Basic Science Review A Tale of Three Proteins by Jack B. Alperin, MD, FACP.

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Presentation transcript:

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 Synthetic Site Endothelium Mol. Weight MD Function Essential for both 1 st and 2 nd hemostasis

Factor VIII Gene LocationChr. Xq28 Cellular OriginHepatic sinusoidal endothelial cells Mol. WeightL 80 KD, H KD FunctionCoag. cascade leading to a stable fibrin thrombus

ADAMTS 13* Gene LocationChr. 9q 34 Cellular OriginHepatic stellate cells Mol. Weight150 KD FunctionVWF proteinase splits the amino bond at … -842(Tyr) - 843(Meth)- *a disintegrin and metalloproteinase with thrombospondin 1 motif 13

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

von Willebrand Factor Monomer NH 2 -SER-ARG-VAL-LYS-GLY-GLU-ARG-GLY-ASP-SER-LYS-COOH Factor VIIIGPIb Collagen GPIIb/IIIa

Polymerization of VWF ER N C S S  Dimer Golgi N C S S S S S S  Multimer

Definitions 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. VWF:Ag An antigenic determinant on the VWF measured by an immunoassay using a heterologous or monoclonal antibody.

1.Normal 2.VWD Type 1 3.VWD Type 2a 4.Normal

X-Chromosome Sinusoidal Liver Cells (2332 aa) F.VIII precursor *(variable) F.VIII molecule Chromosome 12 Endothelial Cells Megakaryocytes Pre-Pro-VWF (2813 aa) VWF monomer (2050 aa) VWF multimer ( x10 6 K) (F.VIII) – (VWF) Complex * light chain 80 x 10 3 D heavy chain x 10 3 D

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

The von Willebrand Factor Cleaving Proteinase (ADAMTS13)* Gene location - Chr. 9q34, 29 exons Synthesis - Stellate Cells in Liver Structure – 1427 aa, Mr 150 KDHalf-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)