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Risk Factors of Genetic Thrombosis:
Factor V-Leiden and Prothrombin 20210A
RDB2005
Reverse hybridization kit for the determination
of the mutation FV:Q506 in the Factor V gene and the mutation
20210A in the Factor ll gene
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Factor V-Leiden
Thromboses are caused by disorders of the coagulation system. One
later complication can be the development of a lung emboly. One of
the regulating factors of the coagulation system is Activated Protein
C (APC), which is a serin protease influencing the coagulation process
together with a cofactor by proteolytic inactivation of Factor Va
and VIIIa, two components of the coagulation cascade. Factor Va is
derived from the Factor V-Protein by cleavage, which in turn is mediated
by Factor IIa.
According to current knowledge, the resistance against Activated Protein
C (APC) is the most common genetic risk factor for venose coagulation
disorders. The cause is a point mutation in the Factor V-gene bringing
about a substitution of guanin (G) by adenin (A) at position 1691.
In the translated protein this results in the substitution of the
amino acid arginin by glutamin at the position 506 (FV:Q506).
The altered Factor V gene product is called Factor V Leiden (FVL).
Since the substitution of the amino acid takes place in the binding
region for the APC protein, the FVL variant can be cleaved and inactivated
by APC only very unsufficiently. The result is an accumulation of
Factor Va increasing the coagulation process and therefore the risk
of thrombosis.
An APC resistance can be found in approximately 5% of the population,
in patient groups with own or familial thrombotic anamnesis this share
is up to 60%. The allelic frequency for the mutation just described
is therefore tenfold higher than for the other genetically occasioned
risk factors for thrombosis like lack of Protein C or Antithrombin.
The risk of homozygous carriers is 50 to 100fold, that of heterozygous
carriers 5 to 10fold higher compared with carriers of the unmutated
gene. In combination with other risk factors the probability of a
thrombosis is augmented even further (smoking, oral contraceptiva).
The determination of the resistance against APC is a very important
diagnostic marker for the detection of functional disturbances of
the coagulation system and can give valuable hints about a FVL-genotype.
For the actual detection of carriers of this mutation, however, an
analysis at the DNA level is absolutely necessary.
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Prothrombin (Factor II)
Mutation 20210A
At the end of 1996 a point mutation of the prothrombin gene leading
to a two- to threefold increased risk of thrombosis was described.
The G ® A substitution in position 20210 in the 3' untranslated regulatory
area of the gene causes an increased activity of prothrombin in the
blood plasma. Prothrombin (Factor II) is the precursor of the active
coagulation enzyme thrombin (Factor IIa), which has a key function
in the regulation of the coagulation process (among others the processing
of Factor V to Factor Va). Preliminary results suggest a heterozygous
prevalence of 1 to 2%.
The measurement of the prothrombin activity in the blood plasma does
allow to infer a mutation, because this risk factor can only be detected
at the DNA level.
The DNA probe kit from AID enables you to identify homo- and heterozygous
carriers of the highly significant mutations in the genes for Faktor
V and Factor II. The assay result is a prognostic parameter for patients
with an inclination to thrombosis. The assay can be utilized even
under oral coagulation therapy.
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References
Bertina, R.M., Koelemann, B.P.C., Koster, T., Rosendaal, F.R.,
Dirven, R.J., de Ronde, H., van der Velden, P.A., Reitsma, P.A. (1994)
Mutation in blood coagulation factor V associated with resistance
to activated protein C.
Nature 369: 64-67
Voorberg, J., Roelse, J., Koopman, R., Büller, H., Berends, F., Cate,
J.W., Mertens, K., van Mourik, J.A. (1994)
Association of idiopathic venous thromboembolism with single point-mutation
at Arg506 of factor V
Lancet 343: 1535-1536
Vandenbroucke, J. P.,Koster, T., Briet, E., Reitsma, P.H., Bertina,
R.M., Rosendaal, F.R. (1994)
Increased risk of venous thrombosis in oral-contraceptive users who
are carriers of factor V leiden mutation.
Lancet 344: 1453-1457
Poort, S.R., Rosendaal, F.R., Reitsma, P.H., Bertina, R.M. (1996)
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 88: 3698-3703
Witt, I. (1997)
Prothrombin (Faktor II)-Mutation 20210. Ein neuer heriditärer Risikofaktor
für Thromboembolien.
Clin Lab 44: 61
Markis, M. et al. (1997)
Co-inheritance of the 20210 A allele of the prothrombin gene increases
the risk of thrombosis in subjects with familial thrombphilia.
Thromb Haemost 78: 1426-1429
Spannagl, M., Schramm W. (1998)
APC-Resistenz bei Faktor-V-Leiden: Wie hoch ist das Thromboserisiko?
Dtsch. med. Wschr. 123: 137-139 |
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