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Acquired bleeding disorders

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  • 1. Acquired Bleeding Disorders Simon Mantha, MD, MPH Memorial Sloan-Kettering Cancer Center October 2013
  • 2. Clinical Case • 53 YO M with HCV and cirrhosis • Screening liver US revealed new nodule 14 months ago – Treated with surgical resection • Multifocal recurrence 3 months ago – Liver, lungs and bones • Chemo started 1 month ago
  • 3. Clinical Case • PMHx: – Variceal bleeding x 2 • s/p banding – CAD • PTCA with 1 stent on LAD 5 years ago – DB2
  • 4. Clinical Case • PSHx: – – – – Resection of liver tumor in 2012 Liver biopsy in 2007 Appendectomy at age 13 Tonsillectomy at age 6 No excessive bleeding with any of the above
  • 5. Clinical Case • FHx: – No history of bleeding disorder in parents or 5 siblings • Meds: – – – – ASA 81 mg daily Atenolol Lisinopril Metformin
  • 6. Clinical Case • Patient admitted through UCC with fever to 102.1 – – Poor PO intake in the previous 3 days Started on broad spectrum AB for neutropenic sepsis – Hematology consulted for worsening coagulation parameters
  • 7. Clinical Case • Baseline values (one month ago): – – – – PT/INR/PTT 14.1/1.3/25.0 Fibrinogen 355 CBC 6.7/12.5/120 AST/ALT/Tbili 54/62/2.1
  • 8. Clinical Case • Recent values: – – – – PT/INR/PTT 24.1/2.2/58.3 Fibrinogen 140 CBC 0.3/10.3/44 AST/ALT/Tbili 66/52/2.5
  • 9. Focus • • • • Liver disease Vitamin K deficiency Disseminated intravascular coagulation Coagulopathy associated with massive transfusion • Uremia • Acquired hemophilia • Acquired von Willebrand’s disease
  • 10. Liver Disease • Decrease in coagulation factors synthesized by the liver: – II, V, VII, IX, X, XI and XIII • Decrease in fibrinogen and dysfibrinogenemia • Hyperfibrinolysis – Decrease in TAFI
  • 11. Liver Disease • Increase in “acute phase reactant” endothelial-derived (?) coagulation factors – Factor VIII and von Willebrand factor • Decreased synthesis of the “natural anticoagulants”: – Protein C, protein S, ATIII and plasminogen
  • 12. Liver Disease • Thrombocytopenia – Increased splenic sequestration secondary to portal hypertension (ie hypersplenism) – Decreased production of TPO • Inhibition of platelet function – NO?
  • 13. Liver Disease • End result is a balanced hemostatic defect: – Decreased capacity to develop a clot in the presence of bleeding, ie decreased hemostatic “reserve” – Increased risk of pathological thrombus formation • Liver disease does not constitute “autoanticoagulation”!
  • 14. Liver Disease • PT prolongs first, with increased PTT in advanced cases • Fibrinogen decreases late in the course • Platelet count of 50-150k is typical, rarely less
  • 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 – 4-factor PCC (Kcentra) “off label” • Factors II, VII, IX and X – Recombinant FVIIa
  • 16. Liver Disease • Treatment: – Anti-fibrinolytics – Platelet transfusions if bleeding and <50k
  • 17. Vitamin K Deficiency • “Koagulationvitamin” • First animal model: chicks fed an etherextracted diet • Liposoluble (“ADEK”): requires bile for absorption
  • 18. Vitamin K Deficiency Wikipedia
  • 19. Vitamin K Deficiency • Necessary for gamma-carboxylation of glutamic acid residues for factors II, VII, IX and X: http://www.enzyme-database.org/reaction/misc/vitKcycle.html
  • 20. Vitamin K Deficiency • Gamma-carboxyglutamic acid moiety mediates interaction with calcium and cell membranes: http://highered.mcgraw-hill.com/sites/dl/free/0071402357/156708/figure53_7.html
  • 21. Vitamin K Deficiency • Deficiency results in factors which do not participate effectively in the coagulation cascade – PIVKA’s – Identical to warfarin effect
  • 22. Vitamin K Deficiency • Human disease seen in the presence of decreased PO intake, GI absorption and/or impaired utilization: – – – – – Malnutrition Short bowel syndrome Inflammatory bowel disease Biliary obstruction “vitamin K deficient bleeding of the newborn”
  • 23. 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
  • 24. Disseminated Intravascular Coagulation • 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
  • 25. Disseminated Intravascular Coagulation • Uncontrolled production of fibrin results in secondary fibrinolysis and consumption of coagulation factors and platelets – Acute vs chronic – In the acute form, liver cannot compensate • Plasmin is not perfectly specific – Fibrinogenolysis worsens the bleeding diathesis • FDP’s act as inhibitors
  • 26. Disseminated Intravascular Coagulation • The cause for 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 • Acute promyelocytic leukemia
  • 27. Disseminated Intravascular Coagulation • Lab findings: – Prolonged PTT > PT – Thrombocytopenia • Can be profound – Fibrinogen decreased in severe cases – High D-dimers • Useless test
  • 28. Disseminated Intravascular Coagulation • 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 thrombotic episode
  • 29. Massive Transfusion • Baseline normal hemostasis • Anatomical defect results in loss of large amount of blood over a few hours • Historical definition: – 10 U RBC / 24 hrs • Alternate definition: – 5 U RBC / 3 hrs
  • 30. Massive Transfusion • Replacement of blood with RBC’s and crystalloid results in coagulation factor deficiency along with thrombocytopenia – Coagulation factor activity decreases by 10% for every 500 ml of blood replaced – Platelets and coagulation factors are consumed at the site of bleeding – Added effect of DIC
  • 31. Massive Transfusion • Shock results in 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
  • 32. Massive Transfusion • Start looking at PT/PTT and platelet count after transfusion of 5 U RBC • Be more proactive for trauma cases: – One unit 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
  • 33. Uremia • Often subtle defect – Mucocutaneous bleeding • Multifactorial: – – – “uremic toxins” inhibit platelet function Hematocrit also seems to influence bleeding Increased NO
  • 34. Uremia • Treatment options: – – – – – Dialysis ddAVP Supplemental epo Estrogens Cryoprecipitate
  • 35. Acquired Hemophilia • Autoimmune disease • 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
  • 36. Acquired Hemophilia • Can be seen in anyone but more common in: – “Older” individuals (ie >50 YO) • • • • Rheumatoid arthritis Cancer SLE Drug reaction – Peripartum
  • 37. Acquired Hemophilia • Typically associated with severe bleeding: – Large hematomas • Soft tissues • Muscle – Extensive ecchymoses – Mucosal bleeding • Epistaxis • GI • GU – Surgical bleeding
  • 38. 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
  • 39. Acquired vWD • Mechanisms: – Adsorption of vWF on cells • Seen in myeloproliferative neoplasms, multiple myeloma, Waldenstrom’s macroglobulinemia, Wilm’s tumor – Auto-antibodies – Proteolysis
  • 40. Heyde’s Syndrome • Acquired type 2A vWD • Associated with aortic stenosis • Colonic angiodysplasia commonly found *Loscalzo J, M Engl J Med 2012
  • 41. Acquired vWD • Lab findings: – Normal PT/PTT – Decreased risto and abnormal electrophoresis • Treatment: address primary condition…
  • 42. Clinical Case • Summary: – Middle-aged man with advanced liver disease, poor oral intake, sepsis and worsening of underlying prolonged PT and thrombocytopenia • New prolongation of PTT – On low-dose ASA for CAD – No personal or family history of bleeding diathesis
  • 43. Clinical Case • Likely contributing problems: – – – – Coagulopathy of liver disease Vitamin K deficiency Disseminated intravascular coagulation ASA effect
  • 44. Clinical Case • Management: – Vitamin K 10 mg PO daily x 3 – Hold blood products for now – Reserve platelets, Kcentra and/or FFP for bleeding – Hold ASA if possible
  • 45. Summary • Acquired bleeding disorders are frequent for the consulting hematologist – Liver disease and DIC are by far the most common – The lab work-up depends mostly on clinical presentation
  • 46. Summary • Fix the cause of the acquired defect if possible – Clotting factors and platelets usually result in temporary/partial relief – Avoid unnecessary use of blood products • Treat the patient, not a number!
  • 47. ?

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