Antithrombin and Heparin

Question 1

How does antithrombin act as an anticoagulant? What is the mechanism and structure?

Answer 1

in the active phase the loop flicks up and is active - its active form is to inhibit - it is a “bait loop” that is presented to serine protease
The thrombin-antithrombin complex is a large conformational change and it is inactive. It involves he insertion of the bait loop into AT which stabilises it

Question 2

How does heparan sulphate potentiate AT’s action?

Answer 2

It causes AT to adopt an active conformation, it is an allosteric activator

Question 3

How does heparin function as an anticoagulant? What are the 2 functions?

Answer 3

2 functions:

1. leads to conformational change of the AT which enhances its inhibitory effect - this inhibits Xas effect (MW ~1500)
2. Longer heparins (>18 saccarides, MW ~ 5000) stimulate antithrombin activity 2000 fold by bridging antithrombin - this inhibits thrombin

Question 4

What is the structure of heparan and heparin?

Answer 4

They are related to each other and made up of repeating disaccharide sugar units
Heparin is not found under physiological states

Question 5

Which part of heparin and heparan sulphate is essential to its function?

Answer 5

They contain a core essential pentasaccharide that binds to and activates antithrombin

Question 6

What happens once heparin/heparan sulphate has activated the AT?

Answer 6

It binds, activates the AT, then this leads to binding of the thrombin to the AT, once bound, heparin/heparan dissociates and goes on to activate other AT

Question 7

What study was used to investigate the length of heparin and its use for AT inhibition?

Answer 7

Li et al
Nature Structural &
Molecular Biology
11, 857-862, 2004

Question 8

Why are LMWH good?

Answer 8

chain length: 5000

1. high anti-factor Xa/antithrombin activity
2. better bioavailability than unfractioned Heparin and preditability - this means no monitoring is needed and a fixed dose is given