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
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
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
17. Vitamin K Deficiency
• “Koagulationvitamin”
• First animal model: chicks fed an etherextracted diet
• Liposoluble (“ADEK”): requires bile for
absorption
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
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*
• Rituximabâ€
– 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!
