Continuing Education Activity

Unfractionated heparin is an anticoagulant indicated for both the prevention and treatment of thrombotic events such as deep vein thrombosis (DVT) and pulmonary embolism (PE) as well as atrial fibrillation (AF). Heparin is also used to prevent excess coagulation during procedures such as cardiac surgery, extracorporeal circulation, or dialysis, including continuous renal replacement therapy. Heparin is also widely used in the hospital for many different off-label indications. This activity outlines the indications, mechanism of action, dosing, important adverse effects, contraindications, monitoring, and toxicity of heparin and increases practitioners' knowledge regarding how to approach this medication and use and monitor it effectively to drive better patient outcomes.

Objectives:

• Review the indications, both approved and off-label, of heparin.
• Identify the potential adverse effects and contraindications of heparin.
• Review the monitoring for toxicity, as well as any potential reversal measures that may be available.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using heparin as anticoagulation therapy.

Indications

Unfractionated heparin is an anticoagulant indicated for both the prevention and treatment of thrombotic events such as deep vein thrombosis (DVT) and pulmonary embolism (PE) as well as atrial fibrillation (AF). Heparin can also be used to prevent excess coagulation during procedures such as cardiac surgery, extracorporeal circulation, or dialysis, including continuous renal replacement therapy (CRRT).[1][2]

Heparin is widely used in the hospital for many different off-label indications, for example, patients who present with acute coronary syndromes (ACS) and who undergo percutaneous coronary intervention (PCI). During hospitalization, heparin will be used to bridge to oral anticoagulation, warfarin for mechanical and bioprosthetic valves. The American College of Chest Physicians (ACCP) recommends using heparin for many other thrombotic states: atrial fibrillation undergoing cardioversion, endocarditis, systemic emboli, or venous thrombosis.[3][4]

Dosing recommendations vary for each indication. 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. In obese populations, these dosages are capped off at a maximum bolus infusion and maximum infusion rate. Dosing in some situations is much lower with different maximum doses. For example, in patients with acute coronary syndrome or stroke, the dose is much lower due to an increased risk for bleeding. When heparin is administered and dosed by indication, there are no dosage adjustments required for renal dysfunction.[1][3]

Heparin is also useful in smaller volumes as lock flushes. Due to the increase in adverse effects and exposure to heparin, these are not used as often in clinical practice. These are intended to maintain patency for IV lines and should not be used to achieve therapeutic anticoagulation. Lock flushes are usually dispensed as a 1 to 5 mL volume syringe used for catheter flush only. A small volume of heparin is instilled into the catheter tip and flushed daily. Extra caution should be observed in the administration of heparin lock solution frequently in a 24 hour period with pediatric patients. Dependent upon the concentration, if instilling a lock flush, this could be close to a therapeutic dose of heparin in some pediatric patients.[1][2][3] 

Mechanism of Action

Once administered, heparin binds to several proteins; however, it is binding to an antithrombin that is important, as this causes a surface change and inactivates thrombin. Binding to antithrombin blocks several different factors of the clotting cascade, but two are predominant: thrombin (Factor IIa) and Factor Xa. By inactivating thrombin, it blocks the conversion of fibrinogen to fibrin; this prevents the formation of clots and prolongs the clotting time of blood. Heparin does not affect bleeding time, but it does prolong the time that blood takes to clot.[1][2]

Administration

Heparin administration can be by intravenous (IV) route or subcutaneous SQ) route. Intravenous heparin is continuously administered for therapeutic anticoagulation, while intermittent subcutaneous administration is used to prevent thromboembolism. Intermittent IV administration is also an option. For example, heparin is given intermittently by the interventional cardiologist in the cardiac catheterization lab, dependent upon laboratory markers throughout the case. When administered SQ, the onset of action is usually within 1 to 2 hours compared to an immediate anticoagulant effect with IV administration of heparin. There was an assessment of intramuscular (IM) injection, but researchers observed an increased level of pain, irritation, and hematoma formation with IM injections of heparin.[1][3]

Adverse Effects

Heparin use's typical adverse effects include bleeding, thrombocytopenia, injection site reactions, and other adverse effects only seen with chronic heparin administration. Bleeding is a major complication associated with heparin use. Patients should undergo monitoring for new bleeding that may present in the urine or stool. Bleeding may also present as bruising, petechial rash, and nosebleeds.[2]

Thrombocytopenia typically occurs in up to 30% of patients who receive heparin. Most often, this is not significant; however, there is a form of thrombocytopenia that is more serious, known as heparin-induced thrombocytopenia (HIT). Thrombocytopenia can be classified as Type I or Type II. Type I is a non-immunogenic interaction with platelets that typically occurs within the first 48 to 72 hours of initiation of heparin. The drop in platelet count is usually temporary and will recover upon cessation of heparin. Type II thrombocytopenia is more commonly known as heparin-induced thrombocytopenia; this is immune-related thrombocytopenia that occurs when heparin binds to the protein platelet factor 4 (PF4). This complex alerts the immune system and causes an immune-mediated reaction with platelets. Platelets are activated and consumed by clot formation providing a pro-thrombotic environment with a low platelet count. Heparin-induced thrombocytopenia usually occurs about five days into heparin therapy. Thrombosis can form and cause severe HITT (heparin-induced thrombocytopenia and thrombosis). Serious events seen with thrombosis include pulmonary embolism, deep vein thrombosis, stroke, myocardial infarction, and thrombosis in main arteries to organs that could lead to severe complications, including limb amputation or death.[5]

Other adverse effects that occur with the use of heparin include injection site reactions, hyperkalemia, alopecia, and osteoporosis. Osteopenia and osteoporosis have correlations with chronic heparin use, but not with acute use of heparin.[5]

Contraindications

A patient should not receive heparin if[5]:

• The platelet count is 100,000/mm or lower.
• The patient cannot have routine monitoring tests performed to monitor therapeutic heparin.
• The patient has an active, uncontrollable bleed except for disseminated intravascular coagulation (DIC).
• Patients with a history of heparin-induced thrombocytopenia should also avoid heparin use.

Monitoring

Therapeutic monitoring for heparin includes activated partial thromboplastin time (aPTT) and activated clotting time (ACT). Both of these are aspects of clotting time, which are prolonged by therapeutic heparin doses. Activated partial thromboplastin time is performed at baseline and every 6 hours until 2 or more therapeutic values are obtained, then aPTT can be assessed every 24 hours. Dose titrations are made based on the results of the aPTT. Hospitals have dosing nomograms specific to their target aPTT, which may vary depending upon the laboratory reagent used for their test. Therapeutic aPTT is considered therapeutic at 1.5 to 2 times control, which also varies from facility to facility based on controls.[1]

ACT is less sensitive than aPTT. ACT will only detect abnormalities when there is a 95% abnormality rate in the factors, whereas aPTT can detect when there is a 70% abnormality. ACT may also be affected when platelets are abnormal, which can result from the administration of heparin. ACT is a point of care test, which makes testing at the bedside more convenient with a quick turnaround. For these reasons, ACT is generally limited to use in cardiopulmonary bypass, ECMO (extracorporeal membrane oxygenation), or PCI (percutaneous coronary intervention). ACT monitoring during bypass is to ensure that the blood is thin enough to prevent clotting of the heart and lung machine. Most practitioners will aim for a goal ACT greater than 400 during CPB (cardiopulmonary bypass).[6][7]

Another form of monitoring includes anti-factor Xa activity levels. A level is considered therapeutic at 0.3 to 0.7 international units/milliliter. This monitoring is often reserved for use in patients where aPTT monitoring is unreliable, but some institutions have protocol-driven titrations based on anti-factor Xa levels.[8]

Monitoring for adverse effects includes hemoglobin, hematocrit, platelet count (every 2 to 3 days while on therapy), and vital signs. If hemoglobin, hematocrit, or blood pressures drop, the possibility of hemorrhage should be investigated. If the platelet count falls below 100000/mm3, then the risk and benefit of continuing heparin should be evaluated, and an alternative anticoagulant is the recommended course. A HIT 4-T score should be calculated when HIT is suspected.[1]

Toxicity

When heparin toxicity occurs, protamine is recommended for reversal of heparin’s anticoagulant effect. Patients with life-threatening or severe bleeding or patients who undergo surgery may require protamine for reversal. Neutralization of heparin occurs when protamine binds to the heparin by ionic properties. The protamine-heparin complex is inactive, and heparin is unable to act as an anticoagulant. Protamine administration should be via slow IV push with no more than 50 mg over 10 minutes. Administration of protamine too rapidly has been associated with severe reactions, most commonly, hypotension, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension. These effects also present with high doses of protamine, repeat doses of protamine, and previous exposure or current exposure. Anaphylaxis can also occur with protamine administration. Because of heparin’s short half-life, time from administration of heparin is used to determine the initial dose of protamine needed for reversal. Every 1mg of protamine administered neutralizes 100 units of heparin. Heparin neutralization should occur within about 5 minutes of protamine administration.[1]

Enhancing Healthcare Team Outcomes

Heparin enjoys wide use in the hospital setting for several different indications that require specific dosing and administration routes. The use of heparin is a balance between effective anticoagulation to treat or prevent thromboembolism and safety. According to ISMP (Institute for Safe Medication Practices), heparin is in the high-risk medication classification that correlates with a multitude of patient safety errors and has the potential to cause significant harm. Many factors can contribute to potential errors, including dosing, monitoring, adverse effects, and dispensing logistics. To mitigate these potential errors, major safety monitoring organizations and several clinical studies have been conducted to delineate the most effective management standards for hospitals. Collectively, more information available about past errors can influence practice to protect patients in the future.[9] 

There are numerous documented heparin errors attributed to manufacturer labeling and the many stock vials and bags available. After fatal errors in the pediatric population, a labeling update was instituted in 2013 to display the total number of units in each heparin vial. Limiting current stock to a standard heparin bag solution and standard vial concentrations for automatic dispensing cabinets may also help to prevent errors.

Dosing of heparin varies from indication, and dosage is by weight. Weight-based dosing offers another area for potential errors with calculations. Whether the initial dose is ordered as a unit/kilogram/hour rate versus a unit/hour versus milliliters/hour can significantly affect the initial dose. Current recommendations are that hospitals have a standard initiation protocol driven by dosing data for each indication.

Monitoring aPTT levels throughout heparin therapy can also offer an area for errors. Protocols are in place to instruct nursing staff on titration instructions based solely on the aPTT level. However, at that time, a new rate must be calculated and titrated based on the instructions on the protocol. These protocols have correlated with an increase in the amount of time that the aPTT is within the therapeutic range, which would improve the outcomes of patients with thromboembolism.[10][11]

The heparin prescribing information states that dosing and titration often require an interprofessional double check to ensure the correct dose and indication. One study evaluated the use of pharmacist management of heparin that showed significantly fewer errors in the hospitals where pharmacists were managing anticoagulation.[12]

In conclusion, heparin is a high-risk medication that requires many safety barriers to avoid errors and protect patients; this takes an interprofessional team approach in the hospitals consisting of clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists. [Level 5] It also requires an even greater approach from safety organizations and manufacturing companies.