Heparin and Warfarin - Complete Pharmacology Guide

HEPARIN

Chemistry

Mechanism of Action (MOA)

1. Heparin binds to antithrombin via a unique pentasaccharide sequence (found on only ~1/3 of commercial heparin chains).
2. This binding causes a conformational change in antithrombin, exposing its active site.
3. The activated antithrombin then rapidly inhibits clotting factors - especially thrombin (IIa) and factor Xa, but also IXa, XIa, XIIa.
4. Heparin is released intact and recycled - it acts as a cofactor, not consumed.

• For factor Xa inhibition: the pentasaccharide-antithrombin conformational change is enough (no need for long chain).
• For thrombin inhibition: heparin must bridge antithrombin and thrombin simultaneously - requires chains of at least 18 saccharide units. This is why UFH (long chains) inhibits both Xa and IIa equally (ratio 1:1), while LMW heparins (shorter chains) preferentially inhibit Xa.

Heparin also causes release of Tissue Factor Pathway Inhibitor (TFPI) from endothelium.

Pharmacokinetics

Indications

• DVT and PE treatment and prophylaxis
• Acute coronary syndromes (NSTEMI, STEMI)
• Prevention of thrombosis in cardiac/arterial surgery (e.g. cardiopulmonary bypass)
• Bridging anticoagulation (when stopping warfarin peri-procedurally)
• Pregnancy (does not cross placenta - safe)

Monitoring

• UFH: aPTT - therapeutic range is 1.5-2.5x the control value (or 60-100 seconds). Can also monitor by anti-Xa units (therapeutic: 0.3-0.7 unit/mL).
• LMWH: anti-Xa levels in special populations (renal insufficiency, obesity, pregnancy). Therapeutic peak for enoxaparin (twice-daily): 0.5-1 unit/mL at 4 hrs post-dose.

Toxicity / Adverse Effects

1. Bleeding (Major)

• Stopping heparin (half-life only ~1 hour for UFH)
• Protamine sulfate for reversal (1 mg per 100 units UFH; neutralizes by forming stable salt complex). Protamine only partially reverses LMWH (~60% of anti-Xa activity).

2. Heparin-Induced Thrombocytopenia (HIT)

• Occurs in 1-4% of UFH patients (surgical > medical patients)
• HIT Type I (non-immune): mild, transient fall in platelets within 1-2 days, self-limiting
• HIT Type II (immune-mediated, more serious): antibodies form against heparin-PF4 complex, activating platelets paradoxically, causing a pro-thrombotic (not bleeding) state
  • Onset: 5-14 days after starting heparin
  • Characterized by: thrombocytopenia + new thrombosis (venous or arterial)
  • Platelet count typically drops >50% from baseline
  • Management: stop all heparin immediately (including flushes), switch to a direct thrombin inhibitor (e.g. argatroban)
  • Do NOT give warfarin until platelets recover (risk of skin necrosis via protein C depletion)

3. Osteoporosis

4. Other

• Transient alopecia (hair loss)
• Hypoaldosteronism (mineralocorticoid deficiency) - can cause hyperkalemia
• Release of lipoprotein lipase - can cause hyperlipidemia reduction (triglyceride clearing)
• Hypersensitivity (animal origin)

Contraindications

• Active HIT or history of HIT
• Active uncontrolled bleeding or hemorrhagic disorders (hemophilia, significant thrombocytopenia, purpura)
• Intracranial hemorrhage or recent brain/spinal cord/eye surgery
• Severe uncontrolled hypertension
• Infective endocarditis (relative)
• Active peptic ulcer / GI ulcerative lesions
• Threatened abortion / visceral carcinoma
• Advanced hepatic or renal disease
• Hypersensitivity to heparin

WARFARIN

History & Chemistry

Mechanism of Action (MOA)

1. Normal physiology: Dietary vitamin K is reduced to vitamin K hydroquinone (KH₂) by vitamin K reductase. KH₂ acts as a cofactor for gamma-glutamyl carboxylase, which adds a carboxyl group to glutamic acid residues on clotting factors (gamma-carboxylation). This carboxylation is essential for calcium-dependent binding of factors to phospholipid surfaces (activation). During this process, KH₂ is oxidized to vitamin K epoxide, then recycled back by vitamin K epoxide reductase (VKORC1).
2. Warfarin's action: Warfarin inhibits VKORC1 - blocking the regeneration of active reduced vitamin K. Without active vitamin K, gamma-carboxylation fails, producing clotting factors that are structurally present but functionally inactive ("PIVKA" - proteins induced by vitamin K absence).
3. Affected factors: Warfarin impairs synthesis of factors II (prothrombin), VII, IX, X (clotting factors) and also Protein C and Protein S (anticoagulants).

Pharmacokinetics

• Route: Oral; 100% bioavailability
• Absorption: Rapid, peak levels at ~90 minutes
• Plasma protein binding: >99% bound to albumin (only free fraction is active)
• Half-life: 36-42 hours (racemic mixture)
• Distribution: Small volume of distribution (albumin space); accumulates in the liver
• Metabolism: Hepatic
  • S-warfarin (4x more potent): metabolized by CYP2C9
  • R-warfarin: metabolized by CYP1A2, CYP3A4
• Excretion: Urinary (as metabolites); no unchanged drug in urine

Pharmacogenomics

Indications

• Atrial fibrillation (stroke prevention)
• Mechanical heart valves (mandatory - DOACs not used here)
• DVT/PE treatment and secondary prevention
• Antiphospholipid syndrome
• Rheumatic mitral stenosis with AF

Monitoring

• INR (International Normalized Ratio) - derived from prothrombin time (PT)
• Target INR: 2.0-3.0 for most indications (AF, DVT/PE)
• Target INR: 2.5-3.5 for mechanical mitral valves
• Must be monitored regularly (especially at initiation, dose changes, illness, new medications)

Toxicity / Adverse Effects

1. Bleeding (Major - Most Common)

• Mild bleeding / elevated INR only: Reduce or hold dose; oral vitamin K
• Significant bleeding: IV/oral vitamin K + Fresh Frozen Plasma (FFP) (contains all clotting factors)
• Life-threatening bleeding: IV vitamin K + 4-factor Prothrombin Complex Concentrate (4F-PCC) or FFP - fastest reversal
• INR correction with vitamin K takes 6-24 hours even IV; PCC is immediate

2. Warfarin-Induced Skin Necrosis

• Rare but serious complication, typically occurring in days 3-5 of therapy
• Caused by early depletion of Protein C (short half-life) before factors II, IX, X are depleted
• Leads to microvascular thrombosis in skin - painful necrotic skin lesions in fatty areas (breasts, buttocks, thighs, abdomen)
• Higher risk in patients with Protein C or S deficiency
• Prevention: overlap with heparin until full therapeutic INR is established

3. Teratogenicity (Warfarin Embryopathy)

• Warfarin crosses the placenta - absolutely contraindicated in 1st trimester
• Causes: warfarin embryopathy (nasal hypoplasia, stippled epiphyses, skeletal abnormalities) in weeks 6-12
• Also causes fetal/neonatal hemorrhage and CNS abnormalities

4. "Purple Toe Syndrome"

• Rare - cholesterol microembolization to toes after warfarin initiation, causing painful purple discoloration

5. Drug Interactions (Extensive)

• CYP2C9 inhibitors: amiodarone, fluconazole, metronidazole, ciprofloxacin
• Protein displacement from albumin: NSAIDs, aspirin
• Decreased vitamin K synthesis: broad-spectrum antibiotics (kill gut flora)
• Direct additive: aspirin, NSAIDs (platelet effects + GI bleeding)

• CYP inducers: rifampin (most potent), carbamazepine, phenytoin, barbiturates, St. John's Wort
• Vitamin K supplementation or diet high in leafy greens (spinach, broccoli, kale)
• Cholestyramine (reduces warfarin absorption)

Contraindications

• Pregnancy (especially 1st trimester and near term) - absolute
• Active uncontrolled bleeding
• Hemorrhagic stroke or intracranial hemorrhage
• Severe uncontrolled hypertension
• Protein C or S deficiency (risk of skin necrosis - use with extreme caution; must bridge with heparin)
• Recent brain, spinal cord, or eye surgery
• Patients unable to comply with monitoring (INR monitoring is mandatory)
• Significant hepatic disease (already impaired clotting factor synthesis)
• Falls risk / history of recurrent falls (relative contraindication)

Side-by-Side Comparison