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Basic Science Review A Tale of Three Proteins

This review examines the essential functions of three critical proteins in hemostasis: Von Willebrand Factor (VWF), Factor VIII, and ADAMTS13. VWF plays a key role in platelet adhesion and aggregation at sites of vascular injury, while Factor VIII is crucial for generating a stable fibrin thrombus through the coagulation cascade. ADAMTS13 regulates VWF activity by cleaving it, preventing excessive clotting. The genetic origins, molecular weights, and clinical implications of these proteins are discussed, shedding light on their interactions and importance in both primary and secondary hemostasis.

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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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