GENE
COAGULATION ABNORMALITIES IN PATIENTS WITH A HISTORY OF ISCHEMIC STROKE.
D. De Lucia, S.
Pezzella, F. Demurtas, D. d'Alessio§, M. Margaglione*, E. Grandone*, N. Giuliani*, G.
Cappucci*, G. D’Andrea*, M. Petruzzellis°, G. Laddomada°, V. Lucivero° and F.
Federico°.
II University of Naples. *
IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (Foggia). §
University Federico II of Naples. ° Neurologic Division, University of Bari.
In many patients, abnormalities affecting plasma coagulation factors
and pathways contribute to venous and arterial thrombosis. Hematologic disorders that
induce a thrombotic tendency contribute to overall ischemic stroke risk and may directly
cause cerebral ischemia in patients without other risk factors. These disorders include
platelet dysfunctions, prothrombotic coagulopathies, defective fibrinolysis, abnormal red
blood cell-vessel interactions, hyperviscosity states (myeloproliferative disorders) and
antiphospholipid antibody syndromes.
Stroke is the third leading cause of death and a leading cause of
serious disability. Genetic factors play a significant role in myocardial infarction and
vascular risk factors. Therefore, primary hematologic abnormalities are a rare but
established cause of ischemic stroke. hematologic disorders per se represent
unusual causes of cerebral ischemia (perhaps 4% of strokes in young adults, 2% in older
adults), whereas their prothrombotic features may augment common stroke risks. There are a
number of genes in which mutations cause predisposition to thrombosis. Many candidate
genes have been cloned and sequenced and their role in hemostasis partially defined.
The aim of our study was to determine the prevalence of Factor V
(FV) Leiden mutation, Methilentetrahydropholate reductase (MTHFR) C-->T 677 gene
mutation, Angiotensin Converting Enzyme (ACE) gene polimorphisms (DD, ID, II) and a novel
sequence variation in the prothrombin gene (nt 20210 G-->A) associated with increased
prothrombin levels.
We genotyped 46 patients who had suffered from ischemic stroke (mean
age ±SD= 52.5±17.5 y, 25 F and 21 M). All subjects were from Southern Italy and all the
cerebral ischemic episodes occurred twelve to fifteen months before and have been
documented by NMR and CT scan. Forty-six controls were enrolled by age-matched healthy
volunteers of our Immunotrasfusion Service.
Fourteen (30.4 %) patients showed FV Leiden mutation (13
heterozygous and 1 homozygous) while 1 (2.1 %) healthy subject had the mutation. MTHFR
C-->T 677 mutation were found in 30 (65 %) patients while 13 (28 %) controls had the
gene mutation. Heterozygotes for MTHFR mutation were 25 among cases and 10 in the control
group. Homozygotes for MTHFR mutation were 5 among cases and 3 in controls. Twenty-two
patients (47.8 %) were shown carriers of DD polimorphism in ACE gene, 19 (41.3%) had I/D
genotype and 5 (10.9%) I/I genotype. Prothrombin 20210 mutation was found in 6 (13 %)
patients; in 5 at heterozygous state and in 1 at homozygous state. In control group only 2
( 4.3 %) subjects had the 20210 mutation.
A prothrombotic tendency underlies many diverse hematologic
disorders, including, but not limited to, hemostatic abnormalities. These disorders are
rarely a primary cause of ischemic stroke, but do enhance common stroke risks. Recent
application of precise molecular markers permits recognition of platelet, vascular,
coagulopathy or fibrinolytic disturnbances. Plasma levels of preexisting hemostatic
factors are generally determined by genetic and enviromental factors. Our data showed that
mutations in the genes predisposing to arterial thrombophilia were significantly more
frequent among cases and significantly discriminate subjects with a stroke history. On the
basis of these findings, it is conceivable that molecular variations may affect gene
expression, expecially in response to enviromental stimuli and in turn plasma protein
concentrations.
These results have raised the exciting possibility of using these
hemostatic factors and their genes as markers for selecting high-risk subjects. Hence,
epidemiological studies provide the population-based data upon which basic experimental
work and clinical trials must be vigorously pursued to define the pathophysiological roles
of hemostatic risk factors. This will lead to more specific therapies to restore
hemostatic balance.
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