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Updated January 23, 2003
'II' BE OR NOT 'II' BE TESTED
PROTHROMBIN GENE MUTATION - A New Thrombophilia Risk
Background
In November 1996, a new genetic marker for Thrombophilia was identified by the same group that
identified Factor V Leiden. Using the same venous thrombosis patient database, they found a genetic
mutation in the 3' untranslated region (3'-UTR) of the prothrombin (Factor II) gene that was
associated with an increased risk of venous thrombosis. Using PCR and gene sequencing, they
identified a point mutation at nucleotide position 20210 involving a G to A transition. The study
involved almost 500 patients and an equal number of controls. The G to A mutation was found in
2.3% of the healthy normals but occurred more frequently in the patient population. In thrombotic
patients with a known family history, 18% of them possessed the mutation compared to a frequency
of 6.3% in patients with a first episode of thrombosis.
Clinical Application
The mutation was equally prevalent in men and woman and was an independent risk factor. The
relative risk (odds ratio) for venous thrombosis associated with the mutation was 2.8, making it a
moderate risk factor. The homozygous state (AA) is very rare with an expected prevalence of
0.014% and only a handful of patients have been identified. At least 3 of the reported 5 homozygous
patients had thrombosis at an early age.
One unexpected sequela of this mutation is the association with higher levels of plasma factor II
activity. Given that the mutation is in the untranslated part of the gene, the factor II protein produced
by the gene is normal. Gehring, et al. demonstrated that the increase in the circulating factor II level
is due to enhanced 3-prime end processing that yields increased mRNA for Factor II. The mean level
of factor II in the heterozygous patients was 132% compared to 105% in the healthy controls.
Several subsequent smaller studies have validated these findings, with the mutation frequency varying
from 0.8% to 4.8% in these other European studies. Data on US populations are also limited, but
studies from Seattle, Atlanta and New York suggest a frequency between 2-5%. The mutation
appears in African Americans (1.7 %) and has not been found in Orientals, although there is very
limited data.
The ethnic distribution of the mutation appears to parallel that of Factor V Leiden and be expressed
almost exclusively in Caucasians, including Hispanics. The prothrombin gene mutation appears to
also co-segregate with factor V Leiden with 10% of these patients also having the prothrombin
mutation in the Atlanta data. These findings further validate the 'double hit' theory, increasingly
being found in young thrombophilia patients. Data from a significant number of normal controls in
the Atlanta study had elevated plasma factor II values but did not express the mutation. This may
be due to some up regulation mechanism when a pathogen or infection is present. In HEMEX studies
of chronically ill patients, greater than 90% of all repeat analyses of factor II that are within +/- 5%
of the original value, indicating little up regulation of this protein. However, caution should be used
in evaluating thrombophilia patients solely with a factor II assay.
HEMEX Laboratories offers the Factor II quantitative assay, the Factor II (Prothrombin) gene
mutation G20210A assay by FRET (Fluorescence Resonance Energy Transfer) methodology, and
a panel containing both assays. Data from new patient testing in 2001 indicates that 38% of patients
with CFS and related chronic illnesses who had the HTRP (Hereditary Thrombosis Risk Panel) tests,
had an elevated Factor II level. In this group of chronic illness patients, a Factor II quantitative
abnormality was the number one hereditary procoagulant defect, followed by Lp(a), PAI-1,
Homocysteine, Protein S deficiency, ACP Resistance (Factor V Leiden), Protein C deficiency and
Antithrombin deficiency (Harrison, et al. 2002).
References
- Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3' untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 55: 3698-703.
- Howard T, Chanell C, Marsura M & Duncan A. Massive thrombosis associated with homozygous 3'UTR prothrombin gene mutation. Blood Coagulation & Fibrinolysis 1997; 8: 316-9.
- Conroy JM, Trivedi G, Sovd T & Caggana M. The allele frequency in four genes that confer enhanced susceptibility to venous thromboembolism in an unselected group of New York State newborns. Thrombosis Research 2000; 99: 317-324.
- Gehring NH, Frede U, Neu-Yilik G, Hundsdoerfer P, Vetter B, Hentze MW, & Kulozik AE. Increased efficiency of mRNA 3-prime end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nature Genet 2001; 28: 389-92.
- Harrison H, Berg L & Berg D. Polygenic contributions of procoagulant genetic factors in Chronic Fatigue Syndrome and related chronic illnesses. Genet Med 2002; 4:181.
Please note:
HEMEX Laboratories also offers Factor V Leiden and the MTHFR C677T and A1298C DNA Testing by FRET methodology. Also available are the more comprehensive functional correlates of APC Resistance and Homocysteine, respectively.