Which plasma coagulation inhibitor(s) does heparin (unfractionated heparin) catalyze the anticoagulant action of, antithrombin (AT) or heparin cofactor II (HCII)?

Heparin Primarily Catalyzes the Anticoagulant Action of Antithrombin

Heparin primarily catalyzes the anticoagulant action of antithrombin (AT), with a secondary effect on heparin cofactor II at higher concentrations, making the correct answer D (both A and C). 1, 2

Primary Mechanism: Antithrombin Activation

• Approximately one-third of administered heparin binds to antithrombin (AT), and this fraction is responsible for most of its anticoagulant effect 1

• Heparin binds to lysine sites on AT through a unique pentasaccharide sequence, producing a conformational change at the arginine reactive center that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor 1, 3

• The heparin-AT complex inactivates multiple coagulation enzymes, including:

  • Thrombin (Factor IIa)
  • Factor Xa
  • Factor IXa
  • Factor XIa
  • Factor XIIa 1

• According to the FDA drug label, "Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa" 2

Secondary Mechanism: Heparin Cofactor II Activation

• The remaining two-thirds of heparin has minimal anticoagulant activity at therapeutic concentrations 1
• At concentrations greater than those usually obtained clinically, both high- and low-affinity heparin catalyze the anticoagulant effect of heparin cofactor II 1
• This anticoagulant effect through heparin cofactor II:
  • Requires high concentrations of heparin
  • Occurs regardless of whether the heparin has high or low affinity for AT
  • Only affects thrombin (Factor IIa) inhibition 1

Molecular Requirements for Inhibition

• For thrombin inhibition, heparin must bind to both the coagulation enzyme and AT 1
• Molecules of heparin with fewer than 18 saccharides cannot bind simultaneously to thrombin and AT, making them unable to catalyze thrombin inhibition 1
• Very small heparin fragments containing the high-affinity pentasaccharide sequence can still catalyze inhibition of factor Xa by AT 1

Clinical Implications

• The heterogeneity of heparin (molecular weight range 3,000-30,000 Da) contributes to its complex pharmacology 1
• Higher-molecular-weight heparin fractions have greater effects on platelet function than lower-molecular-weight fractions 1
• Thrombin is approximately 10-fold more sensitive to inhibition by the heparin-AT complex than factor Xa 1

Important Distinction

• While heparin can activate both antithrombin and heparin cofactor II, the activation of antithrombin occurs at therapeutic concentrations and is responsible for most of heparin's anticoagulant effect 1
• Heparin cofactor II activation requires higher concentrations of heparin than typically used clinically 1
• Protein C (answer choice B) is not directly activated by heparin and is therefore not correct 1, 3, 2