1. Clinical Aspects of Biochemistry
Proteins and Disease
Blood clotting enzymes

2. Blood clotting 1. Platelet aggregation
2. Constriction of injured vessels
3. Fibrin formation

3. THE CLOTTING CASCADE - A SIMPLE VIEW

4. FIBRIN FIBRE

5. FIBRINOGEN - FIBRIN CONVERSION

6. FIBRINOGEN
~450Å
From Voigt & Voigt

7. FIBRINOGEN - POLYPEPTIDE CHAIN ORGANIZATION
From Voigt & Voigt

8. FIBRIN AGGREGATION
From Voigt & Voigt

9. CROSSLINKING FIBRIN
Transamidase (Factor XIIIa)
Gln
Lys

10. From Stryer

11. PROTHROMBIN
g-carboxy glutamic acid (Gla):
~10 residues near N-terminus of prothrombin
also found in other enzymes of clotting cascade
synthesis requires vitamin K (antagonised by dicoumarol and warfarin)
facilitates binding to Ca2+ and membrane localisation

12. Factor X (Stuart factor)
Glycoprotein. Mr 55,000
L chain (16.5K) and H chain (39K) joined by S-S bridge. ‘Pro’ bit stays attached after activation
Activated by cleavage of 51 residues from N-terminus of H chain by factor IXa + factor VIII + Ca2+ + phospholipid or factor VIIa + tissue factor
Factor IX (Christmas factor)
Glycoprotein. Mr 55,000
~ 15% of haemophilia
Activated by removal of 11K fragment from factor XIa:
IXa:
27K S
17K
11K

13. FACTOR VIII (antihaemophilia factor)
Lack of factor VIII causes haemophilia A % of all haemophilia
Protein of 2351 aas; gene ~186,000 bp:.

14. From Stryer

15. CONTROL OF CLOTTING Dilution and localisation
Antithrombin (58K protein; a serpin)
Heparin (sulphated glycosaminoglycan)
Protein C (zymogen; activated by thrombin)
Thrombomodulin (74K glycoprotein)
[hirudin - leeches]

16. INTRINSIC PATHWAY - FEEDBACK

17. tPA: CLOT LYSIS Plasmin:
a serine protease (trypsin like) which specifically breaks down fibrin
formed from plasminogen (86K protein), by action of other proteases : urokinase (kidney) or tissue plasminogen activator (tPA)
From Stryer

18. From Stryer