Low Molecular Weight Heparins (LMWHs)

What are LMWHs?

Mechanism of Action

• Most chains are too short to bridge thrombin to antithrombin → reduced anti-IIa activity
• They retain full capacity to inhibit Factor Xa (pentasaccharide binding induces conformational change in antithrombin)
• Anti-Xa : Anti-IIa ratio = 2:1 to 4:1 (compare: UFH ratio is 1:1)

UFH inhibits both Factor Xa and Thrombin (Factor IIa) equally. LMWHs preferentially inhibit Factor Xa.

Pharmacokinetics — The Key Advantage

• LMWH binds less to endothelial cells, macrophages, and plasma proteins → predictable dose-response, resistance is rare
• Cleared renally → accumulates in renal insufficiency

Monitoring

• Routine monitoring is not required
• When needed, measure anti-Factor Xa levels (aPTT is not useful for LMWH)
  • Therapeutic range: 0.5–1.2 IU/mL (measured 3–4 hrs post-dose)
  • Prophylactic range: 0.2–0.5 IU/mL

• Renal insufficiency (CrCl < 30 mL/min)
• Morbid obesity (>120 kg)
• Low body weight (<60 kg)
• Pregnancy (dose requirements change, especially 3rd trimester)
• Mechanical heart valves

Clinical Uses

1. Deep vein thrombosis (DVT) prophylaxis and treatment
2. Pulmonary embolism (PE) treatment
3. Non-ST elevation acute coronary syndrome (NSTE-ACS):
   • Enoxaparin 1 mg/kg SC twice daily
   • Dalteparin 120 IU/kg SC twice daily (max 10,000 IU)
4. VTE prevention in surgical and medical patients
5. Bridging anticoagulation (e.g., perioperative period)
6. Home treatment of VTE (as effective as in-hospital IV UFH)

Advantages Over UFH

Adverse Effects

1. Bleeding — most important; reversal with protamine sulfate (only ~60% reversal of anti-Xa activity, vs complete reversal of UFH)
2. Heparin-induced thrombocytopenia (HIT) — less common than with UFH but can occur; contraindicated if history of HIT
3. Osteoporosis — with prolonged use (less than UFH)
4. Hyperkalemia — especially in renal failure patients
5. Accumulation in renal failure — dose adjustment required

Reversal

• Protamine sulfate partially reverses LMWH (neutralizes anti-IIa activity but only ~60% of anti-Xa activity)
• Andexanet alfa — newer reversal agent for anti-Xa agents including LMWH

Key Exam Points

• LMWH preferred over UFH for most indications due to predictable pharmacokinetics
• Monitor with anti-Xa, not aPTT
• Renal excretion → use caution / reduce dose in renal failure
• Enoxaparin is the most commonly used LMWH
• Cannot cross the placenta freely — safer in pregnancy than warfarin (which crosses placenta)

Low Molecular Weight Heparins — Goodman & Gilman's (Chapter 36)

Preparation & Source

Comparison Table (Table 36-1): Heparin vs LMWH vs Fondaparinux

Mechanism of Action

• Heparin, LMWH, and fondaparinux have no intrinsic anticoagulant activity — they act by binding to antithrombin and accelerating its inhibition of coagulation proteases.
• Antithrombin (synthesized in liver, plasma conc. ~2.5 μM) inhibits thrombin and Factor Xa as a "suicide substrate" — a stable 1:1 complex is formed.
• All three drugs bind antithrombin via a specific pentasaccharide sequence containing a 3-O-sulfated glucosamine residue.
• This binding induces a conformational change in antithrombin → accelerates Factor Xa inhibition by ≥ 100-fold.

• To inhibit thrombin (IIa), heparin must bridge both antithrombin and thrombin simultaneously → requires chains of ≥18 saccharide units (MW >5,400 Da)
• LMWH mean MW = 5,000 Da (~17 saccharide units) → at least half the chains are too short to bridge thrombin
• These short chains still cause the conformational change in antithrombin → retain full anti-Xa activity
• Result: Anti-Xa : Anti-IIa ratio = 2:1 to 3:1 (UFH is 1:1)

Adverse Effects

1. Heparin-Induced Thrombocytopenia (HIT)

• Occurs in ~0.5% of medical patients on heparin, 5–10 days after starting therapy
• Lower incidence with LMWH (<1%); rare with fondaparinux
• Mechanism: IgG antibodies against heparin–platelet factor 4 (PF4) complexes → platelet activation → paradoxical thrombosis
• Life-threatening thrombotic complications in up to 50% of affected patients
• Women > men; surgical > medical patients
• Manifestations: venous/arterial thrombosis, bilateral adrenal hemorrhage, skin necrosis at injection sites, systemic reactions
• Management:
  • Immediately stop heparin/LMWH
  • Start alternative anticoagulant: bivalirudin, argatroban, or rivaroxaban
  • Fondaparinux is an alternative (rarely causes HIT)
  • LMWH cross-reacts with heparin antibodies — avoid
  • Warfarin contraindicated until platelet count normalizes (risk of venous limb gangrene/skin necrosis)

2. Other Toxicities

• Hepatotoxicity: Reversible abnormalities of liver function tests (common with UFH and LMWH)
• Osteoporosis: With long-term therapeutic doses (>20,000 units/day UFH for 3–6 months). Risk lower with LMWH than UFH
• Hyperkalemia: Heparin inhibits aldosterone synthesis by the adrenal glands

Key Exam Points from Goodman & Gilman

1. LMWH has no intrinsic anticoagulant activity — works through antithrombin
2. Anti-Xa:Anti-IIa = 2:1 to 3:1 (not purely anti-Xa like fondaparinux)
3. Bioavailability SC = ~90%; t½ = ~4 hours
4. Renally excreted — avoid/reduce dose in renal failure
5. No routine monitoring needed; use anti-Xa levels when required
6. HIT with LMWH = <1%; antibodies cross-react with UFH antibodies
7. Protamine: partial reversal only (vs complete reversal of UFH)
8. Platelet factor 4 has lower affinity for LMWH than UFH → more effective near platelet-rich clots

Note: KD Tripathi's Essentials of Medical Pharmacology is not available in this library. The content above from Goodman & Gilman covers the same core LMWH pharmacology tested in 2nd MBBS, and is in fact a more detailed reference. The concepts — mechanism, pharmacokinetics, HIT, adverse effects — are identical across both texts.