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Similar to Acquired Bleeding Disorders
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Acquired Bleeding Disorders
- 1. Acquired Bleeding Disorders SimonMantha, MD, MPH Memorial Sloan-Kettering Cancer Center November 2012
- 2. Clinical Case • 74YO M presenting to the ER for 3rd episode of BRBPR – Other episodes: 2 and 6 months ago • He reports that he stopped his ASA 9 months ago due to concerns over bruising • No other bleeding problems
- 3. Clinical Case • Rx: –Simvastatin – Carvedilol – Fish oil – Paroxetine • NKDA • Drinks 3 or 4 beers/day
- 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. 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 6 No excess bleeding with any procedure…
- 6. Clinical Case • FHx: –Eastern European ancestry – 5 sibs – No bleeding diathesis in the first degree relatives
- 7. Clinical Case • CBC5.7/11.2/603 • MCV 73 • PT/PTT 22/31 • TT normal • Fib 433 • Creat 1.2 • T bil 0.9, AST/ALT normal
- 8. Overview • What cango wrong? – Decrease in coagulation factor synthesis – Increased clearance of coagulation factors • Consumption • Immune effect • Hemodilution – Inhibition of coagulation factor enzymatic activity • Rx/toxin • Antibody • Temperature/pH
- 9. Overview • What cango wrong? – Decreased number of platelets • (…) – Inhibition of platelet adhesion/aggregation • Rx/toxin – Often in the setting of “borderline” function • Activation leading to “exhaustion”
- 10. Focus • Liver disease •Vitamin K deficiency • Uremia • DIC • Coagulopathy associated with exsanguination • Acquired hemophilia • Acquired vWD
- 11. Liver Disease • Liversynthesizes fibrinogen as well as factors II, V, VII, IX, XI and XIII • “natural anticoagulants” protein C, S and AT are also secreted by the liver • The endothelial cells produce FVIII and vWF
- 12. Liver Disease • FVIIIand vWF are increased • Thrombopoietin is produced by the liver – Cleared by the platelets • About a third of the total platelet population “resides” in the spleen
- 13. Liver Disease • Typicalpicture: – Decrease in all coagulation factors except FVIII • PT >> PTT prolonged • Fibrinogen decreased in advanced cases – Decrease in protein C, S and AT
- 14. Liver Disease • Typicalpicture: – Moderate thrombocytopenia (50k or more) • Large number of platelets “available” in the spleen – Possible increased platelet activation Result in balanced hemostatic defect but decreased reserve!
- 15. Liver Disease • Treatment: –Vitamin K challenge sometimes worthwhile – Keep fibrinogen above 100 mg/dl in the acute setting • 10 U cryo – FFP 10-15 ml/kg if bleeding or procedure – Platelet transfusions if bleeding and <50k – Do not give thrombopoietin agonist!
- 16. Vitamin K Deficiency •“Koagulationvitamin” • Necessary for gamma-carboxylation of glutamic acid residues for factors II, VII, IX and X • Deficiency results in factors which do not participate effectively in the coagulation cascade – PIVKA’s
- 17. Vitamin K Deficiency •First animal model: chicks fed an ether- extracted diet • Liposoluble (“ADEK”): requires bile for absorption • Human disease seen in the presence of decreased PO intake and/or biliary obstruction – “vitamin K deficient bleeding of the newborn”
- 18. Vitamin K Deficiency •Lab: mostly prolonged PT • Treatment: – If no severe bleeding, patient eating, gut normal and biliary tree normal: vita K 10 mg PO – Otherwise: administer 10 mg IV – SC route has unreliable absorption and is no faster than PO administration
- 19. Uremia • Often subtledefect – Mucocutaneous bleeding • Multifactorial: – “uremic toxins” inhibit platelet function – Hematocrit also seems to influence bleeding – Increased NO
- 20. Uremia • Treatment options: –Dialysis – ddAVP – Supplemental epo – Estrogens
- 21. DIC • Disseminated IntravascularCoagulation • AKA consumptive coagulopathy • Consists in systemic activation of the coagulation cascade usually by TF from: – Shift of tissue thomboplastin to the circulation – Endothelial injury – Expression of TF by monocytes secondary to bacterial endotoxin • Acute vs chronic
- 22. DIC • Uncontrolled productionof fibrin results in secondary fibrinolysis and exhaustion of all coagulation factors and platelets – In the acute form, liver cannot compensate • Plasmin is not perfectly specific – Fibrinogenolysis worsens the bleeding diathesis • FDP’s act as inhibitors
- 23. DIC • The causefor acute DIC is ALMOST ALWAYS 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. DIC • Lab findings: –Prolonged PTT > PT – Thrombocytopenia • Can be profound – Fibrinogen decreased in severe cases – High D-dimers • Useless test
- 25. DIC • Treatment: – UNDERLYINGCAUSE – 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. Exsanguination • Baseline normalhemostasis • Anatomical defect results in loss of large amount of blood over a few hours – At least 1 blood volume / 10 U RBC • Replacement of blood with RBC’s and crystalloid results in coagulation factor deficiency along with thrombocytopenia
- 27. Exsanguination • Shock resultsin hypoperfusion and lactic acidosis – Coagulation enzymes do not function well at pH<7.2 • Immobility, exposure and infusion of large amounts of cold fluids results in hypothermia – Coagulation enzymes need T>33ºC to work properly
- 28. Exsanguination • Start lookingat PT/PTT and platelet count after transfusion of 5 U RBC • Be more proactive for trauma cases: – One dose of platelets and one unit of FFP for each unit of red cells transfused (1:1:1 ratio)* *Borgman MA et al, J Trauma 2007 Holcomb JB et al, Ann Surg 2008 Perkins JG et al, J Trauma 2009
- 29. Acquired Hemophilia • Autoimmunedisease • Antibody directed against FVIII – Acts as an inhibitor • Isolated prolongation of the PTT – Mixing study often corrects initially, followed by prolongation after incubation • Factor often level very low (<1%) – “corrects” with serial dilutions
- 30. Acquired Hemophilia • Canbe seen in anyone but more common in: – “Older” individuals (ie >50 YO) • Rheumatoid arthritis • Cancer • SLE • Drug reaction – Peripartum
- 31. Acquired Hemophilia • Typicallyassociated with severe bleeding: – Large hematomas • Soft tissues • Muscle – Extensive ecchymoses – Mucosal bleeding • Epistaxis • GI • GU – Surgical bleeding
- 32. Acquired Hemophilia • Treatmentoptions: – 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. Clinical Case • Colonoreveals 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. Clinical Case • Potentialcontributors 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. 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. Heyde’s Syndrome • Acquiredtype 2A vWD • Associated with aortic stenosis • Colonic angiodysplasia commonly found *Loscalzo J, M Engl J Med 2012
- 37. Acquired vWD • Treatment: –Decrease plt count with HU if MPD – “fix” the valve if aortic stenosis – ddAVP – Exogenous vWF (ie Humate-P) for significant bleeding – IVIG if autoimmune mechanism
- 38. Summary • Acquired bleedingdisorders are frequent for the consulting hematologist – Liver disease and DIC are by far the most common • Many drugs/natural products can cause mild platelet dysfunction – Usually do not cause spontaneous bleeding
- 39. Summary • The labwork-up depends mostly on clinical presentation and family history • Fix the cause of the acquired defect if possible – Clotting factors and platelets usually result in temporary/partial relief
- 40.