Factor X Deficiency Management for Elective Cesarean Delivery in a Pregnant Patient.

BACKGROUND Congenital factor X deficiency is a rare inherited coagulopathy. Pregnancies in women with this disorder are often associated with adverse outcomes, including miscarriage, premature labor, and hemorrhage during pregnancy and in the peripartum period. The literature on this disorder is sparse and shows a limited number of successful pregnancies in women with factor X deficiency. CASE REPORT In this report, we present the case of a successful pregnancy and term delivery by elective cesarean section in a 39-year-old primigravida with congenital factor X deficiency. Medical management followed the recommendations of an interdisciplinary team comprising specialists in obstetrics, anesthesia, transfusion medicine, hematology, and neonatology. This high-risk pregnancy was successfully brought to term, and a healthy male neonate was delivered by elective cesarean section at 39 weeks' gestation. The patient's factor X deficiency (0.19 kIU/L) was treated using 4 units of solvent-detergent-treated fresh frozen plasma (SD-FFP) 1 h before the cesarean section, leading to hemostatic levels of factor X and an uneventful intraoperative course. Postoperatively, the patient's factor X levels were controlled daily and corrected using SD-FFP as needed, with no clinically significant blood loss. CONCLUSIONS SD-FFP can be used to manage congenital factor X deficiency in the peripartum period and maintain perioperative blood loss within normal limits.

Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency.

INTRODUCTION: Hereditary factor X (FX) deficiency is a rare bleeding disorder affecting 1:500 000 to 1:1 000 000 of individuals. Until recently, no specific replacement factor concentrate was available. AIM: The aim of this study was to assess safety and efficacy of a new, high-purity plasma-derived FX concentrate (pdFX) in subjects with hereditary FX deficiency. METHODS: Subjects aged ≥12 years with moderate or severe FX deficiency (plasma FX activity <5 IU dL(-1) ) received 25 IU kg(-1) pdFX as on-demand treatment or short-term prophylaxis for 6 months to 2 years. Subjects assessed pdFX efficacy for each bleed; at end-of-study, investigators assessed overall pdFX efficacy. Blood samples for pharmacokinetic analysis were obtained at baseline and ≥6 months. Safety was assessed by adverse events (AEs), inhibitor development and changes in laboratory parameters. RESULTS: Sixteen enrolled subjects (six aged 12-17 years; 10 aged 18-58 years) received a total of 468 pdFX infusions. In the 187 analysed bleeds, pdFX efficacy was categorized as excellent, good, poor or unassessable in 90.9%, 7.5%, 1.1% and 0.5% of bleeds respectively; 83% of bleeds were treated with one infusion. For pdFX, mean (median; interquartile range) incremental recovery and half-life were 2.00 (2.12; 1.79-2.37) IU dL(-1) per IU kg(-1) and 29.4 (28.6; 25.8-33.1) h respectively. No serious AEs possibly related to pdFX or evidence of FX inhibitors were observed, and no hypersensitivity reactions or clinically significant trends were detected in laboratory parameters. CONCLUSION: These results demonstrate that a dose of 25 IU kg(-1) pdFX is safe and efficacious for on-demand treatment and short-term prophylaxis in subjects with moderate or severe hereditary FX deficiency.

Pharmacokinetics of a high-purity plasma-derived factor X concentrate in subjects with moderate or severe hereditary factor X deficiency.

INTRODUCTION: Hereditary factor X (FX) deficiency affects 1:500 000 to 1:1 000 000 of individuals. There are few published data on the pharmacokinetics (PK) of FX for existing treatments for FX deficiency, and no specific replacement factor concentrate exists. A high-purity plasma-derived FX concentrate (pdFX) has been developed for use as replacement therapy in subjects with hereditary FX deficiency. AIM: This analysis assessed pdFX PK after a single 25 IU kg(-1) bolus dose in subjects with hereditary moderate or severe FX deficiency (plasma FX activity [FX:C] <5 IU dL(-1) ). METHODS: For a baseline PK assessment, blood samples were taken predose and at intervals up to 144 h (7 days) post dose. After ≥6 months of on-demand pdFX treatment and treatment of ≥1 bleed with pdFX, subjects underwent repeat PK assessment. Samples were assayed for plasma FX:C (measured using the clotting and chromogenic assays) and FX antigen. RESULTS: FX:C peaked at 0.4-0.5 h and subsequently declined over the course of 144 h with a biphasic decay curve. PK parameters observed at the baseline (n = 16) and repeat (n = 15) assessments were equivalent, therefore summary PK values were obtained by combining data from both visits (n = 31). The mean terminal half-life and incremental recovery of pdFX was 29.4 h and 2.00 IU dL(-1) per IU kg(-1) respectively. CONCLUSION: This is the most comprehensive PK study to date in subjects with hereditary FX deficiency. These results are consistent with the observed haemostatic efficacy of pdFX and provide the PK data required for the treatment of hereditary FX deficiency using pdFX replacement therapy.

Large deletions play a minor but essential role in congenital coagulation factor VII and X deficiencies.

UNLABELLED: Congenital factor VII (FVII) and factor X (FX) deficiencies belong to the group of rare bleeding disorders which may occur in separate or combined forms since both the F7 and F10 genes are located in close proximity on the distal long arm of chromosome 13 (13q34). We here present data of 192 consecutive index cases with FVII and/or FX deficiency. 10 novel and 53 recurrent sequence alterations were identified in the F7 gene and 5 novel as well as 11 recurrent in the F10 gene including one homozygous 4.35 kb deletion within F7 (c.64+430_131-6delinsTCGTAA) and three large heterozygous deletions involving both the F7 and F10 genes. One of the latter proved to be cytogenetically visible as a chromosome 13q34 deletion and associated with agenesis of the corpus callosum and psychomotor retardation. CONCLUSIONS: Large deletions play a minor but essential role in the mutational spectrum of the F7 and F10 genes. Copy number analyses (e. g. MLPA) should be considered if sequencing cannot clarify the underlying reason of an observed coagulopathy. Of note, in cases of combined FVII/FX deficiency, a deletion of the two contiguous genes might be part of a larger chromosomal rearrangement.

Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency.

INTRODUCTION: Congenital factor X (FX) deficiency is a rare bleeding disorder inherited as an autosomal recessive trait with an incidence of 1 : 500 000-1 000 000. A total or partial deficiency of FX causes an impairment of clot formation, leading to a haemorrhagic disease, which manifests with bleeding symptoms of different severity, also unprovoked. AIM: We analysed the clinical manifestations, laboratory phenotype and genotype in 12 patients from Turkey affected with severe FX deficiency. METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT), FX activity (FX:C) and FX antigen level (FX:Ag) were measured, and mutation analysis was performed for all patients. RESULTS: The most frequent bleeding episodes in patients were epistaxis and easy bruising (11/12, 91%), followed by haemarthroses (10/12, 83%). FX:C was <1% in 11 patients, and 4% in one. FX:Ag was reduced in all patients, consistent with type II deficiency. Direct sequencing of the factor X gene (F10) identified two different mutations: the novel 33 bp in-frame deletion p.Thr176_Gln186, c.526_558del, which seems to be associated with milder bleeding symptoms and the c.785G>A, p.Gly262Asp missense mutation (previously reported as Gly222Asp), which is associated with severe bleeding symptoms. CONCLUSION: The p.Gly262Asp missense mutation was identified in 11 of the 12 patients in this study. Previously published cases on the same p.Gly262Asp mutation were Iranian patients originating from the border between Turkey and Iran suggesting that this mutation may be candidate as a good tool for mutational screening analysis in this area.

Unexplained discrepancies in the activity--antigen ratio in congenital FX deficiencies with defects in the catalytic domain.

Studies on molecular biology have considerably enhanced our understanding of congenital coagulation disorders but have failed so far to supply tools for an adequate classification of defects. In fact, mutations in the same domain may give rise to different phenotypes. Conversely, mutations in different domains, controlled by different exons, may cause similar patterns. The 37 kindreds with congenital factor X (FX) deficiency, known to have a defect in the catalytic domain, have been evaluated in an attempt to investigate the genotype-phenotype relation. Discrepant results were obtained because about half kindreds showed a type I pattern, namely a concomitant decrease in FX activity and antigen. The other half showed a type II pattern, namely a decrease in FX activity with a normal or near normal FX antigen. In a few instances, the allocation of the kindred either to type I or to type II defect could not be reached, due to the lack of information about the antigen. The comparison of the kindreds in which the same mutation has been discovered by different investigations is not always possible also for lack of information. The study analyzes the need to have a multipronged approach to the study of congenital FX deficiency. The indication of a mutation in a given domain does not provide clear information about the phenotype.

Congenital factor X deficiencies with a defect only or predominantly in the extrinsic or in the intrinsic system: a critical evaluation.

Congenital Factor X deficiency is commonly classified as type I, in which there is a concomitant decrease of activity and antigen (CRM negative), and in type II, in which activity is low but antigen is normal or near normal (CRM positive). During the past decades it was shown that type II was by itself very heterogeneous. It was shown in fact that some forms showed a defect in all three assay systems (extrinsic, intrinsic, and RVV dependent), whereas others showed a defect only in two of the three systems. Molecular biology analysis, whenever available, has failed so far to supply clear explanations for these discrepancies. The purpose of the present article was an attempt to correlate the clotting activities seen in these two defects with other clotting, chromogenic, immunological assays, and molecular biology results. There are in the literature 10 families that show a predominant defect in the extrinsic system, and four families that show a predominant defect in the intrinsic system. All patients showed a normal, near normal, or reduced level of antigen that is always definitively higher than the clotting counterpart. Molecular biology studies revealed mutations in different exons, namely 2, 4, 5, 6, and 8. These mutations in different exons do not allow any clear genotype-phenotype conclusions, but indicate that mutations in different exons may give rise to the same phenotype. The study underlines the importance of a multipronged evaluation of all cases with Factor X deficiency. In fact only by this approach can an acceptable classification of the defect be reached.

Congenital bleeding disorders of the vitamin K-dependent clotting factors.

Congenital bleeding disorders of the vitamin K-dependent coagulation factors represent only about 15-20% of all congenital bleeding disorders. However, they played an important role of the history of blood coagulation. Prothrombin was the first entity dealt with. Subsequently, in the late 1940s or early 1950s, the discovery of factor IX allowed the separation of hemophilia into two groups, A and B. In the 1950s, the discovery of factors VII and X allowed the formulation of a logic and plausible explanation for the clotting mechanism. The subsequent discovery of vitamin K-dependent proteins with an inhibitory effect on blood coagulation has further enhanced the importance of the vitamin K-dependent clotting factors. Recently, the study of families with multiple defects of the prothrombin complex has spurred the interest in vitamin K metabolism and the gamma-carboxylation system. The relevance of these studies had also an important role in the understanding the mechanism of action of other noncoagulation-related proteins. The vitamin K-dependent clotting factors represent a homeostatic mechanism at the basis of the hypercoagulability (thrombosis)-hypocoagulability (hemorrhagic) system, namely, to a mechanism that is vital for survival. The different bleeding condition will be dealt with separately, namely, prothrombin or Factor II, Factor VII, Factor IX (hemophilia B), and Factor X deficiencies. An additional heading deals with the combined defect of the prothrombin complex, namely, combined deficiency of Factor II, Factor VII, Factor IX, and Factor X. Since, sometimes, a hemorrhagic role has been attributed to Protein Z deficiency, another vitamin K-dependent protein, this defect will also be dealt with, even though briefly. Each deficiency has been approached in a global manner, namely, with adequate reference to history, background, prevalence, classification, hereditary pattern, biochemistry and function, molecular biology, clinical picture, updated laboratory diagnosis, prognosis, and therapy. Particular emphasis has been placed on the significance of cases with "true" deficiency [cross-reacting material (CRM negative)] and cases with abnormalities (CRM positive). The genetic, clinical, and laboratory implications of these two forms have been extensively discussed in every instance. The importance of a multiple, combined diagnostic approach that has to include whenever possible clotting, chromogenic, immunological, and molecular biology studies has been underlined. Clotting tests have to be carried out using different activating agents since results may vary, thereby indicating a different reactivity of the abnormal protein. Molecular biology techniques, alone, are unable to supply plausible diagnostic conclusions. In fact the genotype-phenotype relation has not been clarified so far for most of these bleeding conditions. Recent progress in management such as the use of recombinant factor concentrates, results of liver transplantation, and attempts at genetic therapy has been discussed. Potential complications of therapeutic measures have also been discussed. A section dealing with future putative aims of research in this field will close the chapter.

Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene.

Inherited factor X deficiency (FXD) is a rare (1:1,000,000) recessive bleeding disorder. The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known. To understand the association between clinical manifestations and causative genotype, detailed evaluation of bleeding pattern in a high number of patients is needed. This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing. Twenty-eight homozygous, seven compound-heterozygous and 67 heterozygous FXD subjects were characterized. Twenty-nine different causative mutations, including 15 novel mutations, were analysed. Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%). The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described. The bleeding patterns of the enrolled patients showed differences that are associated with the types of F10 mutation, and the corresponding genotypes. The homozygous patients were evaluated for genotype-phenotype correlation. The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7-1G>A and Tyr163delAT. A tentative association of other mutations to severe symptoms such as haemarthrosis and GI haemorrhage is reported. The severity of FXD, the genotype-phenotype association, and the results of regional studies are discussed.

Candida vertebra osteomyelitis in a girl with factor X deficiency.

Candidal vertebra osteomyelitis is a rare condition which occurs primarily in immunocompromised patients. We report a 14-year-old girl with factor X deficiency who developed candida vertebra osteomyelitis during home therapy. The microorganism was probably from a contaminated peripheral cannula used for infusion of factor concentrate. This is the first such case in bleeding disorders to our knowledge.

Severe congenital factor X deficiency with intracranial bleeding in two siblings.

Congenital factor X deficiency is a rare autosomal recessive disorder that usually presents with variable bleeding tendency, prolonged prothrombin time and partial thromboplastin time. Therefore, it may be misdiagnosed as hemorrhagic disease of the newborn. Factor X level should be investigated for the definite diagnosis. We first report a new family whose two infants presented with severe intracranial bleeding at different times and were found to have congenital factor X deficiency. Plasma replacement therapy was not found to be efficacious in these infants. In conclusion, a possible factor X deficiency should be considered when a newborn presents with intracranial bleeding.