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Clinical Aspects of Biochemistry Proteins and Disease Blood clotting enzymes

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. ~450Å. FIBRINOGEN.

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Clinical Aspects of Biochemistry Proteins and Disease Blood clotting enzymes

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  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. ~450Å FIBRINOGEN From Voigt & Voigt

  7. FIBRINOGEN - POLYPEPTIDE CHAIN ORGANIZATION From Voigt & Voigt

  8. FIBRIN AGGREGATION From Voigt & Voigt

  9. Gln Transamidase (Factor XIIIa) Lys CROSSLINKING FIBRIN

  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. 27K 11K 17K S S • 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:

  13. FACTOR VIII (antihaemophilia factor) Lack of factor VIII causes haemophilia A - 70-80% 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. CLOT LYSIS tPA: • 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

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