Ox Brain versus Rabbit Brain Thromboplastin Assays Are the Best Tool for a Preliminary Diagnosis of the Arg304Gln Factor VII Defect (FVII Padua)

Girolami, Antonio; Marinis, Giulia Berti de; Bonamigo, Emanuela; Sartori, Roberta; Vettore, Silvia

doi:10.1159/000321534

Cited by 12 publications

(12 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The differential activity observed with various TF forms suggests an impact on TF-binding properties and allosteric conformational changes leading to the catalytically competent FVIIa form. In contrast to the well characterized FVII Padua variant 24 which exhibits reduced or normal specific activity with human or bovine thromboplastins, the FVII-462X molecule displays gain-offunction features. However, the very low protein levels secreted in medium mean that detailed information about their biochemical characterization cannot be obtained.…”

Section: Resultsmentioning

confidence: 90%

Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency

Branchini¹,

Rizzotto²,

Mariani³

et al. 2011

Haematologica

View full text Add to dashboard Cite

Articles and Brief Reportshaematologica | 2012; 97 (5) 705 IntroductionThe congenital deficiency of coagulation factor VII (FVII) (OMIM: 227500) is a rare hemorrhagic disorder with an autosomal recessive inheritance pattern.1 Clarification of the relationship between FVII coagulant activity levels in plasma and bleeding diathesis is greatly helped by our understanding of the molecular mechanisms through which F7 gene mutations 2-3 modulate FVII levels. Nonsense mutations, by inducing mRNA degradation 4 and/or premature termination of translation and synthesis of truncated proteins, are often responsible for very severe forms of human diseases. As expected from the crucial role of FVII in coagulation, 5 very few homozygous patients present this type of mutation and these are associated with undetectable FVII levels and severe 6-8 or moderate 9 bleeding. Coagulation serine proteases share extensive homology 10 but are highly variable in their carboxy-terminal region, the functional role of which has still not been established.In this study, we characterized the p.R462X nonsense mutation and provided evidence for its pleiotropic effects, i.e. reduced secretion and increased specific activity, thus explaining the asymptomatic phenotype in patients. Furthermore, a panel of recombinant carboxy-terminal variants contributed to our understanding of the role of this highly variable region in coagulation serine proteases. Design and Methods PatientsThe proposita (PFVII-R462X) is a 12-year old girl who had been diagnosed for FVII deficiency during a routine coagulation screening. The patient presented with a prolonged prothrombin time (8%) and decreased FVII coagulant activity (3 and 5% of normal in 2 samples taken one year apart); all other coagulation factors functioned normally. She had no history of any bleeding and continues to be asymptomatic. F7 gene sequencing 11 identified the c.1384C>T transition (GenBank #NM_000131.3) in a homozygous condition. This Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency 74 -44121 Ferrara, Italy. Phone: international +39.0532974424. Fax: international +39.0532974484. E-mail: pnm@unife.it We report 2 asymptomatic homozygotes for the nonsense p.R462X mutation affecting the carboxy-terminus of coagulation factor VII (FVII, 466 aminoacids). FVII levels of 3-5% and 2.7±0.4% were found in prothrombin time-based and activated factor X (FXa) generation assays with human thromboplastins. Noticeably, FVII antigen levels were barely detectable (0.7±0.2%) which suggested a gain-of-function effect. This effect was more pronounced with bovine thromboplastin (4.8±0.9%) and disappeared with rabbit thromboplastin (0.7±0.2%). This suggests that the mutation influences tissue factor/FVII interactions. Whereas the recombinant rFVII-462X variant confirmed an increase in specific activity (~400%), a panel of nonsense (p.P466X, p.F465X, p.P464X, p.A463X) and missense (p.R462A, p.R462Q, p.R462W) mutations o...

show abstract

Section: Resultsmentioning

confidence: 90%

Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency

Branchini¹,

Rizzotto²,

Mariani³

et al. 2011

Haematologica

View full text Add to dashboard Cite

show abstract

“…25 Girolami et al suggest the use of at least 2 thromboplastins from 2 different sources (rabbit brain vs ox brain) as a surrogate approach to molecular diagnosis to identify this peculiar defect. 25 From a clinical standpoint, results yielded with human recombinant thromboplastin in FVII Padua defect (around 30%) could better reflect the clinical phenotype as all the cases described in the literature have mild bleeding manifestations or are not symptomatic, whereas results obtained with rabbit brain thromboplastin (5%-10%) would suggest a more pronounced defect, and results obtained with ox brain thromboplastin (around 100%) would classify the patient as normal. The use of rabbit brain thromboplastin is, however, recommended as a first-line screening test in case of FVII defect suspicion because of its increased sensitivity.…”

Section: Preanalytical Conditions For Fvii Measurementmentioning

confidence: 99%

“…The use of rabbit brain thromboplastin is, however, recommended as a first-line screening test in case of FVII defect suspicion because of its increased sensitivity. 25 FVII Nagoya (Arg304Trp) and FVII Tondabayashi or Shinjo (Arg79Gln), which are also type II variants, have been shown to exhibit a similar pattern of variable reactivity toward different tissue thromboplastins as FVII Padua. The occurrence of these defects is sporadic.…”

Section: Factor Vii:c Clotting Assaymentioning

confidence: 99%

Factor VII Deficiency: From Basics to Clinical Laboratory Diagnosis and Patient Management

Sevenet

Kaczor

Depasse

2016

Clin Appl Thromb Hemost

View full text Add to dashboard Cite

Factor VII (FVII) deficiency is a rare inheritable bleeding disorder affecting 1/500 000 individuals. Clinical manifestations are heterogeneous, from asymptomatic to severe and potentially fatal bleeding. These clinical manifestations do not correlate well with FVII plasma levels. For this reason, FVII-deficient patient management during surgery or for long-term prophylaxis remains challenging. Laboratory testing for FVII activity is, however, the first-line method for FVII deficiency diagnosis and is helpful for managing patients in combination with clinical history. Additional testing consists of FVII immunoassay and genetic testing. Genetic abnormalities on the FVII gene are heterogeneous and can translate into quantitative or qualitative defects. Some of the latter can react differently with different thromboplastins; this can be misleading for the laboratory as no consensus exists at present on an FVII deficiency diagnosis methodology. Indeed, no single test is able to predict accurately the bleeding risk. This review provides a broad picture of inherited and acquired FVII deficiency with a particular focus on laboratory diagnosis.

show abstract

“…However, it is not uncommon to observe qualitative defects (low activity and normal antigen) partly as a result of variable sensitivities of TF reagents to FVII variants. 98 Common bleeding sites include nose, oral cavity, surgical wound, and in female patients, menorrhagia and postpartum haemorrhage are reported (Table 1). Severe FVII deficiency below 1% activity may exhibit bleeding episodes similar to haemophilia, including haemarthrosis, and intracranial haemorrhage.…”

Section: Rbd In Extrinsic Pathwaymentioning

confidence: 99%

“…Some FVII variants give erroneous quantitation using TF derived from ox or rabbits, but demonstrate improved activity in the presence of human TF. 98 Perioperative Management. Plasma FVII activity can be specifically restored by using rFVIIa or plasma-derived FVII (pdFVII) ( Table 4).…”

Section: Rbd In Extrinsic Pathwaymentioning

confidence: 99%

Perioperative management of rare coagulation factor deficiency states in cardiac surgery

Strauss

Mazzeffi

Williams

et al. 2017

British Journal of Anaesthesia

View full text Add to dashboard Cite

Rare bleeding disorders (RBDs) include the hereditary deficiency of fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, FXI or FXIII. RBDs do not confer a protective effect against atheromatous plaque formation, and thus the need for cardiovascular (CV) surgery in RBD patients is expected to increase with improved healthcare access (diagnosis and management) and longevity of the population. Clinical data regarding the management of RBDs in this setting are sparse, but the perioperative care team is obliged to gain a better understanding on available biological and pharmacological hemostatic agents. Perioperative management of RBDs in CV surgery is further complicated by heparin anticoagulation, haemodilution, and consumption of procoagulant and anticoagulant proteins associated with cardiopulmonary bypass (CPB). The aims of this review are to summarize pathophysiology of RBDs and laboratory monitoring pertinent to CV surgery, available factor replacement agents, and to provide the framework for perioperative coagulation management of RBD patients.

show abstract

Ox Brain versus Rabbit Brain Thromboplastin Assays Are the Best Tool for a Preliminary Diagnosis of the Arg304Gln Factor VII Defect (FVII Padua)

Cited by 12 publications

References 51 publications

Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency

Natural and engineered carboxy-terminal variants: decreased secretion and gain-of-function result in asymptomatic coagulation factor VII deficiency

Factor VII Deficiency: From Basics to Clinical Laboratory Diagnosis and Patient Management

Perioperative management of rare coagulation factor deficiency states in cardiac surgery

Contact Info

Product

Resources

About