Is unfractionated heparin (UFH) bound to proteins?

Unfractionated Heparin Binding to Proteins

Yes, unfractionated heparin (UFH) binds extensively to plasma proteins, blood cells, and endothelial cells, which contributes to its variable anticoagulant response and pharmacokinetic profile. 1

Protein Binding Properties of UFH

• UFH binds to numerous plasma proteins, including fibrinogens, globulins, serum proteases, and lipoproteins, which reduces its anticoagulant activity at low concentrations 2
• This protein binding contributes to the variable anticoagulant response observed among patients with thromboembolic disorders and can lead to the laboratory phenomenon known as "heparin resistance" 1
• UFH also binds to von Willebrand factor, which inhibits von Willebrand factor-dependent platelet function 1
• The binding of UFH to plasma proteins is more extensive compared to low molecular weight heparins (LMWHs) 3

Structural Basis for Protein Binding

• UFH is a heterogeneous mixture of polysaccharide chains with molecular weights ranging from 5,000 to 30,000 Daltons 1
• Only about one-third of UFH molecules contain the high-affinity pentasaccharide sequence that binds to antithrombin (AT) 4
• The remaining two-thirds of UFH molecules bind to other plasma proteins and cellular components 1
• This heterogeneity contributes to UFH's complex pharmacokinetic profile and variable anticoagulant effects 5

Clinical Implications of Protein Binding

• The extensive protein binding of UFH results in:

  • Nonlinear, dose-dependent pharmacokinetics 2
  • Variable anticoagulant response requiring laboratory monitoring 1
  • Shorter plasma half-life compared to LMWHs 1
  • Reduced bioavailability when administered subcutaneously 1

• UFH clearance occurs through two mechanisms:

  • A rapid saturable mechanism involving binding to endothelial cells and macrophages 1
  • A slower, first-order mechanism that is primarily renal 1

Comparison with Low Molecular Weight Heparins

• LMWHs exhibit decreased binding to plasma proteins and endothelial cells compared to UFH 1, 3
• This reduced protein binding of LMWHs results in:
  • More predictable dose-response relationship 1
  • Longer half-life allowing once or twice daily dosing 1
  • Higher bioavailability after subcutaneous administration 5
  • Less need for laboratory monitoring 1

Clinical Relevance

• When administering UFH, clinicians should be aware that:

  • Initial doses may have reduced effect due to protein binding 1
  • Therapeutic effect can be variable between patients due to differences in protein binding 1
  • Laboratory monitoring (typically aPTT or anti-factor Xa) is essential to ensure therapeutic anticoagulation 1
  • Dosing adjustments are often necessary to maintain therapeutic levels 1

• The FDA drug label for heparin specifically notes that UFH is "highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins" 2