1. Approach to the Bleeding Patient
Jack Kuritzky, PGY-2
UNC Internal Medicine
January 15, 2010

2. Outline Focusing on patients with a bleeding diathesis
Initial clinical evaluation
Initial workup
Fun with PT and aPTT
Factor VIII inhibitors
Epidemiology
Presentation
Diagnosis
Treatment

3. Approach to the Bleeding Patient
Initial assessment: Vital signs
Stabilize the patient, then get the details

4. Approach to the Bleeding Patient: Differentiating Disorders of Platelets vs. Coagulation Factors
History and Physical Exam
Platelets: Think small and early
Bleed from skin and mucous membranes (nose, GI/GU)
Petechiae
Tend to bleed after small cuts
Small and superficial ecchymoses
Bleeding after surgery is immediate and mild
Coagulation Factors: Think big and late
Deep in soft tissue
No petechiae and don’t bleed after small cuts
Ecchymoses are common
Bleeding after surgery is delayed and severe

5. Approach to the Bleeding Patient: Initial Laboratory Workup
CBC
Smear
Ensure no “pseudothrombocytopenia” due to platelet clumping from EDTA tube
Can use heparin or citrate instead
Coags
Type and Screen

6. Coagulation Pathways aPTT PT
Leung, L. Overview of Hemostasis. UpToDate. Sept

7. Approach to the Bleeding Patient: Differentials of PT and aPTT
Prolonged PT, Normal aPTT
Inherited: Factor VII deficiency
Acquired:
Warfarin
Vit K deficiency
Acquired Factor VII deficiency or inhibitor
Liver disease

8. Approach to the Bleeding Patient: Differentials of PT and aPTT
Normal PT, Prolonged aPTT
Inherited
Hemophilia A (factor VIII deficiency)
Hemophilia B (factor IX deficiency)
von Willebrand Disease
Binds platelets to endothelium and themselves
Carrier protein for Factor VIII
Account for 95-97% of inherited coag abnormalities
Acquired:
Inhibitor of factors VIII, IX, XI, or XII
Acquired von Willebrand disease
Lupus anticoagulant (often associated with thrombosis)

9. Approach to the Bleeding Patient: Differentials of PT and aPTT
Prolonged PT and aPTT
Inherited
Deficiency of factors required by both pathways
Prothrombin, fibrinogen or factors V or X
Combined factor deficiencies
Acquired:
Liver Disease
DIC
Supratherapeutic heparin or coumadin
Inhibitor of prothrombin, fibrinogen or factors V or X

10. Approach to the Bleeding Patient: Differential of aPTT
In the case of isolated prolonged aPTT…
? Heparin  Redraw to be certain original sample not contaminated with heparin
aPTT would normalize with administration of protamine
Mixing Study
Mix patient plasma with pooled normal plasma
If aPTT normalizes, there is factor deficiency
If not, there is an inhibitor
Add phospholipid
If aPTT normalizes, there is anti-phospholipid antibody

11. Approach to the Bleeding Patient: Differential of aPTT
Measure activity of factors specifically
Bethesda Assay
Serially dilute patient plasma and mix with normal plasma
Measure Factor VIII activity
One Bethesda unit = Dilution of patient plasma that results in 50% Factor VIII activity
The stronger the inhibitor, the greater the dilution required

12. Approach to the Bleeding Patient: Factor VIII Inhibitors
AKA Acquired Hemophilia
Most common autoantibodies affecting clotting factor
Mostly IgG
Epidemiology
patients per million population
>50 years old except post-partum
In series of 250 patients, average Bethesda titer was 10 and average Factor VIII activity was 2%

13. Approach to the Bleeding Patient: Factor VIII Inhibitors
Causes: postpartum, rheumatoid arthritis, malignancy, systemic lupus erythematosus, and drug reaction (penicillin)
Each accounts for ~5-10%
No identifiable cause in ~50% of patients
Multiple types of malignancy
In trial of 41 patients, 25 had solid tumors and 16 hematologic
Prostate and Lung most common

14. Approach to the Bleeding Patient: Factor VIII Inhibitors
Presentation
Hematomas and ecchymosis
Mucosal bleeding
GI bleed
Epistaxis
Hematoma
Hemarthrosis rare
Bleeding often severe
Series of 215 patients post-partum
87% major bleeding
22% died from complications of inhibitor

15. Approach to the Bleeding Patient: Factor VIII Inhibitors
Treatment for acute bleeding
ddAVP for minor bleeding, low Bethesda (<5)
Increases levels of von Willebrand factor and factor VIII
Treat more serious bleeding with factor VIII concentrate for low Bethesda (<5)
For serious bleed and high Bethesda, treat with Novoseven

16. Approach to the Bleeding Patient: Factor VIII Inhibitors
Treatment – Eliminating inhibitor
~1/3 of inhibitors spontaneously disappear at 14 mos
Initial prednisone at 1mg/kg/day x3 weeks
32% response rate (Green D, et al)
If no response, then cyclophosphamide
50% of initial non-responders (Green D, et al)
Response is better in patient with low Bethesda titers (<5)
For immediate removal, can consider plasmapheresis
Rituximab gaining favor, but not yet standard of care

17. References Coutre, S. Acquired Inhibitors of Coagulation. Sept 2009.
Delgado, J, et al. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121:21.
Drews, RE. Approach to the Patient with a Bleeding Diathesis. UpToDate. Sept 2009.
Green, D, et al. A prospective, randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies. Thromb Haemost 1993 Nov 15;70(5):753-7.
Leung, L. Overview of Hemostasis. UpToDate. Sept
Sallah, S and Wan, JY. Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients. Cancer 2001 Mar 15;91(6):
Stachnik, JM. Rituximab in the treatment of acquired hemophilia. Ann Pharmacother 2006; 40:1151.

18. THE END