Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male

Cramer, Thomas J.; Anderson, Kristin; Navaz, Karanjia; Brown, Justin M.; Mosnier, Laurent O.; Drygalski, Annette von

doi:10.1016/j.bcmd.2015.11.004

Cited by 13 publications

(8 citation statements)

References 28 publications

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“…Interestingly, Cramer et al . reported a patient with mild (44%) FVII deficiency who experienced a severe spontaneous intracranial hemorrhage . In this case, the 9729del4‐FVII mutation was predicted to disrupt interactions with natural substrates, including EPCR, which could result in a more severe bleeding phenotype than predicted by FVII activity levels alone.…”

Section: Approaches To An Improved Bypassing Agentmentioning

confidence: 95%

The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

Shapiro

Mitchell²,

Nasr³

2018

Journal of Thrombosis and Haemostasis

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Summary Bypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high‐titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case‐by‐case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once‐weekly or every‐other‐week prophylactic dosing in inhibitor patients. Other non‐traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non‐factor‐based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents.

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Section: Approaches To An Improved Bypassing Agentmentioning

confidence: 95%

The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

Shapiro

Mitchell²,

Nasr³

2018

Journal of Thrombosis and Haemostasis

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“…12 Cases of late-onset ICH with no previous history of bleeding, despite hemostatic challenges and a FVII activity of 44%, highlight the challenge of identifying high-risk individuals through FVII activity alone. 13 …”

Section: Discussionmentioning

confidence: 99%

Phenotypical variability in congenital FVII deficiency follows the ISTH-SSC severity classification guidelines: a review with illustrative examples from the clinic

Jain¹,

Donkin²,

Frey³

et al. 2018

JBM

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BackgroundOne of the most common rare inherited bleeding disorders, congenital factor VII (FVII) deficiency typically has a milder bleeding phenotype than other rare bleeding disorders. Categorizing severity in terms of factor activity associated with hemophilia (severe <1%, moderate 1%–5%, mild 6%–40%) has led to the observation that bleeding phenotype does not follow closely with FVII activity. Over the past decade, large-scale global registries have investigated bleeding phenotype more thoroughly. The International Society on Thrombosis and Haemostasis has reclassified FVII deficiency as follows: severe, FVII <10%, risk of spontaneous major bleeding; moderate, FVII 10%–20%, risk of mild spontaneous or triggered bleeding; mild, FVII 20%–50%, mostly asymptomatic disease.Case reportsEleven illustrative cases of congenital FVII deficiency adapted from clinical practice are described to demonstrate the variability in presentation and in relation to FVII activity levels. Severe FVII deficiency usually presents at a young age and carries the risk of intracranial hemorrhage, hemarthrosis, and other major bleeds. Moderate FVII deficiency tends to present later, often in adolescence and particularly in girls as they reach menarche. Milder disease may not be apparent until found incidentally on preoperative testing, during pregnancy/childbirth, or following unexplained bleeding when faced with hemostatic challenges.ConclusionIt is important for health care professionals to be aware of the new definitions of severity and typical presentations of congenital FVII deficiency. Failure to appreciate the risks of major bleeding, including intracerebral hemorrhage in those with FVII activity <10%, may put particularly young children at risk.

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“…Like other hereditary coagulation defects, such as FIX deficiency (hemophilia B), many mutations occur in CpG hot spot regions. To date, frequent examples of such mutations have been described (R79Q/W, 6071G>A, A244V, R304Q, and T359M) [52] . In a comprehensive study on 717 patients in Latin America and Europe, 131 mutations were observed in 73 homozygotes, 145 heterozygote compounds, and 499 heterozygotes patients, of which 71% of homozygous and 50% of compound heterozygotes cases were symptomatic.…”

Section: F7 Gene Mutationsmentioning

confidence: 99%

Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

Shahbazi¹,

Mahdian²

2019

ibj

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Coagulation factors belong to a family of plasma glycosylated proteins that should be activated for appropriate blood coagulation. Congenital deficiencies of these factors cause inheritable hemorrhagic diseases. Factor VII (FVII) deficiency is a rare bleeding disorder with variable clinical symptoms. Various mutations have been identified throughout the F7 gene and can affect all the protein domains. The results of previous experiments have partly revealed the correlation between genotype and phenotype in patients with FVII deficiency. Nevertheless, each particular variant may affect the coagulative function of FVII, mainly via altering its expression level, extra-cellular secretion, tissue factor binding affinity, or proteolytic activity. The pathogenicity of the variants and molecular mechanisms responsible for clinical symptoms in patients with FVII deficiency should be characterized via in silico and in vitro, as well as in vivo functional studies. This review has highlighted the most important functional studies reported on F7 gene variants, including relevant reports regarding Iranian FVII deficiency patients.

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Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male

Cited by 13 publications

References 28 publications

The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

Phenotypical variability in congenital FVII deficiency follows the ISTH-SSC severity classification guidelines: a review with illustrative examples from the clinic

Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

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