MANAGEMENT OF HEPARIN

RESISTANCELINH HUYNH

MCPHS UNIVERSITY, PHARMD CANDIDATE APPE INSTITUTIONAL ROTATION – VA WEST

ROXBUSRYPRECEPTOR: DR. SUSAN JACOBSON

MARCH 25, 2016

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

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

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

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)

MANAGEMENT OF HEPARIN

RESISTANCE

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

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

IN SETTING OF CARDIAC SURGERY

Heparin Resistance has also been reported in up to 22% of patients undergoing cardiopulmonary bypass 7

1. Additional Heparin administration until the ACT reaches target level 3

2. Antithrombin (AT) supplementation 3

1. via Fresh Frozen Plasma (FFP)2. AT concentrates

3. Nafamostat Mesilate 8

Proposed Treatment Algorithm of Heparin Resistance in

Cardiopulmonary Bypass 3Heparin Resistance with ACT level

target not reached*Preoperative plasma AT

concentration is recommended

Low AT level

AT supplementation 500 – 1000 IU

*AT concentrate is preferred over FFP

If ACT fails to reach target with initial dose, repeated doses should

be given

Normal AT

Administer larger dose of heparin

Check whole blood heparin

concentration to ensure adequate

heparin level ( 4U/mL)

Recheck ACT level

Normal AT and heparin level >

4U/mL

Clinical judgment and empirical

treatment

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

SUMMARY OF HEPARIN RESISTANCE MANAGEMENT

SETTINGS RECOMMENDED TREATMENT OPTIONSVTE/PE 1. Adjust Heparin dose based on anti-factor

Xa level (instead of aPTT level)2. LMWH (unless patients have high risk of

bleeding)

Cardiac Surgery*recommend checking preoperative plasma AT level

1. Increase Heparin dose2. AT supplementation (either FFP or AT

concentrates)3. Nafamostat Mesilate (limited evidence)

Acute Coronary Syndrome

1. Direct Thrombin Inhibitors (Argatroban, Bivalirudin, Lepirudin)

REFERENCES1. 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

2. 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).

3. Finley A, Greenberg C. Heparin Sensitivity and Resistance. Anesthesia & Analgesia 2013;116(6):1210–1222.

4. Chan T, Hwang NC, Lim CH. A statistical analysis of factors predisposing patients to heparin resistance. Perfusion perfusion 2006;21(2):99–103.

5. Mcrae SJ. Initial Treatment of Venous Thromboembolism. Circulation 2004;110(9_suppl_1).

6. 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.

7. Spiess BD. Treating Heparin Resistance With Antithrombin or Fresh Frozen Plasma. The Annals of Thoracic Surgery 2008;85(6):2153–2160.

8. 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.

9. 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.

10.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.