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.

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.

Acquired factor X deficiency in a multiple myeloma without amyloidosis: a case report.

BACKGROUND: Multiple myeloma is one of the most common hematologic malignancies. Acquired factor X deficiencies are often observed in primary (AL) amyloidosis and rarely in multiple myeloma. OBJECTIVE: We report a case of an acquired factor X deficiency in a patient with a newly diagnosed IgA lambda multiple myeloma, without any evidence of concomitant amyloidosis. METHODS: We present the patient's medical history, clinical and physical examinations, laboratory analysis, and outcome. RESULTS: A 76-year-old male presented at the emergency department with ongoing gingival bleeding. Several analytical problems with blood sample analysis arose, which eventually led to the diagnosis of a multiple myeloma. Further exploration revealed an acquired factor X deficiency, explaining the ongoing bleeding. There was no evidence of concomitant amyloidosis. The multiple myeloma was treated, leading to complete remission of the malignancy and bleeding tendency. CONCLUSION: While coagulopathy is rarely observed in patients diagnosed with multiple myeloma, considering an acquired factor X deficiency becomes relevant when such patient present with bleeding diathesis.

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.

Postmortem diagnosis of severe factor X deficiency in a fetus with intracranial hemorrhage resulting in intrauterine death.

In patients with severe congenital factor X deficiency, spontaneous intracranial hemorrhage (ICH) is particularly frequent in early childhood. We describe a case of fetal death at 26 weeks due to massive ICH. Gene panel analysis of postmortem samples revealed homozygosity for a pathologic F10 gene variant (c.1210T>C, p.Cys404Arg), which impedes correct folding of the catalytic serine protease domain and, therefore, causes a significant reduction in FX levels. The parents, not consanguineous but of the same ethnic community, were found to be heterozygous for this variant and did not have any personal or family history of abnormal bleeding. To the best of our knowledge, this is the first reported case of severe FX deficiency resulting in ICH diagnosed through postmortem genetic analysis. It illustrates the importance of exploring the etiology of fetal or neonatal ICH, which may impact future pregnancies, and the treatment of a potential coagulopathy in the child.

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.

Anesthesia strategy for factor X deficiency coagulopathy: case report

Abstract Factor X deficiency ranks among the rarest coagulopathies and has a variable presentation spectrum. We intend to present a proposal for anesthesia protocol for individuals with the coagulopathy. The excision of an ovarian neoplasm was proposed for a 26-year-old, female, ASA II patient, with congenital Factor X deficiency. Physical examination and lab tests were normal, except for Prothrombin Time (PT) 22.1s (VR: 8-14s), International Normalized Ratio (INR) 1.99 (VR: 0.8-1.2) and Activated Partial Thromboplastin Time (aPTT) 41.4s (VR: 25-37s). We concluded that a history of bleeding should always be investigated, along with a pre-anesthetic coagulation study.

Prevalence, clinical characteristics and treatment outcome of factor X deficiency in a consecutive cohort of primary light-chain amyloidosis.

Factor X (FX) deficiency is prevalent in light-chain (AL) amyloidosis but its clinical significance was not investigated deeply. We conducted a retrospective analysis of a consecutive cohort with 207 primary AL amyloidosis patients. FX deficiency was present in 129 patients (62.3%). Those with FX deficiency had higher dFLC (299.6 mg/L vs. 102.3 mg/L, P < 0.001), higher cardiac troponin I (0.05 µg/L vs. 0.02 µg/L, P < 0.001) and N-terminal pro-brain natriuretic peptide (3115 ng/L vs. 392 ng/L, P < 0.001), and more patients with bone marrow plasma cells > 10% (18.0% vs. 4.3%, P = 0.008). The prevalence of FX deficiency increased with the Mayo 2004 stage. FX-deficient patients exhibited inferior overall survival (P < 0.001) and progression-free survival (P < 0.001) than others. Fifty-five patients with FX deficiency received retesting of FX activity after anti-plasma cell therapy. The median variation in FX activity was + 6.8% (range, -24.5% ~ +73.4%). Better improvement of FX activity was observed in patients with complete hematologic response (+18.2% vs. +4.0%, P = 0.036) and at least one organ response (+14.4% vs. +3.4%, P = 0.024). FX deficiency is associated with a heavier disease burden and poorer survival in primary AL amyloidosis. Improvement of FX activity tends to appear in patients with better hematologic and organ responses after chemotherapy.

[IgD multiple myeloma mimicking free light chain myeloma complicated by factor X deficiency: a case report]. / Myélome multiple à IgD mimant un myélome à chaines légères libres et compliqué de déficit en facteur X: à propos d'un cas.

IgD myeloma is an extremely rare haemopathy with severe clinical presentation. It can be confused with non-secretory or free light chain myeloma. We here report the case of a 72-year old female patient presenting with bone pain and diffuse ecchymosis and deterioration of her general condition. Laboratory tests showed monoclonal gammopathy associated with severe acute renal failure and low total protein (TP) (48%) with factor X deficiency. Etiological assessment confirmed the diagnosis of IgD lambda myeloma stage IIIb, according to Durie and Salmon, International Staging System (ISS) score III unfavorable cytogenetics. Patient's outcome was favorable after treatment with proteasome inhibitor, anti-CD 38 and corticosteroid therapy. Adequate treatment of IgD myeloma, using new therapeutic approaches and hematopoietic stem cell autotransplantation, can improve the prognosis.

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.

Anesthesia strategy for factor X deficiency coagulopathy: case report.

Factor X deficiency ranks among the rarest coagulopathies and has a variable presentation spectrum. We intend to present a proposal for anesthesia protocol for individuals with the coagulopathy. The excision of an ovarian neoplasm was proposed for a 26-year-old, female, ASA II patient, with congenital Factor X deficiency. Physical examination and lab tests were normal, except for Prothrombin Time (PT) 22.1s (VR: 8-14s), International Normalized Ratio (INR) 1.99 (VR: 0.8-1.2) and Activated Partial Thromboplastin Time (aPTT) 41.4s (VR: 25-37s). We concluded that a history of bleeding should always be investigated, along with a pre-anesthetic coagulation study.

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.

Response of factor X deficiency to darutumumab in the treatment of AL amyloidosis: a novel finding.

We report a case of progressive light-chain amyloidosis (otherwise known as AL amyloidosis) with acquired factor X (aFX) deficiency with a complete haematological response and rapid normalisation of FX levels following daratumumab monotherapy. To our knowledge, this is the first case report documenting successful treatment with daratumumab of aFX deficiency secondary to AL amyloidosis. The patient responded well to this therapy, with excellent symptomatic and quality of life improvements as well as a reduction in bleeding manifestations. This case highlights the value in considering daratumumab treatment when AL amyloidosis is complicated by FX deficiency.

Successful Treatment of Life-threatening Bleeding Caused by Acquired Factor X Deficiency Associated with Respiratory Infection.

Acquired factor X deficiency (AFXD) is a very rare coagulation disorder. A 40-year-old man with no comorbidities suffering from a fever, malaise, and severe hemorrhagic symptoms, including massive hematuria, was emergently admitted. His platelet count was normal, but his prothrombin time and activated partial thromboplastin time were markedly prolonged, which was thought to be due to autoantibody against a coagulation factor in the common pathway. Despite severe massive hematuria resulting in transient renal failure, he was successfully treated with urgent immunosuppressive therapy. Computed tomography revealed bronchopneumonia, which improved with antibiotic administration. AFXD without evidence of amyloidosis was subsequently diagnosed.

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.

Acquired Factor X Deficiency in Patients With Primary Light Chain Amyloidosis.

Acquired factor X (FX) deficiency is a rare but serious complication of primary amyloidosis, presumably caused by the binding of amyloid proteins to the clotting factors. The prolonged prothrombin time, partial thromboplastin time, and low FX level, which are correctable by mixing study, are the disease hallmarks. An immediate goal of care is to stop bleeding. Clotting factor replacement requires close monitoring of coagulogram and FX levels due to varying FX clearance among patients. High-purity FX is currently approved for hereditary FX deficiency and has been successfully used in some acquired FX deficiency cases. Ongoing bleeding risk complicates the treatment decision. Novel therapies yielding rapid and deep response reduce amyloid protein production and improve long-term outcome.

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.