Severe factor X deficiency due to a homozygous mutation (Cys364Arg) that disrupts a disulphide bond in the catalytic domain

Todd, Tony; Perry, David J.; Hayman, E.; Kingsley, Lawrence A.; Gattens, Michael; Baglin, Trevor

doi:10.1111/j.1365-2516.2006.01315.x

Cited by 12 publications

(16 citation statements)

References 19 publications

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“…Long‐term prophylaxis There are 12 case reports, totalling 23 patients [76–87]. About 21 patients received PCCs the other two received both Danazol and FFP.…”

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confidence: 99%

A review of long‐term prophylaxis in the rare inherited coagulation factor deficiencies

Todd

Perry

2010

Haemophilia

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The rare inherited coagulation factor deficiencies (deficiencies of factors I, II, V, VII, XI, XIII, combined FV + FVII deficiency, combined deficiency of the vitamin K dependent factors and von Willebrand disease type 3) have an aggregate prevalence of approximately 1:100,000. They may cause recurrent life or function threatening haemorrhage. In this article we review the available literature on long-term prophylaxis and, where possible, make recommendations on this important area.

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“…Long‐term prophylaxis There are 12 case reports, totalling 23 patients [76–87]. About 21 patients received PCCs the other two received both Danazol and FFP.…”

mentioning

confidence: 99%

A review of long‐term prophylaxis in the rare inherited coagulation factor deficiencies

Todd

Perry

2010

Haemophilia

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“…The p.Gly244Arg, p.Gly420Arg and p.Cys404Arg (Table ), similarly to the p.Leu251Pro but differently from the GLA domain mutants, lead to very low circulating FX levels. In particular, Gly244 (c25), located in the small Cys241‐Cys246 disulphide‐bridged loop, results in an altered trafficking towards secretion .…”

Section: Discussionmentioning

confidence: 92%

“…It participates to the c43‐c196 contact with a key role for the correct structure and folding of the FXa catalytic domain. Last, the p.Cys404Arg variant disrupts the highly conserved intra‐chain Cys390‐Cys404 (c168‐c182) disulfide bridge in the FX heavy chain . It remains to be investigated how these profound structural changes would alter but not suppress protein folding, secretion and activity, and thus be compatible, as the rFX‐251Pro, with a dysfunctional but not completely inactive FX requiring substitutive therapy immediately after birth.…”

Section: Discussionmentioning

confidence: 99%

Missense changes in the catalytic domain of coagulation factor X account for minimal function preventing a perinatal lethal condition

et al. 2019

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Introduction Inherited deficiencies in the coagulation pathway provide diversified models to investigate the molecular bases of perinatal lethality associated with null‐like variants. Differently from X‐linked haemophilias, homozygous/doubly heterozygous null variants in the rare autosomally inherited deficiency of factor X (FX) might be incompatible with perinatal survival. Aim To provide experimental evidence about the null/close‐to‐null FX function. Methods The residual secreted (ELISA) and functional (thrombin generation assays) protein levels associated with the novel nonsense (c.1382G>A; p.Trp461Ter) and missense (c.752T>C; p.Leu251Pro) variants, found in the proposita with life‐threatening symptoms at birth, were characterized through recombinant (r)FX expression. Results The rFX‐461Ter showed very low secretion and undetectable function. Expression and function of the predicted readthrough‐deriving missense variants (rFX‐461Tyr, rFX‐461Gln) were also severely impaired. These unfavourable features, due to nucleotide and protein sequence constraints, precluded functional readthrough over the 461 stop codon. Differently, the poorly secreted rFX‐251Pro variant displayed residual function that was characterized by anti‐TFPI aptamer‐based amplification or selective inhibition of activated FX function by fondaparinux in plasma and found to be reduced by approximately three orders of magnitude. Similarly to the rFX‐251Pro, a group of catalytic domain missense variants cause poorly secreted molecules with modest function in FX‐deficient patients with life‐threatening symptoms. Conclusions Our data, contributing to the knowledge of the very severe FX deficiency forms, support life‐saving requirement of trace FX function, clearly exemplified by the dysfunctional but not completely inactive rFX‐251Pro variant that, albeit with severely reduced function, is compatible with a residual activity ensuring minimal haemostasis and permitting perinatal survival.

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“…Like in the index case described herein, this requires long‐lasting central venous access with a high potential for complications (thrombosis, bleeding, infection) and repeated surgery. A few plasma‐derived products for the substitution of FX are available and it seems that – like our group – most use preparations containing both, FIX and FX (15–20 IU per kg body weight) [15], or prothrombin complex concentrates (50–70 IU kg −1 ) [2,16,17], given in 1–2(–3) doses per week. There is a potential risk for thromboembolic complications in prothrombin complex concentrates because the concentration of either FIX or FX is unknown or not consistent [15].…”

Section: Discussionmentioning

confidence: 99%

Factor X deficiency and intracranial bleeding: who is at risk?

et al. 2011

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Very few mutations of the gene encoding for coagulation factor X (FX) have been found associated with intracranial haemorrhage (ICH) due to FX deficiency (FXD). No guidelines exist as to when prophylaxis in FXD should be started and how patients at risk for ICH can be identified. We report on a novel mutation causative for ICH in a family of Iranian origin and provide a summary of all published mutations in the FX gene related to ICH. The index patient is an infant with umbilical bleeding requiring blood transfusion in the postnatal period. The international normalized ratio (6.01) and activated partial thromboplastin time (117 s) were prolonged. Coagulation factor analysis was normal except for FX activity (<1%). At 4 months, the child suffered a spontaneous severe intracranial haemorrhage. The child was the product of a consanguineous union. Four of five available family members from three generations displayed minor bleeding symptoms and mildly reduced FX. Sequencing of FX gene demonstrated homozygosity for a novel duplication A (c.1402_1403dupA)* in exon 8 and heterozygosity in four family members. We compare this case to all 15 patients with FXD and ICH and their 11 known mutations described so far. This case illustrates a pattern of FXD (a male neonate with umbilical or gastrointestinal bleeding, very low FX:C (<1%) and an underlying homozygous genotype) who may be at high risk for ICH. In these cases, we recommend to start early prophylactic substitution of FX to prevent a possible life-threatening haemorrhage.

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Severe factor X deficiency due to a homozygous mutation (Cys364Arg) that disrupts a disulphide bond in the catalytic domain

Cited by 12 publications

References 19 publications

A review of long‐term prophylaxis in the rare inherited coagulation factor deficiencies

A review of long‐term prophylaxis in the rare inherited coagulation factor deficiencies

Missense changes in the catalytic domain of coagulation factor X account for minimal function preventing a perinatal lethal condition

Factor X deficiency and intracranial bleeding: who is at risk?

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