Unfractionated heparin (UFH) binds to anti-thrombin III (AT-III), which enhances antithrombin’s inhibition of several coagulation factors – especially factor Xa and factor IIa (thrombin).

Low Molecular-Weight Heparin (LMWH) is a heterogeneous collection of heparin molecules with a lower average molecular weight compared to unfractionated heparin. Since longer length is necessary to facilitate the interaction between anti-thrombin III and factor IIa, LMWH is less effective at inhibiting factor IIa (acting mostly via inhibition of Xa).

LMWH preparations have differences in the distribution of heparin chain lengths. The ratio of anti-Xa activity to anti-IIa activity varies between preparations (between roughly ~2:1 to ~4:1).

Fondaparinux is essentially a synthetic, short molecule shaped like heparin. It exerts no activity against factor IIa, working purely via inhibition of Xa.

All of these agents are effective only against fluid-phase clotting factors.

In contrast, direct thrombin inhibitors may inhibit both fluid-phase and clot-bound thrombin. This might theoretically make direct thrombin inhibitors more potent agents.

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