Clinical Aspects of Biochemistry
Proteins and Disease
Blood clotting enzymes
Blood clotting
1. Platelet aggregation
2. Constriction of injured vessels
3. Fibrin formation
THE CLOTTING CASCADE - A SIMPLE VIEW
FIBRIN FIBRE
FIBRINOGEN - FIBRIN CONVERSION
FIBRINOGEN
~450ÅFrom Voigt & Voigt
FIBRINOGEN - POLYPEPTIDE CHAIN ORGANIZATION
From Voigt & Voigt
FIBRIN AGGREGATION
From Voigt & Voigt
Transamidase (Factor XIIIa)
Gln
Lys
CROSSLINKING FIBRIN
From Stryer
-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
PROTHROMBIN
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:
27K
S S
17K
11KIXa:
FACTOR VIII (antihaemophilia factor)
Lack of factor VIII causes haemophilia A - 70-80% of all haemophiliaProtein of 2351 aas; gene ~186,000 bp:.
From Stryer
CONTROL OF CLOTTING
1. Dilution and localisation
2. Antithrombin (58K protein; a serpin)
3. Heparin (sulphated glycosaminoglycan)
4. Protein C (zymogen; activated by thrombin)
5. Thrombomodulin (74K glycoprotein)
[hirudin - leeches]
INTRINSIC PATHWAY - FEEDBACK
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)
tPA:
From Stryer
From Stryer