The initial screening test for coagulation in most rare bleeding disorders is the PT and PTT. In prothrombin deficiency, the PT and PTT are often prolonged. A mixing study can help differentiate between a factor deficiency and the presence of an inhibitor.33 Specific tests for FII activity and antigen levels are performed to evaluate for prothrombin deficiency. A FII activity assay often utilizes the one-stage standard clotting assay using tissue thromboplastin as the activating agent and FII-depleted plasma as the substrate. The FII antigen level is often detected using a chromogenic/fluorogenic assay to measure the amidolytic activity of thrombin generated toward a peptide that interacts with the thrombin active site.
FII activity and antigen levels can help distinguish between type I defects (i.e. hypoprothrombinemia) and type II defects (i.e. dysprothrombinemia). A person with hypoprothrombinemia will have low FII activity and antigen levels <10-20% of normal. In contrast, a person with dysprothrombinemia will have a low FII activity level but discrepant normal or near-normal FII antigen level. Heterozygotes tend to have FII activity levels ranging from 30-60% of normal, compared to normal relatives with FII activity levels that are usually >70%.
A molecular diagnosis of prothrombin deficiency involves detection of a mutation within the prothrombin gene. Molecular testing can be performed by capillary-based Sanger sequencing or by deletion/duplication testing using array comparative genomic hybridization. However, more rapid next-generation sequencing is becoming increasingly available for the identification of prothrombin gene mutations, but may not be commercially available in many regions. Prenatal diagnosis is available through genetic analysis of blood samples obtained via chorionic villus sampling or amniocentesis. Prenatal testing is only recommended in cases where there is a family history of prothrombin deficiency with a severe bleeding phenotype and the genotype is known.
Imaging studies are not required for all bleeding events. In cases where imaging is indicated to assess the extent of bleeding, the specific modality preferred will depend upon the site of active or suspected bleeding. Imaging modalities may include simple radiographs (x-rays) ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI).
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
