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Congenital prothrombin defects: they are not only associated with bleeding but also with thrombosis: a new
Antonio Girolami1, Silvia Ferrari1, Elisabetta Cosi1
1a Department of Medicine , University of Padua Medical School , Padua , Italy.
Insights
Congenital prothrombin deficiency, a rare clotting disorder, has new classifications. Type III defects, unlike Types I and II, present with venous thrombosis instead of bleeding, linked to specific mutations.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Congenital prothrombin deficiency is a rare inherited bleeding disorder.
- It is classified into Type I (low FII activity and antigen) and Type II (low FII activity, normal antigen).
- Bleeding is typical, though less severe in Type II.
Purpose of the Study:
- To reclassify prothrombin defects based on recent findings.
- To investigate the heterogeneity of Type II prothrombin defects.
Main Methods:
- Extensive literature search of published cases (PubMed, Scopus) from 2012 onwards.
- Analysis of reported families with dysprothrombinemia and venous thrombosis.
Main Results:
- Type II defects are heterogeneous.
- Specific heterozygous mutations (e.g., Arg596) are linked to venous thrombosis, not bleeding.
- Mutations in nearby regions did not show this thrombotic association.
Conclusions:
- A new classification is proposed: Type III defects.
- Type III is characterized by venous thrombosis and absence of bleeding.
- This phenotype may be specific to Arg596 mutations or involve other residues.
Objective:
Congenital prothrombin deficiency is one of the rarest clotting disorders. It is commonly subdivided in Type I defects or cases of 'true' prothrombin deficiency characterized by a concomitant decrease in FII activity and antigen and in Type II or dysprothrombinemias, in which FII activity is low but FII antigen is normal or near normal. A bleeding tendency, often a severe one, is the hallmark of the two-defects even though the bleeding is usually less severe in the Type 2 defects or dysprothrombinemias.
Patients And Methods:
An extensive search of published cases of prothrombin deficiency was carried out in Pubmed and Scopus. The search started in 2012, after the publication of the first family with dysprothrombinemia and venous thrombosis. A few additional families were found.
Results:
Recent studies have demonstrated that the Type 2 defects are heterogeneous. Several heterozygous mutations involving the Arg596 residue of exon 14 have been demonstrated not be associated with a bleeding tendency but, surprisingly, with venous thromboses. Mutations in close areas of prothrombin have failed to show the same pattern.
Conclusions:
These observations have required a reclassification of prothrombin defects. To the Type I and Type II defects, a Type III has to be added characterized by the absence of bleeding and the presence of venous thrombosis. It is not clear yet if this special variant of Type II defect is limited to the Arg596 mutations or if other residues may be involved.
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