Laboratory Limitations of Excluding Hereditary Protein C Deficiency by Chromogenic Assay: Discrepancies of Phenotype and Genotype

Seidel, H.; Haracska, Bianca; Naumann, Jennifer; Westhofen, P.; Hass, Moritz Sebastian; Kruppenbacher, Johannes Philipp

doi:10.1177/1076029620912028

Cited by 7 publications

(8 citation statements)

References 55 publications

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“…The detection of two pathogenic PROC variants supports a diagnosis of SCPCD if they occur on different copies of PROC (i.e., mother and father are both monoallelic). Genetic testing is a valuable adjunct to phenotypic laboratory tests in the diagnosis of SCPCD and in confirming subtype 19 . The greatest value of genetic testing is that it enables prenatal diagnosis in subsequent pregnancies and potentially interventions such as preimplantation embryo selection.…”

Section: Genetic Testingmentioning

confidence: 99%

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

Minford

Brandão

Othman

et al. 2022

Journal of Thrombosis and Haemostasis

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Severe congenital protein C deficiency (SCPCD) is rare and there is currently substantial variation in the management of this condition. A joint project by three Scientific and Standardization Committees of the ISTH: Plasma Coagulation Inhibitors, Pediatric/ Neonatal Thrombosis and Hemostasis, and Women's Health Issues in Thrombosis and Hemostasis, was developed to review the current evidence and help guide on diagnosis and management of SCPCD. We provide a summary of the clinical presentations, differential diagnoses, appropriate investigations to confirm the diagnosis, approaches for management of the acute situation, and options for long-term management including subsequent pregnancies. We finally provide a set of recommendations to help in this regard.

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Section: Genetic Testingmentioning

confidence: 99%

“…Genetic testing is a valuable adjunct to phenotypic laboratory tests in the diagnosis of SCPCD and in confirming subtype. 19 The greatest value of genetic testing is that it enables prenatal diagnosis in subsequent pregnancies and potentially interventions such as preimplantation embryo selection.…”

Section: G Ene Ti C Te S Tingmentioning

confidence: 99%

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

Minford

Brandão

Othman

et al. 2022

Journal of Thrombosis and Haemostasis

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“…The clotting time-based PC activity assay combined with the genetic analysis would be recommended to make the diagnosis. 31 Ser252 to Asn252 substitution introduces a new potential N-linked glycosylation site on the serine protease structural domain of PC. Previous studies have identified four potential N-linked glycosylation sites in PC.…”

Section: Discussionmentioning

confidence: 99%

“…The clotting time-based PC activity assay combined with the genetic analysis would be recommended to make the diagnosis. 31…”

Section: Discussionmentioning

confidence: 99%

Ser252Asn Mutation Introduces a New N-Linked Glycosylation Site and Causes Type IIb Protein C Deficiency

Zhou,

Wu,

Song

et al. 2023

Thromb Haemost

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Background: Protein C (PC) is a vitamin K-dependent anticoagulant serine protease zymogen which upon activation by the thrombin–thrombomodulin (TM) complex downregulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. We identified a thrombosis patient who carried a heterozygous mutation c.881G > A, p.Ser252Asn (S252N) in PROC. This mutation was originally described in a report of novel mutations in patients presenting with defective PC anticoagulant activity in Paris. The research identified PC-S252N (the “Paris” mutation) in a propositus and her family members and highlighted the critical role of Ser252 in the anticoagulation process of activated PC (APC). Material and Methods: We expressed the PC-S252N mutant in mammalian cells and characterized the properties in coagulation assays to decipher the molecular basis of anticoagulant defect of this mutation. Results: We demonstrated that PC-S252N had a diminished ability to TM binding, which resulted in its impaired activation by the thrombin-TM complex. However, APC-S252N exhibited a slightly stronger cleavage capacity for the chromogenic substrate. Meanwhile, the catalytic activity of APC-S252N toward FVa was significantly reduced. Sequence analysis revealed that Ser252 to Asn substitution introduced a new potential N-linked glycosylation site (252NTT254) in the catalytic domain of PC, which adversely affected both the activation process of PC and anticoagulant activity of APC. Conclusion: The new N-glycosylation site (252NTT254) resulting from the mutation of Ser252 to Asn252 in PROC affects the overall structure of the protease, thereby adversely affecting the anticoagulant function of protein C. This modification has a negative impact on both TM-promoted activation of protein C and APC cleavage of FVa, ultimately leading to thrombosis in the patient.

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“…However, while the chromogenic assays will detect quantitative deficiencies and active site defects, they are insensitive to functional defects of substrate and cofactor binding, which are detectable in clotting assays. [120][121][122] Protac is also used to activate endogenous PC in the aPTT-based ProC Global screening test for abnormalities in the PC pathway. 123 It was also used in the now discontinued chromogenic PC pathway screening test, ThromboPath.…”

Section: Protein Cmentioning

confidence: 99%

Snake Venoms in Diagnostic Hemostasis and Thrombosis

Moore

2021

Semin Thromb Hemost

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Snake venoms have evolved primarily to immobilize and kill prey, and consequently, they contain some of the most potent natural toxins. Part of that armory is a range of hemotoxic components that affect every area of hemostasis, which we have harnessed to great effect in the study and diagnosis of hemostatic disorders. The most widely used are those that affect coagulation, such as thrombin-like enzymes unaffected by heparin and direct thrombin inhibitors, which can help confirm or dispute their presence in plasma. The liquid gold of coagulation activators is Russell's viper venom, since it contains activators of factor X and factor V. It is used in a range of clotting-based assays, such as assessment of factor X and factor V deficiencies, protein C and protein S deficiencies, activated protein C resistance, and probably the most important test for lupus anticoagulants, the dilute Russell's viper venom time. Activators of prothrombin, such as oscutarin C from Coastal Taipan venom and ecarin from saw-scaled viper venom, are employed in prothrombin activity assays and lupus anticoagulant detection, and ecarin has a valuable role in quantitative assays of direct thrombin inhibitors. Snake venoms affecting primary hemostasis include botrocetin from the jararaca, which can be used to assay von Willebrand factor activity, and convulxin from the cascavel, which can be used to detect deficiency of the platelet collagen receptor, glycoprotein VI. This article takes the reader to every area of the diagnostic hemostasis laboratory to appreciate the myriad applications of snake venoms available in diagnostic practice.

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Laboratory Limitations of Excluding Hereditary Protein C Deficiency by Chromogenic Assay: Discrepancies of Phenotype and Genotype

Cited by 7 publications

References 55 publications

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

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

Ser252Asn Mutation Introduces a New N-Linked Glycosylation Site and Causes Type IIb Protein C Deficiency

Snake Venoms in Diagnostic Hemostasis and Thrombosis

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