THROMBOTIC DISORDERS: The Final Frontier Jeffrey I. Weitz, MD, FRCP(C), FACP Professor of Medicine and Biochemistry McMaster University Canada Research Chair in Thrombosis Heart & Stroke Foundation/ J.F. Mustard Chair in Cardiovascular Research
Overview Arterial and venous thrombosis Antithrombotic therapy Which drugs for which patients
Thrombosis Blood clot formation
Thrombosis Arterial Venous Stroke (AF) DVT MI PE PAD
Burden of Thrombotic Disease Each year in the USA: 75,000 diagnosed with AF 900,000 suffer VTE 800,000 have a stroke Cost of care enormous; $74 billion annually for care of stroke victims
Pathogenesis of Thrombosis
Thrombosis Threshold Thrombosis + Intrinsic Thrombosis Risk Environmental Factors Surgery Immobilization Pregnancy Estrogens + + Genetic Risk Factors Acquired Risk Factors Loss of function AT deficiency PC deficiency PS deficiency Gain of function FV Leiden FIIG20210A Increased procoagulants Dysfibrinogenemia Age Previous Thrombosis Cancer Obesity
Arterial and Venous Thrombosis Mackman, Nature 2008;451:914-918
Thrombin Generation at Sites of Vascular Injury Platelet activation Thrombin Fibrinogen Prothrombin Plasma clotting factors Tissue factor Fibrin Platelet aggregation Collagen Vessel Injury
Vascular injury Contact activation Extrinsic tenase TF IX VIIa X IXa VIIIa L VIIIa M IXa X Intrinsic tenase Xa Xa Va L Va M Xa II Prothrombinase IIa Fibrinogen Fibrin
Constituents of Thrombi Platelets Fibrin Trapped cells
Antithrombotic Drugs Antiplatelet Drugs ASPIRIN Clopidogrel Prasugrel Ticagrelor Anticoagulant Drugs Heparin LMWH Warfarin Dabigatran RIVAROXABAN Apixaban Edoxaban Fibrinolytic Agents Activase Reteplase Tenecteplase
Major Components of Arterial versus Venous Thrombi Type Major Component Arterial Venous Platelets Fibrin
Antithrombotic Drug Strategies Disorder Drugs Arterial thrombosis Antiplatelet drugs Venous thrombosis Arterial and venous thrombosis Anticoagulants Fibrinolytic drugs
Thrombosis versus Hemostasis Occlusive thrombus obstructs blood flow Hemostatic plug stops bleeding
Implications of Thrombosis versus Hemostasis Need to find the optimal balance between efficacy and safety
Anticoagulants Parenteral Heparin LMWH Fondaparinux Oral Warfarin Dabigatran RIVAROXABAN Apixaban Edoxaban
Use of Parenteral versus Oral Anticoagulants Delivery Route Indication Parenteral Oral Short-term Long-term
Limitations of Warfarin Limitation Consequence Slow onset of action Genetic variation in metabolism Overlap with a parenteral anticoagulant Variable dose requirements Multiple food and drug Frequent coagulation interactions monitoring Narrow therapeutic index Frequent coagulation monitoring
Worldwide Utilization of Oral Anticoagulation in AF: Results from a Global Registry Based on 15,174 patients with AF between Jan. 2008 and Apr. 2011 OAC in CHADS 2 2 TTR* *Based on 3 most recent INR values Healey et al. ESC 2011 Appropriate use of OAC remains low. When used, INR control is suboptimal.
New Oral Anticoagulants Direct inhibitors of factor Xa or thrombin
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Advantages of New Oral Anticoagulants Over Warfarin Feature Warfarin New Orals Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Interactions Many Few Monitoring Yes No Offset Long Short
What Have We Learned From Studies With New Oral Anticoagulants? At least as effective and safe as LMWH for VTE prevention after knee or hip arthroplasty At least as effective as warfarin for stroke prevention in AF and associated with less ICH At least as effective and safe as conventional anticoagulation for VTE treatment
Where Are We Going With New Agents? Replacing LMWH for VTE prevention after hip or knee replacement surgery Increasing use in place of warfarin for stroke prevention in AF Facilitate treatment of VTE
Conclusions Thrombotic diseases are the major cause of morbidity and mortality worldwide New oral anticoagulants represent a major advance for the prevention and treatment of thrombotic disorders