F8 variant does not bind von Willebrand factor

Stable Identifier
Reaction [transition]
Homo sapiens
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Coagulation factor VIII (FVIII) encoded by the F8 gene is synthesized as a 19 amino acid signal peptide followed by 2332 amino acids and includes the A1-A2-B-A3-C1-C2 structural domains (Toole JJ et al. 1984; Wood WI et al. 1984). Upon secretion from the cell, FVIII is cleaved at two sites in the B-domain to form a heterodimer consisting of the heavy chain containing the A1-A2-B domains in a metal ion-dependent complex with the light chain consisting of the A3-C1-C2 domains (Kaufman RJ et al. 1997; Kaufman RJ 1998). The heterodimer circulates in a tight complex with the multimeric glycoprotein von Willebrand Factor (vWF), which is essential for maintaining stable levels of FVIII in the circulation (reviewed by Pipe SW et al. 2016). The structurally homologous C1 and C2 domains of FVIII are believed to have specific functions in interactions with vWF (Pratt KP et al. 1999; Jacquemin M et al. 2000a,b; Ebberink EH et al. 2017). The acidic subdomain a3 of the light chain also controls FVIII binding to vWF (Saenko EL & Scandella D 1997; Dagil L et al. 2019). Sulfation at Tyr1699 in the a3 subdomain was required for high affinity interaction with vWF (Leyte A et al. 1991).

Genetic mutations in the F8 gene can compromise FVIII binding to vWF thus decreasing FVIII values in the plasma causing hemophilia A (HEMA), an X-linked recessive bleeding disorder (Higuchi M et al. 1990; Liu ML et L. 2000; Jacquemin M et al. 2000b; Spiegel PC et al. 2004; d'Oiron R et al. 2004; van den Biggelaar M et al. 2011; Yada K et al. 2015). This Reactome event describes reduced FVIII interaction with vWF caused by the defective Tyr1699 sulfation site (Y1699F) in a3 of FVIII or by mutations in the C domains of FVIII (S2138Y, P2319L, R2169H, R2323H etc.) found in HEMA patients.

Literature References
PubMed ID Title Journal Year
15471879 Surface-exposed hemophilic mutations across the factor VIII C2 domain have variable effects on stability and binding activities

Spiegel, PC, Stoddard, BL, Murphy, P

J. Biol. Chem. 2004
12969981 Deletion of alanine 2201 in the FVIII C2 domain results in mild hemophilia A by impairing FVIII binding to VWF and phospholipids and destroys a major FVIII antigenic determinant involved in inhibitor development

d'Oiron, R, Lavend'homme, R, Lavergne, JM, Jacquemin, M, Vermylen, J, Negrier, C, Bordet, JC, Benhida, A, Saint-Remy, JM, Peerlinck, K

Blood 2004
10910910 A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor

Saint-Remy, JM, Gilles, JG, Schwaab, R, Jacquemin, M, Peerlinck, K, Vanzieleghem, B, Benhida, A, Chuah, MK, d'Oiron, R, Lavergne, JM, Brackmann, HH, Vermylen, J, Hoylaerts, M, VandenDriessche, T, Lavend'homme, R

Blood 2000
21909383 Storage of factor VIII variants with impaired von Willebrand factor binding in Weibel-Palade bodies in endothelial cells

Voorberg, J, Bouwens, EA, van den Biggelaar, M, Mertens, K

PLoS ONE 2011
Normal reaction
Functional status

Loss of function of F8 variant [extracellular region]

Name Identifier Synonyms
factor VIII deficiency DOID:12134 Congenital factor VIII disorder, Subhemophilia, Hemophilia A
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