Antithrombin, already mentioned in the context of heparin, is the most abundantly occurring natural inhibitor of coagulation. It is a single-chain 432 amino acid glycoprotein displaying four oligosaccharide side chains and an approximate molecular mass of 58 kDa. It is present in plasma at concentrations of 150 ^g ml-1 and is a potent inhibitor of thrombin (factor IIa), as well as of factors IXa and Xa. It inhibits thrombin by binding directly to it in a 1:1 stoichiometric complex.

Plasma-derived antithrombin concentrates have been used medically since the 1980s for the treatment of hereditary and acquired antithrombin deficiency. Hereditary (genetic) deficiency is characterized by the presence of little/no native antithrombin activity in plasma and results in an increased risk of inappropriate blood clot/emboli formation. Acquired antithrombin deficiency can be induced by drugs (e.g. heparin and oestrogens), liver disease (decreased antithrombin

Figure 12.10 Outline of the production and purification of antithrombin from the milk of transgenic goats. Purification achieves an overall product yield in excess of 50 per cent, with a purity greater than 99 per cent

synthesis) or various other medical conditions. Recombinant antithrombin has been expressed in the milk of transgenic goats (Chapter 5), and this product (tradename Atryn) was approved for general medical use in Europe in 2006 (Figure 12.10). The recombinant product displays an identical amino acid sequence to that of native human antithrombin, although its oligosaccharide composition does vary somewhat from the native protein.

A related product (tradename Xigiris, also known as drotrecogin alfa) has also been approved for medical use. Xigiris is a recombinant human activated protein C, a molecule that plays an important role in controlling coagulation in vivo. The recombinant product is produced in an engineered mammalian cell line and, like several other blood proteins, is characterized by the presence of several y-carboxyglutamate and P-hydroxylated residues (Chapter 2). Activated protein C is indicated for the treatment of severe sepsis, largely in order to prevent multiple organ failure that can be triggered by sepsis-associated blood clot formation.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment