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).
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 the use of heparin for many other thrombotic states: atrial fibrillation undergoing cardioversion, endocarditis, systemic emboli or venous thrombosis.
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.
Heparin is also useful in smaller volumes as lock flushes. Due to increase is 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.
Once administered, heparin binds to several proteins; however, it is binding to antithrombin that is important, as this causes a surface change and inactivates thrombin. By binding to antithrombin, it 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.
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, in the cardiac catheterization lab, heparin is given intermittently by the interventional cardiologist dependent upon laboratory markers throughout the case. When administered SQ, the onset of action is usually within 1 to 2 hours as 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.
Typical adverse effects from heparin use 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.
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.
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.
A patient should not receive heparin if:
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.
ACT is less sensitive than aPTT. ACT will only detect abnormalities when there is 95% abnormality rate in the factors, whereas aPTT can detect when there is 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).
Another form of monitoring includes antifactor 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 antifactor Xa levels.
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.
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.
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, the more information available about past errors can influence practice to protect patients in the future.
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.
The heparin prescribing information states that dosing and titration often requires a multidisciplinary 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.
In conclusion, heparin is a high-risk medication that requires many safety barriers to avoid errors and protect patients; this takes a multidisciplinary approach in the hospitals and an even greater approach from safety organizations and manufacturing companies.
|||Holbrook A,Schulman S,Witt DM,Vandvik PO,Fish J,Kovacs MJ,Svensson PJ,Veenstra DL,Crowther M,Guyatt GH, Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb; [PubMed PMID: 22315259]|
|||Mulloy B,Hogwood J,Gray E,Lever R,Page CP, Pharmacology of Heparin and Related Drugs. Pharmacological reviews. 2016 Jan; [PubMed PMID: 26672027]|
|||Hirsh J,Anand SS,Halperin JL,Fuster V, AHA Scientific Statement: Guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Arteriosclerosis, thrombosis, and vascular biology. 2001 Jul; [PubMed PMID: 11451763]|
|||Hemker HC, A century of heparin: past, present and future. Journal of thrombosis and haemostasis : JTH. 2016 Dec; [PubMed PMID: 27862941]|
|||Ahmed I,Majeed A,Powell R, Heparin induced thrombocytopenia: diagnosis and management update. Postgraduate medical journal. 2007 Sep; [PubMed PMID: 17823223]|
|||De Waele JJ,Van Cauwenberghe S,Hoste E,Benoit D,Colardyn F, The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive care medicine. 2003 Feb; [PubMed PMID: 12594595]|
|||Atallah S,Liebl M,Fitousis K,Bostan F,Masud F, Evaluation of the activated clotting time and activated partial thromboplastin time for the monitoring of heparin in adult extracorporeal membrane oxygenation patients. Perfusion. 2014 Sep; [PubMed PMID: 24570077]|
|||Vandiver JW,Vondracek TG, Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy. 2012 Jun; [PubMed PMID: 22531940]|
|||Barclay CA,Vonderhaar KJ,Clark EA, The development of evidence-based care recommendations to improve the safe use of anticoagulants in children. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 2012 Apr; [PubMed PMID: 23118667]|
|||Raschke RA,Reilly BM,Guidry JR,Fontana JR,Srinivas S, The weight-based heparin dosing nomogram compared with a [PubMed PMID: 8214998]|
|||Raschke RA,Gollihare B,Peirce JC, The effectiveness of implementing the weight-based heparin nomogram as a practice guideline. Archives of internal medicine. 1996 Aug 12-26; [PubMed PMID: 8694662]|
|||Bond CA,Raehl CL, Pharmacist-provided anticoagulation management in United States hospitals: death rates, length of stay, Medicare charges, bleeding complications, and transfusions. Pharmacotherapy. 2004 Aug; [PubMed PMID: 15338843]|