Heparin

Chemistry

Heparin is a heterogeneous mixture of sulfated glycosaminoglycans (mucopolysaccharides). Most commercial preparations are derived from porcine intestinal mucosa and consist of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues. Unfractionated heparin (UFH) has a molecular weight range of 5,000-30,000 Da (mean ~15,000 Da).

Only about one-third of heparin molecules in commercial preparations carry the unique pentasaccharide sequence required for high-affinity antithrombin binding - the rest have minimal anticoagulant activity.

Mechanism of Action

Heparin works by activating antithrombin (formerly antithrombin III), a serine protease inhibitor synthesized in the liver. Antithrombin acts as a suicide substrate for its target clotting enzymes. The pentasaccharide sequence on heparin binds antithrombin and induces a conformational change in its reactive center loop, accelerating its ability to inhibit coagulation factors:

Factor Xa inhibition: The conformational change alone accelerates inhibition by >100-fold
Thrombin (IIa) inhibition: Requires heparin to act as a template, simultaneously binding both antithrombin and thrombin to bring them into close contact. This requires heparin chains of at least 18 saccharide units (MW ≥5,400 Da)

With UFH (mean MW 15,000 Da), virtually all chains are long enough for the bridging function, giving it an anti-Xa:anti-IIa ratio of 1:1. Heparin also triggers release of tissue factor pathway inhibitor (TFPI) from the endothelium, adding a second antithrombotic mechanism.

Once the antithrombin-protease complex forms, heparin is released intact and recycled.

UFH vs. LMWH vs. Fondaparinux

Feature	UFH	LMWH	Fondaparinux
Source	Biologic	Biologic	Synthetic
Mean MW	15,000 Da	4,500-6,000 Da	1,500 Da
Target	Xa and IIa (1:1)	Xa > IIa	Xa only
SC bioavailability	~30%	~90%	~100%
Half-life	~1 hr	~4 hr	~17 hr
Renal excretion	No	Yes	Yes
Reversal with protamine	Complete	Partial	None
HIT risk	<5%	<1%	Rare

LMWH chains (mean MW ~5,000 Da) are too short to bridge antithrombin to thrombin, so they preferentially inhibit factor Xa. This results in more predictable pharmacokinetics and does not require routine monitoring in patients with normal renal function.

Pharmacokinetics

Route: IV (continuous infusion or bolus) or subcutaneous. Never IM (risk of hematoma)
Half-life: Dose-dependent - 30-60 min at low doses (rapid endothelial binding saturates first), up to 2 hours at high doses
Clearance: Primarily extrarenal; macrophages internalize and depolymerize long chains
Binding: Extensively bound to plasma proteins, endothelial cells, and platelet factor 4 (PF4) - this variability is why fixed-dose UFH produces unpredictable anticoagulation

Clinical Indications

Prevention and treatment of venous thromboembolism (DVT, PE)
Acute coronary syndromes (STEMI, NSTE-ACS)
Cardiac and vascular surgery (including cardiopulmonary bypass)
Bridge therapy while initiating warfarin (overlap 5-7 days due to warfarin's initial hypercoagulable risk from protein C depletion)
Arterial thrombosis prevention

Monitoring

Preparation	Test	Therapeutic Range
UFH	aPTT	1.5-2.5× control (or per nomogram)
UFH	Anti-Xa	0.3-0.7 units/mL
UFH	Protamine titration	0.2-0.4 units/mL
LMWH	Anti-Xa (if needed)	0.5-1.0 units/mL (therapeutic, twice daily dosing)

LMWH levels are generally NOT measured except in renal insufficiency, obesity, and pregnancy.

Adverse Effects

Bleeding

The most common complication. Risk increased with higher doses, recent surgery, thrombocytopenia, and renal failure.

Heparin-Induced Thrombocytopenia (HIT)

A dangerous immune complication in which antibodies form against the heparin-PF4 complex. Two types:

Type I (non-immune): Mild, transient platelet fall in first 1-2 days; benign, self-limiting
Type II (immune-mediated): Occurs days 5-10, platelet count drops >50% from baseline; paradoxically causes thrombosis (arterial and venous). Requires immediate cessation of all heparin and initiation of an alternative anticoagulant (argatroban, fondaparinux, or bivalirudin). Warfarin must NOT be started until platelets recover

Other

Osteoporosis with long-term use (LMWH has lower risk than UFH)
Hyperkalemia (aldosterone suppression)
Transient elevated liver enzymes

Reversal: Protamine Sulfate

Protamine is a positively charged protein that binds and neutralizes heparin (negatively charged). 1 mg protamine neutralizes ~100 units UFH. It provides complete reversal of UFH, only partial reversal of LMWH (~60% of anti-Xa activity), and no reversal of fondaparinux.

Caution: Protamine itself can cause anaphylactic/anaphylactoid reactions, particularly in patients with fish allergy or prior protamine exposure (e.g., NPH insulin users).

Key Points for LMWHs

Common agents and their uses:

Enoxaparin (Lovenox): 1 mg/kg SC q12h (treatment) or 40 mg SC daily (prophylaxis)
Dalteparin: Dosed in anti-Xa units
Tinzaparin: Once daily dosing

All require dose reduction in renal impairment (GFR <30 mL/min), where UFH (renally cleared less) may be preferred.

Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed., pp. 959-960; Braunwald's Heart Disease, 2-Vol Set, pp. 1126-1128

Recent evidence note (2025): A systematic review (PMID 40617505) on anti-Xa monitoring for LMWHs is pending publication in J Thromb Haemost (Oct 2025) and may refine current monitoring recommendations for special populations.

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