Inhibitor in Congenital Factor VII Deficiency; a Rare but Serious Therapeutic Challenge—A Systematic Literature Review

Ramezanpour, Nahid; Zaker, Farhad; Biswas, Arijit; Dorgalaleh, Akbar

doi:10.3390/jcm10020211

Cited by 8 publications

(10 citation statements)

References 24 publications

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“…The development of neutralizing inhibitors against infused FVIII occurs in one-third of the patients with hemophilia A, 29,30 but few cases of inhibitors against FVII concentrate have been reported (for a review, see Ramezanpour et al 31 ). Shortly after initiation of treatment with rFVIIa, a FVII inhibitor developed rapidly in proband 1.…”

Section: Discussionmentioning

confidence: 99%

“…FVII-deficient patients presenting with inhibitor are reported to have increased risk of severe, life-threatening bleeds and in the case of intracranial hemorrhage, the frequency was as high as 60% versus 10% for patients without inhibitor. 31 According to some case reports, treatment with rFVIIa of patients with FVII inhibitor may be successful or unsuccessful irrespective of whether it is given as a single dose or with repetitive dosing. 32,33 In a case where the presence of a FVII inhibitor did not seem to impair the therapeutic effect of rFVIIa, it was speculated that this was caused by low-affinity FVII antibodies, which could be saturated by rFVIIa injection.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Characterization of Two Homozygous Factor VII Variants Associated with Intracranial Bleeding

et al. 2021

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Clinical parameters have been extensively studied in factor (F) VII deficiency, but the knowledge of molecular mechanisms of this disease is scarce. We report on three probands with intracranial bleeds at early age, one of which had concomitant high titer of FVII inhibitor. The aim of the present study was to identify the causative mutations and to elucidate the underlying molecular mechanisms. All nine F7 exons were sequenced in the probands and the closest family members. A homozygous deletion in exon 1, leading to a frame shift and generation of a premature stop codon (p.C10Pfs*16), was found in proband 1. Proband 2 and 3 (siblings) were homozygous for a missense mutation in exon 8, resulting in a glycine (G) to arginine (R) substitution at amino acid 240 (p.G240R). All probands had severely reduced FVII activity (FVII:C < 1 IU/dL). Treatment consisted of recombinant FVIIa and/or plasma concentrate, and proband 1 developed a FVII inhibitor shortly after initiation of treatment. The FVII variants were overexpressed in mammalian cell lines. No FVII protein was produced in cells expressing the p.C10Pfs*16 variant, and the inhibitor development in proband 1 was likely linked to the complete absence of circulating FVII. Structural analysis suggested that the G to R substitution in FVII found in probands 2 and 3 would destabilize the protein structure, and cell studies demonstrated a defective intracellular transport and increased endoplasmic reticulum stress. The molecular mechanism underlying the p.G240R variant could be reduced secretion caused by protein destabilization and misfolding.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Two Homozygous Factor VII Variants Associated with Intracranial Bleeding

et al. 2021

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“…Management of this situation is challenging, as it is attended by a high rate of treatment failure and death. 42…”

Section: Intracerebral Hemorrhage In Bleeding Disordersmentioning

confidence: 99%

“…Management of this situation is challenging, as it is attended by a high rate of treatment failure and death. 42 Among all inherent bleeding disorders, FXIII deficiency has the highest prevalence of ICH, approximately 30%. 43 Among rare bleeding disorders, severe FXIII, FVII, and FX deficiencies present a high risk of ICH during the first week of life.…”

Section: Intracerebral Hemorrhage In Von Willebrand Diseasementioning

confidence: 99%

Risk and Management of Intracerebral Hemorrhage in Patients with Bleeding Disorders

Dorgalaleh

Farshi

Haeri

et al. 2022

Semin Thromb Hemost

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Intracerebral hemorrhage (ICH) is the most dreaded complication, and the main cause of death, in patients with congenital bleeding disorders. ICH can occur in all congenital bleeding disorders, ranging from mild, like some platelet function disorders, to severe disorders such as hemophilia A, which can cause catastrophic hemorrhage. While extremely rare in mild bleeding disorders, ICH is common in severe coagulation factor (F) XIII deficiency. ICH can be spontaneous or trauma-related. Spontaneous ICH occurs more often in adults, while trauma-related ICH is more prevalent in children. Risk factors that can affect the occurrence of ICH include the type of bleeding disorder and its severity, genotype and genetic polymorphisms, type of delivery, and sports and other activities. Patients with hemophilia A; afibrinogenemia; FXIII, FX, and FVII deficiencies; and type 3 von Willebrand disease are more susceptible than those with mild platelet function disorders, FV, FXI, combined FV–FVIII deficiencies, and type 1 von Willebrand disease. Generally, the more severe the disorder, the more likely the occurrence of ICH. Contact sports and activities can provoke ICH, while safe and noncontact sports present more benefit than danger. An important risk factor is stressful delivery, whether it is prolonged or by vacuum extraction. These should be avoided in patients with congenital bleeding disorders. Familiarity with all risk factors of ICH can help prevent occurrence of this diathesis and reduce related morbidity and mortality.

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“…Coagulation defects other than Hemophilia A, Hemophilia B, and von Willebrand's disease, generally autosomal recessive, are rare, and the frequency of homozygous individuals in the general population ranges from 1 in 2,000,000 for FII and FXIII deficiencies to 1 in 500,000 for FVII deficiency (9,52,53). There are some exceptions where these deficiencies have higher frequencies, such as countries with large Jewish populations, the Middle East countries, and South India.…”

Section: Fvii Deficiencymentioning

confidence: 99%

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

Mashayekhi

Ghasemi

2022

Trends in Med Sci

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: Coagulation factor VII (FVII) is a vitamin K-dependent serine protease that plays a pivotal role in normal hemostasis. Mature FVII is a glycoprotein comprised γ-carboxyglutamic acid-rich (Gla) domain, two epidermal growth factor (EGF)-like domains, an activation domain, and a serine protease domain. FVII requires proteolytic activation followed by tissue factor (TF) binding for maximal activity. The F7 gene (14.8 kb) is located on 13q34, composed of nine exons and eight introns. The congenital FVII deficiency is a rare coagulopathy with an autosomal recessive pattern of inheritance that occurs due to mutation in the F7 gene. A considerable number of mutations of different types have been identified throughout this gene affecting the expression, structure, and post-translational alterations of the protein. FVII deficiency is the most frequently recessively inherited bleeding disorder. Subjects with FVII deficiency show a wide range of symptoms, including cutaneous hemorrhage, mucosal hemorrhage, gastrointestinal bleeding, joint bleeding, and central nervous system (CNS) hemorrhage. Unlike other coagulation factor deficiencies, serum levels of FVII do not demonstrate the severity of the disease, and there is no direct correlation between serum levels and clinical complications. Replacement therapy is the treatment of choice for FVII deficiency. Various therapeutic products such as prothrombin complex concentrate, plasma-derived FVII concentrate, fresh frozen plasma, and activated recombinant FVII are available to treat FVII deficient individuals. This review aims to provide information on molecular, biochemical, and clinical aspects of coagulation FVII, its role in hemostasis, and the consequences of its deficiency.

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Inhibitor in Congenital Factor VII Deficiency; a Rare but Serious Therapeutic Challenge—A Systematic Literature Review

Cited by 8 publications

References 24 publications

Molecular Characterization of Two Homozygous Factor VII Variants Associated with Intracranial Bleeding

Molecular Characterization of Two Homozygous Factor VII Variants Associated with Intracranial Bleeding

Risk and Management of Intracerebral Hemorrhage in Patients with Bleeding Disorders

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

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