Diagnosis and management of severe congenital protein C deficiency (SCPCD): Communication from the SSC of the ISTH

Minford, Adrian; Brandão, Leonardo R.; Othman, Maha; Male, Christoph; Abdul‐Kadir, Rezan; Monagle, Paul; Mumford, Andrew D; Adcock, Dorothy M.; Dahlbäck, Björn; Miljić, Predrag; DeSancho, Maria T.; Teruya, Jun

doi:10.1111/jth.15732

Cited by 14 publications

(10 citation statements)

References 40 publications

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“…Even if the patients survive with proper and timely diagnosis and treatments, neonates and children with PC or PS deficiency remain at a risk of developing severe thrombotic complications. These patients require life-long therapy with PC concentrates or fresh frozen plasma and strict anticoagulation treatments, including warfarin or heparin, under frequent monitoring (22) . We succeeded at expressing PC in its active form and showed that genome editing therapy using the engineered PC (PC-2RKR) at the neonatal stage could help in the survival of mice with homozygous PC deficiency.…”

Section: Discussionmentioning

confidence: 99%

Cure of congenital purpura fulminans via expression of engineered protein C through neonatal genome editing in mice

Togashi

Baatartsogt

Nagao

et al. 2023

Preprint

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Protein C (PC) is a plasma anticoagulant encoded by PROC; mutation in both PROC alleles results in neonatal purpura fulminans, a fatal systemic thrombotic disorder. In the present study, we aimed to develop a genome editing treatment to cure congenital PC deficiency. First, we generated an engineered activated PC to insert a self-cleaving peptide sequence between light and heavy chains. The engineered PC could be released in its activated form and significantly prolonged the plasma coagulation time independent of the cofactor activity of protein S in vitro. The adeno-associated virus (AAV) vector-mediated expression of the engineered PC, but not wild-type PC, prolonged coagulation time owing to the inhibition of activated coagulation factor V in a dose-dependent manner and abolished pathological thrombus formation in vivo in C57BL/6 mice. The insertion of EGFP sequence conjugated with self-cleaving peptide sequence at Alb locus via neonatal in vivo genome editing using AAV vector resulted in the expression of EGFP in 7% of liver cells, mainly via homology-directed repair, in mice. Finally, we succeeded in improving the survival of PC-deficient mice by expressing the engineered PC via neonatal genome editing in vivo. These results suggest that the expression of the engineered PC via neonatal genome editing is a potential cure for severe congenital PC deficiency.

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Section: Discussionmentioning

confidence: 99%

Cure of congenital purpura fulminans via expression of engineered protein C through neonatal genome editing in mice

Togashi

Baatartsogt

Nagao

et al. 2023

Preprint

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“…Repeated measurement of anticoagulant activity may allow the efficient selection of cases requiring genetic testing. In neonatal patients with suspected PROC ‐biallelic variants, PC replacement and anticoagulant therapies must be initiated immediately without waiting for the results of genetic testing 20 . Genetic testing for pediatric patients with suspected PROC ‐monoallelic, PROS1 , or SERPINC1 variants is not always necessary in childhood.…”

Section: Discussionmentioning

confidence: 99%

“…Anticoagulant activities vary widely among individuals and with age; therefore, it is difficult to make PC replacement and anticoagulant therapies must be initiated immediately without waiting for the results of genetic testing. 20 Genetic testing for pediatric patients with suspected PROC-monoallelic, PROS1, or SERPINC1 variants is not always necessary in childhood. However, they are at increased risk of thrombosis at the time of infectious disease, surgery, and some systemic diseases.…”

Section: Discussionmentioning

confidence: 99%

The clinical and genetic landscape of early‐onset thrombophilia in Japan

Egami,

Ishimura,

Ochiai

et al. 2023

Pediatric Blood & Cancer

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ObjectivesTo determine the optimal management for early‐onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)‐, protein S (PS)‐, or antithrombin (AT)‐deficient patients of ≤20 years of age were studied in Japan.Methods/resultsClinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One‐hundred‐one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC‐ and PS‐monoallelic variant. Fifty‐five PC‐deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS‐deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT‐biallelic variants. The frequent low‐risk allele p.K193del (PC‐Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low‐risk allele p.K196E (PS‐Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother–newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication‐free survivors. Neurological complications were more frequently found in patients with PC‐biallelic variants than those with PC‐, PS‐, or AT‐monoallelic variants (73% vs. 24%, p = .019).ConclusionsWe demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother–infant pairs may prevent perinatal thrombosis in them.

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“…63 Conversely, the autosomal recessive severe congenital protein C deficiency (SCPCD) typically presents with potentially fatal purpura fulminans and DIC within 72 hours of birth and undetectable plasma PC. 75 Rarely, less severe SCPCD presents with delayed onset at about 10 months of age, or individuals surviving into adulthood before experiencing VTE. 75,76 Observed prevalence of SCPCD is lower than predicted incidence, suggesting fetal demise or undiagnosed perinatal deaths.…”

Section: Protein Cmentioning

confidence: 99%

Thrombophilia Screening: Not So Straightforward

Moore

2024

Semin Thromb Hemost

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Although inherited thrombophilias are lifelong risk factors for a first thrombotic episode, progression to thrombosis is multifactorial and not all individuals with inherited thrombophilia develop thrombosis in their lifetimes. Consequently, indiscriminate screening in patients with idiopathic thrombosis is not recommended, since presence of a thrombophilia does not necessarily predict recurrence or influence management, and testing should be selective. It follows that a decision to undertake laboratory detection of thrombophilia should be aligned with a concerted effort to identify any significant abnormalities, because it will inform patient management. Deficiencies of antithrombin and protein C are rare and usually determined using phenotypic assays assessing biological activities, whereas protein S deficiency (also rare) is commonly detected with antigenic assays for the free form of protein S since available activity assays are considered to lack specificity. In each case, no single phenotypic assay is capable of detecting every deficiency, because the various mutations express different molecular characteristics, rendering thrombophilia screening repertoires employing one assay per potential deficiency, of limited effectiveness. Activated protein C resistance (APCR) is more common than discrete deficiencies of antithrombin, protein C, and protein S and also often detected initially with phenotypic assays; however, some centres perform only genetic analysis for factor V Leiden, as this is responsible for most cases of hereditary APCR, accepting that acquired APCR and rare F5 mutations conferring APCR will go undetected if only factor V Leiden is evaluated. All phenotypic assays have interferences and limitations, which must be factored into decisions about if, and when, to test, and be given consideration in the laboratory during assay performance and interpretation. This review looks in detail at performance and limitations of routine phenotypic thrombophilia assays.

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Diagnosis and management of severe congenital protein C deficiency (SCPCD): Communication from the SSC of the ISTH

Cited by 14 publications

References 40 publications

Cure of congenital purpura fulminans via expression of engineered protein C through neonatal genome editing in mice

Cure of congenital purpura fulminans via expression of engineered protein C through neonatal genome editing in mice

The clinical and genetic landscape of early‐onset thrombophilia in Japan

Thrombophilia Screening: Not So Straightforward

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