Recombinant blood products and therapeutic enzymes - Pharmaceutical Biotechnology: Concepts and Aapplications - page 347

Clarification of milk
(filtration using Transgenic goat herd Milking ≈ 500 kDa

filter)

Hydrophobic interaction
chromatography

Anion-exchange
chromatography

Heparin affinity
chromatography

Figure 12.10 Outline of the production and purifi cation of antithrombin from the milk of transgenic
goats. Purifi cation 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 en-
gineered mammalian cell line and, like several other blood proteins, is characterized by the pres-
ence of several -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.

γ -carboxyglutamate and β

12.4 Thrombolytic agents

The natural process of thrombosis functions to plug a damaged blood vessel, thus maintaining
haemostasis until the damaged vessel can be repaired. Subsequent to this repair, the clot is re-
moved via an enzymatic degradative process known as fi brinolysis. Fibrinolysis normally depends
upon the serine protease plasmin, which is capable of degrading the fi brin strands present in the
clot.
In situations where inappropriate clot formation results in the blockage of a blood vessel, the
tissue damage that ensues depends, to a point, upon how long the clot blocks blood fl ow. Rapid
removal of the clot can often minimize the severity of tissue damage. Thus, several thrombolytic
(clot-degrading) agents have found medical application (Table 12.5). The market for an effective
thrombolytic agent is substantial. In the USA alone, it is estimated that 1.5 million people suffer
acute myocardial infarction each year, and there are another 0.5 million suffer strokes.