Heparin | Nursing Considerations, Patient Teachings and More

Nurse Beth, MSN

Table of Contents

What is Heparin?
History of Anticoagulants
Heparin Overdoses
Indications and Contraindications
Interactions and Adverse Effects
Heparin-induced Thrombocytopenia (HIT)
Pharmacokinetics of Heparin
Nursing Considerations
Nursing Process: Managing a Patient on Heparin
Patient Teachings
Anecdotal Experience

Heparin is both life-saving and life-threatening.

Heparin does not have fibrinolytic properties, and it does not lyse (dissolve) blood clots. It prevents clots from forming.

Heparin prevents and treats certain blood vessel, heart, and lung conditions. Heparin is used to prevent blood from clotting during procedures and prophylactically to prevent patients at risk from forming blood clots.

Heparin Types and Names

There are two types of heparin, low molecular-weight heparin (LMWH) and unfractionated heparin (UFH). Although both prevent blood clotting, they are used in different situations.

LMWH (subcutaneous)

Lovenox (generic name enoxaparin)
Fragmin (generic name dalteparin)
Innohep (generic name, tinzaparin)

UFH (IV and subcutaneous)

Heparin sodium, also known as standard heparin. There are no brand names.

Heparin is not administered IM due to risk of hematoma.

There are advantages to using LMWH over UFH. LMWH has a:

longer half-life.
higher bioavailability.
predictable dose response.
decreased risk for HIT⁽¹⁾.

A Brief History of Anticoagulants

Leeches, dog livers, and sweet clover hay
The history of anticoagulants spans more than a century and includes some interesting and serendipitous discoveries.

Leeches
Hirudin was extracted from blood-sucking leeches in 1909 due to its anticoagulant properties, but there were production and quality control problems involved in working with leeches⁽²⁾.

Dog livers
Jay McLean is widely credited with discovering heparin. In 1915 he was a second-year medical student at John Hopkins School of Medicine. He extracted an anticoagulant substance from dog livers⁽²⁾.

Sweet clover hay
During a wet Summer in 1939 in Wisconsin, Karl Link investigated sweet clover hay when cattle ingesting the wet hay hemorrhaged and died. The bleeding disorder was dubbed sweet clover disease. Link extracted dicumarol from the affected hay. Dicumarol is the parent of warfarin⁽³⁾.

Known Heparin Overdoses

The Institute for Safe Medicine Practice (ISMP) identified heparin as one of the top ten medications involved in severe and fatal errors.

Some of these fatal errors are high-profile, and many were found to be associated with manufacturing labeling.
Typically there are system failures at play in medication errors. Nonetheless, they all involved nursing administration.

2006: Six premature infants

In a NICU at a hospital in Indiana, six premature infants were injected with a 1000-fold higher heparin dose than intended. Three of the infants died⁽⁴⁾.

2007: Newborn Quaid twins
Similarly, the Quaid twins were overdosed 1000-fold at Cedar-Sinai in Los Angeles in 2007. The twins were each injected with

1 mL of heparin drawn from a 10,000 units/mL vial instead of
1 mL of heparin from a 10 units/mL vial⁽⁴⁾.

2010: Twenty-three-month-old toddler
A 23-month-old died after receiving an overdose of heparin during dialysis at the Nebraska Medical Center in Omaha, Nebraska, in 2010.

According to the ISMP, "the overdose occurred due to an infusion pump setting error.” The toddler was on a smart pump and the error was not discovered for 5 hours.

Indications and Contraindications for Use

In the hospital setting, heparin is often preferred over direct oral anticoagulants, such as warfarin. A significant advantage of heparin is that it can easily be reversed in the event of surgery or a procedure. The effects of heparin are reversed by the administration of protamine sulfate.

Indications for LMWH

LMWH indications include:

prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness.
inpatient treatment of acute DVT with or without pulmonary embolism.
outpatient treatment of acute DVT without pulmonary embolism.
prophylaxis of ischemic complications of unstable angina and non–Q-wave myocardial infarction (MI).
treatment of acute ST-segment elevation myocardial infarction (STEMI) managed medically or with subsequent percutaneous coronary intervention⁽⁵⁾.

Clinical practice guidelines from the American Academy of Orthopedic Surgeons and other organizations recommend using LMWH after total joint surgeries and hip fractures as best practice⁽⁶⁾.

Nursing TIP: A test question asked in the Prophecy entrance assessment administered to new hire nurses in many organizations is "What type of anticoagulant is used for DVT prophylaxis after total knee replacement?” The most frequent incorrect answer is UFH (heparin sodium). The correct answer is LMWH (enoxaparin).

Indications for UFH

UFH indications include:

prophylaxis and treatment of venous thrombosis and pulmonary embolism.
prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease.
atrial fibrillation with embolization.
treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation).
prevention of clotting in arterial and cardiac surgery.
prophylaxis and treatment of peripheral arterial embolism.
use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures⁽⁷⁾.

Fact: While disseminated intravascular coagulation (DIC) is a massive bleeding disorder (patients can bleed from every orifice), heparin is used to treat some forms of DIC.

Additionally, UFH is widely used in the hospital for several off-label uses.
They include

continuous renal replacement therapy (CRRT) in ICU settings.
heparin to coumadin bridge.
patients with acute coronary syndromes (ACS).
percutaneous coronary intervention (PCI)⁽⁸⁾.

Contraindications for LMWH and UFH

The following are contraindictions for heparin:

active major bleeding.
history of heparin-induced thrombocytopenia (HIT).
heparin-induced thrombocytopenia and thrombosis (HITT).
known hypersensitivity to heparin or pork products.
patients in whom suitable blood coagulation tests cannot be performed at appropriate intervals.
hypersensitivity to benzyl alcohol⁽⁷⁾.

In addition, heparin is contraindicated for a platelet count of 100,000/mm or lower⁽⁸⁾.

LMWH use in specific populations

The following information is for enoxaparin (Lovenox), a commonly used LMWH.

The following is Use in Specific Populations information.

Pediatrics

Safety and effectiveness of enoxaparin in pediatric patients have not been established.

Neonates and infants

Enoxaprin is not approved for use in neonates or infants.

Pregnancy

While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis.

Geriatric

A higher incidence of bleeding has been reported in patients over 60, especially women. Lower doses of heparin may be indicated in these patients ⁽⁵⁾.

UFH use in specific populations

The following is Use in Specific Populations information:

Pediatrics

There are no adequate and well-controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on the clinical experience of the provider.

Pregnancy

There are no adequate and well-controlled studies on pregnant women. Dosing recommendations for pregnant women are based on the clinical experience of the provider.

While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis.

Geriatric

A higher incidence of bleeding has been reported in patients over 60, especially women. Lower doses of heparin may be indicated in these patients ⁽⁵⁾.

Drug Interactions and Adverse Effects of Heparin

Drug interactions

The following are drug interactions ⁽⁵⁾:

oral anticoagulants.
platelet inhibitors.
drugs that interfere with coagulation, platelet aggregation, or drugs that counteract coagulation may induce bleeding.
digitalis, tetracyclines, nicotine, antihistamines, or intravenous nitroglycerin may partially counteract the action of heparin sodium

Adverse Effects

The following are serious adverse reactions⁽⁵⁾:

hemorrhage.
heparin-induced thrombocytopenia (HIT).
heparin-induced thrombocytopenia and thrombosis (HITT).
thrombocytopenia.
heparin resistance.
hypersensitivity.
elevations of aminotransferase levels.

Benzyl alcohol warning in neonates and infants

Benzyl alcohol is a preservative used in heparin products. Exposure to benzyl alcohol can cause serious and fatal adverse reactions, including "gasping syndrome", in neonates and infants⁽⁵⁾.

What is Heparin-induced Thrombocytopenia (HIT)?

In HIT, the body stops producing platelets, leaving the patient at risk for hemorrhagic events and thrombus formation. There can be severe complications, including:

pulmonary embolism.
deep vein thrombosis.
stroke.
myocardial infarction.
thrombosis in main arteries that could lead to
limb amputation or death⁽⁸⁾

The three main signs of HIT are:

thrombocytopenia that begins between days 5 and 14 after heparin treatment.
platelet counts that rarely fall below 150,000.
development of large-vessel venous or arterial thrombosis ⁽⁹⁾

Immunoassays are used to diagnose HIT ⁽⁹⁾.

All sources of heparin (including heparin flushes) must be discontinued when the reaction occurs. Treatment includes the use of direct thrombin inhibitor agents ⁽⁹⁾.

Pharmacokinetics of Heparin

Mechanism of action

Heparin is an indirect thrombin inhibitor that affects the intrinsic pathway of the clotting cascade following endothelial damage.

What is important to know is that heparin:

inhibits the action of thrombin.
blocks the conversion of fibrinogen to fibrin.
prevents the formation of fibrin clots.

As a result, existing clots are prevented from getting larger, and new clots are prevented from forming⁽⁸⁾.

Excretion and half-life

Heparin is primarily cleared from circulation by the liver ⁽⁷⁾.

Dose reductions are recommended in patients with severe renal impairment. LMWH should be avoided in patients with creatinine clearance <30 mL/min ⁽¹⁰⁾.

Plasma half-life is dose-dependent and ranges from 0.5 to 2 hours.

LMWH Administration (subcutaneous injections)

LMWH is administered subcutaneously but not IM due to the risk of hematoma.

LMWH dosage

Dosage varies by indication (DVT prophylaxis, DVT treatment, treatment of ST elevation MI, use in unstable angina and non-Q wave MI) and inpatient vs. outpatient status.

The following examples of dosages are for enoxaparin (Lovenox), a commonly used LMWH.

The recommended dose for DVT prophylaxis following hip or knee replacement is 30 mg every 12 hours.
The recommended dose for treatment of patients with acute deep vein thrombosis with or without pulmonary embolism (who are not candidates for outpatient treatment) is:
- 1 mg/kg every 12 hours administered subcutaneously or
- 1.5 mg/kg once a day administered subcutaneously at the same time every day for inpatient⁽⁵⁾

Dose reduction is recommended for patients with severe (creatinine clearance <30 mL/min) renal impairment⁽⁵⁾.

Nursing consideration: subcutaneous injection technique

Position patients in a supine position for enoxaparin administration by deep subcutaneous injection.
Do not expel the air bubble from the prefilled syringes before the injection to avoid drug loss.
Do not inject into skin that has bruises or scars.
Do not inject through clothes.
Alternate injection sites between the left and right anterolateral and left and right posterolateral abdominal wall.
Introduce the whole length of the needle into a skin fold held between the thumb and forefinger; hold the skin fold throughout the injection.
To minimize bruising, do not rub the injection site after completion of the injection ⁽⁵⁾

UFH Administration (titratable heparin drips)

UFH is administered IV and can also be administered subcutaneously, but not IM, due to the risk of hematoma.

UFH heparin drip dosage

Dosages vary by indication and risk (DVT, PE, ACS, bleeding risk stratification).

Heparin drip calculations are performed by nurses. Infusion rates and boluses are calculated following facility-specific nonograms or protocols to titrate heparin drips based on coagulation lab results.

Facility-specific nonograms (protocols) vary according to:

coagulation test used: activated partial thromboplastin time (aPTT), partial thromboplastin time (PTT) or anti-factor Xa (anti-Xa) and
dosing ranges

UFH dosage is weight-based, and heparin is ordered in units/kilogram/hour.

Most heparin drips will be initiated with a:

bolus injection of 80 units/kilogram intravenously followed by a
continuous infusion rate of 18 units/kilogram/hour⁽⁸⁾

Monitoring of heparin drips

PTTs, aPTTs, or anti-Xas are initially drawn every 4-6 hours and after rate changes, according to facility-specific nonogram (protocol).
aPtts are most commonly used ⁽¹⁰⁾.
anti-Xa is gaining in use due to efficiency and safety ⁽¹¹⁾.
Anticoagulation labs are typically drawn daily once anticoagulation targets have been achieved.

Therapeutic ranges

Heparin has a narrow therapeutic index, and heparin drips are titrated to therapeutic goals.

In general, 1.5-2 times the normal aPTT or PTT value is the therapeutic target ⁽⁷⁾.

The therapeutic range of aPTT is 30-40 seconds. The therapeutic range of PTT is 60-70 seconds ⁽¹²⁾. The therapeutic range of anti-factor Xa is 0.3 to 0.7 international units/milliliter ⁽¹³⁾.

Ranges vary based on institutional lab reagents.

Nursing TIP: Coagulation (coag) tests used to regulate heparin drips should not be batched with other labs scheduled to be drawn on the unit at approximately the same time. Coags must be drawn at a discrete time, such as 1530, and not during a "sometime between 1500 and 1600" window. Discrete draw times are determined by how the order details are entered. For example, in Cerner, the ordering priority is Timed Study, which ensures it's drawn precisely at the time ordered.

Pediatric dosing

Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients.

Initial Dose

75 units to 100 units/kg (intravenous bolus over 10 minutes)

Maintenance Dose

Infants: 25 units/kg/hour to 30 units/kg/hour
Infants less than 2 months have the highest requirements (average 28 units/kg/hour)
Children greater than 1 year of age: 18 units/kg/hour to 20 units/kg/hour
Older children may require less heparin, similar to weight-adjusted adult dosage

Monitoring: Adjust heparin to maintain aPTT of 60 seconds to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 ⁽⁷⁾.

PTTs and aPTTs: what's the difference?

PTTs and aPTTs both measure the clotting time of plasma, but aPTT has an activator added to speed up the clot. aPTT is considered a more sensitive indicator of PTT ⁽¹²⁾.

Nursing Considerations for Heparin Administration

Nurses must be hypervigilant at every step of heparin administration.

Carefully examine the label on all heparin products to confirm the correct concentration.
Do not assume that drugs are stocked correctly in automatic drug cabinets (ADCs). ADCs are stocked by pharmacy techs, and humans are prone to error.

Avoid shortcuts such as bypassing safety features on smart pumps. In and of themselves, smart pumps do not prevent errors. It takes a human being to program pumps and turn them off and on.

Remember, the 23-month-old toddler who died in Nebraska from a heparin overdose was on a smart pump.

According to the Joint Commission's (JC's) National Patient Safety Goals, healthcare institutions must develop a policy stipulating the required baseline and ongoing laboratory tests for heparin-treated patients ⁽¹⁰⁾.

The JC does not prescribe which labs should be used; it simply requires a policy indicating which labs should be used. A typical policy includes PT, PTT, INR, CBC, or H&H. It is important for nurses to be familiar with their facility's policy.

Nursing TIP: Before starting a heparin drip, ensure you have followed your facility's policy of baseline labs.

Here are some essential safety practices:

Heparin drips should not be started in patients who have received tPA for ischemic stroke within 24 hours.
Heparin drips are administered via dedicated IV lines. Use for heparin only.
Conduct independent double-checks.
Be aware of the bias of seniority as a new nurse. Do not automatically adopt a senior nurse's calculation when an independent double-check results in a different result than your own. Instead, both nurses must independently recalculate.
It is not an independent double-check if another nurse looks at your calculations and co-signs.
Use only saline flushes (not heparin flushes) for peripheral venous access catheters.
Evaluate pertinent lab results before administering heparin.
Report critical values to the provider.
Use safety features on smart pumps to their fullest capacity.
Boluses can be given via smart pumps, but there is a risk of overdosing. Consult with an experienced nurse if you are not familiar with programming and administering boluses using a smart pump.
For smart pumps without interoperability, manually document all boluses, increases, decreases, and holds.
It is common for nurses not to document holds on the MAR.

Nursing TIP: Documenting a temporary heparin drip hold for high coagulation results or critical values is often missed. Think- if complications develop and the hold is not documented, you have no defense. Document the time the drip was turned off. If it wasn't documented, it wasn't done.

Heparin dosing for IV infusions is weight-based. Find out if the pharmacy uses the admission weight or updated daily weights and what your responsibility is. This process may be automated in the EHR.
Pharmacist-directed heparin therapy is best practice. Use your clinical pharmacologist for anticoagulation management if you have one on your unit or available.
Pharmacy should verify all heparin orders before heparin is removed from ADCs.
Review all medications and outstanding lab results during handoff.
Coagulation results and orders span nursing shifts which cause errors. The receiving nurse can miss results by forgetting to check results.

Heparin Antidote: Protamine Sulfate

Nursing TIP: The NCLEX will ask you to identify the antidote to heparin. Vitamin K and Protamine Sulfate will be two of the choices. Vitamin K reverses warfarin. Protamine sulfate reverses heparin.

Protamine sulfate is commonly used in cardiopulmonary bypass surgery to reverse heparin. Anesthesiologists typically administer protamine during cardiac surgery, but trained nurses can administer it elsewhere, depending on hospital policy.

Dose: 1mg protamine sulfate for every 100 units of heparin administered over the last 4 hours.
Administer slow IVP, not to exceed 50 mg over 10 minutes. Each mg of protamine sulfate neutralizes 100 USP heparin units.
Follow-up doses of protamine in the 0.5 mg range per 100 units can be given if bleeding continues 4 hours later ⁽¹⁴⁾.

Anaphylactic reactions are one of the most common adverse effects associated with protamine administration, and a test dose may be given. Protamine excess can lead to coagulopathy.

Protamine has a:

rapid onset of action.
short half-life of approximately 10 minutes ⁽¹⁴⁾.

The Nursing Process: Managing a Patient on Heparin

Use the nursing process to:

assess
plan
implement, and
evaluate

nursing care.

Assess/Nursing Diagnosis

Assess your patient in the context of managing a patient on heparin.

Review all medications for interactions, for example, salicylates, NSAIDs, and other anticoagulants.
Perform a patient history and read the H&P. Pay attention to pertinent details.
Review labs.
Perform a physical assessment.

Gathering all information, identify problems and potential problems (nursing diagnoses) related to heparin management.

For example, during your intake assessment, your patient tells you he is prone to constipation.

Based on your assessment, you choose the following two nursing diagnoses.

Risk of bleeding related to anticoagulant therapy

Rationale: Patients on heparin are at risk of bleeding.

Risk of constipation

Rationale: Constipation places the patient on heparin at risk of bleeding while straining.

Plan/Outcomes

Set measurable goals.

Identify expected outcomes related to risk of bleeding.

No bleeding as evidenced by physical assessment and stable H&H

Identify expected outcomes related to risk of constipation.

Patient will have regular soft bowel movements

Implement/Nursing Interventions

Implement selected nursing interventions related to the nursing diagnoses and individualized to the patient.

Nursing interventions related to risk for bleeding

Obtain baseline labs.
Check for possible drug interactions, such as oral anticoagulants.
Administer heparin as prescribed.
Monitor labs.
Perform ongoing assessment for bleeding (bruising, hematuria, melena, bleeding gums, petechiae).

Nursing interventions related to risk for constipation

Monitor fluid intake and output.
Encourage fluids.
Assess elimination status.
Consider stool softeners to avoid straining.
Evaluate for drugs that cause constipation.

Nursing TIP: Teach your nursing assistant or tech the significance of tarry, black stools so they do not flush them before notifying you. Bleeding from the upper GI tract (for example, from ulcers) turns the stool black (melena) while bleeding from the lower GI tract (for example, from hemorrhoids) is red from frank blood. Coffee-ground emesis is a sign of upper GI bleeding.

Evaluate/nursing care plan and adjust

Evaluate response to treatment against expected outcomes.

Monitor labs.
Assess for bleeding.
Assess for constipation.

Adjust care plan as needed.

Primary Teaching Points for Patients on Heparin

Heparin may cause you to bruise more easily.
It may take longer for bleeding to stop.
If you are bleeding, hold firm and direct pressure on the site.
Avoid constipation or straining for bowel movements.
Monitor for signs and symptoms of excessive bleeding.
Use a soft bristle toothbrush and an electric razor.
Avoid contact sports.
Tell all care providers that you're on heparin, especially before any procedures.
Do not take ASA, NSAIDs (increases risk of bleeding), or OTC health supplements without speaking to your provider.
Call your provider for nosebleeds, blood in the urine, black stools, and bruising.
Wear or carry identification that informs of anticoagulant therapy.
Do not discontinue heparin against your provider's advice.

The patient should also return-demonstrate how to administer subq heparin injections if they are to go home on subq injections. Ensure the patient understands they will have regular blood tests and appointments at the anticoagulation clinic.

Nursing TIP: When teaching patients, ask them to repeat back what you told them (called teach-back method) to ensure they understood.

Anecdotal Experience

I've witnessed plenty of bleeding associated with heparin drips in my nursing practice on telemetry and ICU, from frank bleeding to hematomas to retroperitoneal bleeds.

Most signs of bleeding are visible and can be controlled. It's the bleeds that are not visible that you should worry about.

One such invisible bleed is a retroperitoneal hemorrhage. It's caused by a nick in the femoral artery from percutaneous interventions such as angioplasties and angiograms.

It's possible for a large amount of blood to accumulate in the retroperitoneum, but an astute nurse will recognize the early signs of retroperitoneal bleeding.

Early signs of retroperitoneal bleeding are increased heart rate, back pain, and restlessness. If your patient is on a heparin drip, discontinue the infusion STAT. An H&H and ultrasound will be ordered to confirm the bleed. Anticipate a blood transfusion.

One time I was caring for a sweet elderly lady. After an angioplasty and stent placement, I pulled her sheath and applied manual pressure at the femoral arterial insertion site. I released pressure for a second to see if clotting had started, and arterial blood spurted on the wall behind her bed, her sheets, my arms...everywhere. It looked like a scene from a low-budget horror movie.

I struggled to apply pressure in the right place because everything was covered in blood, and I couldn't visualize the insertion site. She smiled sweetly and said, 'Oh, I forgot to tell you, dear, I'm a bleeder". I managed to locate the femoral pulse and apply pressure- this time, I didn't let up for 30 minutes!

What I learned: Bleeding is not so bad in that it always stops. The good thing is you can see it. Stay calm and hold pressure. Clots will form, and bleeding will stop.

Nursing TIP: Always check if your patient has been typed and crossed for blood, or at least typed. You don't want to waste time checking for this essential information at point of emergency. It's one of the first things the provider will ask.

Conclusion

Heparin is an anticoagulant that is widely used to treat and prevent many heart, blood vessel, and lung conditions.

It is a high-risk medication that comes with serious risks and requires professional nursing oversight.

There are many ways to make mistakes when administering heparin; ordering, dispensing, administering-and all mistakes are serious.

Independent double-checks are one of the safety barriers that are often done incorrectly by nurses.

Working as an interprofessional team with a clinical pharmacist and performing accurate, independent double checks is essential to patient safety.

References

1. Claudel, S.E., Miles, L.A. and Murea, M. (2021), Anticoagulation in hemodialysis: A narrative review. Semin Dial, 34: 103-115. https://doi.org/10.1111/sdi.12932

2. Gómez-Outes, A., Luisa Suarez-Gea, M., Calvo-Rojas, G., Lecumberri, R., Rocha, E., Pozo-Hernández, C., ... & Vargas-Castrillón, E. (2012). Discovery of anticoagulant drugs: a historical perspective. Current drug discovery technologies, 9(2), 83-104. https://pubmed.ncbi.nlm.nih.gov/21838662/

3. Kresge, N., Simoni, R. D., & Hill, R. L. (2005). Hemorrhagic sweet clover disease, dicumarol, and warfarin: the work of Karl Paul Link. Journal of Biological Chemistry, 280(8), e6-e7. https://www.jbc.org/article/S0021-9258(19)62862-0/fulltext

4. Arimura, J., Poole, R. L., Jeng, M., Rhine, W., & Sharek, P. (2008). Neonatal heparin overdose—a multidisciplinary team approach to medication error prevention. The Journal of Pediatric Pharmacology and Therapeutics: JPPT, 13(2), 96.

5. Lovenox (2021). Food and Drug Administration.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020164s129lbl.pdf

6. Muscatelli, S. R., Charters, M. A., & Hallstrom, B. R. (2021). Time for an update? A look at current guidelines for venous thromboembolism prophylaxis after hip and knee arthroplasty and hip fracture. Arthroplasty today, 10, 105-107. https://www.arthroplastytoday.org/article/S2352-3441(21)00112-6/

7 . Heparin Sodium (2021). Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017029s140lbl.pdf

8. Warnock LB, Huang D. Heparin. [Updated 2022 Jul 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538247/

9. Eke, Sancar. Updated: Sep 10, 2021. Retrieved 2/02/2023 from
https://emedicine.medscape.com/article/1357846-workup

10. Smythe, M. A., Priziola, J., Dobesh, P. P., Wirth, D., Cuker, A., & Wittkowsky, A. K. (2016). Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. Journal of thrombosis and thrombolysis, 41, 165-186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715846/

11. Guervil DJ, Rosenberg AF, Winterstein AG, Harris NS, Johns TE, Zumberg MS. Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother. 2011 Jul;45(7-8):861-8. doi: 10.1345/aph.1Q161. Epub 2011 Jun 28. PMID: 21712506.

12. Hammami, M. (Updated July 02, 2021).
Retrieved 2/02/2023 from https://emedicine.medscape.com/article/2085837-overview#a1

13. Vandiver JW, Vondracek TG. Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy. 2012 Jun;32(6):546-58. doi: 10.1002/j.1875-9114.2011.01049.x. Epub 2012 Apr 24. PMID: 22531940.

14. Applefield, D., & Krishnan, S. (2019). Protamine. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022. PMID: 31613533. https://www.ncbi.nlm.nih.gov/books/NBK547753/