Heparins

• Definition and Classification
Heparins are a group of anticoagulant drugs that work by enhancing the activity of antithrombin III (ATIII), leading to inhibition of clotting factors, particularly thrombin (factor IIa) and factor Xa. They are widely used in the prevention and treatment of thromboembolic disorders.
Heparins are classified into:

• Unfractionated Heparin (UFH) – heterogeneous mixture of polysaccharide chains of varying molecular weights

• Low Molecular Weight Heparins (LMWHs) – shorter polysaccharide chains with more predictable pharmacokinetics

• Ultra-Low Molecular Weight Heparins (ULMWHs) – newer agents with even greater specificity for factor Xa inhibition

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• Mechanism of Action

• Heparins bind to antithrombin III, causing a conformational change that accelerates its ability to inactivate clotting factors.

• UFH inhibits both factor Xa and thrombin (factor IIa) equally.

• LMWHs and ULMWHs preferentially inhibit factor Xa more than thrombin due to their shorter chain length.

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• Types and Examples

1. Unfractionated Heparin (UFH)

   • Generic: heparin sodium, heparin calcium

   • Rapid onset of action when given intravenously

   • Short half-life (~1–2 hours), requires continuous infusion or frequent dosing

   • Monitored using activated partial thromboplastin time (aPTT)

2. Low Molecular Weight Heparins (LMWHs)

   • Examples: enoxaparin, dalteparin, nadroparin, tinzaparin

   • Longer half-life (~4–7 hours)

   • More predictable anticoagulant response, less frequent monitoring

   • Primarily renally excreted

3. Ultra-Low Molecular Weight Heparins (ULMWHs)

   • Example: fondaparinux (technically a synthetic pentasaccharide)

   • Selective factor Xa inhibition with no direct thrombin inhibition

   • Long half-life (~17 hours) allowing once-daily dosing

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• Therapeutic Uses

• Prevention and treatment of deep vein thrombosis (DVT)

• Prevention and treatment of pulmonary embolism (PE)

• Acute coronary syndromes (unstable angina, NSTEMI, STEMI)

• Prevention of clotting during cardiac surgery or hemodialysis

• Treatment of disseminated intravascular coagulation (DIC)

• Venous thromboembolism (VTE) prophylaxis in high-risk patients

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• Administration Routes

• UFH: intravenous infusion or subcutaneous injection

• LMWHs: subcutaneous injection only

• Fondaparinux: subcutaneous injection only

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• Dosage Considerations

• UFH: continuous IV infusion with initial bolus; dose adjusted based on aPTT or anti-Xa levels

• LMWHs: fixed or weight-based dosing; renal dose adjustment required for CrCl <30 mL/min

• Fondaparinux: weight-based dosing; contraindicated in severe renal impairment

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• Contraindications

• Active major bleeding

• History of heparin-induced thrombocytopenia (HIT)

• Severe uncontrolled hypertension

• Severe hepatic or renal impairment (depending on agent)

• Recent brain, spinal, or eye surgery

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• Side Effects

• Bleeding (most common)

• Heparin-induced thrombocytopenia (HIT) – immune-mediated, potentially life-threatening

• Osteoporosis with prolonged use

• Hypoaldosteronism leading to hyperkalemia

• Local injection site reactions

• Elevation of liver enzymes (transient)

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• Precautions

• Monitor platelet counts regularly to detect HIT early

• Regular coagulation monitoring for UFH (aPTT)

• Adjust doses in renal impairment for LMWH and fondaparinux

• Use with caution in elderly patients and those with low body weight

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• Antidote

• Protamine sulfate – binds and neutralizes UFH completely; partially reverses LMWH; no effect on fondaparinux

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• Drug Interactions

• Increased bleeding risk with other anticoagulants (warfarin, DOACs)

• Antiplatelet drugs (aspirin, clopidogrel) potentiate bleeding risk

• Certain herbal supplements (e.g., ginkgo, garlic, ginger, ginseng) may increase bleeding tendency

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• Clinical Considerations

• UFH preferred in patients with high bleeding risk due to short half-life and complete reversibility

• LMWH preferred in outpatient settings for ease of dosing and predictable response

• Fondaparinux useful in patients with HIT history (does not cross-react with HIT antibodies)

• Bridging with heparin may be required when initiating oral anticoagulants like warfarin until INR reaches therapeutic range