Autoimmune Coagulation Factor X Deficiency as a Rare Acquired Hemorrhagic Disorder: A Literature Review.

Coagulation factor X (F10) amplifies the clotting reaction in the middle of the coagulation cascade, and thus F10 deficiency leads to a bleeding tendency. Isolated acquired F10 deficiency is widely recognized in patients with immunoglobulin light-chain amyloidosis or plasma cell dyscrasias. However, its occurrence as an autoimmune disorder is extremely rare. The Japanese Collaborative Research Group has been conducting a nationwide survey on autoimmune coagulation factor deficiencies (AiCFDs) starting in the last decade; we recently identified three patients with autoimmune F10 deficiency (AiF10D). Furthermore, an extensive literature search was performed, confirming 26 AiF10D and 28 possible cases. Our study revealed that AiF10D patients were younger than patients with other AiCFDs; AiF10D patients included children and were predominantly male. AiF10D was confirmed as a severe type of bleeding diathesis, although its mortality rate was not high. As AiF10D patients showed only low F10 inhibitor titers, they were considered to have nonneutralizing anti-F10 autoantibodies rather than their neutralizing counterparts. Accordingly, immunological anti-F10 antibody detection is highly recommended. Hemostatic and immunosuppressive therapies may help arrest bleeding and eliminate anti-F10 antibodies, leading to a high recovery rate. However, further investigation is necessary to understand the basic characteristics and proper management of AiF10D owing to the limited number of patients.

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.

Persistent validity of a classification of congenital factor X defects based on clotting, chromogenic and immunological assays even in the molecular biology era.

An adequate classification of congenital bleeding disorders is of great importance in clinical practice. This is true also for factor X (FX) deficiency. This defect is classified in two forms: type I (cases with low activity and antigen) and type II (cases with low activity and variable levels of antigen). The introduction of molecular biology techniques has allowed a classification based on the site of mutation (propeptide, Gla-domain, catalytic domain etc.) or on the type of mutation (missense, nonsense, deletion etc.). However, with a partial exception for defects in the Gla-domain, no site or type of mutation yields a constant and/or typical phenotype. Due to these difficulties, a classification based on clotting, chromogenic or immunological assays is still the most suited for clinical purposes. A satisfactory classification that takes into account recent advances of FX deficiency could read today as follows: • Type I (cross-reacting material (CRM) negative) (Stuart like) • Type II (CRM positive with inert protein) (Prower like) • Type III (CRM positive with disreactive protein) 1. Defects in all activity systems but for RVV activation (Friuli like) 2. Defects only or predominantly in the extrinsic-Xase system (Padua like) 3. Defects only or predominant in the intrinsic-Xase system (Melbourne like) 4. Defects with discrepant (high) chromogenic assays. Finally, type IV should be added to include cases of FX deficiency associated with FVII deficiency usually due to chromosome 13 abnormalities. By using this nosographic approach, all reported cases of FX deficiency can be adequately allocated to one of these groups.

Treatment of acquired factor X inhibitor by plasma exchange with concomitant intravenous immunoglobulin and corticosteroids.

A patient with spontaneous hemorrhage from multiple body sites was found to have markedly prolonged international normalized ratio (INR) and activated partial thromboplastin times (aPTT) with incomplete correction of aPTT on mixing studies using normal plasma. The cause of this severe hemorrhage was due to a specific factor X inhibitor. No underlying or associated diseases were found. Initial treatment with fresh frozen plasma, vitamin K, and recombinant activated factor VII (rFVIIa) was unsuccessful. However, therapy utilizing plasma exchange with concomitant intravenous immunoglobulin and corticosteroids resulted in a rapid and sustained normalization of factor X levels with a clinical hemostatic response.

Acquired-transient factor X deficiency associated with anticardiolipin antibodies in a child with extensive burns.

The article presents the case of an 18-month-old boy with major scald burns complicated by acquired F-X deficiency. On the 15th day of hospitalization, the patient developed sepsis and fever. He also exhibited bruxism, especially during the febrile episodes, which his permanent teeth to luxate and become mobile. Pedodontists decided that all the child's teeth should be extracted to ensure proper development of the jaw with growth. Twelve hours later, he developed a leukemoid reaction, which was attributed to infection with another aerobic organism or development of anaerobic bacteremia after teeth extraction. Twenty-four hours after the extractions, the burn wounds began oozing and there was extensive gingival bleeding and epistaxis. Coagulation parameters were assessed immediately. Disseminated intravascular coagulation was detected initially and was successfully treated with fresh-frozen plasma transfusions, but bleeding from the burn wounds and nasal/oral mucous membranes continued. Further testing revealed the diagnosis of acquired isolated F-X deficiency linked with antiphospholipid antibodies. Treatment with plasmapheresis, steroids, and intravenous immunoglobulin was successful. Hypertrophic scar formation was the only issue during 7 months of follow-up.

Molecular characterization of two novel mutations causing factor X deficiency in a Chinese pedigree.

Factor X (FX) deficiency is a rare bleeding disorder inherited as an autosomal recessive trait. In this study, we investigated the molecular basis of FX deficiency in a Chinese pedigree. The proposita showed a markedly prolonged activated partial thromboplastin time and a mild prolongation of prothrombin time. The levels of FX antigen and FX activity were 58.6% and 2.5%, respectively. Molecular analysis revealed that the proposita was compound heterozygous for two novel mutations: IVS1 + 1G > A and G1185A (Arg347His). The aberrant transcripts from the IVS1 + 1G > A mutant allele were not detected by analyzing the splicing pattern of ectopic transcripts in leukocytes of the patient with nested polymerase chain reaction after reverse transcription. We thus hypothesize that the mRNA molecules originating from the IVS1 + 1G > A mutation were rapidly destroyed in vivo. Site-directed mutagenesis of FX cDNA was used to introduce FXG1185A mutation, and wild-type as well as mutant FX proteins were expressed by transient transfection in HEK 293 cells. Normal FX antigen levels both in the conditioned media of cells expressing the mutant and in cell lysates were detected by an enzyme-linked immunoadsorbent assay. Evaluation of wild-type and mutant coagulant activity demonstrated that the FX molecules carrying the Arg347His mutation have dramatically decreased activity.

Antibody-induced acute factor X deficiency: clinical manifestations and properties of the antibody.

A patient is described with serious bleeding due to a transient selective deficiency of factor X. Crossed immunoelectrophoresis of patient's plasma with anti-factor X antibody revealed an abnormal factor X arc suggestive of the presence of plasma factor X/anti-factor X immune complexes. A similar abnormal arc was obtained on adding the patient's IgG to normal plasma. Immunoblotting of factor X after reduced SDS-PAGE revealed that the patient's IgG bound to the light chain of intact factor X but not Gla-domainless factor X. The patient's IgG inhibited activation of factor X by VIIa/tissue factor (TF), by IXa/VIIIa/phospholipid complex, and by Russell's viper venom. The IgG failed to inhibit the proteolytic activity of factor Xa towards a chromogenic substrate. However, under reaction conditions of limited factor Xa availability, the IgG could be shown to impair hemostatic functions of factor Xa that require the participation of its light chain: activation of prothrombin by prothrombinase; activation of factor VII bound to TF; and inhibition of VIIa/TF activity by factor Xa/tissue factor pathway inhibitor complexes. A few earlier patients have been described with transient, selective factor X deficiency and serious bleeding, but in only one was evidence obtained of an antibody against factor X. It will be of interest to learn whether use of the techniques described in this report will permit the identification of immunoglobulin with similar binding and functional properties in future patients with this rare syndrome.

Combined functional and immunochemical analysis of normal and abnormal human factor X.

Human Factor X was isolated from Cohn fraction III and characterized by polyacrylamide gel electrophoresis, amino acid composition, and isoelectric focusing. Two molecular forms with biological activity were observed at isoelectric points of 4.8 and 5.0. Antisera generated to Factor X was monospecific and used to establish an equilibrium competitive inhibition radioimmunoassay. This assay was specific for human Factor X and did not cross-react with human prothrombin or bovine Factor X within the sensitivity range of 6-300 ng Factor X antigen/ml. The mean concentration of Factor X based on the antigen was 11.9 mug/ml, whereas concentration values based on coagulant activity was 7.8 mug/ml. This 30% difference in measurement appears to result from the presence of a subpopulation of Factor X molecules devoid of coagulant activity. The radioimmunoassay was used to qualitatively and quantitatively compare purified Factor X to plasmic Factor X obtained from normal, warfarintreated, acquired Factor X-deficient, and congenitaldeficient patients. In all but one case, the Factor X present in these plasmas was immunochemically identical to the purified Factor X and permitted precise quantitation of these abnormal Factor X molecules. Factor X procoagulant activity was analyzed relative to Factor X antigen and the specific activities were used to characterize normal and abnormal Factor X molecules. Reduced Factor X activity in plasmas from warfarin-treated and acquired Factor X-deficient patients was attributed to both decreases in Factor X antigen and decreased function of the Factor X molecules. Congenitally deficient patients, in general, showed a reduction in Factor X antigen in parallel with Factor X procoagulant activities resulting from comparable decreases in specific biological activity of the molecules.

Chronic peritoneal dialysis in a patient with primary amyloidosis, renal failure, and factor X deficiency.

Chronic peritoneal dialysis was used in a patient with renal failure due to primary amyloidosis. Paraprotein was demonstrated in serum and urine, and was removed in peritoneal dialysate. The patient objectively improved as long as he was receiving peritoneal dialysis. When dietary indiscretion necessitated hemodialysis for fluid removal, he died shortly thereafter of subdural hematomas, possibly aggravated by factor X deficiency. Reasons for selecting chronic peritoneal dialysis as the treatment of choice in patients with renal failure associated with overproduction of paraprotein are discussed.

Classical factor X deficiency. Report of a further case.

A case of classical factor X deficiency is reported. The propositus is a 28-year-old male who presented easy bruising, epistaxis, hematomas, hematuria and occasional hemartrosis since early childhood. The severely prolonged prothrombin time was corrected by normal serum but not by adsorbed normal plasma. The abnormality was not corrected by the plasma of a patient with factor X deficiency, but by the plasma of patients with factor II or VII deficiencies. Partial thromboplastin time, prothrombin consumption and the thromboplastin generation test were abnormal. The thromboelastogram showed a prolonged 'K' and 'r' together with a normal 'ma'. Factor X was very low (smaller than 1%). Platelet tests were normal. No factor X band or precipitates were seen on electroimmunoassay and on the cross-over electrophoresis. The non-consanguineous parents and several other members of the family were found to be heterozygotes.