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Competing Interests: The authors declare no conflict of interest.

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., (© 2016 John Wiley & Sons Ltd.)

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., (© 2016 John Wiley & Sons Ltd.)

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&#95;Gln186, c.526&#95;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., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

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&#95;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.

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 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., (Copyright 2008 Wiley-Liss, Inc.)

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.

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.

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.

Congenital factor X deficiency is a very rare inherited coagulation disorder. The clinical phenotype is of varying bleeding manifestations depending upon the level of factor activity. We describe a one and a half year old patient with severe deficiency (factor level less than 1%) who manifested with only easy bruisability and epistaxis that does not correlate with level of deficiency.

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.

The clinical manifestation of two episodes of hemoperitoneum from ruptured corpus luteum cysts, during the luteal phase of the cycle in a young patient with the rare congenital factor X deficiency, is reported for the first time in literature. The correct diagnosis of the underlying disorder, the gynecological management and the regular follow-up can minimize the risks of this potentially life-threatening hematological disorder., (Copyright 2003 S. Karger AG, Basel)

Congenital factor X deficiency is a rare inherited coagulation disorder, characterized by prolonged prothrombin time and partial thromboplastin time. For the definite diagnosis, specific factor X level should be investigated. We describe a patient with factor X deficiency who had intracranial hemorrhage. Hematologic tests showed prolonged prothrombin time, partial thromboplastin time, and a factor X level of 5%. The patient's hemorrhage resolved with fresh frozen plasma replacement. In this article, we discuss the clinical features and management of factor X deficiency.

There is little experience in the prevention of the severe hemorrhagic diathesis of factor X coagulation factor deficiency, before surgical procedures. A female with congenital deficiency of factor X that received prothrombin complex concentrates that contained 1.000 IU of factor X (16.7 U/l Kg BW) immediately prior to a cesarean section in two occasions, is reported. Factor X concentration rose from 1 to 25% in the first occasion and from 10 to 63% in the second. In both episodes, factor X decreased in the first 24 h of the postoperative period and required new infusions of prothrombin complex concentrates. No episodes of abnormal bleeding were observed. It is concluded that the infusion of prothrombin complex concentrates prevents the hemorrhagic diathesis of factor X deficiency, despite its modest increase in plasma. A initial infusion of 1.000 UI of factor X (16-20 IU/Kg BW), followed by 500 IU (8-10 IU/Kg) every 24 hours is suggested for an adequate management of this condition.

Pregnancy in women with congenital coagulation factor deficiencies has been associated with adverse fetal outcomes. Recurrent spontaneous abortions, placental abruptions, and premature births are reported, the exact reasons for which are not clear, and management of such patients continues to be a challenge. We reviewed the outcome of four pregnancies in a patient with factor X deficiency, and looked at the effect of factor replacement therapy on pregnancy. Her first two pregnancies resulted in the birth of extremely premature babies at 21 and 25 weeks of gestation, both of which died in the neonatal period. The patient was treated with fresh frozen plasma for acute bleeding episodes during these pregnancies. In addition during her second conception she was given factor IX complex [Konyne] prophylactically, but only in the latter half of her pregnancy. During her next two pregnancies she was treated early on during pregnancy, with prophylactic replacement of factor X. She delivered healthy babies at 34 and 32 weeks of gestation, and they are both doing well. We therefore suggest possible mechanisms by which aggressive prophylactic factor support in a female with severe congenital coagulopathy, may improve on fetal outcome.

Factor X deficiency constitutes one of the most uncommon congenital bleeding disorders. Here we report three families with Factor X deficiency, one of them with an associated deficit of Factor XII. Family I presented Red variant deficiency (low functional and antigenic activity, the latter in higher levels than the former). In Family II functional activity was low but antigenic one was normal (Prower defect). Besides, an heterozygous deficiency of factor XII was diagnosed. Although genetic analysis supports the hypothesis of combined deficiency, the study was possible in only two generations of the propositus, so a multiple familial deficiency could not be discarded. Finally, Family III suffered from a "classic" or Mr. Stuart deficiency (low levels in functional and immunological assays). Besides, crossed immunoelectrophoresis showed a grossly pathological pattern.

Four neonates with congenital Factor X deficiency presented soon after birth with bleeding episodes. Two of the newborns had intracranial hemorrhages; one of them also had antenatal ventricular dilatation and postnatal hydrocephalus and died of massive intracerebral hemorrhage at four months. One patient was lost for follow up. The two surviving infants were followed up for four years and two years respectively, while on replacement therapy with three injections of 40 units/kg prothrombin complex a month. In spite of markedly elevated prothrombin time and partial thromboplastin time, these two infants remain free of major bleeding manifestations except for troublesome petechiae and ecchymoses. A schedule for substitution therapy with Factor X is proposed for infants and children to prevent bleeding in severe Factor X deficiency.

A Saudi Arabian infant with severe factor X deficiency who had had two intracranial haemorrhages is described. Attempts to raise his factor X level and improve his prothrombin time (PT) and partial thromboplastin time (PTT) by using vitamin K, oestradiol and danazol have failed. New therapeutic trials are necessary for patients with severe forms of this rare disorder.

Surgical procedures on patients with congenital disorders of blood coagulation can be performed with a high degree of confidence and an acceptable incidence of complications. During the period 1960-1975, 42 patients with congenital disorders of blood coagulation underwent 94 operative procedures at the New York Hopital-Cornell Medical Center. The coagulation defect was diagnosed preoperatively, in nearly all patients. Careful hematologic management, including specific factor replacement, is essential. The importance of meticulous hemostasis at surgery and careful monitoring of blood coagulation in the postoperative period is strongly emphasized.

The presence of a subdural haemorrhage was observed in a fetus during antenatal ultrasound examination. The infant was found to be a homozygote for factor X deficiency. Prompt recognition permitted replacement treatment from an early stage. Inherited coagulation disorders should be suspected when intracranial haemorrhage is detected antenatally.

This report presents a heretofore undescribed laboratory variant of congenital factor X deficiency, seen in conjunction with a relatively rare tumor. The patient had a history of bleeding, a prolonged prothrombin time, and a factor X value of 4.2 percent of normal activity, but the partial thromboplastin time and Russell's viper venom clotting time were normal. Management of this case required unusual measures to treat the patient's coagulopathy.

Factor X was assayed using chromogenic substrate S-2222 for four patients with severe factor X deficiency and for nine patients with homozygous or heterozygous factor X Friuli disorder. Factor X Friuli disorder is characterized by the presence of an abnormal factor X that is normally activated by Russell's viper venom, but is not activated by tissue thromboplastins. The levels of factor X found in factor X deficiency varied between 2 and 10% of normal and therefore were higher than those found in the same plasmas using "clotting" methods (1% or less than 1% of normal). The levels of factor X found in homozygous factor X Friuli patients varied between 4 and 11% of normal, and therefore were practically identical to those found by means of clotting methods that employed tissue thromboplastins (7-9% of normal). These values were definitely lower than those obtained using a Russell's viper venom and cephalin mixture as thromboplastin (82-92%). A similar pattern was observed for patients heterozygous for the abnormality. These findings indicate that "amidolytic" methods are not necessarily identical to clotting methods. Furthermore, they indicate that substrate S-2222 is not specific for factor X.

An 18-month-old child, who had no evidence of liver disease, malabsorption, or chronic ingestion of coumarin compounds, was found to have plasma deficiencies of factors II, VII, IX and X. Assays for factor II and X by immunological techniques (antibody neutralization and immunoelectrophoresis) revealed normal or elevated antigenic activity of these factors, suggesting the presence of abnormal protein variants in the patient's plasma. On two-dimensional immunoelectrophoresis of the patient's plasma in calcium, a normal and an abnormal population of prothrombin were seen. The abnormal prothrombin had a mobility more anodal than that of normal prothrombin, but less anodal than that of acarboxyprothrombin. The abnormal prothrombin, in contrast to acarboxyprothrombin, adsorbed readily to both aluminum hydroxide and barium citrate, and could be identified by two-dimensional immunoelectrophoresis of a barium citrate eluate. We suspect that the abnormal variant represents a partially carboxylated prothrombin.

Congenital factor X deficiency is a very rare inherited coagulation abnormality. There have been reported 43 cases of this disorder in the world and only 2 cases in Japan. Recently, we have hemostatically and immunologically examined as many as 3 cases of this rare disease, 18-year-old male, 11-year-old male and 6-year-old female. Hemostatic examinations revealed prolonged prothrombin time, partial thromboplastin time and decreased serum thromboplastic activity in these 3 cases. Stypven-cephalin clotting time was also abnormal. Factor X activities of our cases were low when assayed by either tissue thromboplastin and partial thromboplastin or by Stypven-cephalin mixture, which were 2.6, 1.5 and 4.5%, respectively. The half lives of infused factor X were 24, 38.6 and 56 hr, respectively, which are consistent with the data of other authors. Immunological assay of factor X (radioimmunoassay) showed 0.47 microgram/ml in the second case and 0.15 microgram/ml in the third case, from which our cases were considered to be classical factor X deficiency.