# Protamine Reversal Calculator

## Protamine dosing for neutralizing heparin and LMWH

### Type of Anticoagulant

Reversal of a single IV unfractionated heparin bolus
Reversal of a continuous IV infusion of unfractionated heparin
Reversal of a subcutaneous dose of any LMWH, including enoxaparin (Lovenox®) or dalteparin (Fragmin®)

### Anticoagulant Details

 Heparin bolus dose units Time since bolus minutes hours

RESULTS

#### Protamine Dose for Reversal

Protamine 31 mg

Given as a slow IV push or IVPB (diluted in D5W or NS) over 10 minutes. Maximum infusion rate 5 mg per minute.

#### Anticoagulant for Reversal

• Heparin infusion of 18 units/kg/hr
• 18 units/kg/hr in 85 kg patient is equivalent to 1530 units/hr
• Infusion stopped 30 minutes ago

#### Equations for Reversal

$$\\ Heparin\;rate\;(units/hr) = 18\;units/kg/hr * 85\;kg = 1530\;units/hr\\Heparin\;to\;reverse = heparin\;received\;in\;last\;two\;hours\;of\;infusion = 3060\;units\\Protamine\;(mg) = (heparin\;dose)/100 * 1 = 3060\;units/100 * 1 = 31\;mg\;protamine\\(Equation\;if\;protamine\;given\;within\;60\;minutes\;of\;heparin)$$

Protamine sulfate, a derivative of fish sperm, is commonly used for the reversal of anticoagulation effect of unfractionated heparin (UFH) and low-molecular weight heparin (LMWH).3,4 This calculator is intended to dose protamine in adults patients on a medicine floor and in the ICU. It is not appropriate for pediatric patients or for an operating room setting (such as cardiovascular surgery). This calculator determines a neutralizing dose of protamine to reverse both UFH and LMWH in the non-surgical setting based on the anticoagulant to be reversed, the anticoagulant dose, and the time that the anticoagulant was last given.

#### Unfractionated Heparin

One milligram (mg) of protamine sulfate will neutralize approximately 100 units of UFH.3,5 Due to the half-life of heparin (~90 minutes), timing of protamine administration in patients is dependent upon timing of heparin exposure. As more time elapses from heparin administration, less protamine is necessary to reverse the anticoagulant effects. Administration of full dose protamine is indicated in patients who need reversal less than 60 minutes after bolus administration. For patients on heparin infusions, due to the half-life of heparin, the amount of heparin administered over the previous 2 hours should be utilized to calculate a protamine dose.3,5

The half-life of protamine, about 7 minutes, is significantly shorter than UFH.3,5,6 Consideration to measure the activated partial thromboplastin time (aPTT) after protamine administration may be warranted. In patients with elevated aPTTs as a result of heparin after protamine administration, a second dose of protamine may be considered.6

#### Low Molecular Weight Heparin (LMWH)

One milligram (mg) of protamine sulfate will neutralize approximately 100 anti-Xa units of a LMWH.3,5,6 Similar to UFH, protamine dosing for LMWH reversal is dependent on the timing of LMWH administration relative to need for reversal. Taking that into consideration, if reversal is necessary within 8 hours of receiving a LMWH, a full dose of protamine should be administered.3,6

The half-lives of LMWH are longer than UFH, ranging from 4-7 hours. The 7 minute half-life of protamine and the prolonged LMWH half-life lend themselves to consideration of redosing due to LMWH rebound. In patients with elevated LMWH anti-Xa assays 2 to 4 hours after protamine administration, a second dose of protamine to achieve complete reversal may be considered.6 If a second dose is given, it is recommended to administer 0.5 mg of protamine per 1 mg of enoxaparin or 100 units of dalteparin. 1,2

For both enoxaparin and dalteparin, protamine does not provide a complete reversal of anti-Xa activity. It is estimated that protamine will reverse up to about 60% to 75% of anti-Xa activity.1,2

##### Enoxaparin (Lovenox®)

Enoxaparin reversal is determined based on the following table:1

Time Since Enoxaparin Dose Protamine Dose
≤ 8 hours 1 mg protamine for every 1 mg enoxaparin
> 8 hours 0.5 mg protamine for every 1 mg enoxaparin
> 12 to 24 hours Depending on dose received and renal function, protamine reversal may not be necessary due to enoxaparin metabolism
##### Dalteparin (Fragmin®)

Dalteparin reversal is determined based on the following table:2

Time Since Enoxaparin Dose Protamine Dose
≤ 8 hours 1 mg protamine for every 100 units dalteparin
> 8 hours 0.5 mg protamine for every 100 units dalteparin
> 12 to 24 hours Depending on dose received and renal function, protamine reversal may not be necessary due to dalteparin metabolism

#### Protamine Dosage and Adverse Effects

Regardless of the heparin or LMWH dosage, the maximum recommended protamine dose is 50 mg.7,8 Because protamine can exhibit a weak anticoagulant effect at higher doses within a short period of time, excessive protamine dosing to reverse heparin or LMWH can paradoxically result in an increased risk of bleeding.

Hypersensitivity reactions to protamine sulfate have been discovered in patients who are allergic or have sensitivities to fish and other protamine containing medications such as NPH insulin. Anaphylactoid reactions, hypotension, flushing, and pulmonary edema are more likely with larger doses or rapid administration. Additionally, men who have a history of vasectomies may also be at increased risk for these reactions, although newer evidence suggests that may not be true.9 A black box warning exists for protamine regarding these hypersensitivity reactions and caution is advised.

1. Lovenox [package insert]. Sanofi-Aventis U.S. LLC; Bridgewater, NJ. October 2013.
2. Fragmin [package insert]. Pfizer Inc.; New York, NY. August 2016.
3. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e24S-43S. doi: 10.1378/chest.11-2291. PMID 22315264
4. Cushman M, Lim W, Zakai NA. 2011 Clinical Practice Guideline on Anticoagulant Dosing and Management of Anticoagulant Associated Bleeding Complications in Adults. American Society of Hematology. 2011.
5. Caravati EM. Protamine sulfate. Medical Toxicology. 3rd ed. Dart RC, ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2004;243-244.
6. Pai M, Crowther MA. Neutralization of heparin activity. Handb Exp Pharmacol. 2012;(207):265-77. doi: 10.1007/978-3-642-23056-1_11. PMID 22566228
7. Protamine [package insert]. Fresenius Kabi USA, LLC; Lake Zurich, IL. November 2013.
8. Protamine Sulfate. In: McEvoy GK, editor. AHFS drug information 2016 [monograph on the Internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2016.
9. Vézina D, Sheridan P, Blain R, et al. Safety of protamine sulfate administration in vasectomized men. Contraception. 1990 Jun;41(6):605-16. PMID 2193773

### Author Information

#### Alexander Kantorovich, PharmD, BCPS

Dr. Kantorovich is a Clinical Assistant Professor of Pharmacy Practice at Chicago State University College of Pharmacy and Clinical Pharmacy Specialist in the area of Internal Medicine at Advocate Christ Medical Center in Oak Lawn, Illinois. Dr. Kantorovich earned his Associate of Science degree with an emphasis in chemistry from William Rainey Harper College and received his Doctor of Pharmacy degree from the University of Illinois at Chicago College of Pharmacy in 2012. He went on to complete a two year Pharmacotherapy Residency with an emphasis in cardiology and critical care at the Cleveland Clinic in Cleveland, Ohio. Dr. Kantorovich is a Board Certified Pharmacotherapy Specialist.