An acquired, calcium-dependent, factor X inhibitor.

Acquired factor X (FX) deficiency unrelated to amyloidosis is a rare disorder in which an anti-FX antibody is infrequently detected. A patient with severe bleeding due to a calcium ion-dependent anti-FX IgG antibody is described. The FX affinity purified IgG bound the light chain of FX, but not FX lacking its γ-carboxyglutamic acid domain, and binding was enhanced >1000-fold in the presence of calcium ions. The antibody also recognized prothrombin and factor VII with about 100-fold and 1000-fold lower affinity. Like a lupus anticoagulant, increasing concentrations of phospholipids in functional assays reduced the inhibitory activity of the antibody. The effect of these properties of the inhibitor on laboratory diagnostic studies is considered.

Factor X Shanghai and disruption of translocation to the endoplasmic reticulum.

BACKGROUND AND OBJECTIVES: Most secreted proteins, including coagulation factor X (FX), are synthesized with a signal peptide, which is necessary for targeting the nascent polypeptide into the endoplasmic reticulum. Characterization of naturally occurring mutations may provide insights into the functional roles of the amino acids in the signal peptide. DESIGN AND METHODS: A 52-year old male patient with type I FX deficiency was studied. Mutations were searched for by FX gene (F10) sequencing. The wild-type and the mutant FX proteins were expressed in transfected cells and then immunological assays were performed. Pulse-chase experiments and cell-free expression studies were conducted to determine the cellular fate of the mutant FX molecules. RESULTS: The patient we studied was homozygous for a substitution of arginine for serine at codon -30 in the signal sequence of F10. Immunoassays detected low FX antigen levels in both the conditioned media and lysates of the cells expressing the mutant protein. Pulse-chase analysis showed that only trace amounts of the mutant FX protein were detectable in the conditioned media, and that the mutant molecules did not accumulate inside the cells either. The results of cell-free expression studies showed that although the transcription and translation of the mutant construct were normal, no post-translational processing, such as N-linked glycosylation, occurred in the presence of microsomes. INTERPRETATION AND CONCLUSIONS: These findings suggest that substitution of a neutral polar amino acid, serine by arginine, in the hydrophobic core of FX signal peptide severely impairs the ability of the protein to enter the endoplasmic reticulum and results in FX deficiency.

Syndrome of acquired factor X deficiency and systemic amyloidosis; in vivo studies of the metabolic fate of factor X.

To determine the metabolic fate of factor X in primary amyloidosis associated with factor X deficiency, we examined the pathways of its catabolism in a man with this syndrome. Intravenous infusion of human or bovine 131I-labeled factor X established a triphasic plasma clearance pattern for factor X. About 85 per cent of the factor X disappeared, with a disappearance half-time of less than 30 seconds. A second and third phase showed a T1/2 of 90 minutes and nine hours respectively. 131I-labeles factor X in plasma did not appear to be rapidly modified or degraded. Relatively minor quantities of 131I were cleared into the urine. We observed a diffuse distribution of radioactivity over the body surface, with a concentration in the hepatic and splenic regions. These studies demonstrate than factor X deficiency associated with systemic amyloidosis is due to binding of factor X to body tissue, probably within the circulatory system.