Predictive Haemostatic Variables In Cardiovascular
Disease
July 12, 2003
09:00 to 13:00
Hall 11
The International Convention Center, Birmingham
Chairman: L. Iacoviello, Italy
Co-Chairs:; P. Grant, UK; G. Lowe, UK; V. Salomaa, Finland; A. Tosetto,
Italy
The number of attendees of this subcommittee meeting was approximately 100.
Dr. Licia Iacoviello gave an update of the activities of the Subcommittee.
In particular, the WEB site of the SubCommitee at http://www.negrisud.it/ssc , linked
with the official ISTH website and the registry of on-going studies on the
association between genetic and biochemical haemostatic variables and cardiovascular
disease. Dr Iacoviello invited the members in the audience who has such studies
on-going to fill the forms that are available at the website. The forms
can be filled and sent to Dr. Iacoviello directly through the website.
In the first part of the meeting two debates were presented on hot topics
related to risk factors for cardiovascular disease: C reactive protein and
homocysteine.
Should measurements of C reactive protein be done to assess risk in primary
prediction/prevention of cardiovascular disease? C. Kluft – pro;
GDO Lowe – against
Dr. Kluft and Dr. Lowe presented during 10-minutes arguments respectively
pro and against the possibility that CRP could be used to assess risk in primary
prediction of cardiovascular disease.
These presentations were followed by a 10 minutes rebuttal of each discussant
and by a general discussion. The debate on C reactive protein and CVD risk
will be published by the Journal of Thrombosis and Haemostasis, as an
activity of the Subcommittee.
Hyperhomocysteinemia should (not) be looked for and treated in patients
with cardiovascular disease? M. Cattaneo – pro; I. Pabinger – against
Dr. Cattaneo presented evidence from several studies and recent metanalysis
on the association between high homocysteine levels and risk of cardiovascular
disease; in particular he showed that only in retrospective case-control studies
or prospective studies in patients who already had an ischaemic event, a
consistent association between homocysteine and CVD was demonstrated. In contrast,
prospective studies in healthy subjects gave contrasting results. This discrepancy
could be explained by the weak design of the latter studies, by methodological
problems in homocysteine evaluation and to the too long follow-up. Although
there is a clear association between homocysteine and secondary cardiovascular
disease, a criticism is often raised that a casual relationship between homocysteine
and CVD has not been proven. In particular, there is no clear evidence that
by reducing homocysteine levels one may decrease the risk of cardiovascular
disease.
Dr. I. Pabinger pointed the attention on the lack of studies proving the
therapeutic effectiveness of lowering homocysteine. In particular, out of
the only two studies published until now on the use of folic acid to decrease
CVD, one was positive, and one was negative. Moreover, the possibility
that folic acid treatment can mask vitamin B12 deficiency should be taken
into consideration. She proposed that the best attitude is to await the results
of coming studies on the effect of lowering homocysteine by eating more fruit
and vegetables.
Is "candidate" gene still a useful approach to study the genetics of
cardiovascular disease? A. Catto
Dr. A. Catto gave an overview of population association studies on
the genetics of CVD using the approach of candidate genes in relation to the
field of haemostasis. For all candidate genes studied contrasting results
have been published and it is difficult at the moment to establish an unequivocal
association with the risk for any of them. He examined the possible causes
of such a disappointing finding. The small sample size of the studies, the
bad definition of clinical phenotypes, the incorrect selection of control
populations, the lack of linkage disequilibrium between markers and functional
polymorphisms may have the main role. However a recent publication by performing
a metanalysis of several candidate genes associated to a number of different
clinical phenotypes demonstrated that the candidate gene approach is indeed
able to detect genetic associations, although the extent of the association
is small.
Preparing a reference genetic (gDNA) panel for Factor V Leiden. E.
Gray
Dr. Gray presented the first DNA standard obtained by human gDNA to
be used in factor V Leiden evaluation. All people interested to participate
in collaborative studies can contact Dr. Gray (egray@uibsc.ac.uk).
Genetic markers of cardiovascular risk answers from large cohort studies.
V. Salomaa
Dr. Salomaa presented the disadvantages reported in studying genetic association
in case-control studied: small studies, publication bias, cross-sectional
design, only one or two polymorphisms studies in single genes. Large multinational
cohort studies coupled with high throughput genotyping can overcome this problem.
He presented as an example the MORGAM study (http://www.ktl.fi/morgam). This is a
case-cohort design on 2000 incident CHD events and 4000 matched controls,
using a candidate gene approach. Multiple gene and multiple polymorphism in
single gene will be genotyped: 500 SNPs in 60 genes related to coagulation
and inflammation, 150 SNPs related to integrins and 130 SNPs in 63 genes related
to platelet receptors and infection. SNPs have been selected according to
the following principles: candidate genes, systematic approach of certain
biological pathways, all SNPs found within or at close proximity, rare allele
frequency higher than 1%, linkage disequilibrium, SNPs in evolutionary conservative
area according to comparative genomics, density of one SNP per 5 Kb. Finally
he presented preliminary results relative to thrombomodulin (TM) gene pathway
in the FINRISK Study (that will be part of the larger MORGAM Study). The FINRISK
is a population survey study started in 1992 on 5299 subjects, 25-64 years
old, followed-up until 2000. 172 incident CHD, 109 stroke and 257 death were
observed. Preliminary results show association between different polymorphisms
in TM gene and either risk or protection of CVD.
Do markers to predict drug efficacy in thrombotic disease exist? The
case of aspirin. J. Musial
Dr. Musial presented data on the possible genetic modulation of aspirin
activity in an in vivo model of thrombin formation. 300 mg of aspirin prolong
bleeding time and decrease thrombin generation measured as fibrinopeptide
A (FPA) concentration in bleeding time blood. When this experiment was performed
in subjects homozygous for PlA1 allele or carriers of the PlA2 allele of the
GpIIIa platelet polymorphism different results were observed. When the effect
of aspirin was compared to that of clopidogrel, opposite results were observed.
Indeed, while the effect of aspirin on bleeding time and thrombin generation
was reduced in PlA2 carriers, the effect of clopidogrel on the same system
was reduced in PlA1 homozygous. Finally Dr. Musial showed how the effect
of aspirin in inhibiting activation of FXIII was modulated by a polymorphism
(Val34Leu) in FXIIIa subunit gene.
A brief update on the fibrinogen study collaboration. GDO Lowe
Dr. Lowe gave a brief update on Fibrinogen Studies Collaboration. This is
a metanalysis on the relationship between fibrinogen and CVD in prospective
studies, with the main aim to assess: associations, potential confounders,
regression dilution, shape of dose-response relationship.
Until now 160.000 persons in 28 out of 30 studies have been considered.
Interested people can contact the coordinator of the study, Prof. John Danesh
at jd292@medschl.com.ac.uk