Defects in F8 A2 domain accelerate dissociation of the A2 domain

Stable Identifier
Reaction [dissociation]
Homo sapiens
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Factor VIII (FVIII) circulates in plasma as a heterodimer (domain structure A1-A2-B:A3-C1-C2) that requires thrombin cleavage to elicit procoagulant activity (Kaufman RJ et al. 1997). Upon activation by thrombin FVIII is converted to the labile FVIIIa, a heterotrimer of A1, A2 and A3C1C2 subunits, which serves as a cofactor for FIXa (Fay PJ 2006). At physiological concentrations, FVIIIa decays as a result of A2 subunit dissociation, which is weakly associated with the A1:A3-C1-C2 dimer by primarily electrostatic interactions (Fay PJ et al. 1991; Fay PJ & Smudzin TM 1992; Parker ET et al 2006). Retention of A2 polypeptide is required for normal stability of FVIIIa and dissociation of A2 correlates with FVIIIa inactivation and consequent loss of FXase activity. Hemophilia A (HA)-associated mutations (R550H, A303E, S308L, N713I, R717W and R717L) within the predicted A1-A2 and A2-A3 interface are thought to disrupt potential intersubunit hydrogen bonds and have the molecular phenotype of increased rate of inactivation of FVIIIa due to increased rate of A2 subunit dissociation (Pipe SW et al. 1999, 2001; Hakeos WH et al. 2002). Patients with these mutations exhibit a clinical phenotype where the FVIII activity by one-stage clotting assay is at least two-fold higher than by two-stage chromogenic FXa generation assay (Pipe SW et al. 2001; Hakeos WH et al. 2002; Al-Samkari H & Croteau SE 2018). This effect directly relates to enhanced rates of loss of A2 subunit from FVIIIa, which has a more pronounced impact on activity values determined by the two-stage assay (Hakeos WH et al. 2002).
Literature References
PubMed ID Title Journal Year
9864159 Mild hemophilia A caused by increased rate of factor VIII A2 subunit dissociation: evidence for nonproteolytic inactivation of factor VIIIa in vivo

Kaufman, RJ, Saenko, EL, McKinley, SH, Pipe, SW, Eickhorst, AN

Blood 1999
11157485 Hemophilia A mutations associated with 1-stage/2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa

Kaufman, RJ, Saenko, EL, Kemball-Cook, G, Pipe, SW, Eickhorst, AN

Blood 2001
12428094 Hemophilia A mutations within the factor VIII A2-A3 subunit interface destabilize factor VIIIa and cause one-stage/two-stage activity discrepancy

Kaufman, RJ, Miao, H, Kemball-Cook, G, Pipe, SW, Sirachainan, N, Saenko, EL, Hakeos, WH

Thromb. Haemost. 2002
Normal reaction
Functional status

Gain of function of factor VIIIa with defective A2 domain [extracellular region]

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