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Human Coagulation FVII

Human Coagulation FVII. Karsten Lollike. 120. Gamma-carboxyglutamic acid. . L. L. A. S. D. Y. Glycosylation sites. 140. G. G. V. P. C. G. I. K. E. P. I. L. E. Y. Activation site. S. K. H. E. R. C. C. V. C. G. G. L. 260. T. N. N. R. T. P. P. L. C.

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Human Coagulation FVII

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  1. Human Coagulation FVII Karsten Lollike

  2. 120 Gamma-carboxyglutamic acid  L L A S D Y Glycosylation sites 140 G G V P C G I K E P I L E Y Activation site S K H E R C C V C G G L 260 T N N R T P P L C A C E Catalytic site residues E P V S V S A 100 Q N E V L R I K R Y F E H V G K L A G P T D E C C T N P F R S H Q T G I R D S 80 N T H L L D G 200 W L 152 E C C L V N R F R Q L S E V L K L T I C E P D V T C I V I L P Y H H Q V Q D N Q K K A S N D H S G G W D F G S G L Q G A P F V D R A G K Q L 220 R C C S E L H C E V L C Q F C C Q A L D 160 Q K 280 G D S P S A A G G K D L S 180 R S I G Y V V R T D S S V 240 V I H L G A I N W W W W 40 Q N T I F T G V T Q L I G L K I P M L L R P T K V D S T G R S Y W Q R Y R T H Y E T L 320 L G  A P W A T A R G H D S 360 E P T N V G D I P P A K I I Y G K L T G R Q V V F E 400 380 E G S S L S I S V L Q L Y W  340 D G R Q R M M Q G 300 R F G L T K A V C C A C C Y P   L A A F D V S S N F V P R L M T Q G S Y D G S K D T V G H F G 406 C P Q NH2 20 C  R  L S G L P R   L F N A A  COOH K  Human Coagulation Factor VII Hagen FS et al.Proc Natl Acad Sci U S A 1986; 83: 2412

  3. FVII Crystal Structure Heavy chain EGF domains Catalytic site Light chain Gla domain Calcium Hagen FS et al.Proc Natl Acad Sci U S A 1986; 83: 2412

  4. Recombinant vs. Plasma-Derived FVIIa • Amino acid sequence Identical • Amino acid composition Identical • Gamma-carboxylation Identical • Peptide map Identical • Biological activity Identical • Carbohydrate composition Similar Lund-Hansen T, Petersen LC Thromb Haemost 1987; 58: 270; Thim L et al.Biochemistry 1988; 27: 7785

  5. Licensed Indications in the EU: • NovoSeven is indicated for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups: • patients with congenital haemophilia with inhibitors to coagulation factors VIII or IX > 5 BU • patients with acquired haemophilia • patients with congenital FVII deficiency • patients with Glanzmann’s thrombasthenia with antibodies to GP IIb-IIIa and/or HLA, and with past or present refractoriness to platelet transfusions NovoSeven SPC 2004

  6. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa VIIa TF IX V Va Platelet II X IIa IXa VIIIa Xa Va Activated Platelet Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  7. Normal Coagulation (Model) X TF VIIa Xa Va TF-Bearing Cell Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  8. Normal Coagulation (Model) II X TF VIIa Xa IIa Va TF-Bearing Cell Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  9. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  10. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa V Va Platelet Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  11. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa V Va Platelet Activated Platelet Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  12. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa VIIa TF IX V Va Platelet IXa Activated Platelet Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  13. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa VIIa TF IX V Va Platelet X VIIIa IXa Xa Va Activated Platelet Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  14. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa VIIa TF IX V Va Platelet II X IIa VIIIa IXa Xa Va Activated Platelet Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  15. Normal Coagulation (Model) II X VIII/vWF TF VIIa Xa IIa Va TF-Bearing Cell VIIIa VIIa TF IX V Va Platelet II X Fibrinogen IIa Fibrin IXa VIIIa Xa Va XIIIa Activated Platelet Fibrin cross-linked Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  16. Thrombin – Many Functions Thrombin activates: • Factor V • Factor VIII • Factor XI • Factor XIII • TAFI (Thrombin activatable fibrinolysis inhibitor) • Protein C • Platelets

  17. Mechanism of Action of rFVIIa (Model) (Situation in Haemophilia A) X II TF rFVIIa Xa IIa Va TF-Bearing Cell rFVIIa TF IX V Va Platelet II X rFVIIa IIa Xa Va IXa Activated Platelet Hoffman M et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S61

  18. rFVIIa Binding to Platelets 2.0 Activated Not activated Activated, without Ca+2 1.5 Relative fluorescence 1.0 0.5 0.0 0 150 300 450 600 [rFVIIa] (nM) Monroe DM et al.Br J Haematol 1997; 99: 542

  19. rFVIIa Activates FX on Platelets in the Absence of TF 6 50 nM VIIa 20 nM VIIa 10 nM VIIa 5 nM VIIa 2 nM VIIa None [FXa] (nM) 5 4 3 2 1 0 0 10 20 30 40 Time (min) Monroe DM et al.Blood Coagul Fibrinolysis 1998; 9 Suppl 1: S15

  20. Pharmacokinetic Comparison Erhardtsen E et al.Blood Coagul Fibrinolysis 1998; 9: 741

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