Heparin (Unfractionated Heparin)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Treatment of DVT and PE | Adults, Paediatrics | Monotherapy (bridge to warfarin or DOAC) | FDA Approved |
| Prevention of DVT and PE | Adults (perioperative) | Monotherapy (low-dose SC) | FDA Approved |
| Atrial fibrillation with embolisation | Adults | Monotherapy or bridge | FDA Approved |
| Peripheral arterial embolism | Adults | Monotherapy | FDA Approved |
| Anticoagulation during cardiac surgery / extracorporeal circulation | Adults, Paediatrics | Monotherapy | FDA Approved |
| Diagnosis and treatment of DIC (consumptive coagulopathy) | Adults | Monotherapy | FDA Approved |
| Prevention of clotting in blood sampling and heparin lock flush | All ages | Flush | FDA Approved |
Unfractionated heparin remains the parenteral anticoagulant of choice in settings requiring rapid onset, short duration of action, and complete reversibility with protamine. Its short half-life and titrability make it indispensable in the ICU, operating theatre, and cardiac catheterisation laboratory. While LMWH has largely replaced UFH for standard VTE prophylaxis and treatment in haemodynamically stable patients, UFH is preferred in severe renal impairment, high bleeding risk scenarios, and when urgent procedures may require rapid reversal of anticoagulation.
ACS (UA/NSTEMI/STEMI): IV heparin is widely used per ACC/AHA guidelines as adjunctive anticoagulation in ACS. The 2025 ACC/AHA ACS guideline recommends parenteral anticoagulation for all patients with ACS to reduce major adverse cardiovascular events. Evidence: High
Continuous renal replacement therapy (CRRT): Heparin is used for circuit anticoagulation in CRRT, though regional citrate anticoagulation is increasingly preferred. Evidence: Moderate
Acute limb ischaemia: Immediate systemic heparinisation is recommended at diagnosis per 2024 ACC/AHA PAD guidelines. Evidence: High
Dosing
Therapeutic Anticoagulation by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| VTE treatment (DVT/PE) | 80 units/kg IV bolus | 18 units/kg/hr continuous infusion | Weight-based (institution-specific caps) | Titrate to aPTT 1.5–2.5× control (or anti-Xa 0.3–0.7 IU/mL) Raschke nomogram: superior to fixed-dose (5000 U bolus, 1000 U/hr) |
| UA / NSTEMI (ACS) | 60 units/kg IV bolus (max 5,000 units) | 12 units/kg/hr (max 1,000 units/hr) | Bolus max 5,000 U; infusion max 1,000 U/hr | Target aPTT 50–70 sec; co-administer with aspirin and P2Y12 inhibitor Lower dose than VTE to reduce bleeding with concurrent antiplatelets |
| STEMI with fibrinolysis (alteplase) | 60 units/kg IV bolus (max 4,000 units) | 12 units/kg/hr (max 1,000 units/hr) | Bolus max 4,000 U; infusion max 1,000 U/hr | Target aPTT 50–70 sec; continue for 48 h or until revascularisation Per ACC/AHA STEMI guidelines; lower bolus cap than UA/NSTEMI |
| PCI (without GP IIb/IIIa inhibitor) | 70–100 units/kg IV bolus | Additional boluses PRN | Weight-based | Target ACT 250–350 sec (HemoTec) or 300–350 sec (Hemochron) Additional bolus if ACT below target during procedure |
| PCI (with GP IIb/IIIa inhibitor) | 50–70 units/kg IV bolus | Additional boluses PRN | Weight-based | Target ACT 200–250 sec Lower target to reduce bleeding with concurrent GP IIb/IIIa |
| Cardiopulmonary bypass | 300–400 units/kg IV | PRN to maintain ACT | 400 units/kg | Target ACT >480 sec; 300 U/kg for procedures <60 min, 400 U/kg for >60 min Reverse with protamine post-bypass (1 mg per 100 U given) |
Prophylaxis and Other Uses
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Postoperative VTE prophylaxis (low-dose) | 5,000 units SC 2 h before surgery | 5,000 units SC q8–12h | 5,000 units per dose | Continue for 7 days or until fully ambulatory; deep SC into abdominal fat aPTT monitoring not required at prophylactic doses |
| Medical VTE prophylaxis | 5,000 units SC q8–12h | 5,000 units SC q8–12h | 5,000 units per dose | For acutely ill hospitalised patients with restricted mobility LMWH generally preferred over UFH for medical prophylaxis (MEDENOX) |
| Paediatric therapeutic anticoagulation | 75–100 units/kg IV bolus over 10 min | Infants: 25–30 units/kg/hr; Children >1 yr: 18–20 units/kg/hr | Weight-based | Titrate to aPTT or anti-Xa; neonates <2 months may require ~28 U/kg/hr Use preservative-free formulations in neonates (avoid benzyl alcohol) |
| Catheter lock flush | 10–100 units/mL | Instil to fill catheter lumen; flush q6–8h | Per catheter volume | Do not use full-strength heparin vials for flush — fatal overdoses reported ISMP high-alert: verify concentration before use |
Heparin is available in numerous concentrations (from 1 unit/mL flush solution to 20,000 units/mL vials). Fatal haemorrhages have occurred from medication errors involving wrong concentration selection. The FDA and ISMP mandate that all heparin products be carefully examined to confirm the correct container choice prior to administration. Use independent double checks for all heparin infusion calculations. Heparin lock flush vials must never be confused with therapeutic heparin vials.
Heparin resistance is defined as requiring >35,000 units/day to achieve a therapeutic aPTT. Common causes include antithrombin III (AT-III) deficiency (congenital or acquired), elevated factor VIII or fibrinogen (acute-phase reactants), increased heparin clearance, and concurrent medications. When resistance is suspected, check AT-III levels and consider switching to anti-Xa-based monitoring. AT-III concentrate supplementation may restore heparin sensitivity in AT-III-deficient patients.
Pharmacology
Mechanism of Action
Unfractionated heparin is a heterogeneous mixture of glycosaminoglycan chains with molecular weights ranging from 3,000 to 30,000 daltons (mean ~15,000 Da). Its anticoagulant activity depends on a specific pentasaccharide sequence that binds to antithrombin III (AT-III), inducing a conformational change that accelerates AT-III’s inactivation of coagulation serine proteases by approximately 1,000-fold. Unlike LMWHs, UFH chains are long enough to simultaneously bridge AT-III and thrombin (factor IIa), enabling potent inhibition of both factor Xa and thrombin in approximately equal measure (anti-Xa:anti-IIa ratio ~1:1). Heparin also prevents fibrin clot stabilisation by inhibiting factor XIIIa activation but does not possess fibrinolytic activity and will not dissolve existing clots. The broad spectrum of plasma protein binding accounts for its unpredictable dose-response and the necessity for laboratory-guided dose titration.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Not absorbed orally; IV onset immediate; SC onset 1–2 h; SC bioavailability ~30% (variable and unpredictable) | IV route preferred for therapeutic anticoagulation due to immediate onset and predictable delivery; SC reserved for prophylaxis where precise anticoagulation is less critical |
| Distribution | Vd ~0.07 L/kg (~60 mL/kg); distributes primarily within intravascular space; binds extensively to AT-III, fibrinogen, globulins, lipoproteins, endothelial cells, and macrophages | Highly variable protein binding is the principal reason for unpredictable dose-response; acute-phase proteins (factor VIII, fibrinogen) compete for binding sites, contributing to heparin resistance in acute illness |
| Metabolism | Primarily by reticuloendothelial system (liver sinusoidal endothelial cells and macrophages); partially depolymerised and desulfated; not metabolised by CYP enzymes | Saturable binding to endothelial cells and macrophages creates dose-dependent (zero-order) clearance at lower doses; at higher doses, non-saturable renal excretion (first-order) predominates, producing the characteristic non-linear pharmacokinetics |
| Elimination | Biphasic: rapid saturable phase (RES uptake) then slower first-order renal phase; t½ 0.5–2 h (dose-dependent); not removed by haemodialysis | Short half-life is a key clinical advantage: allows rapid reversal by simply stopping the infusion (~4 h to clear); protamine provides immediate full reversal in emergencies; longer aPTT observed in patients ≥60 years |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Bleeding (any site, therapeutic dosing) | 10–33% | Varies widely by intensity and concurrent therapy; most common with supratherapeutic aPTT; risk increases with age ≥60, concurrent antiplatelets, and renal impairment |
| Thrombocytopenia (type I, non-immune) | 10–30% | Mild, transient (platelet count rarely <100,000); occurs within first 2 days; non-immune direct platelet activation; does not require discontinuation; distinguish from HIT |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Elevated hepatic transaminases (AST/ALT) | 5–9% | Transient and typically asymptomatic; occurs in the first week; rarely requires discontinuation; not predictive of hepatic injury |
| Injection site haematoma (SC dosing) | 5–10% | Minimise with proper deep SC technique into abdominal fat fold; avoid IM administration (higher haematoma risk) |
| Minor bleeding (epistaxis, haematuria, ecchymosis) | 3–8% | More common at therapeutic than prophylactic doses; manage conservatively; check aPTT and adjust dose |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Major haemorrhage (GI, retroperitoneal, intracranial, adrenal) | 1–5% (therapeutic dosing) | Any time during therapy | Stop heparin immediately; give protamine sulfate (1 mg per 100 units given in last 2–2.5 h; max 50 mg slow IV over 10 min); transfuse as indicated; evaluate for adrenal haemorrhage if hypotension |
| Heparin-induced thrombocytopenia type II (HIT) | 1–5% (surgical patients); 0.1–1% (medical patients) | Day 5–10 (or within hours if prior heparin exposure in last 100 days) | Stop ALL heparin immediately (including flushes and coated catheters); start non-heparin anticoagulant (argatroban, bivalirudin, or fondaparinux); send PF4/heparin antibodies + functional assay; do NOT give platelets; do NOT start warfarin until platelets ≥150,000 |
| HIT with thrombosis (HITT) | ~50% of HIT patients develop thrombosis | During or shortly after HIT episode | Full therapeutic non-heparin anticoagulation; imaging for DVT/PE; may result in stroke, MI, limb ischaemia, amputation, or death if not promptly treated |
| Osteoporosis | ~2–3% with prolonged use (>6 months) | Months of continuous therapy | Consider switching to LMWH (lower osteoporotic risk) for prolonged anticoagulation (e.g., pregnancy); DEXA monitoring for patients on >3 months of therapy |
| Hyperkalaemia | Uncommon; higher risk in renal impairment / diabetes | Days to weeks | Monitor potassium in patients with renal failure, diabetes, or concurrent K+-sparing drugs; heparin suppresses aldosterone secretion |
| Anaphylactoid reactions | Rare | Minutes to hours after first dose | Discontinue heparin; manage as anaphylaxis with epinephrine; patients with pork allergy at higher risk; consider synthetic alternatives (fondaparinux, argatroban) |
Protamine sulfate fully neutralises heparin’s anti-IIa and anti-Xa activity (unlike ~60% neutralisation of LMWH). Dose is based on the amount of heparin given and elapsed time. If given within 30 minutes of the last heparin dose, use 1 mg protamine per 100 units heparin. If 30–60 minutes have elapsed, use 0.5–0.75 mg per 100 units. If >2 hours, protamine may not be needed. For continuous infusion, calculate the dose based on heparin given in the preceding 2–2.5 hours. Maximum single dose: 50 mg administered slowly over 10 minutes. Monitor for protamine-related hypotension and anaphylactoid reactions (especially in patients with fish allergy, prior protamine exposure, or vasectomy).
Drug Interactions
Heparin is not metabolised by CYP enzymes, so pharmacokinetic drug interactions are uncommon. However, any agent affecting haemostasis has the potential to amplify or attenuate heparin’s anticoagulant effect. The FDA PI specifically notes that drugs interfering with platelet aggregation represent the main haemostatic defence of heparinised patients and should be used with caution.
Monitoring
- aPTTBaseline; 6 h after initiation; q6h until stable; then q12–24h
RoutinePrimary monitoring parameter for IV continuous infusion; therapeutic target 1.5–2.5× control (typically 60–100 sec, institution-specific); draw from non-heparinised line; not reliable in lupus anticoagulant, elevated factor VIII, or DIC - Anti-Factor XaPRN: heparin resistance, discordant aPTT
Trigger-basedTherapeutic target 0.3–0.7 IU/mL; draw 4–6 h after dose change; not affected by lupus anticoagulant or elevated factor VIII; increasingly used as primary monitoring parameter at some institutions - ACTDuring PCI and cardiac surgery
RoutinePoint-of-care test for high-dose heparin (procedures); target ACT varies by procedure and concurrent GP IIb/IIIa use; measured within minutes at bedside - Platelet CountBaseline; q2–3 days for first 2 weeks
RoutineEssential for HIT surveillance; suspect HIT if platelet drop ≥50% from baseline, typically day 5–10; apply 4T score; higher risk with UFH than LMWH (1–5% vs <1%) - Haemoglobin / HaematocritBaseline; periodic
RoutineUnexplained drop may indicate occult bleeding; stool occult blood testing recommended during therapy per FDA PI - Serum PotassiumBaseline; periodic in at-risk patients
Trigger-basedRisk of heparin-induced aldosterone suppression causing hyperkalaemia; highest risk in renal impairment, diabetes, concurrent ACE inhibitors/ARBs/K+-sparing diuretics - Signs of BleedingEvery assessment
RoutineAssess for unexpected blood pressure drops, tachycardia, unexplained back/flank pain (retroperitoneal bleed), abdominal distension (adrenal haemorrhage), haematuria, haematemesis, or prolonged oozing from puncture sites
Contraindications & Cautions
Absolute Contraindications
- Active uncontrolled bleeding: Any uncontrolled haemorrhage (except DIC, where heparin may be indicated)
- Severe thrombocytopenia: Platelets <20,000/mcL (relative risk assessment required)
- History of HIT or HITT: Absolute contraindication to all heparin products including LMWH; use non-heparin alternative
- Hypersensitivity to heparin or pork products: Heparin is derived from porcine intestinal mucosa
- Inability to perform coagulation monitoring: Full-dose heparin requires aPTT or anti-Xa monitoring; this does not apply to low-dose prophylaxis
Relative Contraindications (Specialist Input Recommended)
- Recent CNS surgery or active intracranial bleeding: Extremely high risk of catastrophic haemorrhage
- Severe uncontrolled hypertension: Increased intracranial haemorrhage risk
- Active peptic ulcer disease: GI bleeding risk markedly increased
- Subacute bacterial endocarditis: Risk of mycotic aneurysm rupture
- Threatened abortion: Bleeding risk must be weighed against thrombotic risk
- Recent spinal tap or spinal anaesthesia: Risk of spinal/epidural haematoma
Use with Caution
- Elderly (≥60 years): May have higher plasma levels and prolonged aPTT for equivalent doses; increased bleeding risk; may require lower starting doses
- Renal or hepatic impairment: Decreased clearance may prolong anticoagulant effect; no formal dose adjustment but increased monitoring required
- Recent surgery or invasive procedures: Risk of procedural bleeding; hold heparin per institutional protocols
- Concurrent use of antiplatelet agents: Standard in ACS but requires lower heparin doses and vigilant monitoring
Heparin is supplied in numerous concentrations. Fatal haemorrhages have occurred due to errors in selecting the correct vial or premixed bag. The FDA and ISMP classify heparin as a HIGH-ALERT medication. All healthcare facilities must implement safeguards including independent double checks, barcode scanning, standardised concentrations, and clear labelling. Heparin lock flush solutions (1–100 units/mL) must be stored separately from therapeutic concentrations (1,000–20,000 units/mL) to prevent inadvertent overdose.
Patient Counselling
Purpose of Therapy
Explain that heparin is a blood-thinning medication administered by injection or continuous drip to prevent existing blood clots from growing larger and to reduce the risk of new clots forming. It works rapidly and is closely monitored with frequent blood tests to ensure the correct level of anticoagulation. Heparin is typically a short-term treatment while other longer-term blood thinners are being started.
How It Works in Hospital
Heparin is usually given through an IV line as a continuous drip. The nursing team will draw blood samples every few hours (from the opposite arm) to check the level of anticoagulation and adjust the dose accordingly. You may also receive heparin as injections under the skin in the abdomen after surgery to prevent clots during recovery.
Sources
- Heparin Sodium Injection Prescribing Information. FDA-approved label, revised 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017029s178lbl.pdfPrimary regulatory label with dosing recommendations, adverse reactions, contraindications, and full prescribing information for heparin sodium injection.
- Heparin Sodium in 0.9% Sodium Chloride Injection Prescribing Information. FDA label, revised 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/019953s048lbl.pdfPremixed bag formulation label with pharmacokinetic data, clinical pharmacology, and dose-dependent half-life information.
- Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram: a randomized controlled trial. Ann Intern Med. 1993;119(9):874–881. doi:10.7326/0003-4819-119-9-199311010-00002Landmark RCT establishing the 80 U/kg bolus, 18 U/kg/hr weight-based nomogram as superior to fixed-dose heparin for achieving therapeutic aPTT.
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315–352. doi:10.1016/j.chest.2015.11.026ACCP guidelines on VTE treatment including UFH dosing, aPTT targets, and comparison with LMWH for initial anticoagulation.
- Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes. Circulation. 2025. doi:10.1161/CIR.0000000000001309Most current ACS guideline with UFH dosing for UA/NSTEMI (60 U/kg, 12 U/kg/hr) and STEMI with fibrinolysis; recommends parenteral anticoagulation for all ACS patients.
- Menon V, Berkowitz SD, Antman EM, et al. New heparin dosing recommendations for patients with acute coronary syndromes. Am J Med. 2001;110(8):641–650. doi:10.1016/s0002-9343(01)00715-xReview establishing the ACS-specific lower heparin dosing (60 U/kg bolus max 4000-5000 U, 12 U/kg/hr max 1000 U/hr) to reduce bleeding with concurrent antiplatelets.
- Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257–3291. doi:10.1182/bloodadvances.2018024893ASH guideline on anticoagulation management including transition from heparin to warfarin and monitoring recommendations.
- Gornik HL, Aronow HD, Goodney PP, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease. Circulation. 2024. doi:10.1161/CIR.0000000000001251PAD guideline recommending immediate systemic heparinisation at diagnosis for acute limb ischaemia.
- Hirsh J, Anand SS, Halperin JL, Fuster V. Mechanism of action and pharmacology of unfractionated and low molecular weight heparin. Arterioscler Thromb Vasc Biol. 2001;21(7):1094–1096. doi:10.1161/hq0701.093686Authoritative review of heparin’s AT-III binding mechanism, anti-Xa:anti-IIa ratio, protein binding, and pharmacological differences from LMWH.
- Heparin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. https://www.ncbi.nlm.nih.gov/books/NBK538247/Comprehensive clinical review covering mechanism, biphasic pharmacokinetics, dosing by indication, HIT management, and adverse effects.
- Estes JW. Clinical pharmacokinetics of heparin. Clin Pharmacokinet. 1980;5(3):204–220. doi:10.2165/00003088-198005030-00002Classic PK reference describing heparin’s dose-dependent half-life, plasma protein binding, volume of distribution, and non-linear clearance.
- Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 1992;22(5):359–374. doi:10.2165/00003088-199222050-00003Detailed review of heparin’s intravascular distribution, saturable and non-saturable clearance mechanisms, and concave-convex elimination curves.
- Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e24S–e43S. doi:10.1378/chest.11-2291ACCP guideline chapter on parenteral anticoagulants including UFH monitoring, HIT risk factors, and protamine reversal dosing.