Partial<i>F8</i>gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia

Simioni, Paolo; Cagnin, Stefano; Sartorello, Francesca; Sales, Gabriele; Pagani, Luca; Bulato, Cristiana; Gavasso, Sabrina; Nuzzo, Francesca; Chemello, Francesco; Radu, Claudia; Tormene, Daniela; Spiezia, Luca; Hackeng, Tilman M.; Campello, Elena; Castoldi, Elisabetta

doi:10.1182/blood.2020008168

Cited by 23 publications

(20 citation statements)

References 66 publications

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“…The genetic defects in these families were identified by sequencing the candidate genes (F9, F2, and F8, respectively). [29][30][31] However, the results obtained by massive sequencing (whole exome or whole genome) of thrombophilic families or patients with thrombosis have not been very gratifying, as only a few novel (and conflicting) thrombophilias have been identified. 32,33 We speculated that genetic defects affecting key hemostatic proteins previously involved in classical thrombophilias might not have been detected because of the limitation of current diagnostic functional tests.…”

Section: Discussionmentioning

confidence: 99%

Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays

Morena‐Barrio

Suchon

Jacobsen

et al. 2022

Blood

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Antithrombin deficiency, the most severe congenital thrombophilia, might be underestimated, as some pathogenic variants are not detected by routine functional methods. We have identified two new SERPINC1 variants, p.Glu227Lys and p.Asn224His, in four unrelated thrombophilic patients with early and recurrent thrombosis that had normal antithrombin activity. In one case, the mutation was identified by whole genome sequencing, while in the 3 remaining cases, the mutation was identified by sequencing SERPINC1 based on a single functional positive finding supporting deficiency. The two variants shared a common functional defect, an impaired or null N-glycosylation of Asn224 according to a eukaryotic expression model. Carriers had normal anti-FXa or anti-FIIa activities, but impaired anti-FVIIa activity and a detectable loss of inhibitory function when incubating the plasma 1 hour at 41ºC. Moreover, the beta glycoform of the variants, lacking two N-glycans, had reduced secretion, increased heparin affinity, no inhibitory activity, and a potential dominant negative effect. These results explain the increased thrombin generation observed in carriers. Mutation experiments reflected the role that Lysine residues close to the N-glycosylation sequon have in impairing the efficacy of N-glycosylation. Our study shows new elements involved in the regulation of N-glycosylation, a key post-translational modification that, according to our results affects folding, secretion and function, providing new evidence of the pathogenic consequence of an incorrect N-glycosylation of antithrombin. This study supports that antithrombin deficiency is underestimated and encourages the development of new functional and genetic tests to diagnose this severe thrombophilia.

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Section: Discussionmentioning

confidence: 99%

Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays

Morena‐Barrio

Suchon

Jacobsen

et al. 2022

Blood

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“…In contrast to the discovery of the hyperfunctional FIX Padua variant, to date, no gain‐of‐function FVIII variants have been identified to enhance transgenic FVIII expression, although the very recent finding of a FVIII regulatory variant resulting in 3‐ to 4‐fold increases in FVIII plasma levels may have potential (Table 2). 18 …”

Section: Hemophilia a Gene Therapy Trialsmentioning

confidence: 99%

“… 18. TA B L E 1Nevertheless, in recent phase 2 and 3 clinical trials, plasma FVIII levels between 0.2 and 2.0 IU/mL (one-stage > chromogenic assay results-see below) have been documented in most patients, with very few subjects showing no benefit.…”

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confidence: 99%

Gene therapy for hemophilia: Current status and laboratory consequences

Batty

Lillicrap

2021

Int J Lab Hematology

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Since the cloning and characterization of the factor VIII (FVIII) and factor IX genes in the mid‐1980s, gene therapy has been perceived as having significant potential for the treatment of severe hemophilia. Now, some 35 years later, these proposals are close to being realized through the licensing of the first clinical gene therapy product. Adeno‐associated viral vector‐mediated gene therapy for hemophilia A and B has been extensively investigated in preclinical models over the past 20 years, and since 2011, there has been increasing evidence in early phase clinical trials that this therapeutic strategy can provide safe and effective rescue of the hemostatic phenotype in severe hemophilia. As the uptake of hemophilia gene therapy progresses, it is clear that many aspects of the gene therapy process require crucial laboratory support to ensure safe and effective outcomes from his new therapeutic paradigm. These laboratory contributions extend from evaluations of the gene therapy vehicle, assessments of the patient immune status for the vector, and ultimately the performance of assays to determine the hemostatic benefit of the gene therapy and potentially of its long‐term safety on the host genome. As with many aspects of past hemophilia care, the safe and effective delivery of gene therapy will require an informed and coordinated contribution from laboratory science.

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“… 6 Familial clustering has been observed but so far, only one genetic defect, a partial F8 gene duplication in FVIII Padua has been linked with very high plasma levels of FVIII. 7 …”

Section: Introductionmentioning

confidence: 99%

“…6 Familial clustering has been observed but so far, only one genetic defect, a partial F8 gene duplication in FVIII Padua has been linked with very high plasma levels of FVIII. 7 Elevated FVIII levels are commonly found in patients with inflammatory bowel disease (IBD). [8][9][10][11][12] A study in pediatric patients diagnosed with Crohn's disease found a positive association between FVIII levels, disease activity, and other markers of inflammation such as erythrocyte sedimentation rate, serum orosomucoid, albumin, and C-reactive protein.…”

Section: Introductionmentioning

confidence: 99%

High Factor VIII Levels and Recurrent Thromboembolism in Patients with and without Inflammatory Bowel Disease: A Retrospective Comparative Study

Eagle

Schulman

2022

TH Open

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Background The natural course of elevated factor VIII (FVIII) in patients with venous thromboembolism (VTE) and with or without inflammatory bowel disease (IBD) is not well described. Furthermore, the data on effectiveness and safety of extended anticoagulation in these patients are limited. Methods We performed a retrospective chart review of all patients with VTE, who had an elevated FVIII level (>1.5 IU/mL) during a period of 16 years. FVIII levels, duration of anticoagulation, recurrent thromboembolic events and bleeding requiring hospitalization were captured and compared between patients with and without IBD. Results Fourteen patients with IBD and 66 without IBD were followed for 8.0 years (standard deviation [SD] ±3.5) and 5.6 years (SD ±5.1), respectively. Among the 41 patients with repeat levels, FVIII remained elevated in most patients. None of the IBD patients had thromboembolic events or major bleeding during a mean of 5.6 years (SD ±5.1) of anticoagulation. Three of 5 IBD patients that stopped anticoagulation had thromboembolic events at a median of 9 months after stopping – observed event rate 12 per 100 patient-years. For the 66 non-IBD patients the event rates of thromboembolism on and off anticoagulation were 1.6 and 7.2 per 100 patient-years, respectively, and of major bleeding on anticoagulation 0.8 per 100 patient-years. Conclusion Elevated FVIII in patients with VTE is often a persistent risk factor. The cohort with VTE and elevated FVIII that we analyzed appeared to have a favorable benefit/risk ratio of extended anticoagulation.

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PartialF8gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia

Cited by 23 publications

References 66 publications

Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays

Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays

Gene therapy for hemophilia: Current status and laboratory consequences

High Factor VIII Levels and Recurrent Thromboembolism in Patients with and without Inflammatory Bowel Disease: A Retrospective Comparative Study

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