Epistemis

Unfractionated Heparin (UFH)

  • Parenteral Anticoagulants

Heparin Sodium or Calcium (e.g. *Heparin Rovi*, *Heparin Sodium Hospira*).

Mechanism

Mechanism of Action

Unfractionated Heparin (UFH) is a heterogeneous mixture of anionic mucopolysaccharides (glycosaminoglycans) with an average molecular weight of 15,000 Da (range 3,000 to 30,000 Da). Its anticoagulant action depends on a specific high-affinity pentasaccharide sequence present in approximately one third of heparin molecules.

Molecular Physiology of the HNF-Antithrombin Complex

1. Pentasaccharide binding: The specific pentasaccharide of UFH binds reversibly to antithrombin III (AT-III), inducing a conformational change in the loop of the reactive center of AT-III that accelerates more than 1,000 times the rate of inactivation of active coagulation factors, mainly Factor Thrombin (Factor IIa).
2. Bridging effect (Inactivation of IIa): For the inactivation of thrombin (IIa), the heparin molecule must simultaneously bind to AT-III and thrombin itself, serving as a physical bridge. This requires longer chains (minimum of 18 monosaccharide units, molecular weight > 5,400 Da).
3. Inactivation of Factor Xa: Unlike thrombin, the inactivation of Factor

Pharmacokinetics

Key Pharmacokinetics

  • Routes of administration: Continuous intravenous (IV) or bolus; deep subcutaneous (SC) (never intramuscular due to risk of hematomas).
  • Bioavailability (F): Very low and variable orally (null due to degradation and size). By SC route it is approximately 30%, with wide interindividual variability due to nonspecific binding to plasma proteins and endothelial cells.
  • Distribution: Limited to the intravascular compartment due to its highly negative charge and high molecular weight. The volume of distribution (Vd) approximates the plasma volume (approx. 40 - 60 mL/kg).
  • Metabolism and Excretion: Dual elimination mechanism. At common low/therapeutic doses it is eliminated primarily by a rapid nonlinear saturable phase (cellular uptake by receptors on endothelial cells and macrophages, followed by lysosomal depolymerization). At high doses, slow non-saturable renal clearance predominates.
  • Half-life (t1/2): Depends on the dose. Approx. 30 to 60 minutes after IV bolus of 100 IU/kg; increases up to 150 minutes with doses of 400 IU/kg.

Indicators and dose

Indications

  • Prevention and treatment of venous thromboembolic disease (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE).
  • Atrial fibrillation with embolization or imminent risk of embolization.
  • Treatment of the acute phase of acute coronary syndromes (ACS): unstable angina and acute myocardial infarction (AMI).
  • Anticoagulation in extracorporeal circulation procedures, hemodialysis and cardiovascular surgery.
  • Off-label use: Supportive treatment in disseminated intravascular coagulation (DIC) in the predominantly thrombotic phase.

Dosage and Adjustment

Standard therapeutic dose in adults: Intravenous bolus of 80 IU/kg, followed by continuous infusion of 18 IU/kg/hour. It should be adjusted to maintain activated partial thromboplastin time (aPTT) between 1.5 and 2.5 times the control value (or anti-Xa levels of 0.3 to 0.7 IU/mL).

Renal and hepatic adjustment: It does not require a strict initial dose adjustment in renal or hepatic insufficiency, but clearance may be delayed, requiring close monitoring of aPTT or anti-Xa levels and downward adjustments to the infusion rate if accumulation is evident.

Pregnancy and Breastfeeding

FDA Category C. Unfractionated heparin does not cross the placental barrier due to its large molecular weight and ionic charge, making it the anticoagulant of choice (along with LMWH) in pregnant women who require therapeutic anticoagulation. Compatible with breastfeeding, it is not excreted in breast milk.

Security

Contraindications

Absolute
  • Known hypersensitivity to heparin.
  • Clinically significant severe active bleeding.
  • Confirmed history of antibody-mediated heparin-induced thrombocytopenia type II (HIT).
  • Active acute bacterial endocarditis.
  • Organic lesions prone to bleeding (eg, active peptic ulcer, cerebral or aortic aneurysm).
  • Recent brain, spinal cord or ophthalmic surgery.
Relative
  • Severe liver or kidney failure.
  • Hereditary or acquired hemorrhagic diathesis of any etiology.
  • Severe uncontrolled arterial hypertension (SBP > 180 mmHg or DBP > 110 mmHg).
  • Active hemorrhagic retinopathy.
  • Concomitant use of antiplatelet agents or potent thrombolytics.

Adverse Effects (ADR)

SystemAdverse EffectMechanism / Occurrence
HemostasisMajor hemorrhagePharmacological extension of the anticoagulant effect. Incidence of 1% to 5% depending on population and comorbidities.
HematologicalHeparin-induced thrombocytopenia (HIT)Immune reaction mediated by IgG antibodies against the Heparin-Platelet Factor 4 (FP4) complex. It produces massive platelet activation and hypercoagulability. Incidence: 1-3% after exposure > 5 days.
SkeletalOsteoporosisProlonged use (> 3 months). Stimulation of bone resorption by osteoclasts and suppression of osteoblastic activity.
MetabolicHyperkalemiaSuppression of aldosterone synthesis in the adrenal cortex due to direct cellular toxicity on the zona glomerulosa.

Interactions

  • Pharmacodynamic synergy: Increased risk of major bleeding with antiplatelet agents (ASA, clopidogrel, prasugrel), non-steroidal anti-inflammatory drugs (NSAIDs), serotonin reuptake inhibitors (SSRIs) and thrombolytics.
  • Direct chemical antagonists: Protamine sulfate (basic polypeptide rich in arginine) binds stoichiometrically to heparin (strong acid) forming an inactive complex without anticoagulant effect.

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

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Hematology
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Parenteral Anticoagulants
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