Version November 2024
Dosage guidance:
Safety: Many concentrations of heparin are available ranging from 1 to 20,000 units/mL. Carefully examine each prefilled syringe or vial to ensure the correct concentration is selected.
Dosing: For weight-based IV heparin, an institution-specific dosing nomogram may help to achieve therapeutic anticoagulation more rapidly (see example based on aPTT under "Venous thromboembolism treatment"). If unusually large doses of heparin are required to achieve therapeutic targets, consider possible heparin resistance (Ref).
Antibiotic lock technique, adjunctive therapy (catheter-salvage strategy) (off-label use): Note: Antibiotic lock therapy is used in addition to systemic antibiotics for certain catheter-related infections when the catheter cannot be removed. Heparin is incompatible with ethanol and should not be used with ethanol lock therapy (Ref). Heparin is also incompatible with certain antibiotics; confirm compatibility prior to use (Ref).
Intracatheter: 100 to 5,000 units/mL in combination with an appropriate antibiotic. Heparin concentration depends on compatibility with the selected antibiotic, antibiotic concentration, and catheter type, which may vary by institution (Ref). For patients with end-stage renal disease requiring hemodialysis, maximum final heparin concentration should not exceed 1,000 units/mL due to increased risk of bleeding (Ref). Instill into each lumen of the catheter access port using a sufficient volume to fill the catheter (eg, 2 to 5 mL) with a maximum dwell time of ≤72 hours, depending on frequency of catheter use. Withdraw lock solution prior to catheter use; replace with fresh lock solution after catheter use (Ref).
Atrial fibrillation (to prevent stroke and systemic embolism): Note: When admitted for short-term hospitalization (eg, admission for a procedure or surgery), ambulatory patients taking an oral anticoagulant and not at high risk of immediate thromboembolism typically do not require bridging anticoagulation. Patients at high risk of thromboembolism (eg, recent cardioversion, high CHA2DS2-VASc score, prior cardioembolic stroke, current intracardiac thrombus) may be considered for bridging with a parenteral anticoagulant (see Transitioning between anticoagulants below) (Ref).
IV: Initial bolus of 60 to 80 units/kg (maximum: 5,000 units), followed by a continuous infusion of 12 to 18 units/kg/hour (maximum: 1,000 units/hour). Institutional dosing protocols may vary; adjust infusion rate to maintain anticoagulation target (Ref).
Frostbite (adjunctive agent) (off-label use): Note: Patients should be transferred to a facility that is familiar with managing patients with frostbite. Anticoagulation may be used in conjunction with thrombolytic therapy, either concurrently or following administration of the thrombolytic, but not as monotherapy (Ref). Optimal regimens, administration routes, and doses, including the use of therapeutic or low-dose anticoagulation after thrombolytic therapy, have not been identified; refer to institutional protocols.
Example regimens include:
When thrombolytic is administered IV:
IV: 500 to 1,000 units/hour as a fixed dose or targeted to an aPTT 2× control for up to 6 hours (Ref); some centers extend the duration to up to 5 days (Ref) or transition to therapeutic low-molecular-weight heparin (LMWH) (eg, enoxaparin) (Ref).
When thrombolytic is administered intra-arterial:
Intra-arterial: 500 units/hour administered through the intra-arterial catheter; targeted to a goal aPTT 50 to 70 seconds; after discontinuation of thrombolytic therapy, continue anticoagulation for 72 to 96 hours or transition to therapeutic LMWH (eg, enoxaparin) (Ref). Instead of intra-arterial heparin, some suggest the use of IV heparin after intra-arterial thrombolytic (see IV dosing above) (Ref).
Hemodialysis, anticoagulation of circuit:
Note: Standard dosing has not been established for intermittent hemodialysis or CRRT. Recommendations provided below are example regimens. Refer to institutional protocols. May need to individualize dose based on patient-specific needs.
Intermittent hemodialysis:
Standard risk for bleeding:
IV: Initial: Bolus 1,000 units or 2,000 units at the beginning of hemodialysis, followed by a continuous infusion of 500 units/hour; stop the infusion 60 minutes before the end of hemodialysis (Ref).
If clotting occurs during first half of hemodialysis session: Increase IV bolus by 500 units before each subsequent session (eg, administer 1,500 units or 2,500 units, depending on the previously attempted dose, at the beginning of hemodialysis) until clotting no longer occurs or up to a maximum of 4,000 units; administer continuous infusion as described above (Ref).
If clotting occurs during second half of hemodialysis session: Administer the same IV bolus dose, but increase continuous infusion by 100 units/hour for each subsequent session (eg, administer 600 units/hour) until clotting no longer occurs or up to a maximum of 1,000 units/hour; stop the infusion 30 minutes before the end of hemodialysis (Ref).
High risk for bleeding:
Note: There is no standard practice to prevent clotting of the hemodialysis circuit among patients who are at high risk for bleeding. Dialysis without heparin is preferred, but may consider heparin anticoagulation in patients who continue to have recurrent filter thrombosis (Ref).
IV: Initial: Bolus 1,000 units at the beginning of hemodialysis; do not administer a continuous infusion during the procedure (Ref).
If clotting occurs during hemodialysis: IV: Bolus 1,000 units at the beginning of the subsequent hemodialysis session, followed by a continuous infusion of 500 units/hour; stop the infusion 60 minutes before the end of hemodialysis; if clotting continues, increase continuous infusion by 100 units/hour at each subsequent session (eg, administer 600 units/hour) until clotting no longer occurs or up to a maximum of 1,000 units/hour (Ref).
CRRT:
Note: For patients who require anticoagulation due to repeated clotting of hemofilter and when regional citrate anticoagulation is not feasible or unavailable (Ref).
IV: Initial: Bolus 500 to 1,000 units, followed by a continuous infusion of 500 units/hour; titrate to maintain an aPTT ~1.5 times the control or ~45 seconds (Ref).
Ischemic heart disease:
Acute coronary syndromes:
ST-elevation myocardial infarction (off-label use):
Adjunct to percutaneous coronary intervention: see Percutaneous coronary intervention for dosing guidance.
Adjunct to fibrinolysis: IV: Bolus 60 units/kg (maximum: 4,000 units), followed by 12 units/kg/hour (maximum: 1,000 units/hour); adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours or until revascularization (if performed) (Ref).
No planned reperfusion: IV: Bolus 50 to 70 units/kg (maximum: 5,000 units), followed by 12 units/kg/hour; adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours (Ref).
Non-ST-elevation acute coronary syndromes (off-label use):
Noninvasive, ischemia-guided approach: IV: Bolus 60 units/kg (maximum: 5,000 units), followed by 12 units/kg/hour (maximum: 1,000 units/hour); adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours, until hospital discharge, or until management changes to an invasive strategy (eg, percutaneous coronary intervention [PCI]) (Ref).
Invasive approach (adjunct to percutaneous coronary intervention): see Percutaneous coronary intervention for dosing guidance.
Percutaneous coronary intervention (off-label use):
No prior anticoagulant therapy:
No planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 70 to 100 units/kg (maximum: 10,000 units) to achieve activated clotting time (ACT) of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (Ref).
Planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 50 to 70 units/kg (maximum: 7,000 units) to achieve ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (Ref).
Prior anticoagulant therapy:
Prior anticoagulation with heparin:
No planned glycoprotein IIb/IIIa inhibitor use: IV: Check ACT prior to PCI and administer heparin bolus as needed (eg, 2,000 to 5,000 units) to achieve ACT of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus (maximum: 10,000 units) as needed to maintain goal ACT throughout procedure (Ref).
Planned glycoprotein IIb/IIIa inhibitor use: IV: Check ACT prior to PCI and administer heparin bolus as needed (eg, 2,000 to 5,000 units) to achieve ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus (maximum 7,000 units) as needed to maintain goal ACT throughout procedure (Ref).
Prior anticoagulation with enoxaparin:
If percutaneous coronary intervention occurs ≤12 hours after the last SUBQ dose of enoxaparin: Transition to unfractionated heparin may not be preferred to reduce the risk of bleeding complications (Ref). Refer to Enoxaparin monograph for dosing recommendations.
If percutaneous coronary intervention occurs >12 hours after the last SUBQ dose of enoxaparin: May use unfractionated heparin; refer to recommendations above for PCI with no prior anticoagulant therapy (Ref).
Prior anticoagulation with fondaparinux:
No planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 85 units/kg (maximum: 10,000 units) to achieve ACT of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (Ref).
Planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 60 units/kg (maximum: 7,000 units) to achieve ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (Ref).
Mechanical heart valve, bridging anticoagulation (for interruptions in warfarin therapy) (off-label use): Note: Bridging during intervals of subtherapeutic anticoagulation should be considered for patients with mechanical mitral, tricuspid, or pulmonary valve replacement; however, for patients with mechanical aortic valve replacement, bridging is not required unless an additional thromboembolic risk factor is present or patient has an older-generation mechanical aortic valve (Ref).
IV: Limited data available: Initial: 18 units/kg/hour (no bolus) starting when INR falls below the therapeutic range; adjust infusion rate to maintain anticoagulation target based on institutional protocol. If patient is to undergo an invasive procedure, discontinue heparin 4 to 6 hours prior to procedure; reinitiate heparin infusion ≥24 hours after the procedure when bleeding risk is acceptable. Continue heparin until warfarin has been reinitiated and INR is within therapeutic range for 2 consecutive days (Ref).
Mechanical heart valve, postsurgical management (to transition to warfarin) (off-label use): Note: Initiate postoperatively when risk of bleeding is acceptable (Ref).
IV: Limited data available: Initial: 12 to 18 units/kg/hour (no bolus); adjust infusion rate to maintain anticoagulation target based on institutional protocol. Overlap with warfarin until INR is stable and within therapeutic range for ≥2 consecutive days (Ref).
Peripheral arterial occlusion, acute (off-label use): Note: Specific dosing information is limited, but anticoagulation is commonly used at the time of diagnosis to limit thrombus propagation while the patient is evaluated for other possible interventions (Ref).
IV: Initial bolus of 60 to 80 units/kg, followed by an initial continuous infusion of 12 to 18 units/kg/hour; adjust infusion rate to maintain anticoagulation target based on institutional protocol (Ref).
Venous thromboembolism prophylaxis (alternative agent): Note: Low-weight patients (eg, <50 kg) may be more sensitive to routine prophylactic doses, increasing the potential for higher than intended levels of anticoagulation; consider adhering to every-12-hour dosing interval (Ref).
Medical patients with acute illness at moderate to high risk for venous thromboembolism: SUBQ: 5,000 units every 8 to 12 hours; continue for length of hospitalization or until fully ambulatory (Ref); extended prophylaxis beyond acute hospital stay is not routinely recommended (Ref).
Nonorthopedic surgery:
Patients with active cancer:
SUBQ: 5,000 units 2 to 4 hours prior to surgery, then 5,000 units every 8 hours thereafter (Ref) or 5,000 units every 8 to 12 hours started ~6 to 24 hours after surgery (Ref). Note: The optimal duration of prophylaxis has not been established, but it is usually given for a minimum of 7 to 10 days; extending for up to 4 weeks may be reasonable in those undergoing major abdominal or pelvic surgery (Ref).
Patients without cancer: Note: For patients with moderate or high risk of venous thromboembolism (VTE) and low risk of bleeding.
SUBQ: 5,000 units every 8 to 12 hours, with initial dose given ≥2 hours prior to surgery. Alternatively, may postpone pharmacologic prophylaxis until after surgery (eg, high bleeding risk) when it is safe to initiate. Continue until fully ambulatory and risk of VTE has diminished (typically up to 10 days) (Ref).
Orthopedic surgery (eg, hip fracture surgery, total hip arthroplasty, total knee arthroplasty): SUBQ: 5,000 units every 8 to 12 hours, with initial dose administered ≥12 hours preoperatively or ≥12 hours postoperatively once hemostasis is achieved; optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days; some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty or higher end of the range (~30 days) for total hip arthroplasty (Ref). For extended duration of prophylaxis, may transition to an oral anticoagulant or alternative SUBQ anticoagulant with less frequent dosing (Ref).
Pregnancy: Note: Dose intensity is individualized based on risk of thrombosis and bleeding complications (Ref).
Prophylactic dose (also referred to as intermediate dose to account for weight gain during pregnancy):
First trimester: SUBQ: 5,000 to 7,500 units every 12 hours (Ref).
Second trimester: SUBQ: 7,500 to 10,000 units every 12 hours (Ref).
Third trimester: SUBQ: 10,000 units every 12 hours (reduce dose if the aPTT becomes elevated) (Ref).
Adjusted dose (therapeutic): Note: For patients at the highest risk of developing VTE (eg, history of recurrent thrombosis, severe thrombophilia), especially those who are receiving long-term therapy with an oral anticoagulant prior to pregnancy (Ref).
SUBQ: 10,000 units every 12 hours; adjust dose to target an aPTT of 1.5 to 2.5 times control, measured 6 hours after injection; monitor aPTT once daily until stable and within therapeutic range, then monitor every 1 to 2 weeks (Ref).
Management around labor and delivery:
Prior to delivery: Discontinue heparin at the onset of spontaneous labor. Prior to planned induction of labor or cesarean delivery, discontinue heparin ≥12 hours before in patients receiving 7,500 to 10,000 units every 12 hours or ≥24 hours before in patients receiving >10,000 units/dose, >20,000 units/day, or an adjusted therapeutic dose. Consider checking coagulation parameters before delivery. Appropriate discontinuation is particularly important if neuraxial anesthesia is planned (Ref).
Postpartum : In patients at high risk of VTE who require an adjusted therapeutic dose, may restart ≥4 to 6 hours after vaginal delivery or ≥6 to 12 hours after cesarean delivery unless significant bleeding occurred or traumatic neuraxial catheter placement. For patients who require lower VTE prophylaxis doses (eg, patients not receiving an adjusted therapeutic dose during pregnancy) or those without an acute VTE, restart prophylaxis 6 to 12 hours after vaginal delivery and 12 to 24 hours after cesarean delivery (Ref). Anticoagulation should continue for up to 6 weeks postpartum, but potentially longer (Ref).
Venous thromboembolism treatment, deep vein thrombosis and/or pulmonary embolism: Note: IV heparin may be preferred for initial therapy in patients who are hemodynamically unstable, may need invasive procedures or thrombolysis due to extensive clot burden, are obese, have renal failure, or when rapid reversal of anticoagulation may be needed (Ref). If thrombolytics are used, it is recommended to discontinue heparin during administration then resume upon completion of the thrombolytic infusion (Ref).
Inpatient treatment: IV: Initial: 80 units/kg bolus followed by a continuous infusion of 18 units/kg/hour or 5,000 unit bolus followed by 1,333 units/hour; adjust infusion rate to maintain target laboratory values based on institutional protocol (Ref). Note: Weight-based dosing is more effective than fixed dosing at reaching therapeutic anticoagulation (Ref).
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aHull 2022a | |||
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bThis is one example of a weight-based heparin dosing nomogram. Each institution should establish their own heparin dosing nomogram. Other heparin nomograms based on aPTT or anti-Factor Xa monitoring may be employed. Therapeutic range for aPTT must be established at each individual laboratory (Dager 2018). | |||
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cUse actual body weight for calculations. | |||
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Initial dose and monitoring |
→ |
80 units/kg bolus (maximum dose: 10,000 units)c, then 18 units/kg/hour (maximum initial infusion: 2,000 units/hour)c |
Obtain aPTT 6 hours after initial heparin bolus |
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Dosing adjustments and monitoring | |||
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If using anti-Factor Xa activity (units/mL) |
Response |
If using aPTT (seconds) | |
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0 to 0.09 |
• Bolus 25 units/kg • Increase infusion by 3 units/kg/hour • Repeat assay in 6 hours |
<40 | |
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0.1 to 0.19 |
• Increase infusion by 2 units/kg/hour • Repeat assay in 6 hours |
40 to 49 | |
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0.2 to 0.29 |
• Increase infusion by 1 unit/kg/hour • Repeat assay in 6 hours |
50 to 69 | |
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0.3 to 0.7 |
• No change (within therapeutic range) • Repeat assay in 6 hours • Once therapeutic for 2 consecutive assays, may change to once-daily assays |
70 to 110 | |
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0.71 to 0.79 |
• Decrease infusion by 1 unit/kg/hour • Repeat assay in 6 hours |
111 to 120 | |
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0.8 to 0.89 |
• Stop infusion for 1 hour, then decrease by 2 units/kg/hour • Repeat assay 6 hours after restarting the infusion |
121 to 130 | |
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0.9 to 0.99 |
• Stop infusion for 1 hour, then decrease by 3 units/kg/hour • Repeat assay 6 hours after restarting the infusion |
131 to 140 | |
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1 to 1.09 |
• Stop infusion for 2 hours, then decrease by 4 units/kg/hour • Repeat assay 6 hours after restarting the infusion |
141 to 150 | |
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≥1.1 |
• Stop infusion for 2 hours, then decrease by 5 units/kg/hour and notify clinician • Repeat assay 6 hours after restarting the infusion |
>150 | |
Outpatient treatment: Note: Alternative for patients who have a contraindication to other anticoagulants.
SUBQ: Initial: 333 units/kg, followed by 250 units/kg every 12 hours (Ref).
Pregnancy (therapeutic, adjusted dose):
SUBQ: Initial: 10,000 units every 12 hours; adjust dose to target an aPTT of 1.5 to 2.5 times control, measured 6 hours after injection; monitor aPTT once daily until stable and within therapeutic range, then monitor every 1 to 2 weeks (Ref).
Management around labor and delivery:
Prior to delivery: Discontinue heparin at the onset of spontaneous labor. Prior to planned induction of labor or cesarean delivery, discontinue heparin ≥24 hours before in patients receiving a therapeutic adjusted dose of heparin. Consider checking coagulation parameters before delivery. Appropriate discontinuation is particularly important if neuraxial anesthesia is planned (Ref).
Postpartum: May restart ≥4 to 6 hours after vaginal delivery or ≥6 to 12 hours after cesarean delivery, unless significant bleeding occurred or traumatic neuraxial catheter placement. Optimal duration of anticoagulation is unknown. In general, total duration of anticoagulation (antepartum plus postpartum) should be at least 3 to 6 months with at least 6 weeks postpartum (Ref).
Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail.
Transitioning from another anticoagulant to IV heparin:
Transitioning from a therapeutic dose of SUBQ low-molecular-weight heparin or SUBQ fondaparinux to a therapeutic dose of IV heparin: Start IV heparin without a bolus dose (infusion rate depends on the indication) 1 to 2 hours before the next dose of low-molecular-weight heparin (LMWH) or fondaparinux would have been due (Ref).
Transitioning from warfarin to a therapeutic dose of IV heparin: Stop warfarin and, when INR is as close as possible to the lower end of the targeted INR range, start IV heparin without a bolus dose (infusion rate depends on the indication) (Ref).
Transitioning from a direct-acting oral anticoagulant to a therapeutic dose of IV heparin: Stop direct-acting oral anticoagulant (DOAC) and, when the next DOAC dose would have been due, start IV heparin without a bolus dose (infusion rate depends on the indication) (Ref).
Transitioning from IV heparin to another anticoagulant:
Transitioning from a therapeutic dose of IV heparin to therapeutic SUBQ low-molecular-weight heparin or SUBQ fondaparinux: Stop IV heparin and within 1 hour start SUBQ LMWH or SUBQ fondaparinux. Note: If aPTT is not within therapeutic range at the time heparin is stopped, consult local protocol (Ref).
Transitioning from a therapeutic dose of IV heparin to warfarin: Start warfarin and continue IV heparin until INR is within therapeutic range (Dager 2018; Hull 2022a). Note: Overlap IV heparin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart (duration of overlap is ~5 days) (Ref).
Transitioning from a therapeutic dose of IV heparin to a direct-acting oral anticoagulant: Start DOAC when the heparin infusion is stopped (consult local protocol if the aPTT is above the target range) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: IV, SUBQ: Mild to severe impairment: No initial dosage adjustment necessary; adjust to maintain anticoagulation target based on institutional protocol (Ref).
Renal replacement therapies: Poorly dialyzed (Ref): IV, SUBQ: No supplemental dose or initial dosage adjustment necessary in patients receiving renal replacement therapies (eg, hemodialysis, peritoneal dialysis, CRRT, PIRRT); adjust to maintain anticoagulation target based on institutional protocol (Ref).
No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Factor Xa activity.
The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.
Venous thromboembolism prophylaxis:
Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):
SUBQ: 5,000 to 7,500 units every 8 hours (Ref). Note: Until large prospective studies are available evaluating dosing and outcomes, it is reasonable to use 5,000 units every 8 hours. In patients with a BMI >50 kg/m2, consider 7,500 units every 8 hours (Ref).
Therapeutic anticoagulation, treatment:
Class 1 or 2 obesity (BMI 30 to 39 kg/m2):
IV: Use actual body weight for dosing calculation; adjust infusion rate to maintain target laboratory values based on institutional protocol (Ref). Refer to indication-specific dosing recommendations.
Class 3 obesity (BMI ≥40 kg/m2):
IV: Use adjusted body weight for dosing calculation; adjust infusion rate to maintain target laboratory values based on institutional protocol (Ref). Alternatively, dosing based on actual body weight (with or without a bolus) may be considered with an initial reduced maintenance dose (eg, 12 units/kg/hour for VTE treatment) (Ref). Refer to indication-specific dosing recommendations.
Rationale for recommendations:
Heparin is extensively bound to plasma proteins and has a low Vd, which is similar to blood volume. However, increased blood volume is expected with increasing body weight, resulting in increased dosing requirements for patients with obesity (Ref).
Venous thromboembolism prophylaxis: Due to increases in blood volume and likely decreased bioavailability of SUBQ heparin in patients with obesity, higher dosing (7,500 units every 8 hours) has been recommended in those who require venous thromboembolism prophylaxis (Ref). However, a large retrospective cohort study suggests similar occurrence of venous thromboembolism and major bleeding in patients without obesity and those with obesity (BMI ≥30 kg/m2) when administered prophylactic unfractionated heparin at 5,000 units every 8 hours (Ref). Data are lacking in patients with a BMI >50 kg/m2.
Therapeutic anticoagulation, treatment: Retrospective studies show no difference in time to achievement of therapeutic aPTT or bleeding rates when actual body weight was used for bolus and maintenance treatment dosing without dose capping in the following weight classifications: BMI <30 kg/m2, BMI 30 to 39.9 kg/m2, or BMI ≥40 kg/m2 (Ref). In patients with a BMI ≥40 kg/m2, a retrospective study using actual body weight for weight-based dosing showed higher likelihood of supratherapeutic aPTT values compared to patients with a BMI <40 kg/m2 (Ref).
Heparin-induced thrombocytopenia: Immediately discontinue all heparin therapy and exposures (eg, heparin flushes and heparin-coated catheters) for intermediate probability or high probability heparin-induced thrombocytopenia or heparin-induced thrombocytopenia with thrombosis based on the 4T score; switch to an alternative nonheparin anticoagulant (Ref).
Patients >60 years of age may have higher serum levels and clinical response (longer aPTTs) as compared to younger patients receiving similar dosages. Lower dosages may be required.
(For additional information see "Heparin (unfractionated): Pediatric drug information")
Dosage guidance:
Safety: Many concentrations of heparin are available and range from 1 to 20,000 units/mL. Carefully examine each prefilled syringe, bag, or vial prior to use to ensure that the correct concentration is chosen. Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.
Central line flush, patency (intermittent doses): Limited data available (Ref): Infants, Children, and Adolescents: When using intermittent flushes of heparin to maintain patency of single and double lumen central catheters, various recommendations exist; refer to institution-specific protocols. Capped polyvinyl chloride catheters and peripheral heparin locks require flushing more frequently (eg, every 6 to 8 hours). Volume of heparin flush is usually similar to volume of catheter (or slightly greater). Dose of heparin flush used should not approach therapeutic unit per kg dose. Additional flushes should be given when stagnant blood is observed in catheter, after catheter is used for drug or blood administration, and after blood withdrawal from catheter.
Congenital heart defect palliated with systemic to pulmonary artery shunts (eg, Sano shunt, Blalock-Taussig shunt, central shunt) or with high-risk central venous lines (eg, previous thrombosis or hypercoagulable states), thromboprophylaxis: Infants, Children, and Adolescents: Low Dose: Continuous IV infusion: 10 to 15 units/kg/hour (Ref).
Extracorporeal membrane oxygenation (ECMO) (venoarterial [VA]/cardiac), anticoagulation:
Note: While used to prevent thrombosis, full anticoagulation dosing is necessary.
Infants, Children, and Adolescents: IV: 100 units/kg prior to ECMO cannulation followed by continuous IV heparin infusion to maintain the activated clotting time (ACT) between 180 and 220 seconds; ACT should be checked hourly while patient is on ECMO; additional monitoring targets for heparin therapy are prolongation of the PTT to 1.5 to 2.5 times the control value or an anti-Xa level of 0.3 to 0.7 units/mL (Ref).
Parenteral nutrition (PN) additive, venous access patency: Infants, Children, and Adolescents: 1 unit/mL (final heparin concentration in PN), both central and peripheral. The final concentration of heparin used for PN solutions may need to be decreased to 0.5 units/mL in small infants receiving larger PN volumes in order to avoid approaching therapeutic amounts (Ref).
Peripheral arterial catheters in situ, thromboprophylaxis: Infants, Children, and Adolescents: Intra-arterial (via arterial catheter): Continuous infusion of heparin at a final concentration of 5 units/mL at 1 mL/hour (Ref).
Thrombosis, treatment:
Systemic heparinization:
Infants: IV: Initial loading dose: 75 units/kg over 10 minutes; then initial continuous maintenance infusion at 28 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7 units/mL or an aPTT range that correlates to this anti-Xa range or a protamine titration range of 0.2 to 0.4 units/mL (Ref).
Children and Adolescents: IV: Initial loading dose: 75 units/kg over 10 minutes, then initial continuous maintenance infusion at 20 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7 units/mL or an aPTT range that correlates to this anti-Xa range or a protamine titration range of 0.2 to 0.4 units/mL (Ref). Note: A lower initial continuous maintenance infusion dose of 18 units/kg/hour in older patients has also been suggested (Ref).
Note: Because of variation among hospitals with reagents (lot numbers) and corresponding control of aPTT values, individual institutions should establish unique, institution-specific nomograms based on current reagent. Due to extensive variability within reagents and anti-Xa levels with corresponding aPTTs, a specific nomogram has not been provided; refer to guidelines for a specific nomogram (Ref).
Systemic to pulmonary artery shunt thrombosis (eg, Sano shunt, Blalock-Taussig shunt, central shunt); treatment in patients with congenital heart disease (CHD): Infants, Children, and Adolescents: IV: Bolus: 50 to 100 units/kg, ongoing continuous infusion should be considered (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
All patients: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity
All patients: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity
Heparin increases the risk of bleeding (hemorrhage), including major bleeding. Bleeding may occur at any site and may be severe enough to be life-threatening, with reports of fatal cases (eg, intracranial bleeding) (Ref). Bleeding is reversible with the use of protamine.
Mechanism: Dose-related; binds to antithrombin III, increasing its activity 1,000-fold (Ref). This complex inactivates factors IIa (thrombin), Xa, IXa, XIa, and XIIa, leading to decreased coagulation (Ref).
Onset: Varied; may occur at any time but data show that it is more common toward the end of planned therapy (Ref). Bleeding may occur sooner; however, this is largely driven by other risk factors for bleeding that are present (Ref).
Risk factors:
• Supratherapeutic dosing (excess bolus or infusion) or aPTT level (Ref)
• Kidney impairment (Ref)
• Uncontrolled and severe hypertension
• History of hemorrhagic stroke
• Recent gastrointestinal bleed
• Females
• Age >60 years
• Concurrent antiplatelet therapy (eg, P2Y12 inhibitors, GPIIb/IIIa inhibitors) (Ref)
• Concurrent use of thrombolytics (Ref)
• Liver disease with impaired hemostasis
• Ulcerative GI lesions
• Continuous GI tube drainage
• Subacute bacterial endocarditis
• Concurrent coagulation disorders (Ref)
• Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy
• Recent brain, spinal, or ophthalmic surgery
• Recent surgery, trauma, or invasive procedures (Ref)
• Spinal interventions, including epidurals or spinal taps (Ref)
Studies primarily in patients who are pregnant show that heparin may cause significant decreased bone mineral density (BMD) ≥10% decrease from baseline femur measurements (Ref). A study in patients on hemodialysis showed decreases in BMD primarily in the lumbar spine (Ref). BMD losses may still be significant 6 months after discontinuation (Ref). Bone fractures are uncommon (Ref).
Mechanism: Dose- and time-related (Ref); binds to osteoprotegerin, sterically inhibiting its interaction with RANKL on osteoblasts. This promotes RANK-RANKL linkages, activating osteoclasts and causing bone resorption (Ref).
Onset: Delayed; occurs after about 3 to 6 months (Ref).
Risk factors:
• High doses (15,000 to 30,000 units/day), but this is controversial (Ref)
• Long-term use of at least 3 to 6 months (Ref)
• Use of unfractionated heparin (versus low-molecular weight heparin) (Ref)
• Pregnancy (Ref)
Mild thrombocytopenia may occur during therapy (Ref). Heparin-induced thrombocytopenia without thrombosis (HIT) or with thrombosis (HITT) may also occur, warranting discontinuation of therapy, and can be fatal without treatment (Ref). HIT/HITT should be suspected if there is a 30% to 50% reduction in platelet count from baseline with or without new thrombosis formation while on heparin therapy (Ref). The 4T score can be used to evaluate the probability of HIT and whether to further pursue laboratory evaluation (Ref). HIT/HITT antibodies resolve approximately 90 to 100 days after discontinuation of therapy; however, it is unknown if those with a history of HIT/HITT are more likely to develop the reaction again if re-exposed to heparin. Therefore, avoidance of heparin is recommended (or allowance of only short-term use for specific indications) even after resolution of antibodies (Ref).
Mechanism: Time-related; HIT is an immune-mediated complication where IgG antibodies directed at complexes of heparin and the platelet protein, platelet factor 4 (PF4), bind to the FcγIIa receptors on platelets (Ref). This causes platelet activation, aggregation, and significant thrombin generation, leading to thrombosis (Ref). Thrombocytopenia is secondary to the significant activation and usage of platelets, effectively removing them from circulation (Ref).
Onset: Varied; the decrease in platelet count typically occurs 5 to 10 days after heparin initiation; however, platelet count can fall within 24 hours after heparin initiation in “rapid-onset HIT,” which tends to occur in individuals with circulating heparin antibodies secondary to a recent exposure (Ref). “Delayed-onset HIT” is also possible, which occurs when platelet count fall occurs weeks after heparin is discontinued (Ref). Thrombosis can precede thrombocytopenia in up to 25% of cases (Ref).
Risk factors for HIT:
• Longer courses of heparin (Ref)
• Use of unfractionated heparin (versus low molecular weight heparin) (Ref)
• Bovine heparin (Ref)
• Patients undergoing surgery (particularly cardiac and orthopedic surgery) (Ref)
• Patients presenting with major trauma (Ref)
• Females (Ref)
Additional risk factors for HITT:
• High antibody levels (optical density or titer) (Ref)
• Marked thrombocytopenia (>90% decline from baseline) (Ref)
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Postmarketing:
Cardiovascular: Cardiac tamponade (Su 2005), vasospasm
Dermatologic: Transient alopecia
Endocrine & metabolic: Hyperkalemia (Su 2005), suppression of aldosterone synthesis
Genitourinary: Priapism (Burke 1983)
Hematologic & oncologic: Hemorrhage (including adrenal hemorrhage, ovarian hemorrhage, retroperitoneal hemorrhage) (Krishnaswamy 2011), heparin-induced thrombocytopenia, thrombocytopenia, thrombosis in heparin-induced thrombocytopenia (including acute myocardial infarction, cerebral thrombosis, cerebrovascular accident, deep vein thrombosis, mesenteric thrombosis, peripheral gangrene, pulmonary embolism, renal artery thrombosis, skin necrosis)
Hepatic: Increased serum alanine aminotransferase, increased serum aspartate aminotransferase
Hypersensitivity: Anaphylactic shock (Bottio 2003), hypersensitivity reaction (including pruritus and burning sensation of feet [plantar side]), infusion-related reaction (skin necrosis), nonimmune anaphylaxis
Local: Erythema at injection site (SUBQ), hematoma at injection site (SUBQ), irritation at injection site (SUBQ), pain at injection site (SUBQ), skin ulceration at injection site (SUBQ), tissue necrosis at injection site (SUBQ)
Neuromuscular & skeletal: Bone fracture (Barbour 1994), decreased bone mineral density (Douketis 1996), osteoporosis (with long-term use) (Casele 2006)
Hypersensitivity to heparin or any component of the formulation (unless a life-threatening situation necessitates use and use of an alternative anticoagulant is not possible); severe thrombocytopenia; history of heparin-induced thrombocytopenia; history of heparin-induced thrombocytopenia with thrombosis; uncontrolled active bleeding (except when this is due to disseminated intravascular coagulation); not for use when appropriate blood coagulation tests cannot be obtained at appropriate intervals (applies to full-dose heparin only).
Note: Some products contain benzyl alcohol as a preservative; their use in neonates, infants, or pregnant or breastfeeding patients is contraindicated by some manufacturers.
Concerns related to adverse effects:
• Heparin resistance: Dose requirements >35,000 units/24 hours to maintain a therapeutic aPTT may occur in patients with antithrombin deficiency, increased heparin clearance, elevations in heparin-binding proteins, and elevations in factor VIII and/or fibrinogen; frequently encountered in patients with fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, and in postsurgical patients; measurement of anticoagulant effects using anti-Factor Xa levels may be of benefit.
• Hepatic effects: Elevations in serum aminotransferases have been observed during therapy. These elevations should be evaluated with caution as they may occur and resolve in the setting of the underlying condition for which heparin is being used.
• Hypersensitivity reactions: Hypersensitivity reactions, including fever, chills, urticaria, asthma, rhinitis, lacrimation, and anaphylaxis, have been reported. In patients with a documented hypersensitivity reaction, heparin should only be considered in life-threatening situations when use of an alternative anticoagulant is not possible. Some products are derived from animal tissue and may be contraindicated in patients with animal allergies (ie, pork); consult individual prescribing information.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol as a preservative. In neonates, large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome"); the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling. Use in neonates, infants, or pregnant or nursing mothers is contraindicated by some manufacturers; the use of preservative-free heparin is, therefore, recommended in these populations.
• Sulfites: Some preparations contain sulfite which may cause allergic reactions.
Other warnings/precautions:
• Fatal medications errors: Many concentrations of heparin are available ranging from 1 unit/mL to 20,000 units/mL. Clinicians must carefully examine each prefilled syringe or vial prior to use ensuring that the correct concentration is chosen; fatal hemorrhages have occurred related to heparin overdose especially in pediatric patients.
Confirm the concentration of all heparin injection vials prior to administration; do not use heparin injection as a "catheter lock flush" as the injection is supplied in various concentrations including highly concentrated strengths. Fatal hemorrhages have occurred in pediatric patients when higher concentrations of heparin injection were confused with lower concentrations of heparin lock flush.
Heparin-induced thrombocytopenia (HIT) has been reported in pediatric patients; incidence and risk factors are not well-defined due to variability related to patient inclusion and laboratory techniques; incidence rates up to 2.3% in PICU patients have been reported, and cases observed at both low and high levels of heparin exposure (eg, venous access device line flushes and supratherapeutic doses associated with hemodialysis and during cardiopulmonary bypass). Monitor platelet count closely; if HIT develops, consider alternate anticoagulation therapy (eg, danaparoid, argatroban) (ACCP [Monagle 2012]).
Heparin resistance should be suspected in pediatric patients if unable to achieve an activated clotting time (ACT) >300 seconds after administration of >600 units/kg (ACCP [Giglia 2013]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous:
Generic: 2000 units (1000 mL); 25,000 units (500 mL); 2000 units in 0.9% NaCl per liter (1000 mL); 25,000 units/500 mL (500 mL); 25,000 units/500 mL in NaCl 0.45% (500 mL)
Solution, Intravenous [preservative free]:
Generic: 2000 units in 0.9% NaCl per liter (1000 mL); 25,000 units/500 mL in NaCl 0.45% (500 mL)
Solution, Injection, as sodium:
Generic: 1000 units/mL (1 mL, 10 mL, 30 mL); 5000 units/mL (1 mL, 10 mL); 5000 units/0.5 mL (0.5 mL); 10,000 units/mL (1 mL, 4 mL, 5 mL); 20,000 units/mL (1 mL)
Solution, Injection, as sodium [preservative free]:
Generic: 1000 units/mL (2 mL); 5000 units/mL (1 mL); 5000 units/0.5 mL (0.5 mL)
Solution, Intravenous, as sodium:
Generic: 1000 units (500 mL); 10,000 units (250 mL [DSC]); 12,500 units (250 mL [DSC]); 20,000 units (500 mL); 25,000 units (250 mL); 1 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL); 10 units/mL (1 mL, 3 mL [DSC], 5 mL, 10 mL); 100 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL); 1000 units/500 mL in NaCl 0.9% (500 mL); 12,500 units/250 mL in NaCl 0.45% (250 mL); 25,000 units/250 mL in Dextrose 5% (250 mL); 25,000 units/250 mL in NaCl 0.45% (250 mL)
Solution, Intravenous, as sodium [preservative free]:
Generic: 10 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL); 100 units/mL (3 mL [DSC], 5 mL [DSC]); 25,000 units/250 mL in Dextrose 5% (250 mL)
Solution Prefilled Syringe, Injection, as sodium [preservative free]:
Generic: 5000 units/0.5 mL (0.5 mL)
Yes
Solution (Heparin (Porcine) in NaCl Intravenous)
1000UT/500ML 0.9% (per mL): $0.01
2000UNIT/L 0.9% (per mL): $0.01
12500UT/250ML 0.45% (per mL): $0.06
25000UT/250ML 0.45% (per mL): $0.05 - $0.07
25000UT/500ML 0.45% (per mL): $0.02 - $0.03
Solution (Heparin Na (Pork) Lock Flsh PF Intravenous)
1 units/mL (per mL): $1.16 - $1.25
10 units/mL (per mL): $1.00 - $1.10
100 units/mL (per mL): $1.03 - $1.13
Solution (Heparin Sod (Porcine) in D5W Intravenous)
40UNIT/ML 5% (per mL): $0.03
100 units/mL (per mL): $0.05 - $0.07
25000UT/500ML 5% (per mL): $0.03 - $0.04
Solution (Heparin Sod (Pork) Lock Flush Intravenous)
10 units/mL (per mL): $0.13
100 units/mL (per mL): $0.19 - $0.50
Solution (Heparin Sodium (Porcine) Injection)
1000 units/mL (per mL): $0.26 - $0.91
5000 units/mL (per mL): $1.16 - $5.40
10000 units/mL (per mL): $2.52 - $9.16
20000 units/mL (per mL): $12.00 - $20.95
Solution (Heparin Sodium (Porcine) PF Injection)
1000 units/mL (per mL): $5.70 - $8.24
5000 units/0.5 mL (per 0.5 mL): $2.64 - $7.20
5000 units/mL (per mL): $7.20
Solution Prefilled Syringe (Heparin Sodium (Porcine) Injection)
5000 units/0.5 mL (per 0.5 mL): $3.72 - $3.72
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 25,000 units/500 mL (500 mL)
Solution, Injection, as sodium:
Generic: 1000 units/mL (1 mL, 2 mL, 10 mL, 30 mL); 10,000 units/mL (0.5 mL, 1 mL, 5 mL); 1000 units (500 mL, 1000 mL)
Solution, Intravenous, as sodium:
Generic: 20,000 units/500 mL in Dextrose 5% (500 mL); 100 units/mL (2 mL, 10 mL); 25,000 units/250 mL in Dextrose 5% (250 mL)
Solution Prefilled Syringe, Subcutaneous:
Generic: 5000 units/0.5 mL (0.5 mL)
SUBQ: Inject in subcutaneous tissue only (not muscle tissue). Injection sites should be rotated (usually left and right portions of the abdomen, above iliac crest).
IM: Do not administer IM due to pain, irritation, and hematoma formation.
Continuous IV infusion: Infuse via infusion pump. If preparing solution, mix thoroughly prior to administration.
Catheter patency: Practice is variable. If used for this purpose, refer to institution-specific protocols. The intention is only to maintain patency of IV catheters and is not to be used for anticoagulant therapy.
Intravesical (off-label use): Various dosage regimens of heparin (20,000 to 50,000 units) alone or with alkalinized lidocaine (1% to 4%) have been instilled into the bladder.
Intra-arterial (off-label use): Infuse via infusion pump. If preparing solution, mix thoroughly prior to administration (Ref).
Note: Many concentrations of heparin are available and range from 1 to 20,000 units/mL. Carefully examine each prefilled syringe, bag, or vial prior to use to ensure that the correct concentration is chosen.
Parenteral: Do not administer IM due to pain, irritation, and hematoma formation.
IV:
IV bolus: Administered over 10 minutes (Ref).
Continuous IV infusion: Infuse via infusion pump.
Heparin lock: Inject via injection cap using positive pressure flushing technique. Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.
Central venous catheters: Must be flushed with heparin solution when newly inserted, daily (at the time of tubing change), after blood withdrawal or transfusion, and after an intermittent infusion through an injectable cap.
SubQ: Not all preparation intended for SubQ administration, verify product selection. Inject in subcutaneous tissue only (not muscle tissue). Injection sites should be rotated (usually left and right portions of the abdomen, above iliac crest).
Note: Premixed solutions available
IV infusion: 25,000 units in 250 mL (concentration: 100 units/mL) of D5W, 1/2NS, or NS
Note: Premixed solutions available
IV infusion: 100 units/mL
Anticoagulation: Prophylaxis and/or treatment of thromboembolic disorders (eg, venous thromboembolism, pulmonary embolism) and thromboembolic complications associated with atrial fibrillation or other disease states; prevention of clotting in arterial and cardiac surgery; as an anticoagulant for blood transfusions, extracorporeal circulation, and dialysis procedures.
Note: Heparin lock flush solution and certain premixed infusion bags (eg, 2 units/mL) are intended only to maintain patency of IV devices and are not to be used for systemic anticoagulant therapy.
Antibiotic lock technique, adjunctive therapy (catheter-salvage strategy); Frostbite; Mechanical heart valve, bridging anticoagulation (for interruptions in warfarin therapy); Mechanical heart valve, postsurgical management (to transition to warfarin); Non-ST-elevation acute coronary syndromes; Percutaneous coronary intervention; Peripheral arterial occlusion, acute; ST-elevation myocardial infarction
Heparin may be confused with Hespan
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (anticoagulants, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, renal function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).
Heparin is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) with a history of gastric antral vascular ectasia (O’Mahony 2023).
The 100 unit/mL concentration should not be used to flush heparin locks, IV lines, or intra-arterial lines in neonates or infants <10 kg (systemic anticoagulation may occur). The 10 unit/mL flush concentration may inadvertently cause systemic anticoagulation in infants <1 kg who receive frequent flushes.
Heparin sodium injection 10,000 units/mL and Hep-Lock U/P 10 units/mL have been confused with each other. Fatal medication errors have occurred between the two whose labels are both blue. Never rely on color as a sole indicator to differentiate product identity.
Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification
Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Alteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Anacaulase: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anagrelide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Andexanet Alfa (Coagulation Factor Xa [Recombinant], Inactivated): May diminish the therapeutic effect of Heparin. Risk X: Avoid combination
Angiotensin II Receptor Blockers: Heparin may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Heparin may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Antithrombin: May enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
Corticorelin: Heparin may enhance the adverse/toxic effect of Corticorelin. Significant hypotension and bradycardia have been previously attributed to this combination. Risk X: Avoid combination
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Defibrotide: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modification
Dipyridamole: May enhance the adverse/toxic effect of Heparin. Specifically, the risk of bleeding may be increased. Management: Use caution and reduce the dose of heparin or dipyridamole if these agents are combined. Risk D: Consider therapy modification
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Heparin. Risk C: Monitor therapy
Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combination
Eplerenone: Heparin may enhance the hyperkalemic effect of Eplerenone. Risk C: Monitor therapy
Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy
Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Landiolol: Heparin may enhance the hypotensive effect of Landiolol. Heparin may decrease the serum concentration of Landiolol. Risk C: Monitor therapy
Lecanemab: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
Levothyroxine: Heparin may decrease the serum concentration of Levothyroxine. Risk C: Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Nitroglycerin: May diminish the anticoagulant effect of Heparin. Nitroglycerin may decrease the serum concentration of Heparin. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents (Ophthalmic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Oritavancin: May diminish the therapeutic effect of Heparin. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor IV heparin effectiveness, which could lead to incorrect decisions to decrease heparin doses. Risk X: Avoid combination
Palifermin: Heparin may increase the serum concentration of Palifermin. Management: If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after palifermin administration. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Pentoxifylline: May enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy
Pirtobrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Potassium Salts: Heparin may enhance the hyperkalemic effect of Potassium Salts. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Heparin may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy
Protein C Concentrate (Human): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Reteplase: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Streptokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Telavancin: May diminish the therapeutic effect of Heparin. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor IV heparin effectiveness, which could lead to incorrect decisions to decrease heparin doses. Risk X: Avoid combination
Tenecteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tobacco (Smoked): May decrease the serum concentration of Heparin. Risk C: Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Management: Consider avoiding this combination due to an increased risk of hemorrhage. If anticoagulants are coadministered with urokinase, monitor patients closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Volanesorsen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Heparin does not cross the placenta (ESC [Regitz-Zagrosek 2018]).
Due to pregnancy-induced physiologic changes, the risk of thromboembolism is increased during pregnancy and the immediate postpartum period. Heparin may be used for anticoagulation in pregnancy (ACOG 2018). Due to a better safety profile and ease of administration, the use of low molecular weight heparin (LMWH) is generally preferred over heparin (unfractionated heparin [UFH]) in pregnancy (ACOG 2018; Bates 2018; ESC [Regitz-Zagrosek 2018]); however, heparin may be preferred in pregnant patients with kidney dysfunction (Bates 2018). Anticoagulant therapy for the prevention and treatment of thromboembolism in pregnant patients can be discontinued prior to induction of labor or a planned cesarean delivery (Bates 2018) or LMWH can be converted to UFH in higher risk patients (ESC [Regitz-Zagrosek 2018]). Consult current recommendations for appropriate use in pregnancy.
Patients with mechanical heart valves have an increased risk of adverse maternal and fetal outcomes and these risks are greater without appropriate anticoagulation. UFH or LMWH may be used in pregnant patients with mechanical heart valves. Increased monitoring is required to maintain adequate therapeutic concentrations during pregnancy (consult current recommendations for details) (ESC [Regitz-Zagrosek 2018]; ACC/AHA [Otto 2021]).
Some products contain benzyl alcohol as a preservative; their use in pregnant patients is contraindicated by some manufacturers; use of a preservative-free formulation is recommended.
Heparin is not present in breast milk (Bates 2018).
Heparin is considered acceptable for use in patients who are breastfeeding (Bates 2018; ESC [Regitz-Zagrosek 2018]). However, some products contain benzyl alcohol as a preservative; their use in breastfeeding patients is contraindicated by some manufacturers due to the association of gasping syndrome in premature infants.
Hemoglobin, hematocrit, platelet count, PT, aPTT, signs/symptoms of bleeding, risk factors for bleeding, fecal occult blood test (if clinically indicated); potassium.
Level of anticoagulation can be monitored by anti-Factor Xa activity or aPTT (calibrated by anti-Factor Xa activity or by protamine titration assay) or activated clotting time depending upon the indication (ACCP [Garcia 2012]; ACCP [You 2012]; Bates 2001; Hirsh 1994; Vandiver 2012).
Patients with antiphospholipid syndrome may have a prolonged aPTT at baseline due to effects of the antiphospholipid antibodies. In order to prevent a prolonged value from being mistaken for therapeutic anticoagulation, aPTT should be measured at baseline. In this situation, anti-Factor Xa monitoring may be preferred (Hull 2019a).
Platelet count should be routinely monitored to assess for risk of heparin-induced thrombocytopenia (HIT). If the patient experienced HIT within the past 100 days after receiving heparin or low-molecular-weight heparin, risk of recurrence is higher. Monitor closely if pre-exposure history is uncertain (ACCP [Guyatt 2012]).
Adult:
Treatment of venous thromboembolism and atrial fibrillation:
IV administration:
Anti-Factor Xa activity: 0.3 to 0.7 unit/mL.
Protamine titration: 0.2 to 0.4 unit/mL.
aPTT: Therapeutic range must be established in individual laboratories to target an aPTT prolongation that corresponds to anti-Factor Xa activity or protamine titration values (ACCP [Garcia 2012]; ACCP [You 2012]; Bates 2001; Hirsh 1994; Vandiver 2012).
SUBQ administration:
Anti-Factor Xa activity: 0.3 to 0.7 unit/mL or equivalent aPTT, obtained 6 to 8 hours after injection (ACOG 2018; Dager 2018).
ST-elevation myocardial infarction as adjunct to fibrinolysis or when no reperfusion is planned: aPTT of 1.5 to 2 times control (or an aPTT of ~50 to 70 seconds) is recommended (ACCF/AHA [O’Gara 2013]; Lincoff 2020). Note: An anti-Factor Xa target has not been established for this indication.
Non-ST-elevation acute coronary syndrome: aPTT of 1.5 to 2 times control (or an aPTT of ~50 to 70 seconds) is recommended (ACCF/AHA [Amsterdam 2014]; Cutlip 2024). Note: An anti-Factor Xa target has not been established for this indication.
Postmechanical heart valve replacement surgery (to transition to warfarin therapy): Some experts recommend an aPTT of 1.5 to 2 times control when bleeding risk is acceptable postoperatively and heparin is initiated (ACCP [Douketis 2022]). Note: An anti-Factor Xa target has not been established for this indication.
Potentiates the action of antithrombin III and thereby inactivates thrombin (as well as other coagulation factors IXa, Xa, XIa, XIIa, and plasmin) and prevents the conversion of fibrinogen to fibrin; heparin also stimulates release of lipoprotein lipase (lipoprotein lipase hydrolyzes triglycerides to glycerol and free fatty acids)
Note: Increased interpatient variability of pharmacokinetic parameters in pediatric patients compared to adults; however, age-related decreases in volume of distribution and clearance with increasing pediatric patient age have been reported (ACCP [Monagle 2012]; McDonald 1981).
Onset of action: Anticoagulation: IV: Immediate; SUBQ: ~20 to 30 minutes.
Absorption: Oral, rectal: Erratic at best from these routes of administration; SUBQ absorption is also erratic, but considered acceptable for prophylactic use.
Distribution:
Premature neonates (data based on single dose of 100 units/kg within 4 hours of birth) (McDonald 1981): Inversely proportional to gestational age (GA).
GA 25 to 28 weeks: 81 ± 41 mL/kg.
GA 29 to 32 weeks: 73.3 ± 24.8 mL/kg.
GA 33 to 36 weeks: 57.8 ± 32.2 mL/kg.
Adults: Following a single 75 unit/kg dose: 36.6 ± 7.4 mL/kg (McDonald 1981).
Metabolism: Complex; thought to occur by depolymerization and desulphation via the reticuloendothelial system primarily in the liver and spleen (ACCP [Garcia 2012]; Dawes 1979; Estes 1980; Kandrotas 1992).
Half-life elimination:
Age-related: Shorter half-life reported in premature neonates compared to adult patients.
Premature neonates GA 25 to 36 weeks (data based on single dose of 100 units/kg within 4 hours of birth): Mean range: 35.5 to 41.6 minutes (McDonald 1981).
Dose-dependent: IV bolus: 25 units/kg: 30 minutes (Bjornsson 1982); 100 units/kg: 60 minutes (de Swart 1982); 400 units/kg: 150 minutes (Olsson 1963).
Mean: 1.5 hours; Range: 1 to 2 hours; affected by obesity, renal function, malignancy, presence of pulmonary embolism, and infections.
Note: At therapeutic doses, elimination occurs rapidly via nonrenal mechanisms. With very high doses, renal elimination may play more of a role; however, dosage adjustment remains unnecessary for patients with renal impairment (Kandrotas 1992).
Excretion: Urine (small amounts as unchanged drug); Note: At therapeutic doses, elimination occurs rapidly via nonrenal mechanisms. With very high doses, renal elimination may play more of a role; however, dosage adjustment remains unnecessary for patients with renal impairment (Kandrotas 1992).
Clearance: Age-related changes; within neonatal population, slower clearance with lower GA; however, when compared to adults, the overall clearance in neonatal and pediatric patients is faster than adults (ACCP [Monagle 2012 ]; McDonald 1981).
Altered kidney function: The half-life may be increased.
Hepatic function impairment: The half-life may be increased or decreased.
Older adult: Plasma levels may be higher.
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