less likely </li></ul></ul><ul><li>Differential diagnosis </li></ul><ul><ul><li>Autoimmune disease: SLE </li></ul></ul><ul><ul><li>Infection: HIV, HCV, malaria </li></ul></ul><ul><ul><li>Lymphoproliferative disease: lymphoma </li></ul></ul><ul><ul><li>Medication </li></ul></ul><ul><ul><li>DIC/TTP </li></ul></ul><ul><ul><li>Bone marrow disease </li></ul></ul>
  41. 42. NEJM 2002;346(13):995 Pathophysiology of ITP
  42. 43. Clinical Presentation <ul><li>Mucocutaneous bleeding </li></ul><ul><li>Incidence of ICH:~1% </li></ul>
  43. 44. Diagnosis <ul><li>By exclusion </li></ul><ul><li>CBC: </li></ul><ul><ul><li>Isolated thrombocytopenia </li></ul></ul><ul><li>Bone marrow examination </li></ul><ul><ul><li>Not routinely performed </li></ul></ul><ul><li>Indication for BM study </li></ul><ul><ul><li>Suspected secondary cause or in atypical case </li></ul></ul><ul><ul><li>Prior to splenectomy </li></ul></ul>
  44. 45. Treatment <ul><li>Goal: to induce long-term remission </li></ul><ul><ul><li>Indication: Platelet < 30,000 or if bleeding is present </li></ul></ul><ul><li>Corticosteroid is the first-line therapy </li></ul><ul><ul><li>Oral Prednisolone: 1 mg/kg/D </li></ul></ul><ul><ul><li>Pulse dexamethasone 40 mg/d x 4 d </li></ul></ul><ul><ul><li>Dexamethasone IV, Methylprednisolone IV </li></ul></ul><ul><li>Intravenous immune globulin (IVIG) or anti-D may be used to induce more rapid platelet response </li></ul>
  45. 46. Treatment (cont.) <ul><li>Second-line treatment </li></ul><ul><ul><li>Azathioprine </li></ul></ul><ul><ul><li>Cyclophosphamide </li></ul></ul><ul><ul><li>Vincristine </li></ul></ul><ul><ul><li>Danazol </li></ul></ul><ul><li>Splenectomy </li></ul><ul><ul><li>Considered in refractory case </li></ul></ul><ul><ul><li>Response rate: ~60%-70% </li></ul></ul>
  46. 47. Treatment (cont.) <ul><li>Emergency situation </li></ul><ul><ul><li>ICH, intraperitoneal bleeding, etc. </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>Platelet transfusion </li></ul></ul><ul><ul><li>Splenectomy </li></ul></ul><ul><ul><li>Intravenous immunoglobulin (IVIg) </li></ul></ul>
  47. 48. TTP <ul><li>Microangiopathic hemolytic anemia </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>Neurologic symptoms </li></ul><ul><li>Fever </li></ul><ul><li>Renal disease </li></ul><ul><li>Idiopathic </li></ul><ul><li>Toxin-associated </li></ul><ul><li>Familial </li></ul><ul><li>Drugs:Quinine, CyA </li></ul><ul><li>Transplantation </li></ul><ul><li>Malignancy/ treatment </li></ul><ul><li>HIV </li></ul><ul><li>Pregnancy </li></ul>
  48. 49. Emergency Treatment <ul><li>Plasma exchange (FFP) </li></ul><ul><li>Plasma infusion </li></ul>
  49. 50. Disorder of Platelet Function <ul><li>Inherited </li></ul><ul><li>von Willebrand disease </li></ul><ul><li>Glanzmann’s Thrombasthenia </li></ul><ul><li>Bernard-Soulier syndrome </li></ul><ul><li>Storage Pool disease </li></ul><ul><li>Hereditary hemorrhagic telangiectasia </li></ul><ul><li>Acquired </li></ul><ul><li>Aspirin-like drugs </li></ul><ul><li>Uremia </li></ul>
  50. 51. von Willebrand Disease <ul><li>Autosomal dominant </li></ul><ul><li>Clinical presentation: primary hemostatic defects </li></ul><ul><li>Lab: </li></ul><ul><ul><li>Prolonged bleeding time </li></ul></ul><ul><ul><li>↓ vWF Ag or activity, NL or ↓ FVIII </li></ul></ul><ul><ul><li>NL or ↑ aPTT </li></ul></ul><ul><li>Treatment: DDAVP, cryoprecipitate </li></ul>
  51. 52. von Willebrand Disease: vWF <ul><li>Synthesized in endothelial cells and megakaryocytes </li></ul><ul><li>Two important functions: </li></ul><ul><ul><li>Carrier protein for plasma FVIII </li></ul></ul><ul><ul><li>Ligand biding to platelet GPIb receptor to initiate platelet adhesion </li></ul></ul>
  52. 53. Primary Hemostasis: vWF <ul><li>von Willebrand Factor (vWF) Panel </li></ul><ul><ul><li>vWF antigen </li></ul></ul><ul><ul><li>vWF ristocetin cofactor activity </li></ul></ul><ul><ul><li>vWF multimer study </li></ul></ul><ul><ul><li>FVIII level </li></ul></ul>
  53. 54. Diagnosis <ul><li>Clinical evidence of mucocutaneous bleeding or postsurgical bleeding </li></ul><ul><li>Female:male ~ 1:1 </li></ul><ul><li>Lab: </li></ul><ul><ul><li>Primary and secondary hemostatic defects </li></ul></ul><ul><ul><li>Typical case: prolonged BT and aPTT </li></ul></ul><ul><ul><li>Lab may be normal in mild form </li></ul></ul>
  54. 55. vWF panel: Interpretation Test/Type 1 2A 2B 2M 2N 3 BT N or ↑ ↑ ↑ N or ↑ ↑ ↑ N ↑↑↑↑ vWF:Ag ↓ ↓ ↓ ↓ or N ↓ or N ↓↓↓↓ vWFR:Co ↓ ↓↓↓ ↓↓ ↓ ↓ or N ↓↓↓↓ LD-RIPA - - ↑ - - - FVIII N or ↓ N or ↓ N or ↓ N ↓↓↓ ↓↓↓ Multimer N but ↓ abnormal abnormal N but ↓ N but ↓ absent
  55. 56. Treatment <ul><li>Treatment depends upon classification </li></ul><ul><li>Choices of therapy </li></ul><ul><ul><li>DDAVP: primary treatment for type I vWD </li></ul></ul><ul><ul><ul><li>0.3 µg/kg (max 28 µg) </li></ul></ul></ul><ul><ul><li>Cryoprecipitate </li></ul></ul><ul><ul><li>vWF concentrates </li></ul></ul><ul><ul><li>Antifibrinolytic agents </li></ul></ul>
  56. 57. Emergency Treatment <ul><li>DDAVP </li></ul><ul><ul><li>Dose: 0.3 µg/kg in 50-100 mL NSS IV over 30 min </li></ul></ul><ul><ul><li>Common side effects: flushing, headache, nausea. </li></ul></ul><ul><ul><li>Watch for hyponatremia </li></ul></ul><ul><li>Cryoprecipitate </li></ul><ul><li>vWF concentrates </li></ul><ul><li>Antifibrinolytic agent </li></ul>
  57. 58. Drugs Affecting Platelet Function <ul><li>ASA </li></ul><ul><li>NSAIDs (COX-1 inhibitors) </li></ul><ul><li>Ticlopidine </li></ul><ul><li>Clopidrogrel </li></ul><ul><li>Abciximab </li></ul><ul><li>Tirofiban </li></ul><ul><li>Eptifibatide </li></ul><ul><li>Emergency Treatment </li></ul><ul><li>D/C medication </li></ul><ul><li>Platelet transfusion </li></ul>
  58. 59. Uremia-Induced Platelet Dysfunction <ul><li>Bleeding time is frequently prolonged </li></ul><ul><li>Treatment: </li></ul><ul><ul><li>Dialysis to control azotemia </li></ul></ul><ul><ul><li>DDAVP </li></ul></ul><ul><ul><li>Cryoprecipitate </li></ul></ul><ul><ul><li>Platelet transfusion in severe uremic bleeding </li></ul></ul><ul><ul><li>Correct anemia: Hct >30% </li></ul></ul>
  59. 60. Major Secondary Hemostatic Disorders <ul><li>Inherited </li></ul><ul><li>Hemophilia A </li></ul><ul><li>Hemophilia B </li></ul><ul><li>Acquired </li></ul><ul><li>Liver disease </li></ul><ul><li>Vitamin K deficiency </li></ul><ul><li>DIC </li></ul><ul><li>Anticoagulant drugs </li></ul><ul><ul><li>Heparin </li></ul></ul><ul><ul><li>Warfarin </li></ul></ul><ul><li>Acquired coagulation factor inhibitor (FVIII) </li></ul>
  60. 61. Laboratory Evaluation PT aPTT TCT Fibrinogen D-dimer Hemophilias NL ↑↑ NL NL NL Liver disease ↑↑ ↑ NL or ↑ NL or ↓ NL or ↑ DIC (acute) ↑ ↑ NL or ↑ NL or ↓ ↑↑ Vit K Def. ↑ ↑ NL NL NL Heparin NL ↑↑ ↑↑ NL NL Warfarin ↑↑ NL or ↑ NL NL NL Acquired ↑* ↑* NL NL NL Inhibitors (*depends on type of inhibitors)
  61. 62. Hemophilias
  62. 63. Hemophilias <ul><li>X-linked recessive </li></ul><ul><li>Bleeding type: Secondary hemostasis </li></ul><ul><li>Hallmark: hemarthrosis </li></ul><ul><li>Lab: </li></ul><ul><ul><li>Bleeding time: NL </li></ul></ul><ul><ul><li>PT: NL </li></ul></ul><ul><ul><li>aPTT: prolonged </li></ul></ul><ul><ul><li>Factor assay: low </li></ul></ul>
  63. 64. Hemophilia <ul><li>Hemophilia A: Inherited deficiency of FVIII </li></ul><ul><li>Hemophilia B: Inherited deficiency of FIX </li></ul><ul><li>X-linked recessive inheritance </li></ul><ul><li>Bleeding type: secondary hemostatic defect </li></ul>
  64. 65. Clinical Manifestations <ul><li>Hallmark: hemarthrosis, intramuscular hematoma </li></ul><ul><li>Diagnosis </li></ul><ul><ul><li>Clinical evidence of 2 ◦ hemostatic defects </li></ul></ul><ul><ul><li>Isolated prolonged aPTT </li></ul></ul><ul><ul><li>Normal bleeding time </li></ul></ul><ul><ul><li>Low FVIII or FIX level on specific factor assay </li></ul></ul>
  65. 66. Classification Severity % Factor Clinical Bleeding Mild 5-25 Associated with moderate degree of injuries Moderate 1-5 Associated with mild degree of injuries Severe < 1 Spontaneous bleeding
  66. 67. Emergency Treatment <ul><li>Save plasma for coagulation factor assay </li></ul><ul><li>Known case: </li></ul><ul><ul><li>Hemophilia A: Cryoprecipitate, FFP, FVIII concentrates </li></ul></ul><ul><ul><li>Hemophilia B: FFP </li></ul></ul><ul><li>Hematology consult should be notified </li></ul>
  67. 68. Treatment <ul><li>Hemophilia A:FVIII replacement </li></ul><ul><ul><li>Sources: FFP, cryoprecipitate, FVIII concentrate </li></ul></ul><ul><li>Hemophilia B: FIX replacement </li></ul><ul><ul><li>Source: FFP, FIX concentrate* </li></ul></ul><ul><li>Hemophiliacs with inhibitor present </li></ul><ul><ul><li>Bypassing agents: rFVIIa, APCC, PCC </li></ul></ul>
  68. 69. Factors Replacement Calculation (1) <ul><li>Determine desired plasma factor level </li></ul><ul><ul><li>Minor 30%-50% </li></ul></ul><ul><ul><ul><li>Joint bleeding </li></ul></ul></ul><ul><ul><ul><li>Muscle (limited bleeding) </li></ul></ul></ul><ul><ul><ul><li>Oropharynx </li></ul></ul></ul><ul><ul><li>Major 80%-100% </li></ul></ul><ul><ul><ul><li>Surgery/Trauma </li></ul></ul></ul><ul><ul><ul><li>CNS hemorrhage </li></ul></ul></ul><ul><ul><ul><li>GI bleeding </li></ul></ul></ul>
  69. 70. Factors Replacement Calculation (2) <ul><li>FVIII 1 U/kg raises plasma FVIII level by 2% </li></ul><ul><li>FIX 1 U/kg raises plasma FIX level by 1% </li></ul><ul><li>FVIII half-life: ~ 12 hrs </li></ul><ul><li>FIX half-life: ~ 24 hrs </li></ul>
  70. 71. <ul><li>Hemophilia A Pt’s wt. is 60 kg. Desired plasma level is 50%. </li></ul><ul><li>FVIII replacement = 60 x 25  1500 U </li></ul><ul><li>(1 U/kg by raises plasma FVIII level 2%) </li></ul><ul><li>Half of 1 st dose given every 12 hrs (if necessary, depends on clinical setting) </li></ul><ul><li>FFP contains FVIII 1 U/ml </li></ul><ul><li>Cryoprecipitate contains FVIII 100 U/bag </li></ul><ul><li>FVIII concentrates: see package </li></ul>Example of Dose Calculation (1)
  71. 72. <ul><li>Hemophilia B Pt’s wt. is 60 kg. Desired plasma level is 50%. </li></ul><ul><li>FVIII replacement = 60 x 50  3000 U </li></ul><ul><li>(1 U/kg by raises plasma FIX level 1%) </li></ul><ul><li>Half of 1 st dose given every 24 hrs ( repeated dose depends on clinical setting) </li></ul><ul><li>FFP contains FIX 1 U/ml </li></ul>Example of Dose Calculation (2)
  72. 73. Treatment of Other Acquired Secondary Hemostatic Defects (1) <ul><li>Liver disease: </li></ul><ul><ul><li>FFP (10-15 ml/kg) </li></ul></ul><ul><ul><li>Vitamin K </li></ul></ul><ul><li>Vitamin K deficiency: warfarin, ↓ intake, prolonged antibiotic use </li></ul><ul><ul><li>FFP </li></ul></ul><ul><ul><li>Vitamin K: low dose in pt who requires anticoagulation effect, e.g. AF, prosthetic valve </li></ul></ul><ul><li>Heparin: D/C, Protamine sulfate (UFH) </li></ul>
  73. 74. Disseminated Intravascular Coagulation (DIC) <ul><li>Pathologic process with generalized activation of hemostatic system leads to thrombin generation. </li></ul><ul><li>Thrombohemorrhagic phenomenon </li></ul><ul><li>Classification </li></ul><ul><ul><li>Acute (uncompensated) </li></ul></ul><ul><ul><li>Chronic (compensated) </li></ul></ul>
  74. 75. Thrombosis Organ dysfunction DVT Thrombolysis Increased FDP Platelet dysfunction Coagulation activation Prolonged PT Prolonged aPTT Hemorrhage Trigger agents Hypofibrinogenemia Platelet activation Thrombocytopenia Pathophysiology
  75. 76. Group Associated Diseases Trigger Agents 1 - Septicemia Endotoxin - Gram negative bacili 2 - Obstetric complications Thromboplastin - Malignancy - Burn/crush injuries - Snake bite - Hemorrhagic pancreatitis 3 - Anaphylaxis Ag-Ab complex 4 - Infection from rickettsial, virus Endothelial injuries - Giant hematoma 5 - Malaria Unknown - Hemolytic transfusion reaction
  76. 77. Advanced CA prostate with bone marrow involvement and DIC
  77. 78. Diagnosis <ul><li>Clinical presentation </li></ul><ul><ul><li>Bleeding (acute) </li></ul></ul><ul><ul><li>Thrombosis </li></ul></ul><ul><li>Lab: acute </li></ul><ul><ul><li>Thrombocytopenia </li></ul></ul><ul><ul><li>Microangiopathic hemolytic anemia </li></ul></ul><ul><ul><li>Prolonged PT and aPTT </li></ul></ul><ul><ul><li>Hypofibrinogenemia </li></ul></ul><ul><ul><li>Elevated D-dimer and FDP </li></ul></ul>
  78. 79. Microangiopathic Hemolytic Anemia Schistocytes
  79. 80. Treatment <ul><li>Treat underlying disease </li></ul><ul><li>Blood product replacement therapy if clinically indicated </li></ul><ul><li>Heparin may have role in chronic DIC with thrombosis </li></ul>
  80. 81. Treatment of Other Acquired Secondary Hemostatic Defects (2) <ul><li>DIC </li></ul><ul><ul><li>Treat underlying conditions </li></ul></ul><ul><ul><li>Acute DIC: bleeds > clots </li></ul></ul><ul><ul><li>Supportive measures: bleeding case </li></ul></ul><ul><ul><ul><li>Platelet transfusion </li></ul></ul></ul><ul><ul><ul><li>FFP </li></ul></ul></ul><ul><ul><ul><li>Cryoprecipitate: fibrinogen, vWF/FVIII, FXIII </li></ul></ul></ul><ul><ul><ul><li>Avoid antifibrinolytic agent </li></ul></ul></ul>
  81. 82. Treatment of Other Acquired Secondary Hemostatic Defects (3) <ul><li>Acquired coagulation factor inhibitor </li></ul><ul><ul><li>Common: FVIII </li></ul></ul><ul><ul><li>No prior personal or FH of bleeding disorders </li></ul></ul><ul><ul><li>Severe bleeding can occur </li></ul></ul><ul><ul><li>Lab: </li></ul></ul><ul><ul><ul><li>Prolongation of PT or aPTT </li></ul></ul></ul><ul><ul><ul><li>Uncorrected mixing study </li></ul></ul></ul><ul><ul><ul><li>Coagulation factor assay </li></ul></ul></ul><ul><ul><li>Hematology consultant should be notified </li></ul></ul>
  82. 83. Uremia-Induced Platelet Dysfunction <ul><li>Bleeding time is frequently prolonged </li></ul><ul><li>Treatment: </li></ul><ul><ul><li>Dialysis to control azotemia </li></ul></ul><ul><ul><li>DDAVP </li></ul></ul><ul><ul><li>Cryoprecipitate </li></ul></ul><ul><ul><li>Platelet transfusion in severe uremic bleeding </li></ul></ul><ul><ul><li>Correct anemia: Hct >30% </li></ul></ul>
  83. 84. Mixing Study + = Patient Normal O% 100% 50%
  84. 85. XII XIIa XI XIa HMWK IXa IX VIIIa/PL Ca ++ X Xa VIIa/TF VII VIIa TF Tenase II IIa Va/PL Ca ++ Fibrinogen Fibrin X-linkedFibrin XIIIa Prothrombinase Intrinsic Pathway Extrinsic Pathway Common Pathway
  85. 86. NL PT, ↑ aPTT ↑ PT, NL aPTT ↑ PT, ↑ aPTT NL PT, NL aPTT 50:50 mixing study Factor def.: FXI,IX, VIII Inhibitor Specific: XI, IX, VIII NS:antiphos-pholipid FVII def., Vit. K def, liver dz, DIC Normal Prolonged Inhibitor Specific: VII (rare) NS:antiphos-pholipid Factor def.: V, X, II, I Inhibitor Specific: X, V, II, I NS:antiphos-pholipid -Dysfibrinogenemia -FXIII deficiency - α 2-Antiplasmin def -Mild isolated factor def. -Elevated FDP -Monoclonal gammopathy -Qualitative or quantitative platelet disorders -Vascular Disorders
  86. 87. Acute Anemia <ul><li>Hemolytic anemia </li></ul><ul><ul><li>Immune hemolytic anemia </li></ul></ul><ul><ul><ul><li>Alloimmune, autoimmune or drug-induced </li></ul></ul></ul><ul><ul><li>RBC membrane defects </li></ul></ul><ul><ul><ul><li>Hereditary Spherocytosis </li></ul></ul></ul><ul><ul><li>RBC enzyme defects </li></ul></ul><ul><ul><ul><li>G-6-PD deficiency, Pyruvate kinase deficiency, etc. </li></ul></ul></ul><ul><ul><li>Hemoglobinopathy </li></ul></ul><ul><ul><ul><li>Hb H disease </li></ul></ul></ul><ul><ul><li>Paroxysmal Nocturnal Hemoglobinuria (PNH) </li></ul></ul><ul><li>Acute blood loss </li></ul>
  87. 88. Approach to Anemic Patient <ul><li>History </li></ul><ul><ul><li>Onset </li></ul></ul><ul><ul><li>? Source of bleeding </li></ul></ul><ul><ul><li>Severity: symptoms, blood transfusion requirement </li></ul></ul><ul><ul><li>Associated symptoms: fever, jaundice, dark urine </li></ul></ul><ul><ul><li>Precipitating factors: drug </li></ul></ul><ul><ul><li>Family history </li></ul></ul>
  88. 89. Acute Anemia: Lab studies <ul><li>CBC, reticulocyte count </li></ul><ul><li>Blood smear </li></ul><ul><li>Bilirubin </li></ul><ul><li>LDH </li></ul><ul><li>Coombs test </li></ul><ul><li>Others </li></ul><ul><ul><li>Urinary hemosiderin/ flow cytometry </li></ul></ul><ul><ul><li>Osmotic fragility test </li></ul></ul><ul><ul><li>Hb typing </li></ul></ul><ul><ul><li>G-6-PD level </li></ul></ul>
  89. 90. Immune Hemolytic Anemia
  90. 91. Hereditary Spherocytosis
  91. 92. Oxidative Hemolysis
  92. 93. Hemoglobin H Disease
  93. 94. Treatment <ul><li>Supportive treatment </li></ul><ul><ul><li>PRBC transfusion in symptomatic patient </li></ul></ul><ul><ul><li>Correct precipitating factors: infection, stop triggering medications </li></ul></ul><ul><li>Specific treatment </li></ul><ul><ul><li>Corticosteroids: AIHA (warm type), PNH </li></ul></ul>
  94. 95. Acute Leukemia <ul><li>Problems that may arise </li></ul><ul><ul><li>Bleeding: ↓ Platelet, DIC </li></ul></ul><ul><ul><li>Anemia-related symptoms </li></ul></ul><ul><ul><li>Febrile neutropenia </li></ul></ul><ul><ul><li>Leukostasis: usually occur if blast >50,000/mm 3 </li></ul></ul><ul><ul><li>Tumor lysis syndrome </li></ul></ul>
  95. 96. Acute Myeloid Leukemia Auer Rod
  96. 97. Acute Lymphoblastic Leukemia
  97. 98. Laboratory Evaluation <ul><li>CBC </li></ul><ul><li>Blood smear </li></ul><ul><li>Chemistries: LFT, RFT, Uric acid, Ca, P </li></ul><ul><li>Coagulogram/ DIC screening (M3) </li></ul><ul><li>Bone marrow aspirate and biopsy </li></ul><ul><ul><li>Immunophenotype </li></ul></ul><ul><ul><li>Cytogenetic </li></ul></ul><ul><ul><li>Molecular study </li></ul></ul>
  98. 99. Treatment <ul><li>Specific treatment </li></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Leukapheresis and hydroxyurea in leukostasis </li></ul></ul><ul><li>Supportive treatment </li></ul><ul><ul><li>IV fluid hydration </li></ul></ul><ul><ul><li>Supportive blood product transfusion </li></ul></ul>
  99. 100. Tumor Lysis Syndrome <ul><li>Laboratory studies: </li></ul><ul><ul><li>Hyperkalemia </li></ul></ul><ul><ul><li>Hyperuricemia </li></ul></ul><ul><ul><li>Hyperphosphatemia </li></ul></ul><ul><ul><li>Hypocalcemia </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>Vigorous IV hydration </li></ul></ul><ul><ul><li>Alkalinization of urine </li></ul></ul><ul><ul><li>Allopurinol </li></ul></ul>
  100. 101. Febrile Neutropenia <ul><li>Definition: </li></ul><ul><ul><li>Single oral Temp ≥ 38.3 C or ≥ 38.0 for ≥ 1 hr </li></ul></ul><ul><ul><li>Neutrophil < 500/mm 3 or < 1,000/mm 3 with a predicted decline to ≤ 500/mm 3 over the next 48 hrs </li></ul></ul>
  101. 102. Management <ul><li>Admit </li></ul><ul><li>Septic work up </li></ul><ul><ul><li>Hemoculture x 2 sets </li></ul></ul><ul><ul><li>Urine culture </li></ul></ul><ul><ul><li>Site specific cultures: e.g. skin, stool, mucosa </li></ul></ul><ul><ul><li>CXR if respiratory symptoms or signs present </li></ul></ul><ul><li>Empirical antibiotic treatment </li></ul>

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