Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate

Togashi, Tomoki; Nagaya, Satomi; Nagasawa, Mitsuru; Meguro‐Horike, Makiko; Nogami, Keiji; Imai, Yasuhito; Kuzasa, Kana; Sekiya, Akiko; Horike, Shin‐ichi; Asakura, Hitoshi; Morishita, Eriko

doi:10.1007/s12185-019-02767-y

Cited by 3 publications

(3 citation statements)

References 19 publications

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“…Therefore, we may preliminarily conclude that these two sequence variant sites have a dose-effect relationship and cause FX deficiency. Similar cases of compound heterozygous mutations have been also reported by many studies [14,[38][39][40][41][42]. Our research reported two novel unreported mutations for the first time, and conducted in vitro functional studies on them to find potential pathogenic mechanism also.…”

Section: Discussionsupporting

confidence: 84%

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Feng

Tang

et al. 2021

Genes

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Background: Congenital coagulation factor X (FX) deficiency is a rare bleeding disorder with an incidence of one in one million caused by mutations in the FX-coding gene(F10), leading to abnormal coagulation activity and a tendency for severe hemorrhage. Therefore, identifying mutations in FX is important for diagnosing congenital FX deficiency. Results: Genetic analysis of the proband identified two single-base substitutions: c.794T > C: p.Ile265Thr and c.865 + 5G > A: IVS7 + 5G > A. His FX activity and antigen levels were < 1% and 49.7%, respectively; aPTT and PT were prolonged to 65.3 and 80.5 s, respectively. Bioinformatics analysis predicted the two novel variants to be pathogenic. In-vitro expression study of the missense mutation c.794T > C: p.Ile265Thr showed normal synthesis and secretion. Activation of FXs by RVV, FVII/TF, and FVIII/FIX all showed no obvious difference between the variant and the reference. However, clotting activity by PT and aPTT assays and activity of thrombin generation in a TGA assay all indicated reduced activity of the mutant FX-Ile265Thr compared to FX-WT. Minigene assay showed a normal splicing mode c.865 + 5G > A: IVS7 + 5G > A, which is inconsistent with clinical phenotype. Conclusions: The heterozygous variants c.794T > C: p.Ile265Thr or c.865 + 5G > A: IVS7 + 5G > A indicate mild FX deficiency, but the compound heterozygous mutation of the two causes severe congenital FX deficiency. Genetic analysis of these two mutations may help characterize the bleeding tendency and confirm congenital FX deficiency. In-vitro expression and functional study showed that the low activity of the mutant FX-Ile265Thr is caused by decrease in its enzyme activity rather than self-activation. The minigene assay help us explore possible mechanisms of the splicing mutation. However, more in-depth mechanism research is needed in the future.

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Section: Discussionsupporting

confidence: 84%

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Feng

Tang

et al. 2021

Genes

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“…For example, hereditary factor V deficiency has been shown to prolong PT and APTT to 20.3 s and 59.2 s, respectively [ 23 ], and to reduce coagulation factor V activity to 3% [ 24 ]. Also, congenital FX deficiency has been shown to prolong PT to >40 s and APTT to 65.0 s [ 25 ]. TT is the time taken for the plasma to clot after addition of standardized thrombin and primarily reflects the time needed for conversion of fibrinogen to fibrin.…”

Section: Introductionmentioning

confidence: 99%

Coagulation Dysfunction in Patients with Liver Cirrhosis and Splenomegaly and Its Countermeasures: A Retrospective Study of 1522 Patients

Liu

Li³

et al. 2023

Disease Markers

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Objective. Patients with cirrhosis and splenomegaly often have coagulation dysfunction which affects treatment and prognosis. This study explores the status, grading, and treatment strategies of coagulation dysfunction in patients with liver cirrhosis and splenomegaly. Methods. A retrospective cohort study was conducted on the clinical data on consecutive patients with cirrhosis and splenomegaly treated at Hainan General Hospital, China, from January 2000 to December 2020. Starting research in January 2022. Results. Among 1522 patients included into this study, 297 (19.5%) patients had normal results in all five coagulation tests (prothrombin time, prothrombin activity, activated partial thromboplastin time, thrombin time, and fibrinogen), and 1225 (80.5%) had coagulation dysfunction in at least one of these tests. There were significant differences ( P < 0.05 ) in treatment efficacy on these patients for three of these five coagulation tests, with the exception of prothrombin activity and thrombin time. When coagulation dysfunction was classified into grades I, II, and III based on scores from the three significant coagulation tests, prothrombin time, activated partial thromboplastin time, and fibrinogen, significant differences in surgical outcomes were found among the three grades of coagulation dysfunction and between grades I and III ( P < 0.05 ). The operative mortality rate in patients with grade III in treating liver cancer, portal hypersplenism, and/or splenomegaly was 6.5%. There was no significant difference between patients with grades I and II ( P > 0.05 ). Conclusions. Approximately, 80% of patients with liver cirrhosis and splenomegaly had coagulation dysfunction. Surgery is feasible for grade I and II patients. For grade III patients, nonsurgical treatment should be given first, and surgery should only be considered when the coagulation function returns to normal or near-normal levels after treatment. This trial is registered with MR-46-22-009299.

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“…The harm to patients caused by FX coagulation deficiency is second only to that of hemophilia A and hemophilia B. When FX activity is <1%, patients have a moderate-to-severe bleeding tendency, including deep hematoma, joint cavity hemorrhage, menorrhagia, and postoperative bleeding [8]. In infants and neonates, FX deficiency can cause intracranial hemorrhage, and even fatal gastrointestinal bleeding or umbilical cord stump bleeding [9, 10].…”

Section: Introductionmentioning

confidence: 99%

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

Lin

et al. 2020

Acta Haematol

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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.

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Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate

Cited by 3 publications

References 19 publications

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Coagulation Dysfunction in Patients with Liver Cirrhosis and Splenomegaly and Its Countermeasures: A Retrospective Study of 1522 Patients

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

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