Heparin

Mechanism of Action

After administration, heparin primarily binds to several plasma proteins, most notably antithrombin III, a key regulatory protein. This binding induces a conformational change in antithrombin III, significantly enhancing its ability to inactivate several clotting factors, most notably thrombin (factor IIa) and factor Xa. By inactivating thrombin, heparin blocks the conversion of fibrinogen to fibrin, thereby preventing clot formation and prolonging the clotting time of blood. Although heparin does not affect bleeding time, it does increase the time required for blood to clot, as measured by coagulation tests.[1][2][19]

Pharmacokinetics

Absorption: Heparin is not absorbed through the gastrointestinal tract and therefore requires parenteral administration. IV injection results in a rapid onset of action, quickly achieving peak plasma concentrations.

Distribution: Heparin exhibits high affinity for plasma proteins and binds extensively to antithrombin, fibrinogen, globulins, serum proteases, and lipoproteins. The volume of distribution is approximately 0.07 L/kg. 

Metabolism: Heparin is not metabolized through enzymatic degradation. Instead, it is primarily cleared via hepatic metabolism and uptake by the reticuloendothelial system into the extravascular compartment.[20] In older adults, these clearance processes may be altered, resulting in prolonged anticoagulant effects.

Excretion: Heparin elimination follows biphasic kinetics.[21] The initial phase is a rapid, saturable, zero-order process mediated by binding to endothelial cells, macrophages, and plasma proteins. This is followed by a slower, first-order elimination phase. The terminal half-life is dose-dependent, typically ranging from 0.5 to 2 hours. In individuals aged 60 or older, equivalent doses may result in higher plasma concentrations, suggesting age-related changes in pharmacokinetics. In geriatric patients, slower elimination may contribute to prolonged activated partial thromboplastin time (aPTT).

Administration

Available Dosage Forms and Strengths

Heparin can be administered via the IV or subcutaneous (SQ) routes, depending on the clinical indication. Continuous IV infusion is commonly used for therapeutic anticoagulation, whereas intermittent SQ administration is typically used for thromboembolism prophylaxis. Intermittent IV administration is also used in certain settings; for example, interventional cardiologists may administer heparin intermittently during cardiac catheterization, guided by real-time laboratory markers. Subcutaneous heparin has an onset of action within 1 to 2 hours, whereas IV administration provides an immediate anticoagulant effect. Although intramuscular (IM) injection of heparin was previously evaluated, it is not recommended due to a higher incidence of pain, irritation, and hematoma formation.[1][3]

Heparin is available as an injectable solution in concentrations of 1000 units/mL, 2500 units/mL, 5000 units/mL, 10,000 units/mL, and 20,000 units/mL. Heparin is also supplied as IV solutions in concentrations of 12,500 units/250 mL, 20,000 units/500 mL, 25,000 units/250 mL, and 25,000 units/500 mL. Additionally, heparin lock flush solutions are available in concentrations of 1 unit/mL, 2 units/mL, 10 units/mL, and 100 units/mL.

Adult Dosage 

Heparin dosing varies depending on the clinical indication. For most therapeutic infusions, treatment begins with an IV bolus injection of 80 units/kg, followed by a continuous infusion at 18 units/kg/h. In patients with obesity, heparin dosages are capped at a maximum bolus infusion and maximum infusion rate to minimize the risk of adverse effects. In certain clinical scenarios, lower dosing regimens with adjusted maximum limits are used. For example, in patients with acute coronary syndrome or stroke, reduced doses are recommended due to an increased risk of bleeding.

Lock flushes are typically dispensed in 1- to 5-milliliter volume syringes and are intended solely for catheter flushing. A small volume of heparin is instilled into the catheter tip and flushed daily. Extra caution is advised when administering heparin lock solutions frequently over a 24-hour period, especially in pediatric patients. Depending on the concentration, the amount of heparin instilled through a lock flush may approach a therapeutic dose in some pediatric patients.[1][3][2]

Specific Patient Populations

Hepatic impairment: Anticoagulation may reduce portal hypertension and liver fibrosis in cirrhosis, as demonstrated in preclinical models and retrospective studies involving heparin and acenocoumarol. Prophylactic use of LMWH has been associated with a decreased risk of decompensation and mortality. Anticoagulants appear to improve outcomes in cirrhosis, potentially through mechanisms beyond the prevention of portal vein thrombosis. Although data on UFH are limited, existing evidence suggests a similar benefit. Some studies have also reported reduced hepatic decompensation and mortality with anticoagulation therapies such as warfarin and DOACs. However, current evidence remains limited, and further research is warranted.[22][23]

Renal impairment: UFH may be used in patients with chronic kidney disease, as dose adjustment based on renal function is not required. However, antithrombin concentrations may be decreased in chronic kidney disease, which can potentially alter the response to UFH.[24]

Pregnancy considerations: According to the 2023 guidelines from the ACC, AHA, ACCP, and HRS, as well as the ACC/AHA 2020 guidelines on valvular heart disease, anticoagulation during pregnancy should be individualized based on maternal thromboembolic risk and fetal safety. In the first trimester, vitamin K antagonists, such as warfarin, may be continued if the required daily dosage is 5 milligrams or less. If the dosage exceeds 5 milligrams per day, LMWH is preferred due to the teratogenicity of warfarin. LMWH should be weight-adjusted and monitored with anti–factor Xa levels. If LMWH monitoring is not feasible, dose-adjusted IV UFH is a recommended alternative.

During the second and third trimesters, patients may be transitioned back to warfarin with international normalized ratio (INR) monitoring. Warfarin should be discontinued by 36 weeks’ gestation or before planned delivery and replaced with IV UFH, which is typically discontinued 4 to 6 hours before labor or neuraxial procedures to minimize bleeding risk. In cases of urgent delivery while on warfarin, cesarean section following anticoagulation reversal is preferred. Postpartum anticoagulation should be resumed based on maternal risk, bleeding status, and breastfeeding considerations.[25][26]

Breastfeeding considerations: Heparin has a high molecular weight ranging from 3000 to 30,000 daltons; therefore, it is not expected to be significantly excreted into breast milk or absorbed by the infant. No special precautions are required during breastfeeding.[27] During pregnancy and lactation, the manufacturer recommends using preservative-free formulations.

Pediatric patients: The correct vial strength should be confirmed before administration, as fatal dosing errors have been reported in neonates. Preservative-free heparin should be used in neonates and infants. Benzyl alcohol, a common preservative, has been associated with serious and potentially fatal reactions, including gasping syndrome, particularly in preterm and low-birth-weight infants. Reported adverse effects include seizures and cardiovascular collapse. Total daily exposure to benzyl alcohol from all sources should be carefully considered.

Older patients: An increased risk of bleeding has been observed in patients aged 60 or older, especially women. Lower doses of heparin are recommended in this population.

Adverse Effects

Common adverse effects of heparin use include bleeding, thrombocytopenia, and injection site reactions. Other adverse effects are primarily seen with chronic heparin use. Bleeding is the most significant complication and requires careful monitoring. Patients should be observed for signs of new bleeding, such as blood in the urine or stool. Other manifestations may include bruising, petechial rash, and nosebleeds.[2]

Thrombocytopenia occurs in up to 30% of patients receiving heparin, although it is usually mild and clinically insignificant. However, a more severe form, known as HIT, may develop. Heparin-associated thrombocytopenia is classified as either type I or type II.

• Type I thrombocytopenia is a non-immunogenic platelet interaction that typically arises within 48 to 72 hours of heparin initiation. The resulting decrease in platelet count is usually transient and resolves spontaneously upon discontinuation of heparin.
• Type II thrombocytopenia, more commonly known as HIT, is an immune-related thrombocytopenia that occurs when heparin binds to the protein platelet factor 4 (PF4). This heparin-PF4 complex triggers an immune response, initiating an immune-mediated reaction involving platelets.

Platelets are activated and consumed during clot formation, creating a pro-thrombotic state despite a low platelet count. HIT typically develops about 5 days after initiating heparin therapy. Thrombosis can progress to HIT with thrombosis (HITT), which may result in severe thrombotic events. These complications include pulmonary embolism, DVT, stroke, myocardial infarction, and thrombosis in main arteries affecting major organs, potentially leading to severe complications such as limb amputation or death.[28]

Other adverse effects associated with heparin use include injection site reactions, hyperkalemia, alopecia, and osteoporosis. Osteopenia and osteoporosis have been linked to chronic heparin use but are not typically seen with short-term or acute use.[28]

Drug-Drug Interactions

Thrombolytics: Concurrent administration of thrombolytics, such as alteplase or tenecteplase, increases the risk of bleeding in patients receiving heparin.[16]

Platelet inhibitors: Concomitant use of agents that impair platelet function, including nonsteroidal anti-inflammatory drugs (NSAIDs; such as aspirin, ibuprofen, and celecoxib), dextran, dipyridamole, phenylbutazone, hydroxychloroquine, and glycoprotein IIb/IIIa inhibitors (such as abciximab, tirofiban, and eptifibatide), increases the risk of bleeding in patients receiving heparin.

Oral anticoagulants: Heparin may prolong the one-stage prothrombin time. To ensure accurate measurement of prothrombin time or INR in patients receiving warfarin or related oral anticoagulants, blood samples should be obtained at least 5 hours after the last IV dose of heparin or 24 hours after the last SQ dose. Heparin should be used with extreme caution in patients concurrently receiving apixaban, rivaroxaban, or dabigatran.

Antithrombin III: In patients with hereditary antithrombin III deficiency, the anticoagulant effect of heparin is enhanced when administered with antithrombin III concentrate. To reduce the risk of bleeding, heparin dosage should be adjusted accordingly during combined therapy.

Other drugs: Medications such as digoxin, tetracyclines, and nitroglycerin may interact with heparin, potentially reducing its anticoagulant effect. Clinical monitoring is recommended, and dosage adjustments should be made as needed.

Contraindications

Heparin is contraindicated in the following situations:

• Platelet count of 100,000/mm³ or lower.
• Inability of patients to undergo routine monitoring to assess the therapeutic effect of heparin.
• Active, uncontrollable bleeding, except in cases of disseminated intravascular coagulation.
• Patients with a history of HIT.
• Presence of a known hypersensitivity to heparin.[28][29]

Warnings and Precautions

Hematoma and bleeding: According to the ACC/AHA 2023 guidelines, periprocedural bridging with UFH is associated with an increased risk of pocket hematoma following pacemaker or implantable cardioverter-defibrillator procedures.[25] According to the American Society of Interventional Pain Physicians, heparin is a known risk factor for the development of spinal bleeding.[30]

Surgery: According to the guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain, IV heparin should be discontinued at least 6 hours before low-, medium-, or high-risk procedures.

Heparin may be resumed a minimum of 2 hours after the procedure; however, if the procedure was moderate- or high risk and involved significant bleeding, a 24-hour delay is recommended. Whenever possible, pain procedures in patients receiving IV heparin should be avoided, and alternative analgesics should be considered until anticoagulation can be safely withheld.[31]

Heparin-induced thrombocytopenia: According to the American Society of Hematology guidelines, if HIT is suspected, the 4Ts score (thrombocytopenia, timing, thrombosis, and other causes) should be calculated. A score of 3 or less effectively rules out HIT; further testing is not required, and heparin may be resumed if clinically indicated. A score of 4 or more warrants immediate discontinuation of heparin and initiation of a non-heparin anticoagulant (eg, argatroban, fondaparinux, or bivalirudin), along with PF4-heparin antibody testing. If the immunoassay is negative, HIT is unlikely to occur. If the result is positive, treatment should be continued, and a functional assay (eg, serotonin release assay) should be performed to confirm the diagnosis.

In cases of confirmed or likely HIT, therapeutic (not prophylactic) dosing of a non-heparin anticoagulant should be initiated. Vitamin K antagonists should be avoided until the platelet count reaches 150×10⁹/L or more. If the patient is already receiving a vitamin K antagonist, it should be discontinued, and IV vitamin K administered. Antiplatelet agents should not be used unless clearly indicated. The use of inferior vena cava filters and platelet transfusions is generally discouraged unless the risk of bleeding is high.

In isolated HIT, screening for DVT with ultrasound—particularly in the presence of a central venous catheter—is recommended, and treatment should continue until platelet recovery. In patients with subacute HIT A, DOACs (such as rivaroxaban, apixaban, or dabigatran) are preferred over vitamin K antagonists in stable patients at average risk for bleeding.[32]

Fatal medication errors: Heparin injection must not be used for catheter flush purposes. This is available in various concentrations, including high-dose vials (eg, 10,000 units/mL), and administration errors involving incorrect dosing have resulted in fatal outcomes. Careful verification of the vial concentration is essential before administration.[33]

Heparin resistance: Heparin resistance is commonly observed in clinical conditions such as systemic inflammation, thrombosis, myocardial infarction, malignancy, postoperative states, and antithrombin III deficiency. In these situations, standard aPTT-based dosing may be unreliable, necessitating monitoring of anti–factor Xa activity for accurate dose titration.[34][35] Treatment strategies for heparin resistance include weight-based dosing, administration of additional UFH, antithrombin supplementation, or use of alternative anticoagulants such as bivalirudin or argatroban.[36]

Hypersensitivity: In patients with known hypersensitivity, heparin should be used only when the potential therapeutic benefit outweighs the associated risk. As heparin is derived from animal tissue, caution is advised in individuals with a history of allergic reactions to animal-derived products.[37]

Hyperkalemia: Heparin may impair aldosterone synthesis, increasing the risk of hyperkalemia, particularly in patients with renal dysfunction, diabetes, metabolic acidosis, or those taking potassium-sparing medications.[38][39] The risk correlates with treatment duration and is typically reversible upon discontinuation of the treatment. Baseline and periodic potassium monitoring is recommended for individuals at high risk and those receiving long-term therapy.

Monitoring

Therapeutic monitoring of heparin involves measuring aPTT and ACT, both of which are prolonged with therapeutic doses of heparin. The aPTT is measured at baseline and every 6 hours until 2 or more consecutive therapeutic values are achieved; thereafter, it can usually be assessed every 24 hours. Dosage titrations are made based on the results of the aPTT. Most hospitals use dosing nomograms tailored to their target aPTT, which may vary depending on the laboratory reagents used for their test. Therapeutic aPTT is generally defined as 1.5 to 2 times the control value, though exact target ranges may vary between facilities depending on their specific control standards.[1]

ACT is less sensitive than aPTT, and it detects abnormalities only when clotting factors are reduced by 95%, whereas aPTT can detect abnormalities at a 70% abnormality rate. ACT results may also be influenced by platelet abnormalities, which can occur with the administration of heparin. As a point-of-care test, ACT offers the convenience of rapid bedside testing with quick turnaround times. For these reasons, ACT monitoring is generally reserved for specific settings such as CPB, ECMO, and PCI. ACT monitoring during bypass ensures the blood remains thin enough to prevent clotting in the heart-lung machine. Most practitioners aim for an ACT score greater than 400 during CPB.[40][41]

Another form of monitoring involves measuring anti–factor Xa activity levels, with therapeutic levels considered to be between 0.3 and 0.7 international units per milliliter. This method is often reserved for patients in whom aPTT monitoring is unreliable, although some institutions use protocol-driven dosage adjustments based on anti–factor Xa levels.[42]

Monitoring for adverse effects involves assessing hemoglobin, hematocrit, and platelet count (every 2-3 days during therapy), as well as vital signs. If hemoglobin, hematocrit, or blood pressure drops, the possibility of hemorrhage should be investigated. A drop in hemoglobin, hematocrit, or blood pressure should prompt evaluation for possible hemorrhage. If the platelet count falls below 100,000/mm³, the risks and benefits of continuing heparin should be carefully reassessed, and switching to an alternative anticoagulant is recommended. When HIT is suspected, a 4Ts score should be calculated.[1]

Toxicity

Signs and Symptoms of Overdose

Bleeding is the major complication associated with heparin overdose. Severe and potentially fatal hemorrhages, such as adrenal, ovarian, or retroperitoneal bleeding, may occur, particularly in women and individuals aged 60 or older, and can lead to acute adrenal insufficiency. Any unexplained decline in hematocrit, blood pressure, or other clinical indicators should prompt immediate evaluation for possible bleeding.

Heparin should be used cautiously in patients with an increased risk of bleeding, including those with subacute bacterial endocarditis, severe hypertension, recent or ongoing spinal tap or spinal anesthesia, or those undergoing major surgery involving the brain, spinal cord, or eye. Caution is also warranted in patients with hematological disorders, such as hemophilia, thrombocytopenia, or vascular purpura; those with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy (in whom the heparin dose should be reduced); those with gastrointestinal ulcerative lesions or continuous gastric or intestinal drainage; and during menstruation or in the presence of liver disease.[43]

Management of Overdose

In cases of heparin toxicity, protamine is recommended to reverse heparin’s anticoagulant effects. Patients experiencing life-threatening or severe bleeding, or those undergoing surgery, may require protamine for reversal. Heparin is neutralized when protamine binds to it through ionic interactions, forming an inactive protamine-heparin complex that prevents heparin from exerting its anticoagulant action. Protamine should be administered via slow IV push, with a maximum dose of 50 milligrams administered over 10 minutes. Rapid administration of protamine has been associated with severe adverse reactions, including hypotension, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension. These effects are also observed with high or repeated doses of protamine, as well as in individuals with prior or ongoing exposure to the drug. Anaphylaxis may also occur with protamine administration.

As heparin has a short half-life, the timing of its administration is used to calculate the initial protamine dose for reversal. Each 1 milligram of protamine neutralizes approximately 100 units of heparin. Heparin neutralization typically occurs within about 5 minutes of protamine administration.[1] In cases of significant bleeding associated with heparin, the drug should be discontinued immediately. Supportive care includes volume resuscitation and transfusion of blood products as clinically indicated. Ongoing assessment of vital signs, hemoglobin, hematocrit, and coagulation parameters is essential. Thromboelastography is a valuable tool for guiding heparin reversal during various types of emergency surgical procedures.[44][45]

Enhancing Healthcare Team Outcomes

Heparin is widely used in hospital settings for several indications that require specific dosing and administration routes. The use of heparin involves striking a balance between adequate anticoagulation to treat or prevent thromboembolism and ensuring patient safety. The Institute for Safe Medication Practices (ISMP) classifies heparin as a high-risk medication due to its strong association with medication errors and its potential to cause significant harm.

Multiple factors can contribute to potential errors with heparin use, including dosing inaccuracies, challenges in monitoring, adverse effects, and complexities in dispensing logistics. To mitigate these risks, major safety monitoring organizations and numerous clinical studies have sought to identify and establish the most effective management standards for hospitals. Collectively, by analyzing previous errors, these efforts aim to refine protocols and enhance patient protection in the future.[46] 

Numerous documented heparin errors have been linked to manufacturer labeling and the wide range of available stock vials and bag concentrations. Following fatal errors in the pediatric population, a labeling update was implemented in 2013 to display the total number of units of heparin in each vial. Limiting current stock to standard heparin bag solutions and vial concentrations for automatic dispensing cabinets may also help prevent errors.

Heparin dosing varies by clinical indication, and the dosage is based on the patient's weight. Weight-based dosing presents another area for potential calculation errors. The initial dose—whether ordered as units per kilogram per hour, units per hour, or milliliters per hour—can significantly impact the administered amount. Current recommendations encourage hospitals to establish standardized initiation protocols tailored to dosing data for each specific indication.

Monitoring aPTT levels throughout heparin therapy can also identify potential areas for error. Protocols guide nursing staff to titrate heparin doses based solely on aPTT results. However, at that time, a new infusion rate must be calculated and titrated based on the instructions in the protocol. These protocols have been associated with increased time that aPTT remains within the therapeutic range, which improves patient outcomes in cases of thromboembolism.[47][48]

The heparin prescribing information states that dosing and titration often require an interprofessional double check to ensure the correct dose and indication. A study demonstrated that hospitals with pharmacist-managed anticoagulation programs experienced significantly fewer medication errors related to heparin.[49] Clinicians select and adjust heparin therapy based on the clinical conditions and laboratory values. Nurses are responsible for the safe administration of medications, monitoring for adverse effects, and promptly reporting concerns.

Pharmacists play a critical role in ensuring accurate dosing, preventing drug interactions, and guiding the safe use of various heparin formulations. Given that heparin is a high-risk medication, multiple safety measures are essential to prevent errors and protect patients. This necessitates a coordinated, interprofessional team approach in hospital settings, involving clinicians, nurses, and pharmacists. Additionally, a more comprehensive strategy from regulatory bodies and manufacturers is required to enhance overall safety.