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

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

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

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

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

Coagulation Pathways aPTT PT Leung, L. Overview of Hemostasis. UpToDate. Sept. 2009.

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

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)

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

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

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

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

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

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

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

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

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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