1. Acquired Bleeding Disorders
Simon Mantha, MD, MPH
Memorial Sloan-Kettering Cancer Center
November 2012

2. Clinical Case
• 74 YO 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
• 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. Overview
• What can go 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 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. Focus
• Liver disease
• Vitamin K deficiency
• Uremia
• DIC
• Coagulopathy associated with
exsanguination
• Acquired hemophilia
• Acquired vWD

11. Liver Disease
• Liver synthesizes 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
• FVIII and 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
• Typical picture:
– 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
• Typical picture:
– 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 subtle defect
– 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 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
• Acute vs chronic

22. DIC
• Uncontrolled production of 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 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
• 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:
– 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. Exsanguination
• Baseline normal hemostasis
• 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 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

28. Exsanguination
• Start looking at 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
• 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

30. Acquired Hemophilia
• Can be seen in anyone but more common
in:
– “Older” individuals (ie >50 YO)
• Rheumatoid arthritis
• Cancer
• SLE
• Drug reaction
– Peripartum

31. Acquired Hemophilia
• Typically associated with severe bleeding:
– Large hematomas
• Soft tissues
• Muscle
– Extensive ecchymoses
– Mucosal bleeding
• Epistaxis
• GI
• GU
– Surgical bleeding

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. 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. 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. 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
• Acquired type
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 bleeding disorders 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 lab work-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. ?