Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency.

Factor X deficiency is a rare coagulation disorder that can be hereditary or acquired. The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management. Evidence-based guidelines and reviews on factor X deficiency are generally limited to publications covering a range of rare bleeding disorders. Here we provide a comprehensive review of the literature on factor X deficiency, focusing on the hereditary form, and discuss the evolution in disease management and the evidence associated with available treatment options. Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates. Consensus in treatment guidelines is still urgently needed to ensure optimal management of patients with factor X deficiency across the spectrum of disease severity.

Acquired factor X deficiency in a patient with multiple myeloma: a rare case highlighting the significance of comprehensive evaluation and the need for antimyeloma therapy for bleeding diathesis.

Factor X deficiency is a rare bleeding disorder that can be associated with life-threatening bleeding events. Factor X deficiency can either be inherited or acquired. Acquired cases of factor X deficiency can be seen in patients with plasma cell dyscrasias as well as amyloidosis. Coagulopathy, with clinically relevant bleeding events, although rare, is not an unusual phenomenon for patients with systemic amyloidosis. However, clinically relevant bleeding in patients with symptomatic multiple myeloma, without associated amyloidosis, has not been reported in literature before. We present a rare case of multiple myeloma without concomitant amyloidosis that presented with life-threatening bleeding from acquired deficiency of factor X and responded remarkably to treatment for underlying multiple myeloma. This case not only highlights the diagnostic workup required in patients with factor X deficiency but also provides the principles of management of acquired coagulopathy in plasma cell dyscrasias.

Immunoglobulin Light Chain Amyloidosis with Severe Liver Dysfunction Accompanied by Factor X Deficiency.

Severe hepatic failure is rarely a cause of death in patients with immunoglobulin light chain (AL) amyloidosis. We herein report a case of AL amyloidosis involving a bleeding tendency due to factor X deficiency and marked hepatic involvement of amyloidosis. The patient died due to severe liver dysfunction two weeks after admission. The diagnosis was confirmed histologically by AL-λ amyloidosis, with the liver and spleen as the main lesions, on an autopsy. As treatment-related toxicity is strong in advanced cases, appropriate treatments are required to improve the prognosis of AL amyloidosis with severe liver dysfunction.

Acquired factor X deficiency in light-chain (AL) amyloidosis is rare and associated with advanced disease.

INTRODUCTION: Systemic light chain (AL) amyloidosis can lead to an acquired coagulopathy secondary to acquired factor X (aFX) deficiency. However, it is not very clear who develops aFX deficiency in AL amyloidosis. METHODS: We therefore undertook this single centre, retrospective study to better characterize AL amyloidosis-associated aFX deficiency. RESULTS: Out of 121 AL patients who had FX testing at the time of their first evaluation at our institution, including 17 patients on warfarin at the time of testing, 10 out of 104 patients (9.6%) with systemic AL amyloidosis were found to have FX levels below 50%. Acquired FX deficiency was associated with advanced stage of AL amyloidosis and elevated cardiac biomarkers. Lower FX activity, advanced stage, and cardiac involvement by disease were associated with higher hazard of death on univariate analysis. On multivariate analysis, stage of AL amyloidosis was the only significant predictor of survival. Median survival time of patients with FX deficiency was 9.3 months compared to 118.4 months in those without. CONCLUSIONS: We conclude that while aFX deficiency is rare in systemic AL amyloidosis, it is a marker of advanced disease.

Genotype analysis and identification of novel mutations in a multicentre cohort of patients with hereditary factor X deficiency.

: The objective was to examine the genotypic and phenotypic characteristics of individuals with hereditary factor X deficiency (FXD), a rare autosomal recessive bleeding disorder caused by mutations in the F10 gene located on chromosome 13q34-ter. To date, 149 F10 mutations have been identified as contributory to FXD. Three open-label phase 3 trials enrolled individuals with mild, moderate, or severe FXD. Individuals received plasma-derived factor X concentrate as routine prophylaxis, to treat bleeds, and/or during or after surgery. F10 genotyping was performed (studies 1 and 2) or genotype data was collected at screening (study 3), and identified F10 mutations were compared against the Human Gene Mutation Database to assess novelty. Genotype data were combined to evaluate the number, type, and novelty of the F10 mutations identified. Genotype data were available for 24 of 27 individuals with mild (n = 2), moderate (n = 2), or severe (n = 20) FXD. Analyses identified 22 separate mutations, including 15 missense mutations, 2 deletions, 4 splice site mutations, and 1 nonsense mutation. Sixteen individuals had homozygous mutations; 8 had compound heterozygous mutations. Eleven unique novel mutations (all compound heterozygous) were identified in seven individuals: six missense mutations, three splice site mutations, one exon deletion, and one nonsense mutation. In silico analyses strongly supported the pathogenicity of all novel mutations. The identification of 11 novel F10 mutations provides a substantial contribution to the mutations known to cause 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.

[Acquired, non-amyloid related factor X deficiency: A first case associated with atypical chronic lymphocytic leukemia and literature review]. / Déficit non amyloïde acquis en facteur X : un premier cas satellite d'une leucémie lymphoïde chronique atypique et revue de la littérature.

INTRODUCTION: Acquired factor X deficiency is in most cases associated with AL amyloidosis. Acquired non-amyloid related factor X deficiency (DNAA-FX) has been exceptionally reported in the literature. CASE REPORT: We report the first case of acquired, non-amyloid related factor X deficiency associated with atypical chronic lymphoid leukemia in a 66-year-old patient with spontaneous hematomas. After therapeutic failure with polyclonal intravenous immunoglobulins, specific lymphoid malignancy treatment allowed symptoms and coagulation disorder resolution. CONCLUSION: DNAA-FX should be considered in case of bleeding events or coagulation disorders during low-grade hematological malignancies. Its occurrence can be considered as a treatment indication to prevent potentially fatal bleeding complications.

A case of factor X deficiency in a Chihuahua dog.

A juvenile Chihuahua dog developed hemoperitoneum after routine ovariohysterectomy. She was managed with packed red blood cell and fresh frozen plasma transfusions as well as an exploratory laparotomy to verify ligature sites. No recurrence of hemorrhage occurred. Factor X deficiency was diagnosed and confirmed with repeat analysis including during times of health.

Cas de carence du facteur X chez une chienne Chihuahua. Une jeune chienne Chihuahua a développé un hémopéritoine après une ovariohystérectomie de routine. Elle a été gérée à l'aide de concentrés de globules rouges et de transfusions de plasma frais congelé ainsi que d'une laparotomie exploratoire pour vérifier les sites de ligature. Aucune récurrence d'hémorragie ne s'est produite. La carence du facteur X a été diagnostiquée et confirmée par une analyse répétée durant des périodes de santé.(Traduit par Isabelle Vallières).

Importance of pharmacokinetic studies in the management of acquired factor X deficiency.

Up to 14% of individuals with systemic AL amyloidosis develop acquired factor X deficiency, which occurs due to adsorption of factor X onto amyloid fibrils. Although baseline factor X levels are not predictive of bleeding risk in these patients, serious hemorrhagic complications can occur, particularly during invasive procedures. Optimal management strategies to attenuate bleeding risk in these patients are unknown. We describe our experience in the management of acquired factor X deficiency, secondary to systemic AL amyloidosis, in a case series of three patients who received prothrombin complex concentrates (PCCs) for treatment and prevention of bleeding events. We performed a retrospective review extracting information on baseline demographics, laboratory data, pharmacokinetic (PK) studies, and clinically documented bleeding events. Our case series demonstrates that individuals with acquired factor X deficiency secondary to amyloidosis have variable laboratory and clinical responses to PCCs. This is likely due to distinct amyloid loads and fibril sequences, leading to different binding avidities for factor X. Our data emphasize the importance of performing PK testing prior to any invasive procedures to determine the dose and frequency interval to achieve adequate factor X levels for hemostasis, given the variable response between individuals.

Déficit adquirido de factor X en leucemia mielomonocítica crónica: reporte de un caso / Isolated factor X deficiency in chronic myelomonocytic leukemia: Report of one case

Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia.

[Isolated factor X deficiency in chronic myelomonocytic leukemia: Report of one case]. / Déficit adquirido de factor X en leucemia mielomonocítica crónica: reporte de un caso.

Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia.

Spontaneous spinal epidural hematoma in a patient with acquired Factor X deficiency secondary to systemic amyloid light-chain amyloidosis.

BACKGROUND: Spontaneous spinal epidural hematoma (SSEH) is relatively rare. SSEH with anticoagulants including warfarin and rivaroxaban (Factor Xa inhibitor) have been reported; however, SSEH with Factor X deficiency has not been described yet. METHODS: Case report. FINDINGS: An 82-year-old woman with acquired Factor X deficiency complained of sudden onset of severe posterior neck pain. Magnetic resonance imaging demonstrated an epidural hematoma from C3 to T3 levels. Because she showed tetraparesis on the third hospital day, we performed surgery. Just before surgery, her prothrombin time-international normalized ratio was 2.49, which was immediately reversed by infusion of prothrombin complex concentrate. The patient safely underwent an emergency laminectomy from C3 to T2, in which the epidural hematoma was evacuated. Post-operatively, the patient recovered completely without rebleeding. Hematologists found acquired deficiency of Factor X in this patient with systemic amyloid light-chain amyloidosis. CONCLUSION: To our knowledge, this is the first report of a case of SSEH with Factor X deficiency. A blood coagulation disorder should be considered in patients with SSEH.

Acquired factor X deficiency associated with atypical AL-amyloidosis.

We herein describe the case of a 77-year-old woman with acquired factor X deficiency that was likely caused by atypical amyloidosis. The patient developed severe gastrointestinal bleeding as a result of a significant decrease of factor X activity. Neither proteinuria nor diarrhea was observed as an initial manifestation. Although a bone marrow examination revealed direct fast scarlet-positive extracellular deposits, they did not exhibit red-to-green dichroism under polarized light. Immunofluorescence microscopy showed that the fibrillar proteins were positive for CD138 but negative for ß2-microglobulin or amyloid A antibodies. These atypical pathological features of immunoglobulin light chain-amyloidosis in this patient might be related to its unique clinical presentation.

Acquired factor X deficiency developed four years after autologous transplantation in a patient with multiple myeloma associated with systemic AL amyloidosis.

We describe a case of acquired factor X deficiency after high-dose melphalan with autologous stem cell transplantation (HDM/ASCT) for multiple myeloma (MM) with systemic AL amyloidosis. A 68-year-old woman with renal amyloidosis was diagnosed as having MM in 2007. She achieved a partial response after VAD (vincristine, adriamycin, dexamethasone) therapy and HDM/ASCT. In December 2011, coagulation tests revealed a prolonged prothrombin time (PT) of 17.6 sec and she was administered vitamin K. In January 2012, she received low anterior resection with colostomy for rectal cancer. She received fresh frozen plasma (FFP) infusion but the perioperative bleeding tendency persisted. In February 2012, she was referred from surgery for colostomy closure. She showed no progression of MM and had prolonged PT, corrected by mixing with normal plasma. Factor X activity was markedly decreased. She was diagnosed as having an acquired factor X deficiency and was given FFP infusion for colostomy closure. Although acquired factor X deficiency after HDM/ASCT for MM with systemic AL amyloidosis is rare, we should be aware of the possibility of this disease in MM patients with a bleeding tendency.

[AL amyloidosis-associated factor X deficiency]. / Factor X-deficiëntie bij AL-amyloïdose.

BACKGROUND: An acquired bleeding tendency is a specific symptom that can indicate an underlying disease. CASE DESCRIPTION: Here we describe a 69-year-old patient with an acquired bleeding tendency resulting from a factor X deficiency due to an underlying amyloid light-chain (AL) amyloidosis. Factor X deficiency in AL amyloidosis arises from a quantitative and qualitative deficiency of factor X because it binds to amyloid fibrils exposed to circulating blood. CONCLUSION: Bleeding tendency is a rare complication of AL amyloidosis, often resulting from a factor X deficiency.