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Tests of Hemostasis Path 430/826 David Lillicrap Department of Pathology and Molecular Medicine Queen’s University, Kingston, Canada
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Inherited Bleeding Disorders Hemophilia A and B von Willebrand disease “Rare Bleeding Disorders” Factor deficiencies:ie. FXI, FVII, FX Platelet disorders:ie. Glanzmann’s Disease, Bernard-Soulier
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Acquired Bleeding Disorders Liver dysfunction Vitamin K deficiency DIC: sepsis, cancer, obstetric pathologies Drugs: anticoagulants/anti-platelet agents
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Clinical Evaluation of Bleeding
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Excessive Mucocutaneous Bleeding Bruising Epistaxis Oral cavity bleeding GI/GU bleeding Menorrhagia
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Musculoskeletal Bleeding Hemarthroses Soft Tissue/Muscle Bleeds
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Prior Challenges to the Hemostatic System Surgery Tonsillectomy Dental Procedures Wisdom teeth extraction
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1.Anecdotal bleeding histories vs 2.Validated bleeding scores (bleeding assessment tools)
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2005 Vicenza 0 to +3 40 min 2006 MCMDM-1VWD -1 to +4 40 min 2008 Condensed MCMDM-1VWD -1 to +4 10 min 2009 PBQ -1 to +4 20 min 2010 ISTH BAT 0 to +4 20 min Rydz and James Nov 2012 JTH Recent Evolution of Bleeding Assessment Tools
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p<0.001 p=0.173p<0.005 Previously Diagnosed with VWD (n=42) ANOVA p<0.001
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Utility of Bleeding Assessment Tools 1. Facilitate caregiver communication concerning severity of bleeding phenotype. 2. Justification for intensity of laboratory investigation.
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Laboratory Tests of Hemostasis Test Analyte Platelet poor plasma
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Routine Hemostasis Testing Platelet poor plasma Activator + Phospholipid Thromboplastin Ca 2+ ++ APTTPT
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Initiation Phase
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TFPI Extrinsic Pathway Inhibition TFPI Inhibits TF/FVIIa/FXa complex
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Amplification Phase Initiated by positive thrombin feedback * * *
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Extrinsic Pathway (prothrombin time - PT)
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Intrinsic Pathway (aPTT)
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Final Reaction Thrombin Time Addition of Exogenous Thrombin
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Limitations to Current Hemostasis Tests Insensitive to many bleeding pathologies No detection of hypercoagulability Standardization challenging Mild hemophilia, VWD Antithrombin, Protein C and S deficiency TFPI, Thrombomodulin
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Assessment of Platelet Contribution to Hemostasis 1. Platelet number 2. Platelet morphology 3. Platelet function Platelet aggregation studies with panel of agonists
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Light Transmission Aggregometry
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Light Transmission Platelet Aggregation Testing Result in Bernard-Soulier Syndrome – Absent GPIb receptor
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Development of New “Global” Hemostasis TestsDevelopment of New “Global” Hemostasis Tests Enhanced sensitivity Reflection of complete hemostatic system More physiological But equally (if not more) difficult to standardize
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Global Tests of Hemostasis a) Thrombin generation assays(TGA) a) Thromboelastography
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IIa Thrombin Pro-coagulant effects Fibrinogen Fibrin FVIII FVIIIa FV FVa FXIII FXIIIaTAFI TAFIa PAR1 PAR4 FXI FXIa
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TAT = thrombin – antithrombin complexes Absent in Hemophilia
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0 100 200 300 400 500 600 700 800 12345678910111213 Subjects Total thrombin (nM) Thrombin at 20 Minutes Over 6 Months Brummel et al 2008
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After – Confirmation of a clinical bleeding phenotype Extensive hemostasis laboratory investigation 30-40% of bleeding conditions are without a definitive diagnosis Potential role for genome-wide searches Whole exome/Whole genome analysis
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