This document defines heparin resistance and discusses its management in different clinical settings. Heparin resistance is when high doses of heparin are needed to achieve therapeutic anticoagulation levels. It can occur in patients with venous thromboembolism, during cardiac surgery, or with acute coronary syndromes. Risk factors include antithrombin deficiency and high platelet counts. Management involves adjusting heparin doses based on anti-Factor Xa levels, supplementing with antithrombin, or using direct thrombin inhibitors as alternatives to heparin. The optimal treatment depends on the specific clinical situation and aims to safely achieve adequate anticoagulation.

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
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

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

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 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 dose
2. AT supplementation (either FFP or AT
concentrates)
3. Nafamostat Mesilate (limited evidence)
Acute Coronary
Syndrome
1. Direct Thrombin Inhibitors (Argatroban,
Bivalirudin, Lepirudin)

14. REFERENCES
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
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.