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Heparin cofactor II is a serpin that inhibits thrombin rapidly in the presence of heparin or dermatan sulfate.  The reactive site of HCII contains leucine in the P1 position, which governs the protease specificity of HCII and controls the basal rate of thrombin inhibition.  As shown here, heparin increases the rate of inhibition of thrombin by native HCII about 2000-fold.  Replacement of the P1 leucine by arginine increases the rate of inhibition about 2 orders of magnitude in the absence of a glycosaminoglycan.  This mutation also increases the stoichiometry of inhibition of thrombin about 10-fold in the presence of heparin.