Approach to the Bleeding Patient

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. 2009.

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 • 1.3-1.5 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% http://www.sanidadanimal.info/cursos/inmun/images/4igg.gif

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. 2009. • Sallah, S and Wan, JY. Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients.Cancer 2001 Mar 15;91(6):1067-74. • Stachnik, JM. Rituximab in the treatment of acquired hemophilia. Ann Pharmacother 2006; 40:1151.

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