Author(s): Steven Pipe, M.D., 2009License: Unless otherwise noted, this material is made available under the termsof the C...
Citation Key                          for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Ada...
Acquired Bleeding Disorders        M2 Hematology/Oncology Sequence               Steven Pipe, MDWinter 2009
Acquired Bleeding Disorders•  Can be a recognized manifestation of a   known disorder                        or•  Can prom...
Promoters and Inhibitors of            Coagulation•  Coagulation cascade  –  Tissue factor (Extrinsic) Pathway  –  Intrins...
PTT                                     PT      Mechanisms In Hematology Israel        6
7Mechanisms In Hematology Israel
Protein C - Protein S SystemMechanisms In Hematology Israel                                           8
9Mechanisms In Hematology Israel
Acquired Bleeding Disorders     associated with PT and aPTT•  Various Medical Conditions  –  Anticoagulation  –  Dissemina...
Disseminated Intravascular         Coagulation (DIC)•  DIC is evidence for the simultaneous   presence of:  –  thrombin(pr...
Primary Events in DIC                                          Underlying Disorder                         Systemic Activa...
Pathophysiology                    of DICBlue (dotted) indicates inhibitors of coagulation                                ...
Etiology of DIC•  Acute DIC   –  Infection: Gram -ve sepsis, viremia, parasitic   –  Obstetric: Abruption, amniotic fluid ...
Post-varicella purpura fulminans    DeLoughery, ASH Image Bank, 2004   15
Diagnosis of DIC•  Screening tests:   –  Activated partial thromboplastin time (prolonged)   –  Prothrombin time (prolonge...
17Mechanisms In Hematology Israel
Value of the D-dimer•  Measure of D-dimers liberated from fibrin by   action of plasmin  –  Evidence of prior thrombin act...
Treatment of DIC•  Treat the underlying condition first!   –  Antibiotics, surgery, chemotherapy, embolization   –  diseas...
Microangiopathic Hemolytic Anemia                   K. McInerny. American Academy of Pediatrics textbook of pediatric care...
Microangiopathic Hemolytic Anemias                    Pathophysiology•  Hallmarks are red cell fragmentation   (shistocyte...
Microangiopathic Hemolytic Anemias                 Differential Diagnosis•    Disseminated intravascular coagulation (DIC)...
Thrombotic Thrombocytopenic Purpura•  Classic pentad:   –    Microangiopathic hemolytic anemia   –    Thrombocytopenia   –...
Pathogenesis of Idiopathic TTP caused by ADAMTS13 Deficiency            Sadler, J. E. Blood 2008;112:11-18                ...
DIC vs TTPAbnormality                  DIC      TTPAbnormal PT/                             Y        N    PTT Hemolysis   ...
Acquired Bleeding Disorders     associated with PT and aPTT•  Various Medical Conditions  –  Anticoagulation  –  Dissemina...
Vitamin K deficiency•  Vitamin K cycle•  Mechanisms of Vitamin K deficiency•  Warfarin action                             ...
28Mechanisms In Hematology Israel
Mechanisms of Vitamin K             deficiency•  Nutritional depletion  –  Alcoholics, long-term IV nutrition•  Antibiotic...
Liver Disease•  Liver synthesizes and clears both procoagulants and   inhibitors•  Paradoxically factor VIII is often elev...
Massive Transfusion•  Defined as transfusion of more than 1.5 times   the patient s blood volume in 24 h•  Acquired coagul...
Other uncommon acquired  coagulation protein defects•  Dysfibrinogenemia    –  Acquired liver disease (EtOH, immunologic, ...
Acquired bleeding disorders associated       with prolonged aPTT only•  Inhibitors to factor VIII   –  Elderly, post-partu...
Additional Source Information                    for more information see: http://open.umich.edu/wiki/CitationPolicySlide ...
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01.08.09: Acquired Bleeding Disorders

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01.08.09: Acquired Bleeding Disorders

  1. 1. Author(s): Steven Pipe, M.D., 2009License: Unless otherwise noted, this material is made available under the termsof the Creative Commons Attribution – Share Alike 3.0 License:http://creativecommons.org/licenses/by-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. Acquired Bleeding Disorders M2 Hematology/Oncology Sequence Steven Pipe, MDWinter 2009
  4. 4. Acquired Bleeding Disorders•  Can be a recognized manifestation of a known disorder or•  Can prompt a differential diagnosis to identify an underlying disease 4
  5. 5. Promoters and Inhibitors of Coagulation•  Coagulation cascade –  Tissue factor (Extrinsic) Pathway –  Intrinsic Pathway –  Fibrinogen, Factor XIII and Fibrinolysis•  Inhibitors –  Physiologic –  Acquired –  Therapeutic 5
  6. 6. PTT PT Mechanisms In Hematology Israel 6
  7. 7. 7Mechanisms In Hematology Israel
  8. 8. Protein C - Protein S SystemMechanisms In Hematology Israel 8
  9. 9. 9Mechanisms In Hematology Israel
  10. 10. Acquired Bleeding Disorders associated with PT and aPTT•  Various Medical Conditions –  Anticoagulation –  Disseminated Intravascular Coagulation –  Vitamin K Deficiency –  Liver Disease –  Massive Transfusion•  Dysfibrinogenemias•  Acquired Inhibitors to Factors V, II & X 10
  11. 11. Disseminated Intravascular Coagulation (DIC)•  DIC is evidence for the simultaneous presence of: –  thrombin(procoagulation) –  plasmin(fibrinolysis)•  Presentations: –  an acute hemorrhagic disorder –  an indolent, subacute thrombotic disorder 11
  12. 12. Primary Events in DIC Underlying Disorder Systemic Activation of CoagulationWidespread Consumption ofIntravascular Platelets andFibrin Deposition Clotting Factors Thrombosis Bleeding K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009 12
  13. 13. Pathophysiology of DICBlue (dotted) indicates inhibitors of coagulation 13 K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009
  14. 14. Etiology of DIC•  Acute DIC –  Infection: Gram -ve sepsis, viremia, parasitic –  Obstetric: Abruption, amniotic fluid embolism, eclampsia –  Malignancy: Acute promyelocytic leukemia –  Trauma: Crush injury, freshwater drowning, heat stroke, snakebite –  Other: Homozygous protein C and S deficiency (infants), severe liver disease, HIT•  Subacute DIC –  Malignancy: mucinous adenocarcinoma (Trousseau syndrome) –  Obstetric: retained dead fetus –  Vascular: hemangioendothelioma (Kasabach-Merritt), venous thromboembolic disease, chronic renal failure 14
  15. 15. Post-varicella purpura fulminans DeLoughery, ASH Image Bank, 2004 15
  16. 16. Diagnosis of DIC•  Screening tests: –  Activated partial thromboplastin time (prolonged) –  Prothrombin time (prolonged) –  Fibrinogen (decreased) –  Platelet count (decreased)•  Confirmatory tests: –  D-dimer (elevated) –  Fibrin degradation products (elevated) 16
  17. 17. 17Mechanisms In Hematology Israel
  18. 18. Value of the D-dimer•  Measure of D-dimers liberated from fibrin by action of plasmin –  Evidence of prior thrombin activity followed by fibrinolysis•  Should be part of evaluation of DIC•  Also now an important screening and prognostic tool in venous thromboembolic disease –  Good positive predictive value for DVT and PE –  Very high negative predictive value Source: Wells et al., NEJM, 2003;349:1227-1235 18 Eichinger et al., JAMA, 2003;290:1071-1074
  19. 19. Treatment of DIC•  Treat the underlying condition first! –  Antibiotics, surgery, chemotherapy, embolization –  disease-specific therapy •  APML - all trans-retinoic acid (ATRA)•  Replacement therapy –  Platelets, FFP, cryoprecipitate•  Heparin –  May be useful in certain situations •  Acral cyanosis and digital ischemia, purpura fulminans, retained dead fetus, migratory thrombophlebitis 19
  20. 20. Microangiopathic Hemolytic Anemia K. McInerny. American Academy of Pediatrics textbook of pediatric care. 20091.  Shistocyte * Note absence of platelets 202.  Microcyte
  21. 21. Microangiopathic Hemolytic Anemias Pathophysiology•  Hallmarks are red cell fragmentation (shistocytes, microcytes) on peripheral blood smear, often accompanied by thrombocytopenia•  Intravascular hemolysis as red cells are damaged traversing small blood vessels with fibrin deposition or platelet aggregates –  Can also occur in areas of high turbulence (eg. Aortic stenosis)•  Red cell fragments are targeted for destruction in the reticuloendothelial system (eg. spleen) 21
  22. 22. Microangiopathic Hemolytic Anemias Differential Diagnosis•  Disseminated intravascular coagulation (DIC)•  Thrombotic thrombocytopenic purpura (TTP)•  Hemolytic uremic syndrome (HUS)•  Malignant hypertension•  Aortic stenosis•  HELLP syndrome and eclampsia•  Heparin-induced thrombocytopenia•  Severe glomerulonephritis 22
  23. 23. Thrombotic Thrombocytopenic Purpura•  Classic pentad: –  Microangiopathic hemolytic anemia –  Thrombocytopenia –  Renal involvement –  Neurologic signs –  Fever•  Most cases in adults are caused by acquired autoantibodies that inhibit ADAMTS13, a metalloprotease that cleaves vWF within platelet-rich thrombi –  Congenital form (Upshaw-Schulman syndrome) is the result of a deficiency of ADAMTS13•  Treatment is plasma exchange +/- immunosuppression 23
  24. 24. Pathogenesis of Idiopathic TTP caused by ADAMTS13 Deficiency Sadler, J. E. Blood 2008;112:11-18 24
  25. 25. DIC vs TTPAbnormality DIC TTPAbnormal PT/ Y N PTT Hemolysis Y YThrombocytopenia Y Y Abnormal N YRenal Tests Source Undetermined 25
  26. 26. Acquired Bleeding Disorders associated with PT and aPTT•  Various Medical Conditions –  Anticoagulation –  Disseminated Intravascular Coagulation –  Vitamin K Deficiency –  Liver Disease –  Massive Transfusion•  Dysfibrinogenemias•  Acquired Inhibitors to Factors V, II & X 26
  27. 27. Vitamin K deficiency•  Vitamin K cycle•  Mechanisms of Vitamin K deficiency•  Warfarin action 27
  28. 28. 28Mechanisms In Hematology Israel
  29. 29. Mechanisms of Vitamin K deficiency•  Nutritional depletion –  Alcoholics, long-term IV nutrition•  Antibiotic administration –  Interfere with bacteria synthesis and absorption•  Warfarin –  Inhibition of epoxide reductase and (to a lesser degree) quinone reductase 29
  30. 30. Liver Disease•  Liver synthesizes and clears both procoagulants and inhibitors•  Paradoxically factor VIII is often elevated –  Likely due to decreased clearance•  Reduced factor V helps distinguish liver synthetic dysfunction from vitamin K deficiency•  Fibrinogen the last to fall•  Structural manifestations of liver disease contribute to bleeding –  Portal hypertension, varices, gastritis, hemorrhoids 30
  31. 31. Massive Transfusion•  Defined as transfusion of more than 1.5 times the patient s blood volume in 24 h•  Acquired coagulopathy results from dilution of plasma and platelets and excess anticoagulant –  10% of transfusion is anticoagulant•  Prevention: –  Administer 1 unit FFP and calcium chloride for every 4-6 units PRBC s 31
  32. 32. Other uncommon acquired coagulation protein defects•  Dysfibrinogenemia –  Acquired liver disease (EtOH, immunologic, toxic, viral)•  Inhibitors to X, V, II and fibrinogen•  Hypergammaglobulinemia –  Multiple myeloma (IgG) –  Waldenstrom macroglobulinemia (IgM)•  Systemic amyloidosis –  Decreased factor X or IX•  Heparinoids –  Heparin-like anticoagulants produced in patients with an underlying malignancy•  Factitious –  Self-administered heparin/warfarin 32
  33. 33. Acquired bleeding disorders associated with prolonged aPTT only•  Inhibitors to factor VIII –  Elderly, post-partum, connective tissue disorder, B cell malignancy –  Prolonged aPTT but normal PT –  Skin ecchymoses and tissue hematomas –  Respond to immunosuppressive therapy –  bypassing agents to treat bleeding •  Activated prothrombin complex concentrates •  Recombinant factor VIIa (Novoseven) –  Prognosis generally favorable 33
  34. 34. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 6: Mechanisms In Hematology IsraelSlide 7: Mechanisms In Hematology IsraelSlide 8: Mechanisms In Hematology IsraelSlide 9: Mechanisms In Hematology IsraelSlide 12: K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009 – From the chapter Disseminated Intravascular CoagulationSlide 13: K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009 – From the chapter Disseminated Intravascular CoagulationSlide 15: DeLoughery, ASH Image Bank, 2004Slide 17: Steven PipeSlide 20: K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009 – From the chapter Disseminated Intravascular CoagulationSlide 24: Sadler, J. E. Blood 2008;112:11-18, http://bloodjournal.hematologylibrary.org/cgi/content/full/112/1/11/F2, 2008 American Society of HematologySlide 25: Source UndeterminedSlide 28: Mechanisms In Hematology Israel

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