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 ~450Å From Voigt & Voigt
FIBRINOGEN - POLYPEPTIDE CHAIN ORGANIZATION From Voigt & Voigt
FIBRIN AGGREGATION From Voigt & Voigt
CROSSLINKING FIBRIN Transamidase (Factor XIIIa) Gln Lys
From Stryer
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
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
FACTOR VIII (antihaemophilia factor) Lack of factor VIII causes haemophilia A - 70-80% of all haemophilia Protein of 2351 aas; gene ~186,000 bp:.
From Stryer
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]
INTRINSIC PATHWAY - FEEDBACK
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
From Stryer