Defective F8 cleavage by thrombin

Stable Identifier
Homo sapiens
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In normal human plasma, thrombin cleaves factor VIII (FVIII) after arginine residues 391 (A1-A2 domain junction) and 759 (A2-B domain junction) to yield heavy chain fragments and at R1708 (a3-A3 junction) to yield the light chain fragment (Eaton D et al. 1986; Hill-Eubanks DC et al. 1989). Mutations affecting arginine residues located at the thrombin cleavage sites of factor VIII protein result in mild/moderate hemophilia A (HA) (Pattinson JK et al. 1990; Arai M et al. 1990; Schwaab R et al. 1991). The Reactome event describes failed thrombin-mediated activation of HA-associated FVIII variants (R391C, R391H, S392L, R1708C and R1708H) due to defects at or close to thrombin cleavage sites.

Literature References
PubMed ID Title Journal Year
8052958 Factor VIII S373L: mutation at P1' site confers thrombin cleavage resistance, causing mild haemophilia A

O'Brien, DP, Tuddenham, EG, Pemberton, S, Acquila, M, Mori, PG, Johnson, DJ

Thromb. Haemost. 1994
1973901 CRM+ haemophilia A due to a missense mutation (372----Cys) at the internal heavy chain thrombin cleavage site

Tuddenham, EG, Boon, M, McVey, JH, Pattinson, JK, Ajani, A

Br. J. Haematol. 1990
19240027 Cleavage at Arg-1689 influences heavy chain cleavages during thrombin-catalyzed activation of factor VIII

Newell, JL, Fay, PJ

J. Biol. Chem. 2009
2109644 Purification and characterization of factor VIII 372-Cys: a hypofunctional cofactor from a patient with moderately severe hemophilia A

Tuddenham, EG, O'Brien, DP, Pattinson, JK

Blood 1990
15705787 Thrombin-catalyzed activation of factor VIII with His substituted for Arg372 at the P1 site

Zhou, Q, Fay, PJ, Wakabayashi, H, Nogami, K

Blood 2005
2104766 Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in the factor VIII gene of two unrelated patients with cross-reacting material-positive hemophilia A

Antonarakis, SE, Janco, RL, Kazazian, HH, Higuchi, M, Hoyer, LW, Arai, M, Phillips, JA

Blood 1990
1851341 Detection and characterisation of two missense mutations at a cleavage site in the factor VIII light chain

Ludwig, M, McVey, JH, Oldenburg, J, Kochhan, L, Schwaab, R, Brackmann, HH, Egli, H, Olek, K

Thromb. Res. 1991
Name Identifier Synonyms
factor VIII deficiency DOID:12134 Congenital factor VIII disorder, Subhemophilia, Hemophilia A
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