heparin Resistance

1. MANAGEMENT OF HEPARIN RESISTANCE LINH HUYNH MCPHS UNIVERSITY, PHARMD CANDIDATE APPE INSTITUTIONAL ROTATION – VA WEST ROXBUSRY PRECEPTOR: DR. SUSAN JACOBSON MARCH 25, 2016

2. OBJECTIVES Define Heparin Resistance and Understand the Mechanisms of Heparin Resistance Evaluate Different Risk Factors for Heparin Resistance Discuss the Therapeutic Management of Heparin Resistance in Various Settings

3. DEFINITION OF HEPARIN RESISTANCE For VTE/PE treatment or prevention: A situation wherein patients require unusually high doses of heparin to achieve a therapeutic aPTT 1 Daily heparin requirement is >35,000U per 24 hours 2 During cardiac surgery: Failure to achieve target ACT (activated clotting time) with unusually high doses of heparin 3

4. MECHANISMS OF HEPARIN RESISTANCE Mechanism of Action of Heparin: Proposed Mechanisms of Action of Heparin Resistance : Antithrombin (AT) deficiency Increased heparin clearance Elevation in heparin-binding proteins High levels of factor VIII and/or fibrinogen 1. Garcia, David A., et al. "Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines." CHEST Journal 141.2_suppl (2012): e24S-e43S

5. RISK FACTORS FOR HEPARIN RESISTANCE AT-mediated: Reduced AT synthesis (heredity or acquired such as liver disease, malnutrition) Accelerated AT clearance Nephropathy Accelerated AT consumption: Preoperative use of UFH or LMWH (>24- 48hours) Endocarditis Cardiopulmonary bypass, ventricular assist device, intra-aortic balloon pump Non AT-mediated: High preoperative platelet counts (> 300,000/mL) Plasma albumin concentration <35g/ dL Hypovolemia Medications: nitroglycerin (concomitant infusion)

6. MANAGEMENT OF HEPARIN RESISTANCE

7. IN SETTING OF VTE/PE Heparin Resistance occurs in 25% of patients with VTE 5 Assessing anti-factor Xa heparin level has been shown to be more safe and effective in monitoring heparin resistance than targeting therapeutic aPTT level 2,6 Heparin dose should be adjusted to maintain anti-factor Xa heparin level of 0.35 – 0.70 IU/mL Substitution of LMWH can be an option but may be inadvisable in patients with high risk of bleeding

8. EXAMPLE OF WEIGHT-BASED HEPARIN DOSING USING APTT AND ANTI-FACTOR XA MONITORING Adapted from University of Wisconsin Hospital and Clinics. Therapeutic Dosing of UFH – Adult – Inpatient – Clinical Practice Guideline. Assessed at: http://www.uwhealth.org/files/uwhealth/docs/anticoagulation/ Therapeutic_Unfractionated_Heparin_Infusion_Guideline.pdf

9. IN SETTING OF CARDIAC SURGERY Heparin Resistance has also been reported in up to 22% of patients undergoing cardiopulmonary bypass 7 Additional Heparin administration until the ACT reaches target level 3 Antithrombin (AT) supplementation 3 via Fresh Frozen Plasma (FFP) AT concentrates Nafamostat Mesilate 8

10. Proposed Treatment Algorithm of Heparin Resistance in Cardiopulmonary Bypass 3

11. OTHER SETTINGS ACUTE CORONARY SYNDROMES A cohort study showed use of bivalirudin resulted in a more consistent anticoagulation activity compared to heparin 9 COMORBIDITY OF OBESITY WITH HEPARIN RESISTANCE A case report of use of subcutaneous lepirudin after subtherapeutic AT level and aPTT were reported with an escalated dose of heparin 10

12. SUMMARY OF HEPARIN RESISTANCE MANAGEMENT SETTINGS RECOMMENDED TREATMENT OPTIONS VTE/PE Adjust Heparin dose based on anti-factor Xa level (instead of aPTT level) LMWH (unless patients have high risk of bleeding) Cardiac Surgery *recommend checking preoperative plasma AT level Increase Heparin dose AT supplementation (either FFP or AT concentrates) Nafamostat Mesilate (limited evidence) Acute Coronary Syndrome Direct Thrombin Inhibitors ( Argatroban , Bivalirudin , Lepirudin )

13. REFERENCES Garcia, David A., et al. "Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines." CHEST Journal 141.2_suppl (2012): e24S-e43S Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety. Chest 2001;119(1). Finley A, Greenberg C. Heparin Sensitivity and Resistance. Anesthesia & Analgesia 2013;116(6):1210–1222 . Chan T, Hwang NC, Lim CH. A statistical analysis of factors predisposing patients to heparin resistance. Perfusion perfusion 2006;21(2):99–103. Mcrae SJ. Initial Treatment of Venous Thromboembolism. Circulation 2004;110(9_suppl_1). Levine MN. A Randomized Trial Comparing Activated Thromboplastin Time With Heparin Assay in Patients With Acute Venous Thromboembolism Requiring Large Daily Doses of Heparin. Arch Intern Med Archives of Internal Medicine 1994;154(1):49. Spiess BD. Treating Heparin Resistance With Antithrombin or Fresh Frozen Plasma. The Annals of Thoracic Surgery 2008;85(6):2153–2160. Kikura M, Tanaka K, Hiraiwa T, Tanaka K. Nafamostat Mesilate , as a Treatment for Heparin Resistance, Is Not Associated With Perioperative Ischemic Stroke in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass. Journal of Cardiothoracic and Vascular Anesthesia 2012;26(2):239–244. Rich JD, Maraganore JM, Young E, et al. Heparin resistance in acute coronary syndromes. Journal of Thrombosis and Thrombolysis J Thromb Thrombolysis 2007;23(2):93–100. Inman KR, Gerlach AT. Use of Subcutaneous Lepirudin in an Obese Surgical Intensive Care Unit Patient with Heparin Resistance. Annals of Pharmacotherapy 2009;43(10):1714–1718.