Fitusiran reduces bleeding in factor X-deficient mice.

ABSTRACT: Factor X (FX) deficiency is a rare bleeding disorder manifesting a bleeding tendency caused by low FX activity levels. We aim to explore the use of fitusiran (an investigational small interfering RNA that silences antithrombin expression) to increase thrombin generation and the in vivo hemostatic potential under conditions of FX deficiency. We therefore developed a novel model of inducible FX deficiency, generating mice expressing <1% FX activity and antigen (f10low mice). Compared with control f10WT mice, f10low mice had sixfold and fourfold prolonged clotting times in prothrombin time and activated partial prothrombin time assays, respectively (P < .001). Thrombin generation was severely reduced, irrespective of whether tissue factor or factor XIa was used as an initiator. In vivo analysis revealed near-absent thrombus formation in a laser-induced vessel injury model. Furthermore, in 2 distinct bleeding models, f10low mice displayed an increased bleeding tendency compared with f10WT mice. In the tail-clip assay, blood loss was increased from 12 ± 16 µL to 590 ± 335 µL (P < .0001). In the saphenous vein puncture (SVP) model, the number of clots generated was reduced from 19 ± 5 clots every 30 minutes for f10WT mice to 2 ± 2 clots every 30 minutes (P < .0001) for f10low mice. In both models, bleeding was corrected upon infusion of purified FX. Treatment of f10low mice with fitusiran (2 × 10 mg/kg at 1 week interval) resulted in 17 ± 6% residual antithrombin activity and increased thrombin generation (fourfold and twofold to threefold increase in endogenous thrombin potential and thrombin peak, respectively). In the SVP model, the number of clots was increased to 8 ± 6 clots every 30 minutes (P = .0029). Altogether, we demonstrate that reduction in antithrombin levels is associated with improved hemostatic activity under conditions of FX deficiency.

Plasma-derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency.

INTRODUCTION: Hereditary factor X (FX) deficiency (HFXD) is an autosomal recessive rare bleeding disorder that leads to defects in the FX protein. Depending on the degree of deficiency, patients may be at risk of life-threatening bleeding episodes. Historical treatments for FX deficiency include prothrombin complex concentrates, which can increase the risk of thrombosis, and fresh frozen plasma, which can cause volume overload and transfusion reactions. Plasma-derived FX (pdFX), a single-factor, high-purity, high-potency human FX treatment, was approved in 2015 in the United States and in 2016 in Europe for on-demand treatment and prophylaxis of bleeding episodes and perioperative management of patients with HFXD. METHODS: Five studies that examined the use of pdFX in patients with mild (plasma FX activity [FX:C] ≥5 IU/dL), moderate (FX:C ≥1 and <5 IU/dL), or severe (FX:C < 1 IU/dL) HFXD were reviewed: TEN01, TEN02 and TEN03 were prospective, open-label, multicentre, nonrandomised studies, and TEN05 and TEN06 were multicentre retrospective studies. RESULTS: When used as an on-demand treatment, pdFX was judged by investigators to be successful in treating 41/42 (97.6%), 2/3 (66.6%) and 79/79 (100%) bleeds in TEN01, TEN02 and TEN05, respectively. When used prophylactically, pdFX was judged 'excellent' for the prevention of bleeds in nine (100%) and eight (100%) patients in TEN02 and TEN05, respectively. Perioperative treatment and pharmacokinetics were also assessed. pdFX was safe and well tolerated. CONCLUSIONS: Together, these studies support the use of pdFX for on-demand treatment of bleeding, routine prophylaxis, and perioperative management of bleeding in patients with HFXD.

Role of individual factor X concentrate pharmacokinetic studies in perioperative management of AL amyloidosis-associated acquired factor X deficiency.

BACKGROUND: AL amyloidosis is associated with acquired factor X (FX) deficiency. Experience related to its management is limited to case reports and series using prothrombin complex concentrate, fresh frozen plasma, plasma exchange, recombinant activated factor seven, and desmopressin with limited and variable efficacy. FX concentrate has not been widely used in its management. STUDY DESIGN AND METHODS: We report our experience with the perioperative use of FX concentrate (Coagadex) in two patients with AL amyloidosis-associated acquired FX deficiency requiring surgery, using their individual pharmacokinetic studies to manage perioperative hemostasis. Pharmacokinetic studies involved obtaining post-infusion FX activity at 10 min, 2, and 4 h following the administration of FX concentrate to calculate the FX half-life. RESULTS: Both patients' plasma FX activity was successfully increased to provide perioperative hemostatic support. Monitoring FX activity post-surgery was also utilized to maintain FX activity levels to prevent post-operative bleeding. CONCLUSION: Pharmacokinetic studies have a useful role in tailoring preoperative FX repletion in patients with AL amyloidosis associated with acquired FX deficiency.

Five new F10 variants in hereditary factor x deficiency detected by high-throughput sequencing.

INTRODUCTION: Factor X deficiency is a rare inherited bleeding disorder. To date, 181 variants are reported in the recently updated F10-gene variant database. AIM: This study aimed to describe new F10 variants. METHOD: The F10 gene was analysed in 16 consecutive families with FX deficiency by a targeted high-throughput sequencing approach, including F10, F9, F8 genes, and 78 genes dedicated to haematological malignancies. RESULTS: We identified 19 variants (17 missense, one nonsense and one frameshift) and two copy number variations. Two patients presenting a combined FVII-FX deficiency showed a loss of one F10 gene copy (del13q34) associated with a missense variant on the remaining allele, leading to a FX:C significantly lower than the FVII:C level and explaining their unusual bleeding history. We reported five novel variants. Three missense variants (p.Glu22Val affecting the signal peptide cleavage site, p.Cys342Tyr removing the disulphide bond between the FX heavy and light chains, and p.Val385Met located in FX peptidase S1 domain) were detected at compound heterozygosis status in three patients with severe bleeding symptoms and FX:C level below 10 IU/dL. Two truncating variants p.Tyr279* and p.Thr434Aspfs*13 leading to an altered FX protein were found at heterozygous state in two patients with mild bleeding history. CONCLUSION: This study showed the feasibility and the interest of high-throughput sequencing approach for rare bleeding disorders, enabling the report of F10 gene screening in a 3-weeks delay, suitable for clinical use. The description of five new variants may contribute to a better understanding of the phenotype-genotype correlation in FX deficiency.

Identification of non-neutralizing anti-factor X autoantibodies in three Japanese cases of autoimmune acquired factor X deficiency.

INTRODUCTION: Autoimmune factor X (FX or F10) deficiency (AiF10D) is an extremely rare acquired haemorrhagic disorder characterized by a severe reduction in FX activity due to autoantibodies against FX. AIM: Anti-FX autoantibodies were investigated in four patients with suspected AiF10D, and their properties were analysed. METHODS AND RESULTS: Anti-FX auto antibodies in plasma were detected by ELISA with three of four cases. One case of anti-FX autoantibody negativity was later diagnosed as AL-amyloidosis. IgG1 and IgG3 coexisted in all anti-FX autoantibodies of the three patients with AiF10D (cases X1, X2, and X3). Western blot analysis showed that the antibodies were bound to the FX light chain for cases X2 and X3, but the binding was weak for case X1. When the fusion proteins of a secretory luciferase with full-length FX or its γ-carboxylated glutamic acid (Gla) domain were added to the plasma of the three patients, both fusion proteins were immunoprecipitated as antigen-antibody complexes. Contrarily, the latter fusion protein produced in the presence of warfarin demonstrated a decrease in the collection rate, suggesting that their autoantibodies recognized the light chain and regions containing Gla residues. Since all three patients were essentially negative for FX inhibitors, it was concluded that the anti-FX autoantibodies for these cases were predominantly non-neutralizing. The concentration of the FX antigen also significantly reduced in these patients, suggesting that anti-FX autoantibodies promote the clearance of FX. CONCLUSION: Immunological anti-FX autoantibody detection is highly recommended to ensure that AiF10D cases are not overlooked, and to start necessary immunosuppressive therapies.

Preclinical development and characterization of a human plasma-derived high-purity factor X concentrate for therapeutic use.

INTRODUCTION: Hereditary factor X deficiency is a rare bleeding disorder, with limited treatment options. This paper describes the approach to pre-clinical development and characterization of a high-purity plasma-derived factor X concentrate, to achieve orphan drug marketing authorization for the treatment of hereditary factor X deficiency. METHODS: A chromatographic process was developed, to purify factor X from human plasma for fractionation. The product was characterized using in vitro, in vivo and ex vivo tests for potency, purity, thrombogenicity, immunogenicity, toxicity and stability. RESULTS: The production process complied with good pharmaceutical manufacturing practice. It achieved 6000-fold purification and 100-fold concentration of the factor X protein compared to human plasma. The factor X protein was 94%-96% pure. Other residual plasma proteins were well below levels in plasma, minimizing potential interference in hemostasis after therapeutic administration. Effective virus-reduction during manufacture, and the absence of thrombogenicity, toxicity and immunogenic potential were confirmed, addressing the main safety concerns historically associated with plasma-derived therapeutics. The freeze-dried product remained stable between +2°C and +30°C for at least three years. After reconstitution with water for injections, the factor X activity was maintained for at least 48 h at +18°C to +22°C. CONCLUSION: Targeted pre-clinical development of the first highly-purified concentrate to treat hereditary factor X deficiency is described. Following international guidelines for nonclinical safety testing, particular strategies were adopted for unmodified products derived from human blood plasma. This approach may also be relevant to the development of other ultra-orphan medicinal products.

A review of the pharmacokinetics, efficacy and safety of high-purity factor X for the prophylactic treatment of hereditary factor X deficiency.

INTRODUCTION: Hereditary factor X (FX) deficiency (FXD) is a rare autosomal recessive bleeding disorder. Plasma-derived FX (pdFX) is a high-purity FX concentrate approved in the United States and Europe for the treatment and prophylaxis of bleeding episodes and for peri-operative management in patients with hereditary FXD (HFXD). AIM: To review pharmacokinetic dosing, efficacy, and safety data for pdFX as routine prophylaxis for HFXD. METHODS: Summary of the published pharmacokinetic and safety data from TEN01, TEN02, TEN05, and real-world publications of pdFX for prophylaxis. RESULTS: Pharmacokinetic modelling data from the phase 3 TEN01 study supported administration of pdFX 25 IU/kg twice weekly for routine prophylaxis in adolescents/adults (aged ≥12 years). Results from nine paediatric patients in the phase 3 TEN02 study and eight adolescents/adults (aged ≥12 years) in the retrospective data-collection TEN05 study, along with real-world evidence, showed that routine prophylaxis with pdFX ≈40 IU/kg twice weekly in patients aged <12 years and pdFX ≈25 IU/kg twice weekly in patients aged ≥12 years was effective in bleeding prevention. CONCLUSIONS: pdFX was well tolerated in clinical studies, with no new safety signals identified during routine prophylactic use. Based on current evidence, it is recommended that routine prophylaxis with pdFX be initiated at 25 IU/kg twice weekly in adults/adolescents ≥12 years of age, and at a dosage of 40 IU/kg twice weekly in children <12 years of age. Thereafter, FX levels should be closely monitored, and dosages should be adjusted according to clinical response and to maintain trough levels ≥5 IU/dl.

Occurrence and management of severe bleeding episodes in patients with hereditary factor X deficiency.

Vitamin K-dependent factor X (FX) plays an important role in thrombin formation, and a deficiency in FX can cause impaired coagulation, the severity of which is usually correlated with the degree of deficiency. Due to the critical role that FX plays in the coagulation cascade, FX deficiency is associated with a higher risk of bleeding than deficiencies in other coagulation factors. Patients with the hereditary autosomal-recessive homozygous form of FX deficiency, which occurs in approximately 1:1,000,000 individuals worldwide, are often diagnosed when they present with spontaneous life-threatening haemorrhage (most often intracranial haemorrhage) during the first month of life. In addition to central nervous system bleeds, other severe bleeding types experienced by such patients may include umbilical cord bleeding, gastrointestinal or pulmonary haemorrhage, intramuscular haematomas and/or haemarthrosis. Delayed treatment or inadequate replacement of FX may result in developmental delays, musculoskeletal disabilities or death. The high risk of recurrent severe bleeding necessitates prophylactic replacement therapy for many individuals with severe FX deficiency. Available products for replacement therapy include plasma-derived FX concentrate and prothrombin complex concentrates. Fresh-frozen plasma may be used when concentrates are not available but is a less efficient means of FX replacement. This article reviews the literature on severe bleeding in individuals with hereditary FX deficiency and discusses current treatment options.

A Compound Heterozygosis of Two Novel Mutations Causes Factor X Deficiency in a Chinese Pedigree.

BACKGROUND: Mutations in the F10-coding gene can cause factor X (FX) deficiency, leading to abnormal coagulation activity and severe tendency for hemorrhage. Therefore, identifying mutations in F10 is important for diagnosing congenital FX deficiency. METHODS: We studied a 63-year-old male patient with FX deficiency and 10 of his family members. Clotting and immunological methods were used to determine activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), fibrinogen levels, FX activity, and FX antigen levels. The platelet count was determined. A mixing study was performed to eliminate the presence of coagulation factor inhibitors and lupus anticoagulant. Mutations were searched using whole-exome sequencing and certified by Sanger sequencing. RESULTS: Genetic analysis of the proband identified two single-base substitutions: c.1085G>A (p.Ser362Asn) and c.1152C>A (p.Tyr384Ter, termination codon, caused by the DNA sequence TAA). His FX activity and antigen levels were 1.7% and 408.53 pg/mL, respectively; aPTT and PT were 52.3 and 48.0 s, respectively. One brother had the same compound heterozygous mutations, and his FX activity and antigen levels were 1.3% and 465.47 pg/mL, respectively; his aPTT and PT were 65.2 and 54.5 s, respectively. His mother, another brother, and one sister were heterozygous for c.1085G>A (p.Ser362Asn), and his daughter and grandson (6 years old) were heterozygous for c.1152C>A (p.Tyr384Ter). CONCLUSION: The heterozygous variants p.Ser362Asn or p.Tyr384Ter indicate mild FX deficiency, but the compound heterozygous mutation of the two causes severe congenital FX deficiency and bleeding. Genetic analysis of these two mutations may help characterize the bleeding tendency and confirm congenital FX deficiency.

Severe Factor X Deficiency Presenting as Febrile Seizure in an Infant.

Factor X deficiency is a severe inherited coagulation disorder, which is characterized by severe systemic bleeding manifestations in affected individuals. It is a rare disorder with a frequency of around 1:1,000,000 in the general population. We present the case of an infant with factor X deficiency who presented with complex febrile seizure. Although febrile seizures are very common in children, a closer scrutiny leads to neuroimaging and finding of intracranial bleed. Hematologic and genetic investigations confirmed the diagnosis. A high index of suspicion should be maintained to diagnose uncommon bleeding disorders in children.

Evaluation of the anticoagulant effect of low-molecular-weight heparins based on the anti-Xa level during haemodialysis.

AIM: Evaluate the relationship between anti-Xa activity and anticoagulant effect, and ascertain whether accumulation of low-molecular-weight heparins (LMWH) occurs during haemodialysis. METHODS: There was an observational, single-centre study among participants who received the LMWH dalteparin, enoxaparin or nadroparin. A standard haemodialysis session lasted 4 hours. All included participants had anti-Xa activity measures at 0.5 and 4 hours. Extracorporeal circuit (ECC) clotting was evaluated by visual inspection of the haemodialyser and bubble trap after each haemodialysis session. The same person was tested at three consecutive haemodialysis sessions. RESULTS: Overall, 90 participants were enrolled and 259 haemodialysis sessions assessed. There was no significant difference in the mean anti-Xa activity at 0.5 and 4 hours for three consecutive sessions, so LMWH accumulation did not occur. There were 69 (26.6%) sessions in which, ECC clotting was visible. Compared with the group where circuit clotting did not occur, the LMWH dose and anti-Xa activity in the group where circuit clotting occurred were significantly lower. At 0.5 hour, anti-Xa <0.88 IU/mL had significantly higher odds of ECC clotting than that at ≥0.88 IU/mL. At 4 hours, anti-Xa <0.35 IU/mL had significantly higher odds of ECC clotting than that at ≥0.35 IU/mL. CONCLUSION: We found that over three haemodialysis sessions, no significant accumulation of LMWH was evident in subjects receiving a LMWH dose of between 2000 and 5000 IU for regular. Anti-Xa activity measurement can be used to adjust the dosage of LMWH and predict the anticoagulant effect during haemodialysis.

Genome editing of factor X in zebrafish reveals unexpected tolerance of severe defects in the common pathway.

Deficiency of factor X (F10) in humans is a rare bleeding disorder with a heterogeneous phenotype and limited therapeutic options. Targeted disruption of F10 and other common pathway factors in mice results in embryonic/neonatal lethality with rapid resorption of homozygous mutants, hampering additional studies. Several of these mutants also display yolk sac vascular defects, suggesting a role for thrombin signaling in vessel development. The zebrafish is a vertebrate model that demonstrates conservation of the mammalian hemostatic and vascular systems. We have leveraged these advantages for in-depth study of the role of the coagulation cascade in the developmental regulation of hemostasis and vasculogenesis. In this article, we show that ablation of zebrafish f10 by using genome editing with transcription activator-like effector nucleases results in a major embryonic hemostatic defect. However, widespread hemorrhage and subsequent lethality does not occur until later stages, with absence of any detectable defect in vascular development. We also use f10-/- zebrafish to confirm 5 novel human F10 variants as causative mutations in affected patients, providing a rapid and reliable in vivo model for testing the severity of F10 variants. These findings as well as the prolonged survival of f10-/- mutants will enable us to expand our understanding of the molecular mechanisms of hemostasis, including a platform for screening variants of uncertain significance in patients with F10 deficiency and other coagulation disorders. Further study as to how fish tolerate what is an early lethal mutation in mammals could facilitate improvement of diagnostics and therapeutics for affected patients with bleeding disorders.

Complex formation with pentraxin-2 regulates factor X plasma levels and macrophage interactions.

Recently, we have identified scavenger receptor class A member I (SR-AI) as a receptor for coagulation factor X (FX), mediating the formation of an FX reservoir at the macrophage surface. Here, we demonstrate that the FX/SR-AI-complex comprises a third protein, pentraxin-2 (PTX2). The presence of PTX2 is essential to prevent internalization of FX by SR-AI, and the presence of FX is needed to interfere with internalization of PTX2. Binding studies showed that FX, SR-AI, and PTX2 independently bind to each other (KD,app: 0.2-0.7 µM). Surprisingly, immunoprecipitation experiments revealed that FX and PTX2 circulate as a complex in plasma, and complex formation involves the FX activation peptide. No binding of PTX2 to other vitamin K-dependent proteins was observed. Short hairpin RNA-mediated inhibition of PTX2 levels in mice resulted not only in reduced levels of PTX2, but also in similarly reduced FX levels. Moreover, PTX2 and FX levels were correspondingly reduced in SR-AI-deficient mice. Analysis of 71 human plasma samples uncovered a strong correlation between FX and PTX2 plasma levels. Furthermore, plasma samples of patients with reduced FX levels (congenital/acquired FX deficiency or after anti-vitamin K treatment) were characterized by concomitantly decreased PTX2 levels. In conclusion, we identified PTX2 as a novel partner for FX, and both proteins cooperate to prevent their SR-AI-mediated uptake by macrophages. Interestingly, their respective plasma levels are interdependent. These findings seem of relevance in perspective of ongoing clinical trials, in which plasma depletion of PTX2 is used as a therapeutical approach in the management of systemic amyloidosis.

Plasma-derived Factor X therapy for treatment of intracranial bleeding in a patient with Factor X deficiency: a case report.

BACKGROUND: Factor X (FX) deficiency (FXD) is an extremely rare autosomal recessive hereditary hematologic disorder, affecting approximately one in 1,000,000 of the general population. CASE REPORT: This case report describes an infant with hereditary severe FXD who presented with a spontaneous, life-threatening intracranial hemorrhage and was treated with the first licensed plasma-derived FX (pdFX) concentrate. On admission, laboratory assays showed severe coagulopathy of unknown cause; the patient was empirically treated using a multimodal hemostatic approach with prothrombin complex concentrate, fresh-frozen plasma, and tranexamic acid. Subsequent single-factor coagulation and genetic analyses confirmed the hereditary FXD diagnosis, and the therapeutic regimen was changed to a targeted regimen of 250 IU pdFX daily. Based on careful monitoring of the coagulation profile, pdFX administration frequency was increased to twice daily, followed by a reduction to once every 18 hours. The patient was discharged after 7 weeks of hospitalization in good clinical condition and now receives prophylactic pdFX three times weekly.

Congenital Factor X deficiency in women: A systematic review of the literature.

Factor X deficiency (FXD) is a rare autosomal recessive bleeding disorder with a variable phenotypic severity. In women, heavy menstrual bleeding (HMB), recurrent ovulation bleeding with haemoperitoneum and bleeding complications in pregnancy such as retroplacental haematoma and postpartum haemorrhage have been reported. The aim of this review was to examine gynaecological problems and obstetric complications in women with congenital FXD. A total number of 49 relevant articles were identified, including 332 women, dating from 1960 to 2018. Heavy menstrual bleeding was reported in 72/284 (25%) women in total, 14/30 (47%) in case reports and 58/254 (23%) in 11 case series, 64% and 10% required blood products and blood transfusion, respectively. Haemoperitoneum from ovulation bleeding or ruptured haemorrhagic ovarian cyst requiring blood transfusion occurred in 8/322 (2.4%) women, six required surgical intervention, including oophorectomy in two. 31 pregnancies were reported in 19 women. There were four miscarriages (including a late miscarriage at 21 weeks). There was a high rate of preterm birth and neonatal death occurring in eight (30%) and three (11%) of pregnancies reaching viability stage. Postpartum haemorrhage (PPH) occurred in six (22%) of deliveries, one requiring hysterectomy. In conclusion, women with FXD are at an increased risk of heavy bleeding during menstruation and ovulation as well as adverse pregnancy outcome and postpartum haemorrhage. Collaboration in a multidisciplinary team including an obstetrician/gynaecologist, a perinatologist and a haematologist is necessary for the prevention and management of these complications.

Congenital coagulation factor X deficiency: Genetic analysis of five patients and functional characterization of mutant factor X proteins.

Congenital factor X (FX) deficiency is a rare bleeding disorder that is inherited as an autosomal recessive trait. In this study, a genetic analysis of the FX gene was performed in five families with this disorder. Four heterozygous mutations [p.Gly154Arg, p.Val236Met, p.Gly263Val and p.Arg387Cys] and one pair of compound heterozygous FX gene mutations consisting of p.Gly406Ser and p.Val424Phe were identified. Mutant FX proteins containing the identified amino acid substitutions were also expressed in cultured cells. These proteins were analysed by enzyme-linked immunosorbent assay and pulse-chase experiments. The results demonstrated normal intracellular synthesis and extracellular secretion of mutant FX proteins carrying the p.Val236Met, p.Arg387Cys and p.Gly406Ser amino acid substitutions. However, the results also showed that the p.Gly154Arg, p.Gly263Val and p.Val424Phe proteins were secreted less efficiently than the wild-type protein, although they were synthesized normally in the cell. Collectively, these observations suggest that the amino acid substitutions p.Gly154Arg, p.Gly263Val and p.Val424Phe induce protein misfolding, leading to the intracellular degradation of many FX proteins containing any of these mutations, and ultimately to the development of FX deficiency. On the other hand, for the p.Val236Met, p.Arg387Cys and p.Gly406Ser mutant proteins, we hypothesize that secreted FX proteins have impaired coagulant activities due to functional defects caused by these amino acid substitutions.

Prophylactic treatment of bleeding episodes in children <12 years with moderate to severe hereditary factor X deficiency (FXD): Efficacy and safety of a high-purity plasma-derived factor X (pdFX) concentrate.

BACKGROUND: Hereditary factor X (FX) deficiency (FXD) affects 1:500 000-1:1 000 000 people worldwide. A novel, high-purity plasma-derived FX concentrate (pdFX) is available in the United States and European Union as replacement therapy for FXD, but data are scarce on pdFX use in children <12 years. AIM: This prospective, open-label phase 3 study assessed the safety, efficacy and pharmacokinetics of pdFX in children <12 years with moderate/severe FXD. METHODS: Subjects aged <12 years with basal plasma FX activity (FX:C) <5 IU/dL received pdFX as prophylactic and on-demand treatment, with doses adjusted to maintain FX:C > 5 IU/dL. After ≥26 weeks and ≥50 exposure days, investigators rated pdFX efficacy for preventing/decreasing bleeds. Secondary endpoints included number and severity of bleeds, trough FX:C and incremental recovery. Safety parameters were adverse events (AEs), inhibitor development and changes in laboratory parameters. RESULTS: The study enrolled 9 subjects (0-5 years, n = 4; 6-11 years, n = 5) with severe (n = 8) or moderate (n = 1) FXD. At end of study, investigators rated pdFX efficacy excellent for all subjects. Ten bleeds occurred (n = 3 subjects; 6 major, 3 minor, 1 unassessed for severity). Trough FX:C levels remained >5 IU/dL for all subjects after the last dose adjustment study visit. Mean incremental recovery was significantly lower for younger vs older subjects (1.53 vs 1.91 IU/dL per IU/kg; P = .001). All AEs were unrelated to treatment; no inhibitor development or clinically significant changes in laboratory parameters were observed. CONCLUSIONS: These results demonstrate the efficacy and safety of pdFX for treating children <12 years with moderate/severe hereditary FXD.

Factor X Deficiency Caused by Nonsecretory Myeloma Successfully Corrected with Bortezomib: A Case Report and Review of the Literature.

A 62-year-old female presenting with anemia and extensive hemorrhages is reported. Coagulation tests showed significantly prolonged prothrombin time (PT) and activated partial thromboplastin time. Decreased levels of clotting factor X activity were determined (5.4%). Bone marrow biopsy revealed neoplastic plasma cells. Serum and urine protein electrophoresis were both negative for monoclonal gammopathy, and both bone marrow and abdominal fat biopsies were negative for amyloid deposition. The patient was diagnosed as suffering from nonsecretory multiple myeloma (MM) complicated by acquired factor X deficiency. A complete response (CR) of the myeloma and recovery of factor X activity (56.6%) were achieved after the administration of treatment, including chemotherapy and bortezomib. We suggest that patients with nonsecretory MM might present with factor X deficiency and should be carefully screened for light chain amyloidosis. Novel agents such as bortezomib should be highly considered as treatment in these patients.