Heparin depolymerization

LMWHs are formed by various methods of fractionation or depolymerization of polymeric heparin (Table 7.1). Although they are enzymatically derived from UFH, they have a different site of achon and can be administered subcutaneously. LMWHs exert their anhcoagulant effect by inhibiting factor Xa and augmenting tissue-factor-pathway inhibitor, but minimally affect thrombin or factor Ila (Figs. 7.1 and 7.2)." Thus, the PTT, a measure of antithrombin (anh-factor Ila) achvity, is not used to measure the achvity of LMWHs. 

Major Fragments from Exhaustive Depolymerization of Heparin with Nitrous Acid (A) and Heparinase (B)... 

Low-molecular-weight fragments produced by chemical depolymerization and extraction of standard heparin consist of heterogeneous polysaccharide chains of molecular weight 2,000 to 9,000. The LMWH molecules contain the pentasaccharide sequence necessary for binding to antithrombin III but not the 18-saccharide sequence needed for binding to thrombin. Compared to standard heparin, LMWH has a 2- to 4-fold greater antifactor Xa activity than antithrombin activity. 

Chemical Class Heparin derivative, depolymerized low-molecular-weight heparin Clinical Pharmacology ... 

Self-Regulated Depolymerization of Heparin and Production of MPS of Low Molecular Weight. 

There was now fairly good agreement between the various laboratories regarding the qualitative composition of heparin. Jorpes and Bergstrom offered an explanation for the failure by Charles and Scott to obtain a positive naphthoresorcinol test for uronic acid when they showed that highly active heparin is resistant to depolymerization by acid. 

Figure 3. A diagrammatic illustration of the molecular heterogeneity in unfracdonated heparin and a rdated depolymerized agent Beside compoational variation, hq>arin and low molecular wdght heparins exhibit finctional heterogeneity in terms of its interaction with endogenous proteins and cdls The antithrombotic and anticoagulant effects of heparin are based on its polypharmacologic actions.

Low molecular weight components in unfiactionated heparins have been identified long before the development of clinically effective agents. However, because of technologic problems, they were not made available for clinical use. The very first LMWH was obtained by a fractionation method (3). However, this method only yielded a limited amount of the active product and was cost prohibitive. During the past decade, different chemical and enzymatic processes have been developed to obtain LMWH from the parent unfiactionated heparin (UFH). The depolymerization process for the production of LMWH is shown in Figure 5. Such methods as chemical degradation, enzymatic depolymerization... 

The reverse of sulfation is desulfation, which can be effected under mild enzymic conditions [96]. Similarly, enzymic depolymerization, closely guarded by trade secrets, is routinely used in the production of heparin-derived dmgs. 

Linhardt RJ (1992) Chemical and enzymatic methods for the depolymerization and modification of heparin. In Ogura H (ed) Carbohydrates—synthetic methods and application in medicinal chemistry. KodanshaWCH Publishers, Tokyo, p 387... 

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