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Basic Science Review A Tale of Three Proteins

Basic Science Review A Tale of Three Proteins. by Jack B. Alperin, MD, FACP. The Proteins Are…. Von Willebrand Factor Factor VIII ADAMTS 13. von Willebrand Factor. Gene Location Chr. 12p 12.2 - 12.3 Synthetic Site Endothelium Mol. Weight 0.5 - 20 MD

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Basic Science Review A Tale of Three Proteins

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  1. Basic Science ReviewA Tale of Three Proteins by Jack B. Alperin, MD, FACP

  2. The Proteins Are… • Von Willebrand Factor • Factor VIII • ADAMTS 13

  3. von Willebrand Factor Gene Location Chr. 12p 12.2 - 12.3 Synthetic Site Endothelium Mol. Weight 0.5 - 20 MD Function Essential for both 1st and 2nd hemostasis

  4. Factor VIII Gene Location Chr. Xq28 Cellular Origin Hepatic sinusoidal endothelial cells Mol. Weight L 80 KD, H 90 - 200 KD Function Coag. cascade leading to a stable fibrin thrombus

  5. ADAMTS 13* Gene Location Chr. 9q 34 Cellular Origin Hepatic stellate cells Mol. Weight 150 KD Function VWF proteinase splits the amino bond at … -842(Tyr) - 843(Meth)- *a disintegrin and metalloproteinase with thrombospondin 1 motif 13

  6. von Willebrand Factor Role in Primary Hemostasis • Platelet adhesion to collagen at • sites of vascular injury • Platelet aggregation at sites of • vascular injury Role in Secondary Hemostasis • Binds and stabilizes factor VIII • in plasma • Transports factor VIII to sites of • vascular injury

  7. von Willebrand Factor Monomer 1 272 449 728 911 1365 1744 1747 2050 NH2-SER-ARG-VAL-LYS-GLY-GLU-ARG-GLY-ASP-SER-LYS-COOH GPIIb/IIIa Collagen Factor VIII GPIb Collagen

  8. Polymerization of VWF } ER N C Golgi { N C S S Dimer S S N C N C S Multimer S N C S S N C

  9. Definitions VWF:Ag An antigenic determinant on the VWF measured by an immunoassay using a heterologous or monoclonal antibody. VWF:RCo A property of VWF that supports ristocetin- induced aggregation of normal platelets. Commonly called ristocetin cofactor activity. VWF Multimer Analysis Multimers of different molecular weights found in plasma by chromatography and electrophoresis.

  10. Normal • VWD Type 1 • VWD Type 2a • Normal

  11. X-Chromosome Sinusoidal Liver Cells Chromosome 12 Endothelial Cells Megakaryocytes (2332 aa) F.VIII precursor Pre-Pro-VWF (2813 aa) *(variable) F.VIII molecule VWF monomer (2050 aa) VWF multimer (0.5-20 x106K) (F.VIII) – (VWF) Complex *light chain 80 x 103D heavy chain 90-200 x 103D

  12. 1ULVWF 2VWFCP VWF multimers multimers ENDOTHELIAL CELL • Ultra Large von Willebrand Factor Multimers • von Willebrand Factor Cleaving Proteinase or ADAMTS 13

  13. von Willebrand Factor Cleaving Proteinase(ADAMTS13) • Absent in inherited TTP • Inhibited by antibodies in acquired TTP • Recombinant form may be used to treat TTP • Destroys specific VWF mutations causing some forms of VWD Type 1 and Type 2a • Variant may be a risk factor for myocardial infarction

  14. The von Willebrand Factor Cleaving Proteinase(ADAMTS13)* Gene location - Chr. 9q34, 29 exons Synthesis - Stellate Cells in Liver Structure – 1427 aa, Mr 150 KD Half-life 2-4 Days Splits the amino bond between -842 (Tyr)-843 (Meth)- Most effective when substrate (VWF) is denatured by shear stress *ADAMTS 13 - (a disintegrin and metalloproteinase with thrombospodin 1 motif 13)

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