Acute deep vein thrombosis with concurrent new diagnosis of AL-amyloid-induced factor X deficiency.

Acquired factor X (FX) deficiency is a rare but well-documented clinical feature of AL amyloidosis. Patients with FX deficiency can present with clinically significant bleeding diathesis due to the adsorption of circulating FX to amyloid fibrils. Here, we report an unusual case of a man in his 60s who presented with 6 months of intermittent bruising, labs demonstrating new FX deficiency, elevated free lambda light chains for underlying AL amyloidosis and concurrent new peroneal vein thrombosis. This is the first report of concurrent thrombotic complications in the setting of AL-amyloid-induced FX deficiency. We discuss the diagnostic and therapeutic conundrum of diagnosing AL amyloidosis with bruising as the leading clinical symptom and the management of acute deep vein thrombosis in the setting of FX deficiency.

Acquired factor V and factor X Deficiency coexisting with acquired dysfibrinogenaemia in a patient with light chain myeloma.

An elderly woman with light chain myeloma presented with prolonged epistaxis and extensive cutaneous haematomas: her kappa/lambda ratio was high at 395, her coagulation screen, thrombin and reptilase times were abnormal, her FV and FX were in the low range in the absence of specific inhibitors, her Clauss fibrinogen was low at 0.95 g/l but antigenic FNG was 1.58 g/l. The patient denied treatment and died of progressive renal failure. We wish to describe the unusual association of FX and FV deficiency co-existing with an acquired dysfibrinogenaemia.

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.

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.

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.

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.

[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.

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.

[Congenital factor X deficiency: a retrospective analysis of 11 cases].

Objective: To analyze the clinical characteristics, laboratory examination, diagnosis, treatment, and outcome of hereditary factor Ⅹ (FⅩ) deficiency. Methods: Clinical data of 11 patients with congenital FⅩ deficiency were retrospectively analyzed from July 2009 to February 2021. Results: There were 3 males and 8 females. Median age was 39 (5-55) years. The media duration of follow-up was 81.67 (1.87-142.73) months. Of the 11 patients, 10 had bleeding symptoms, 7 had ecchymosis or hemorrhage after skin bump, 7 had nosebleed, 6 had gingival hemorrhage, and 1 had muscle hematoma. Among the female patients, 6 had menorrhagia and 1 experienced bleeding after vaginal delivery. Family history of FⅩ deficiency was found in one case. Eight patients had a history of surgery, and four had postoperative bleeding. Laboratory findings were characterized by significantly prolonged activated partial thromboplastin time, prothrombin time, and decreased FⅩ activity (FⅩ∶C) . Four cases underwent gene mutation analysis and five new mutations were found. Four cases were treated with prothrombin complex concentrates (PCC) and seven cases with fresh frozen plasma (FFP) . One female patient had significantly reduced menstrual volume after PCC prophylactic therapy. One patient received FFP for prophylactic infusion with no bleeding during and after the operation. Conclusion: Most patients with congenital FⅩ deficiency had bleeding symptoms and there was no significant correlation between severity of bleeding symptoms and FⅩ∶C. Prophylaxis should be applied in patients with severe bleeding tendencies. Gene mutation test is significant for screening, diagnosis, and prognosis prediction of congenital FX deficiency.

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.

Upregulating sirtuin 6 ameliorates glycolysis, EMT and distant metastasis of pancreatic adenocarcinoma with krüppel-like factor 10 deficiency.

Krüppel-like factor 10 (KLF10) is a tumor suppressor in multiple cancers. In a murine model of spontaneous pancreatic adenocarcinoma (PDAC), additional KLF10 depletion accelerated distant metastasis. However, Klf10 knockout mice, which suffer from metabolic disorders, do not develop malignancy. The mechanisms of KLF10 in PDAC progression deserve further exploration. KLF10-depleted and KLF10-overexpressing PDAC cells were established to measure epithelial-mesenchymal transition (EMT), glycolysis, and migration ability. A murine model was established to evaluate the benefit of genetic or pharmacological manipulation in KLF10-depleted PDAC cells (PDACshKLF10). Correlations of KLF10 deficiency with rapid metastasis, elevated EMT, and glycolysis were demonstrated in resected PDAC tissues, in vitro assays, and murine models. We identified sirtuin 6 (SIRT6) as an essential mediator of KLF10 that modulates EMT and glucose homeostasis. Overexpressing SIRT6 reversed the migratory and glycolytic phenotypes of PDACshKLF10 cells. Linoleic acid, a polyunsaturated essential fatty acid, upregulated SIRT6 and prolonged the survival of mice injected with PDACshKLF10. Modulating HIF1α and NFκB revealed that EMT and glycolysis in PDAC cells were coordinately regulated upstream by KLF10/SIRT6 signaling. Our study demonstrated a novel KLF10/SIRT6 pathway that modulated EMT and glycolysis coordinately via NFκB and HIF1α. Activation of KLF10/SIRT6 signaling ameliorated the distant progression of PDAC.Clinical Trial Registration: ClinicalTrials.gov. identifier: NCT01666184.

Cardiac Amyloidosis Presenting with Pre-Excitation Syndrome, Heart Failure, and Severe Factor X Deficiency as Part of Systemic Amyloid Light-Chain (AL) Amyloidosis - A Fatal Combination.

BACKGROUND Amyloid light-chain (AL) amyloidosis is a disease that results in systemic amyloid deposition, which may present with multi-organ dysfunction. It carries a poor prognosis at the time of diagnosis. CASE REPORT A 37-year-old patient with a history of Wolff-Parkinson-White syndrome and thyroiditis presented with syncope and hypovolemia. ECG showed non-specific T wave inversions in the lateral leads with no signs of ischemia. Laboratory investigations revealed deranged coagulation parameters with prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) and follow-up factor assays revealed severe factor X deficiency. A transthoracic echocardiogram and subsequent cardiac MRI showed signs of cardiac amyloidosis. Bone marrow biopsy was consistent with AL amyloidosis, demonstrating period acid-Schiff (PAS)-positive adipose deposits and interstitial infiltration by clusters of lambda restricted plasma cells with aberrant expression of CD 56 and CD 117.The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, but died early during his treatment due to cardiac arrest, suspected to be secondary to conduction abnormalities caused by cardiac infiltration. CONCLUSIONS This case represents a novel pattern of disease in AL amyloidosis with cardiac, thyroid, and hematological involvement as a result of systemic amyloid deposition.Our report highlights the need for physicians to be aware of cardiac amyloidosis-related complications and the morbidity and mortality associated with concurrent hematological involvement in these cases.

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.

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.