Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1828-1829
CORRESPONDENCE
Double-Homozygosity for Factor V Leiden and the Prothrombin Gene
G20210A Variant in a Young Patient With Idiopathic Venous
Thrombosis
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LETTER |
To the Editor:
There is growing evidence that environmental and genetic risk factors
often interact to induce clinically manifest venous thromboembolism
(VTE). The role of gene-gene interactions, although much rarer, is
supported by cosegregation of genetic defects observed in patients with
familial thrombophilia. In this context, factor V (FV) Leiden and the
prothrombin G20210A gene (FII) mutation are of particular interest
because of their high prevalence in the normal population; about 5%
and 2%, respectively, in whites.1,2 The FII mutation has
been reported in 10% of FV Leiden carriers with VTE,3
while FV Leiden is present in 30% to 40% of symptomatic carriers of
the FII mutation.2,4 Homozygosity for these mutations is
less common, with a prevalence of 0.02% for FV Leiden and 0.014% for
the FII mutation.1,2 We present here a case of
double-homozygosity for these defects.
A 34-year-old man presented with a first episode of idiopathic
deep-vein thrombosis. He had never been exposed to environmental risk
factors for thrombosis. Treatment consisted of subcutaneous low-molecular-weight heparin for 1 week followed by acenocoumarol for 3 months. At 18 months follow-up, he had experienced no
recurrence. Laboratory studies for thrombophilic disorders
showed double-homozygosity for FV Leiden and the FII mutation, detected
by polymerase chain reaction. None of his 15 relatives had a history of
VTE. Four were double-heterozygous carriers, 4 were single carriers of
the FII mutation, and 3 were noncarriers (Fig
1). Four relatives, 2 of whom had died,
were not tested but they were obligate carriers of at least 1 (N = 1)
or both (N = 3) mutations. The patient's father, who had a history of
smoking and hypercholesterolemia, died of myocardial infarction at 57 years of age and a son died from cribdeath. His mother experienced a
myocardial infarction when she was 61 years old; she had a history of
hypertension and diabetes mellitus. Fetal loss had occurred only in 1 noncarrier. Table 1 summarizes
characteristics of this family.
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| Fig 1.
Pedigree of the reported family. The arrow indicates the
propositus, who is a double-homozygous carrier of factor V Leiden (FVL)
and the prothrombin G20210A gene mutation (FII). Individuals with a
slash through the symbol are deceased. TE, venous thromboembolism.
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Double-homozygosity for FV Leiden and the FII mutation is extremely
rare. Theoretically, it is expected in 3 per 100 million whites. The
thrombotic risk of this combined abnormality is unknown. Homozygosity
for FV Leiden increases the risk of VTE approximately 80-fold compared
with noncarriers.1 The risk in homozygous carriers of the
FII mutation has not yet been estimated; only case reports have been published.
Remarkably, only our double-homozygous patient has developed venous
thrombosis, while none of his single- or double-heterozygous carrier
relatives have experienced VTE thus far, despite their exposure to
several environmental risk factors (Table 1). The compound carriership
in this family is apparently not associated with a high risk of VTE.
This finding agrees with a recent observation that the thrombotic risk
in FII mutants is hardly influenced by the simultaneous presence of FV
Leiden.4 Others, however, reported a high risk of
recurrence in double-heterozygous mutants.3 Concomitant
protective genetic factors in families with a hardly increased risk of
VTE may explain this discrepancy.
Both mutations have also been associated with myocardial
infarction.5 Their contribution to this event in 2 double-heterozygous carriers, who already exhibited several established
risk factors, remains speculative. None of the carriers showed fetal
loss, another possible expression of thrombophilia.6
Elevated plasma levels of prothrombin in carriers of the FII mutation
have been correlated with the thrombotic risk.2 In our
double-homozygous patient, prothrombin activity was shown to be clearly
higher than in noncarriers, while heterozygous carriers had values that
fell in between.
This family illustrates that expression of the supposed high risk of
thrombosis, due to gene-gene interaction and exposure to environmental
risk factors, is not a matter of course in compound carriers of FV
Leiden and the FII mutation. Our findings emphasize the need for
further studies to assess the implications of these common mutations in
compound carriers.
Johan R. Meinardi
Peter M. Pelsma
Hans Koning
Jan van der Meer
Division of Haemostasis,
Thrombosis and Rheology
University Hospital
Groningen, The
NetherlandsSaskia Middeldorp
Harry R. Büller
Center for Haemostasis, Thrombosis, Atherosclerosis
and Inflamma tion Research
Academic Medical Center
Amsterdam, The
Netherlands
Karly Hamulyák
Department of
Haematology
University Hospital
Maastricht, The
Netherlands
| |
REFERENCES |
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Blood
88:3698, 1996[Abstract/Free Full Text]
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Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia.
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