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Acquired Bleeding Disorders

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Acquired Bleeding Disorders

  1. 1. Acquired Bleeding DisordersSimon Mantha, MD, MPHMemorial Sloan-Kettering Cancer CenterNovember 2012
  2. 2. Clinical Case• 74 YO M presenting to the ER for 3rdepisode of BRBPR– Other episodes: 2 and 6 months ago• He reports that he stopped his ASA 9months ago due to concerns over bruising• No other bleeding problems
  3. 3. Clinical Case• Rx:– Simvastatin– Carvedilol– Fish oil– Paroxetine• NKDA• Drinks 3 or 4 beers/day
  4. 4. Clinical Case• PMHx:– CAD• CABG 5 years ago, no recent symptoms– Aortic stenosis (area=0.7 cm2)• Declined surgery– Depression– Prostate CA, s/p resection, NED
  5. 5. Clinical Case• PSHx:• CABG 5 years ago• Laparoscopic CCY 10 y ago• Hernia repair• Open prostatectomy 12 years ago• Wisdom tooth extraction at age 13• Tonsillectomy at age 6No excess bleeding with any procedure…
  6. 6. Clinical Case• FHx:– Eastern European ancestry– 5 sibs– No bleeding diathesis in the first degreerelatives
  7. 7. Clinical Case• CBC 5.7/11.2/603• MCV 73• PT/PTT 22/31• TT normal• Fib 433• Creat 1.2• T bil 0.9, AST/ALT normal
  8. 8. Overview• What can go wrong?– Decrease in coagulation factor synthesis– Increased clearance of coagulation factors• Consumption• Immune effect• Hemodilution– Inhibition of coagulation factor enzymaticactivity• Rx/toxin• Antibody• Temperature/pH
  9. 9. Overview• What can go wrong?– Decreased number of platelets• (…)– Inhibition of platelet adhesion/aggregation• Rx/toxin– Often in the setting of “borderline” function• Activation leading to “exhaustion”
  10. 10. Focus• Liver disease• Vitamin K deficiency• Uremia• DIC• Coagulopathy associated withexsanguination• Acquired hemophilia• Acquired vWD
  11. 11. Liver Disease• Liver synthesizes fibrinogen as well asfactors II, V, VII, IX, XI and XIII• “natural anticoagulants” protein C, S andAT are also secreted by the liver• The endothelial cells produce FVIII andvWF
  12. 12. Liver Disease• FVIII and vWF are increased• Thrombopoietin is produced by the liver– Cleared by the platelets• About a third of the total plateletpopulation “resides” in the spleen
  13. 13. Liver Disease• Typical picture:– Decrease in all coagulation factors exceptFVIII• PT >> PTT prolonged• Fibrinogen decreased in advanced cases– Decrease in protein C, S and AT
  14. 14. Liver Disease• Typical picture:– Moderate thrombocytopenia (50k or more)• Large number of platelets “available” in the spleen– Possible increased platelet activationResult in balanced hemostatic defect butdecreased reserve!
  15. 15. Liver Disease• Treatment:– Vitamin K challenge sometimes worthwhile– Keep fibrinogen above 100 mg/dl in the acutesetting• 10 U cryo– FFP 10-15 ml/kg if bleeding or procedure– Platelet transfusions if bleeding and <50k– Do not give thrombopoietin agonist!
  16. 16. Vitamin K Deficiency• “Koagulationvitamin”• Necessary for gamma-carboxylation ofglutamic acid residues for factors II, VII, IXand X• Deficiency results in factors which do notparticipate effectively in the coagulationcascade– PIVKA’s
  17. 17. Vitamin K Deficiency• First animal model: chicks fed an ether-extracted diet• Liposoluble (“ADEK”): requires bile forabsorption• Human disease seen in the presence ofdecreased PO intake and/or biliaryobstruction– “vitamin K deficient bleeding of the newborn”
  18. 18. Vitamin K Deficiency• Lab: mostly prolonged PT• Treatment:– If no severe bleeding, patient eating, gutnormal and biliary tree normal: vita K 10 mgPO– Otherwise: administer 10 mg IV– SC route has unreliable absorption and is nofaster than PO administration
  19. 19. Uremia• Often subtle defect– Mucocutaneous bleeding• Multifactorial:– “uremic toxins” inhibit platelet function– Hematocrit also seems to influence bleeding– Increased NO
  20. 20. Uremia• Treatment options:– Dialysis– ddAVP– Supplemental epo– Estrogens
  21. 21. DIC• Disseminated Intravascular Coagulation• AKA consumptive coagulopathy• Consists in systemic activation of thecoagulation cascade usually by TF from:– Shift of tissue thomboplastin to the circulation– Endothelial injury– Expression of TF by monocytes secondary tobacterial endotoxin• Acute vs chronic
  22. 22. DIC• Uncontrolled production of fibrin results insecondary fibrinolysis and exhaustion ofall coagulation factors and platelets– In the acute form, liver cannot compensate• Plasmin is not perfectly specific– Fibrinogenolysis worsens the bleedingdiathesis• FDP’s act as inhibitors
  23. 23. DIC• The cause for acute DIC is ALMOSTALWAYS OBVIOUS:– Sepsis– Obstetrical catastrophe• Amniotic fluid embolism, abruptio placentae, HELLP,eclampsia/severe preeclampsia, retained dead fetus, septic abortion– Trauma with crush injury and/or brain damage– Intravascular hemolysis– Snake venom– Fulminant liver failure– Acute leukemia• APL
  24. 24. DIC• Lab findings:– Prolonged PTT > PT– Thrombocytopenia• Can be profound– Fibrinogen decreased in severe cases– High D-dimers• Useless test
  25. 25. DIC• Treatment:– UNDERLYING CAUSE– Keep the fibrinogen > 100 mg/dl• 10 U cryo– FFP for bleeding or procedures– Avoid inhibitors of fibrinolysis (EACA,tranexamic acid, aprotinin)• Risk of VTE
  26. 26. Exsanguination• Baseline normal hemostasis• Anatomical defect results in loss of largeamount of blood over a few hours– At least 1 blood volume / 10 U RBC• Replacement of blood with RBC’s andcrystalloid results in coagulation factordeficiency along with thrombocytopenia
  27. 27. Exsanguination• Shock results in hypoperfusion and lacticacidosis– Coagulation enzymes do not function well atpH<7.2• Immobility, exposure and infusion of largeamounts of cold fluids results inhypothermia– Coagulation enzymes need T>33ºC to workproperly
  28. 28. Exsanguination• Start looking at PT/PTT and platelet countafter transfusion of 5 U RBC• Be more proactive for trauma cases:– One dose of platelets and one unit of FFP foreach unit of red cells transfused (1:1:1 ratio)**Borgman MA et al, J Trauma 2007Holcomb JB et al, Ann Surg 2008Perkins JG et al, J Trauma 2009
  29. 29. Acquired Hemophilia• Autoimmune disease• Antibody directed against FVIII– Acts as an inhibitor• Isolated prolongation of the PTT– Mixing study often corrects initially, followedby prolongation after incubation• Factor often level very low (<1%)– “corrects” with serial dilutions
  30. 30. Acquired Hemophilia• Can be seen in anyone but more commonin:– “Older” individuals (ie >50 YO)• Rheumatoid arthritis• Cancer• SLE• Drug reaction– Peripartum
  31. 31. Acquired Hemophilia• Typically associated with severe bleeding:– Large hematomas• Soft tissues• Muscle– Extensive ecchymoses– Mucosal bleeding• Epistaxis• GI• GU– Surgical bleeding
  32. 32. Acquired Hemophilia• Treatment options:– Elimination of the inhibitor:• Prednisone +/- cyclophosphamide*• Rituximab†– Control of bleeding:• Low titer inhibitor: FVIII concentrate• Activated PCC• rFVIIa*Collins PW et al, Blood 2007; Collins P et al, Blood 2012; Green D et al,Thromb Haemost 1993†Boles JC et al, J Thromb Haemost 2011
  33. 33. Clinical Case• Colono reveals angiodysplasia• Additional testing?– Risto 23%– vWF Ag 60%– Decreased high molecular weight vWF MM’s– RIPA normal– SPEP revealed no M-protein– II, V, VII, VIII, IX, X, XI and XIII normal– Alpha-2-AP and PAI-1 normal
  34. 34. Clinical Case• Potential contributors to bleeding events:– Lesions (ie angiodysplasias)– Rx; beta-blocker, SSRI, fish oil– Liver disease– vW disease type 2• Inherited disorder unlikely:– Negative family history– Multiple major hemostatic challenges
  35. 35. Acquired vWD• Mechanisms:– Adsorption of vWF on cells• Seen in MPD’s, MM, WM, Wilm’s tumor– Auto-antibodies– Proteolysis• Lab findings:– Normal PT/PTT– Decreased risto and abnormal electrophoresis
  36. 36. Heyde’s Syndrome• Acquired type2A vWD• Associated withaortic stenosis• Colonicangiodysplasiacommonlyfound*Loscalzo J, M Engl J Med2012
  37. 37. Acquired vWD• Treatment:– Decrease plt count with HU if MPD– “fix” the valve if aortic stenosis– ddAVP– Exogenous vWF (ie Humate-P) for significantbleeding– IVIG if autoimmune mechanism
  38. 38. Summary• Acquired bleeding disorders are frequentfor the consulting hematologist– Liver disease and DIC are by far the mostcommon• Many drugs/natural products can causemild platelet dysfunction– Usually do not cause spontaneous bleeding
  39. 39. Summary• The lab work-up depends mostly onclinical presentation and family history• Fix the cause of the acquired defect ifpossible– Clotting factors and platelets usually result intemporary/partial relief
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