Abstract
Heparin is a vital pharmaceutical anticoagulant drug and remains one of the few naturally sourced pharmaceutical agents used clinically. Heparin possesses a structural order with up to four levels of complexity. These levels are subject to change based on the animal or even tissue sources that they are extracted from, while higher levels are believed to be entirely dynamic and a product of their surrounding environments, including bound proteins and associated cations. In 2008, heparin sources were subject to a major contamination with a deadly compound—an over-sulphated chondroitin sulphate polysaccharide—that resulted in excess of 100 deaths within North America alone. In consideration of this, an arsenal of methods to screen for heparin contamination have been applied, based primarily on the detection of over-sulphated chondroitin sulphate. The targeted nature of these screening methods, for this specific contaminant, may leave contamination by other entities poorly protected against, but novel approaches, including library-based chemometric analysis in concert with a variety of spectroscopic methods, could be of great importance in combating future, potential threats.
Highlights
The anticoagulant drug heparin is one of the oldest drugs to date in clinical use and is the second most widely used pharmaceutical drug by mass [1]
The absolute arrangement of atoms in a three-dimensional space is driven by the aforementioned features of the heparin chain [35,36] and as a result it is not currently possible determine the 3D structure for an entire heparin chain [37]. This high level of complexity affords heparin the ability to interact with many distinct biomolecules, the effects of which propagate beyond the binding region, for example upon antithrombin binding, the entire population of iduronic acid (IdoA) that is in the 2 S0 configuration within the heparin chain increases, despite the fact that not all of iduronates are involved directly in antithrombin binding
Alongside the techniques employed within the heparin monograph, there are a multitude of other techniques that are well documented for the study of heparin that may be applied to its quality control and can be broadly separated into three orthogonal methodologies: species separation, structural elucidation, and size definition
Summary
The anticoagulant drug heparin is one of the oldest drugs to date in clinical use and is the second most widely used pharmaceutical drug by mass [1]. Heparin chains contain motifs that bind with high affinity to antithrombin (AT), allowing the inhibition of both factor Xa and thrombin, and thereby the common pathway in the coagulation cascade [3,4]. Heparin activity is not limited solely to antithrombin and both are known to bind and regulate many proteins. Heparin and HS are associated with numerous disease states owing to their ability to bind and regulate a multitude of distinct molecules, including histamine, cytokines (e.g., interleukins (IL) 2 through 4), chemokines (e.g., IL-8 and PF4), growth factors (e.g., transforming growth factor beta (TGFbeta), fibroblast growth factors (FGFs), vascular endothelial growth factor and hepatocyte growth factor/scatter factor) and selectins (e.g., L- and P-selectin). A number of protein binding features within heparin and HS have been proposed and the nature of these interactions with the aforementioned proteins have been reviewed extensively in [7]
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