This document discusses a clinical case of acquired bleeding disorder in a 74-year-old man presenting with bruising. Testing revealed von Willebrand disease type 2 and angiodysplasias. The key considerations for this patient include potential medication and liver disease contributions to bleeding, as well as the diagnosis of acquired von Willebrand disease. Treatment focuses on managing the underlying cause of the acquired bleeding disorder.

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. ?