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Acquired Bleeding Disorders

Simon Mantha, MD, MPH
Memorial Sloan-Kettering Cancer Center
October 2013
Clinical Case
• 53 YO M with HCV and cirrhosis
• Screening liver US revealed new nodule
14 months ago
– Treated with surgi...
Clinical Case
• PMHx:
– Variceal bleeding x 2
• s/p banding

– CAD
• PTCA with 1 stent on LAD 5 years ago

– DB2
Clinical Case
• PSHx:
–
–
–
–

Resection of liver tumor in 2012
Liver biopsy in 2007
Appendectomy at age 13
Tonsillectomy ...
Clinical Case
• FHx:
– No history of bleeding disorder in parents or
5 siblings

• Meds:
–
–
–
–

ASA 81 mg daily
Atenolol...
Clinical Case
• Patient admitted through UCC with
fever to 102.1
–
–

Poor PO intake in the previous 3 days
Started on bro...
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...
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
Focus
•
•
•
•

Liver disease
Vitamin K deficiency
Disseminated intravascular coagulation
Coagulopathy associated with mass...
Liver Disease
• Decrease in coagulation factors
synthesized by the liver:
– II, V, VII, IX, X, XI and XIII

• Decrease in ...
Liver Disease
• Increase in “acute phase reactant”
endothelial-derived (?) coagulation
factors
– Factor VIII and von Wille...
Liver Disease
• Thrombocytopenia
– Increased splenic sequestration secondary to
portal hypertension (ie hypersplenism)
– D...
Liver Disease
• End result is a balanced hemostatic defect:
– Decreased capacity to develop a clot in the
presence of blee...
Liver Disease
• PT prolongs first, with increased PTT in
advanced cases
• Fibrinogen decreases late in the course
• Platel...
Liver Disease
• Treatment:
– Vitamin K challenge sometimes worthwhile
– Keep fibrinogen above 100 mg/dl in the
acute setti...
Liver Disease
• Treatment:
– Anti-fibrinolytics
– Platelet transfusions if bleeding and <50k
Vitamin K Deficiency
• “Koagulationvitamin”
• First animal model: chicks fed an etherextracted diet
• Liposoluble (“ADEK”)...
Vitamin K Deficiency

Wikipedia
Vitamin K Deficiency
•

Necessary for gamma-carboxylation of glutamic acid residues for
factors II, VII, IX and X:

http:/...
Vitamin K Deficiency
•

Gamma-carboxyglutamic acid moiety mediates interaction with
calcium and cell membranes:

http://hi...
Vitamin K Deficiency
• Deficiency results in factors which do not
participate effectively in the coagulation
cascade
– PIV...
Vitamin K Deficiency
• Human disease seen in the presence of
decreased PO intake, GI absorption
and/or impaired utilizatio...
Vitamin K Deficiency
• Lab: mostly prolonged PT
• Treatment:
– If no severe bleeding, patient eating, gut
normal and bilia...
Disseminated Intravascular Coagulation
• AKA consumptive coagulopathy
• Consists in systemic activation of the
coagulation...
Disseminated Intravascular Coagulation
• Uncontrolled production of fibrin results in
secondary fibrinolysis and consumpti...
Disseminated Intravascular Coagulation
• The cause for acute DIC is ALMOST
ALWAYS OBVIOUS:
– Sepsis
– Obstetrical catastro...
Disseminated Intravascular Coagulation
• Lab findings:
– Prolonged PTT > PT
– Thrombocytopenia
• Can be profound

– Fibrin...
Disseminated Intravascular Coagulation
• Treatment:
– UNDERLYING CAUSE
– Keep the fibrinogen > 100 mg/dl
• 10 U cryo

– FF...
Massive Transfusion
• Baseline normal hemostasis
• Anatomical defect results in loss of large
amount of blood over a few h...
Massive Transfusion
• Replacement of blood with RBC’s and
crystalloid results in coagulation factor
deficiency along with ...
Massive Transfusion
• Shock results in hypoperfusion and lactic
acidosis
– Coagulation enzymes do not function well at
pH<...
Massive Transfusion
• Start looking at PT/PTT and platelet count
after transfusion of 5 U RBC
• Be more proactive for trau...
Uremia
• Often subtle defect
– Mucocutaneous bleeding

• Multifactorial:
–
–
–

“uremic toxins” inhibit platelet function
...
Uremia
• Treatment options:
–
–
–
–
–

Dialysis
ddAVP
Supplemental epo
Estrogens
Cryoprecipitate
Acquired Hemophilia
• Autoimmune disease
• Antibody directed against FVIII
– Acts as an inhibitor

• Isolated prolongation...
Acquired Hemophilia
• Can be seen in anyone but more common
in:
– “Older” individuals (ie >50 YO)
•
•
•
•

Rheumatoid arth...
Acquired Hemophilia
• Typically associated with severe bleeding:
– Large hematomas
• Soft tissues
• Muscle

– Extensive ec...
Acquired Hemophilia
• Treatment options:
– Elimination of the inhibitor:
• Prednisone +/- cyclophosphamide*
• Rituximab†

...
Acquired vWD
• Mechanisms:
– Adsorption of vWF on cells
• Seen in myeloproliferative neoplasms, multiple
myeloma, Waldenst...
Heyde’s Syndrome
• Acquired type
2A vWD
• Associated with
aortic stenosis
• Colonic
angiodysplasia
commonly
found

*Loscal...
Acquired vWD
• Lab findings:
– Normal PT/PTT
– Decreased risto and abnormal
electrophoresis

• Treatment: address primary ...
Clinical Case
• Summary:
– Middle-aged man with advanced liver
disease, poor oral intake, sepsis and
worsening of underlyi...
Clinical Case
• Likely contributing problems:
–
–
–
–

Coagulopathy of liver disease
Vitamin K deficiency
Disseminated int...
Clinical Case
• Management:
– Vitamin K 10 mg PO daily x 3
– Hold blood products for now
– Reserve platelets, Kcentra and/...
Summary
• Acquired bleeding disorders are frequent
for the consulting hematologist
– Liver disease and DIC are by far the ...
Summary
• Fix the cause of the acquired defect if
possible
– Clotting factors and platelets usually result
in temporary/pa...
?
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Acquired bleeding disorders

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Acquired bleeding disorders

  1. 1. Acquired Bleeding Disorders Simon Mantha, MD, MPH Memorial Sloan-Kettering Cancer Center October 2013
  2. 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. 3. Clinical Case • PMHx: – Variceal bleeding x 2 • s/p banding – CAD • PTCA with 1 stent on LAD 5 years ago – DB2
  4. 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. 5. Clinical Case • FHx: – No history of bleeding disorder in parents or 5 siblings • Meds: – – – – ASA 81 mg daily Atenolol Lisinopril Metformin
  6. 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. 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. 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. 9. Focus • • • • Liver disease Vitamin K deficiency Disseminated intravascular coagulation Coagulopathy associated with massive transfusion • Uremia • Acquired hemophilia • Acquired von Willebrand’s disease
  10. 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. 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. 12. Liver Disease • Thrombocytopenia – Increased splenic sequestration secondary to portal hypertension (ie hypersplenism) – Decreased production of TPO • Inhibition of platelet function – NO?
  13. 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. 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. 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. 16. Liver Disease • Treatment: – Anti-fibrinolytics – Platelet transfusions if bleeding and <50k
  17. 17. Vitamin K Deficiency • “Koagulationvitamin” • First animal model: chicks fed an etherextracted diet • Liposoluble (“ADEK”): requires bile for absorption
  18. 18. Vitamin K Deficiency Wikipedia
  19. 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. 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. 21. Vitamin K Deficiency • Deficiency results in factors which do not participate effectively in the coagulation cascade – PIVKA’s – Identical to warfarin effect
  22. 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. 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. 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. 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. 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. 27. Disseminated Intravascular Coagulation • Lab findings: – Prolonged PTT > PT – Thrombocytopenia • Can be profound – Fibrinogen decreased in severe cases – High D-dimers • Useless test
  28. 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. 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. 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. 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. 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. 33. Uremia • Often subtle defect – Mucocutaneous bleeding • Multifactorial: – – – “uremic toxins” inhibit platelet function Hematocrit also seems to influence bleeding Increased NO
  34. 34. Uremia • Treatment options: – – – – – Dialysis ddAVP Supplemental epo Estrogens Cryoprecipitate
  35. 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. 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. 37. Acquired Hemophilia • Typically associated with severe bleeding: – Large hematomas • Soft tissues • Muscle – Extensive ecchymoses – Mucosal bleeding • Epistaxis • GI • GU – Surgical bleeding
  38. 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. 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. 40. Heyde’s Syndrome • Acquired type 2A vWD • Associated with aortic stenosis • Colonic angiodysplasia commonly found *Loscalzo J, M Engl J Med 2012
  41. 41. Acquired vWD • Lab findings: – Normal PT/PTT – Decreased risto and abnormal electrophoresis • Treatment: address primary condition…
  42. 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. 43. Clinical Case • Likely contributing problems: – – – – Coagulopathy of liver disease Vitamin K deficiency Disseminated intravascular coagulation ASA effect
  44. 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. 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. 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!
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