Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3150-3152
CORRESPONDENCE
The 20210A Allele of the Prothrombin Gene Is an
Independent Risk Factor for Perception Deafness in Patients With Venous
Thromboembolic Antecedents
 |
LETTER |
To the Editor:
One of the main factors of sudden hearing impairment, vestibular
disturbance, or tinnitus is generally thought to be an acute labyrinthine ischemia of varying degrees. Despite the most common mechanism of sudden hearing loss appearing to be impaired cochlear blood circulation,1 the scientific basis of this assumption has not yet been proven. Experimental studies performed in animals through ferromagnetic obstruction of cochlear blood vessels have shown
that vascular impairment of the inner ear results in a considerable decrease in intracochlear oxygenation, causing a significant loss in
the auditory response.2 In humans, deafness associated with small infarctions of cochlear tissue have exceptionally been reported in the context of rare multifocal microangiopathic
encephalopathies,3 but no data are available in the field
of current sudden hearing impairment.
Our attention was stimulated by some of our patients with
thromboembolic disease who spontaneously reported unilateral acute perception deafness. We thus performed a retrospective case-control study.
Three hundred sixty-eight patients, corresponding to 101 men and 267 women, median age 41 years (range, 17 to 72), with antecedents of
spontaneous deep vein thrombosis (thrombosis group: TG), were investigated over a 3-year period in the outpatient Department of
Hematology. Eighteen of them, 12 women and 6 men, 38 to 69 years old,
had also suffered from acute unilateral hearing impairment. Explorations were in favor of a pure unexplained perception auditory defect, with computed tomography scanning and magnetic resonance imaging showing no cerebral lesion. These 18 patients had no
antecedents of symptomatic atherosclerosis, except the oldest man who
had angina pectoris, and ultrasound exams performed on asymptomatic patients gave no evidence of atherosclerotic lesions on carotid arteries. None of the women had hypertension and seven of them were
smokers: the three youngest, aged 38, 43, and 45 years, were also
oral-contraceptive takers. Three of the men were heavy smokers, including the one with angina pectoris; two of them had mild hypertension.
During the same period of time, acute unilateral perception deafness
could only be found in 4 of 395 nonthrombotic consecutive patients
studied for hemorrhagic symptoms or thrombocytopenia (hemorrhage group:
HG), and in 6 of the 395 nonthrombotic and nonhemorrhagic sex- and
age-matched control individuals (control group: CG) who had a
systematic medical check-up in a Public Health Center (Pearson
chi-square test: P = .0008). No difference could be evidenced
between the hemorrhage group and the control group.
Concerning biological risk factors for thrombosis, the prothrombin
20210A allele was positive in 25 patients from TG (6.8%), in 4 patients from HG (1%), and in 3 patients from CG (0.7%)
(P = .0008). The factor V gene G1691A mutation (factor V
Leiden) was positive in 63 patients from TG (61 heterozygous and 2 homozygous; 17.1%), in 5 from HG (1.3%), and in 6 from CG (1.5%;
P < .0001). Antithrombin deficiency was evidenced in 5 patients from TG (1.4%), but in none from HG or CG
(P = .005). Protein C deficiency was found in 11 patients
from TG (3%), in 2 patients from HG (0.5%), and in 3 patients from CG
(0.8%; P = .006). Protein S deficiency was confirmed in 8 patients from TG (2.2%), in 1 patient from HG (0.25%), and in 1 patient from CG (P = .005). Antiphospholipid antibodies could
be found in 35 patients from TG (9.5%), in 6 patients from HG (1.5%),
and in 7 patients from CG (1.8%; P < .0001). Concerning
the type of positive antiphopholipid antibodies, a lupus anticoagulant
was found in 22 patients from TG but in only 4 patients from HG and 5 patients from CG (P < .001). Twenty-seven patients from TG
had positive anticardiolipin IgG antibodies whereas only 3 patients
from HG and 4 patients from CG were positive (P < .001).
Finally, 23 patients from TG were positive for anti-
2-glycoprotein I IgG antibodies, but only 3 patients from HG and 2 from CG
(P < .0001). The prevalence of positive biological risk
factors for thrombosis was the same in the hemorrhage group and in the
control group.
Due to the absence of differences in terms of prevalence of deafness
and of biological risk factors for thrombosis, we defined a normal
group as the addition of the hemorrhage group and of the control group.
Taking into account this reference group and the thrombosis group, we
calculated crude odds ratios (cOR) for perception deafness and 95%
confidence intervals (95%CI) using logistic regression
for each biological venous thrombosis risk factor and for
thromboembolic antecedents (Table 1).
Thereafter, a multivariate logistic regression was performed to adjust
to potential confounding factors (adjusted odds ratio, aOR; a stepwise procedure entering each variable with P lower than .20 in
monovariate logistic regression; table 1): only a positive
thromboembolic antecedent and a positive prothrombin gene 20210 A
allele were confirmed to be independent risk factors for perception
deafness.
View this table:
[in this window]
[in a new window]
|
Table 1.
Odds Ratios and 95%CI for Perception
Deafness and Type of Positive Biological Risk Factor for Thrombosis in
Thrombotic Patients, With the Normal Group as Reference: Results of
the Univariate and of the Multivariate Logistic Regressions
|
|
Among the 18 thrombotic patients with deafness, 6 were
heterozygous carriers of the prothrombin gene 20210A allele. Among these 6 carriers were the 3 young smoking and
oral-contraceptive-taking women, another nonsmoking woman and
two smoking men, including the oldest one with angina
pectoris. The introduction of gender, oral contraceptives, and smoking
as new parameters for logistic regression analysis gave nonsignificant
results, showing that these parameters are not independent risk factors
for perception deafness: results concerning smoking are concordant with
available published data.4 However, in young thrombotic
women with the 20210A allele in the prothrombin gene, we cannot exclude
that smoking and oral contraceptive use may be clinical cofactors of the disease.
In conclusion, these data seem to indicate that, in patients with
thromboembolic antecedents, the prothrombin 20210A allele is an
independent risk factor for perception deafness. This may constitute a
new indirect argument for the vascular/thrombotic origin of some of
these accidents. As a consequence, patients with thrombotic antecedents
and the prothrombin 20210A allele should be preserved from aggressive
conditions for the internal ear (excessive noise, scuba diving,
treatments with a known specific toxicity, etc). If patients are young
women, as they may be putative clinical cofactors, hearing preservation
may be an additional argument for oral contraceptive and smoking
cessation. The prothrombin 20210 allele has already been described to
increase the risk of myocardial infarction among non-Mediterranean
young women and the relative risk was higher in smoking
carriers.5 We have previously described cases of spinal
cord infarction in young smoking and oral-contraceptive-taking women
with the prothrombin 20210A allele.6 The 20210A
allele of the prothrombin gene may thus have a more general status of
risk factor for arteriolar thrombosis, a generally
difficult-to-diagnose and sometimes silent event. Some anatomical
localizations, due to their dramatic consequences, are however evident.
Future questions should address the identification of the spectrum of
additional abnormalities acting to increase the penetrance of clinical
arteriolar thrombotic manifestations associated with the prothrombin
20210A allele.
Eric Mercier
Consultations et
Laboratoire d'Hématologie
CHU, Nîmes,
France
Isabelle Quere
Médecine Interne B et Maladies
Vasculaires
CHU, Montpellier, France
René Chabert
Jean-Gabriel Lallemant
Service
d'Oto-Rhino-Laryngologie
CHU, Nîmes,
France
Jean-Pierre Daures
Département d'Information
Médicale
CHU, Nîmes, France
Jacques Berlan
Jean-Christophe Gris
Laboratoire
d'Hématologie
Faculté de Pharmacie
Montpellier,
France
| |
REFERENCES |
1.
Von Scheel J:
Physiologischer Ansatz zur Durchblotungsforderung bei der akuten Labyrinth-Ischamia. Ein neues.
Laryngorhinootologie
76:395, 1997[Medline]
[Order article via Infotrieve]
2.
Scheibe F, Haupt H, Baumgartl H:
Effects of experimental cochlear thrombosis on oxygenation and auditory function in the inner ear.
Eur Arch Otorhinolaryngol
254:91, 1997[Medline]
[Order article via Infotrieve]
3.
Schwitter J, Agosti R, Ott P, Kalman A, Waespe W:
Small infarctions of cochlear, retinal and encephalitic tissue in young women.
Stroke
23:903, 1992[Abstract/Free Full Text]
4.
Linke R, Matschke RG:
Besteht ein Zusammenhand zwischen Horsturz und Tabakrauchen?
Laryngorhinootologie
77:48, 1998[Medline]
[Order article via Infotrieve]
5.
Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL:
A common prothrombin variant (20210G to A) increases the risk of myocardial infarction in young women.
Blood
90:1747, 1997[Abstract/Free Full Text]
6.
Mercier E, Quéré I, Campello C, Marès P, Gris JC:
The 20210A allele of the prothrombin gene is frequent in young women with unexplained spinal cord infarction.
Blood
92:1840, 1998[Free Full Text]
