Heparin Sodium and Enoxaparin

Mechanism

Pharmacological Class and Group

Antithrombotics, prophylactics and parenteral anticoagulants of the class of sulfated glycosaminoglycans of indirect action. Heparin sodium is a high molecular weight unfractionated heparin (UFH); Enoxaparin is a low molecular weight heparin (LMWH) obtained by chemical depolymerization of UFH.

Mechanism of Action

Antithrombin III (ATIII) is a plasma glycoprotein that acts as a slow and natural inhibitor of coagulation proteases, mainly Factor IIa (thrombin) and activated Factor Xa.

Molecular Mechanism Mediated by Antithrombin III

1. Allosteric binding to Antithrombin III by pentasaccharide sequence: Both heparins bind specifically and immediately through an active pentasaccharide sequence to the lysine of ATIII, inducing a rapid conformational change in ATIII that increases the rate of inactivation of coagulation factors up to 1000 times.

2. Differential Effect of Chain Length (HNF vs LMWH):

• Heparin Sodium (HNF): It has long chains composed of more than 18 saccharide units. This length allows it to form a physical ternary bridge complex that simultaneously surrounds ATIII and Factor IIa (thrombin), effectively inactivating it. Likewise, it inactivates Factor Xa. Its anti-Xa:anti-IIa activity ratio is strictly 1:1.
• Enoxaparin (LMWH): Its chains are short (less than 18 units). They do not have sufficient length to form the physical ternary bridge around thrombin, limiting their ability to inactivate Factor IIa. However, they retain the ability to inactivate Factor Xa intact. Its anti-Xa:anti-IIa activity ratio is 3:1 to 4:1 with a selective profile.

Pharmacokinetics

High Resolution Pharmacokinetics

• Heparin Sodium (UFH): It is administered exclusively intravenously or deep subcutaneously in the hospital. It has a variable subcutaneous bioavailability of 30%. High binding to plasma proteins and endothelial cells in a non-specific manner. It is not eliminated through the kidneys in a dominant manner at conventional therapeutic doses (it is metabolized by the cellular reticulo-endothelial system and hydrolyzed by the endogenous heparinase enzyme), which makes it the priority anticoagulant of choice in patients with advanced renal failure. It has a short plasma half-life of 1 to 2 hours, dose-dependent.
• Enoxaparin (LMWH): It is administered subcutaneously. It has an excellent bioavailability of 90% constantly. Low nonspecific plasma protein binding, offering a highly predictable anticoagulant response. It is eliminated exclusively by renal clearance through glomerular filtration, accumulating dangerously in patients with progressive kidney damage. It has a long plasma half-life of 4.5 to 7 hours, allowing doses every 12 or 24 hours.

Indicators and dose

Clinical Indications and Uses

• Acute Phase of Acute Coronary Syndrome (ACS): Intravenous infusion of UFH or subcutaneous administration of enoxaparin in acute myocardial infarction without and with elevation of the ST segment (NSTEACS / STEACS).
• Treatment of Acute Venous Thromboembolism (DVT and PE): Rapid onset anticoagulation.
• Prophylaxis of Thromboembolic Events in Critical Patients: Daily subcutaneous enoxaparin in hospitalized patients with restricted mobility.
• Anticoagulation in Extracorporeal Circulation Circuits: Hemodialysis or cardiopulmonary bypass in cardiac surgery (using UFH due to its rapid clearance and reversibility).

Dosage and Clinical Adjustment

Heparin Sodium (UFH):

• Therapeutic Scheme in ACS / DVT: Initial intravenous bolus of 60 IU to 80 IU/kg (maximum 4000-5000 IU), followed by continuous intravenous infusion of 12 IU to 18 IU/kg/hour. Requires strict adjustment of the infusion rate every 4-6 hours to maintain the activated Partial Thromboplastin time (aPTT) within the target therapeutic range (1.5 to 2.5 times the laboratory control value, or a plasma heparin activity of 0.3 to 0.7 IU/mL).

Enoxaparin (LMWH):

• Standard Therapeutic Dose: 1 mg/kg administered subcutaneously every 12 hours, or 1.5 mg/kg once daily.
• DVT prophylaxis: 40 mg subcutaneously once daily.
• Renal Dose Adjustment: If the eGFR is less than 30 mL/min/1.73 m², the therapeutic dose must be reduced to 1 mg/kg once a day. Generally contraindicated if it is less than 15 mL/min, preferring the use of monitored intravenous UFH.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Active severe bleeding or underlying symptomatic bleeding diathesis.
• Confirmed history of Heparin-Induced Thrombocytopenia (HIT) type II (autoimmune).
• Known hypersensitivity to heparins or derivatives.
• Active bacterial endocarditis.

Relative Contraindications

• Severe Renal Failure (eGFR < 30 mL/min/1.73 m²): Contraindicates the use of therapeutic doses of enoxaparin on an outpatient basis due to the cumulative risk of major bleeding (requires monitoring of anti-Xa activity or mandatory therapeutic rotation to UFH).
• Epidural anesthesia or recent scheduled lumbar puncture (catastrophic risk of development of compressive spinal hematoma with secondary permanent paraplegia).

Adverse Effects and Toxicity

• Systemic Hemorrhage (main ADR): Major bleeding from any location.
• Heparin-Induced Thrombocytopenia (HIT) Type II (Critical ADR): Of autoimmune origin. Antibodies directed against the complex formed by heparin and Platelet Factor 4 (FP4) are generated, activating circulating platelets and inducing severe thrombocytopenia with a paradoxical risk of lethal arterial and venous vascular thrombosis:

Emergency Alert: Diagnosis and Suspected HIT Type II

Type II HIT classically occurs between day 5 and day 14 after the start of exposure to any heparin (it is 10 times more common with UFH compared to LMWH). It is suspected when there is a persistent drop in the platelet count of more than 50% compared to the patient's baseline value, or when new acute arterial or venous thromboses appear during treatment:

Platelet drop > 50% of baseline value Discontinue Heparin immediately and start Argatroban or Danaparoid

Platelet transfusions should not be routinely administered and it is formally prohibited to switch the patient to LMWH or initiate warfarin during the acute phase of HIT. A parenteral direct thrombin inhibitor of choice should be used.

Relevant Drug Interactions

• Antiplatelet Agents (ASA, Clopidogrel) and DOACs: Synergistically enhance the probability of major bleeding of digestive or systemic location.
• Vitamin K Antagonists: Synergism to prolong clotting times during the transition phase ("bridge therapy").