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Title: A hypersulphated oligosaccharide inhibits intrinsic tenase and prothrombinase : key components of the blood coagulation cascade
Author: Anderson, Julia A. M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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The action of thrombin is central to the processes of thrombosis and haemostasis. Thrombin is generated following the activation of prothrombin by 'prothrombinase' (II-ase), the phospholipid membrane-bound factor Xa (fXa)-factor Va (fVa) complex, which in turn is dependent upon the generation of fXa by 'intrinsic tenase' (X-ase), the phospholipid membrane-bound factor IXa (fIXa)-factor VIIIa (fVIIIa) complex. Thrombin not only converts fibrinogen to fibrin, but also amplifies its own formation by activating the cofactors in II-ase and X-ase, factor V and factor VIII, respectively. The critical role played by II-ase and X-ase towards thrombin generation makes these membrane-bound enzyme complexes attractive targets for inhibition and offers an effective approach to blocking coagulation. Heparin acts as an anticoagulant by activating antithrombin (AT), which then inactivates thrombin, fXa and other activated clotting factors. However, the heparin-AT complex has limited activity against membrane-bound fIXa and fXa. Recently, in buffer systems, heparin has been shown to have an AT-independent effect on coagulation by directly inhibiting X-ase, an effect that is minimal in plasma where the AT-dependent heparin effect predominates. To capitalise on this AT-independent effect, heparin was chemically modified by periodate oxidation and borohydrate reduction to lower its affinity for AT (from Kd value of 25nM to 43μM); we used LMWH rather than heparin to take advantage of the superior pharmacokinetic profile of LMWH. Using this low affinity LMWH (LA-LMWH), N-desulphated LMWH was prepared using a solvolytic desulphation method. Whereas LA-LMWH inhibited X-ase to a similar extent as LMWH with high AT-affinity (IC50 of 16μg/ml and 13μg/ml respectively), N-desulphated LMWH had minimal inhibitory activity (IC50 of 166μg/ml).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available