Heparins (UFHs) and low molecular weight heparins (LMWHs) are blockbuster drugs used in several clinical indications as anticoagulants and antithrombotics. LMWHs are derived from UFH using a variety of chemical and biochemical techniques. As a result there are differences in the fine chemical structures of LMWHs in terms of their molecular composition, chemical differences in the end groups and distribution of different oligosaccharide chains. While several LMWHs have been approved by FDA as clinical anticoagulants/antithrombotics, they vary significantly in their activity and pharmacological profile. As a consequence, it has been challenging both in terms of determining optimal dosing for a given indication as well as using these drugs interchangeably to achieve the best therapeutic outcome. While the overall structural differences between LMWHs have been generally attributed to the differences in their activity and pharmacokinetic properties, it is still unclear how specific structural properties correlate with the function of different LMWHs. The molecular basis of heparin' s anticoagulant activity has shown that a specific pentasaccharide motif found in low abundance (6-8 mol percent) in heparin binds with high affinity to antithrombin III (AT III) and activates AT-III to primarily inhibit factor Xa and factor IIa (thrombin). Since each LMWH is derived through random (and distinct chemical or enzymatic) cleavage of UFH, there are differences in the quantitative abundance of the AT-III binding pentasaccharide and the chain length distribution and location of this motif in the different oligosaccharide chains that make up the LMWH. Perhaps the key functional (clinical) attribute of LMWHs is the anti-Xa/anti-IIa ratio and the pharmacokinetic/dynamic features of these activities (i.e., their clearance). In this study, we propose to utilize analytical tools that we had developed to determine the structural parameters that govern the abundance and location of the AT-III binding pentasaccharide motif and to correlate these structural parameters to the two primary activities of LMWHs viz. anti-Xa and anti-IIa and their pharmacokinetic in vivo elimination
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