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EUROPEAN FORUM ON ANTIPHOSPHOLIPID ANTIBODIES |
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Dr Wolfgang Miesbach
University Hospital Frankfurt
Department of Internal Medicine and Haemostaseology
Theodor Stern Kai 7
60590 Frankfurt, Germany
Telephone: 0049/6963015051
Fax: 0049/6963016738
e-mail: miesbach@em.uni-frankfurt.de
Prof Dr
Detlef Claus
Head of the
Department of Neurology, Klinikum Darmstadt, Germany
Prof Dr
Inge Scharrer
Head of the
Department of Haemostaseology, University Hospital Frankfurt, Germany
Andreas
Gilzinger, M.D.
Buket
Gokpinar, medical student
Geneth
Asmelash, laboratory technician
Birgit
Putz, laboratory technician
Title: Follow up- investigation of patients with ischemic cerebral
manifestations of the antiphospholipid syndrome – predictive role of
high-sensitive C-reactive Protein (hs-CRP)
60 patients from two centres were included
in a national project which lasted two years[1].
All patients were suffering from cerebral manifestations of the APS.
The hs-CRP level was measured in all patients at
enrollment by a standard clinical immunoassay (Dade Behring).
A follow-up investigation was carried out in order
to explore the occurrence of further onsets of the thrombotic disease.
Atherosclerosis
is characterized by a non-specific inflammatory process which is accompanied by
a systemic response. Recent evidence suggests that CRP may be directly involved
in atherothrombogenesis.
CRP is
present in the vessel wall and induces an expression of binding molecules. It
does participate in the cholesterol loading of macrophages and stimulates
tissue factor biosynthesis. CRP also binds to the complement factor and
activates the complement by the classical pathway.
Several
studies from both Europe and the United States indicate that elevated levels of
CRP are a strong predictor of future cardiovascular events:
In an extensive
prospective study concerning the risk of future cardiovascular events the level
of CRP was the single strongest predictor (Danesh J, Whincup P, Walker M,
Lennon L, Thomson A, Appleby P, Gallimore JR, Pepys MB. Low grade inflammation
and coronary heart disease: prospective study and updated meta-analyses. BMJ
2000;321:199-204).
Levels of
CRP and Troponin found in over 900 patients with unstable angina, at enrolment
are strongly related to the long-term risk of death from cardiac causes. CRP
seems to be even more significant as Troponin, a marker of myocardial damage
(Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial
damage and inflammation in relation to long-term mortality in unstable coronary
artery disease. FRISC Study Group. Fragmin during instability in coronary
artery disease. N Engl J Med 2000;343:1139-47).
Studies
indicate also that elevated levels of
hs-CRP among apparently healthy men and women are a strong predictor of future
cardiovascular events. In a cohort of 22,000 middle-aged men with no clinical
evidence of disease, those with baseline levels of hs-CRP in the highest quartile had a 2-fold increase in risk of
stroke or peripheral vascular diseases and a 3-fold increase in risk of
myocardial infarction (Ridker PM.High-sensitivity C-reactive protein: potential
adjunct for global risk assessment in the primary prevention of cardiovascular
disease. Circulation 2001;103:1813-8).
These
effects were independent of all other lipid and nonlipid risk factors and were
present among smokers as well as non-smokers.
A recently
published study, however, indicates that the role of hs-CRP in predicting
coronary heart disease might be less important (Danesh J, Wheeler JG,
Hirschfield GM, et al. C-reactive protein and other circulating markers of
inflammation in the prediction of coronary heart disease. N Engl J Med
2004;350:1387-97). Patients with APS, however, were not included in this study.
Various
lifestile lifestyle changes and pharmacological interventions are able to
reduce elevated CRP concentrations. Mainly, smoking, hypertensive, overweight
and people with a sedentary lifestyle tend to have high levels. Whereas thin,
athletic individuals tend to have lower levels. Postmenopausal women who took
hormone replacement therapy tended to have elevated levels of CRP, too.
Especially
smoking seems to be the strongest stimulus for CRP production.
Current
smokers usually show a twofold-increased concentration of CRP compared with
never-smokers (Rosenson RS, Koenig W. Utility of inflammatory markers in the
management of coronary artery disease. Am J Cardiol 2003;92:10i-8i).
Several
limitations of CRP evaluation should be considered.
Inflammatory
markers are non-specific and increase with acute infection or trauma.
CRP evaluation during times of infection or trauma
should be avoided.
CRP levels can be elevated in patients with known
systemic inflammatory conditions.
It has been
shown that CRP levels remain elevated for at least three months after the index
event in a large population of patients with unstable angina (Biasucci LM,
Liuzzo G, Grillo RL, Caligiuri G, Rebuzzi AG, Buffon A, Summaria F, Ginnetti F,
Fadda G, Maseri A. Elevated levels of C-reactive protein at discharge in
patients with unstable angina predict recurrent instability. Circulation 1999;
99:855-60).
APS can
affect any part of the body by involving large and small vessels. A variety of
cardiac, neurological and gynecological manifestations are associated with the
presence of aPL.
Cerebral
involvement is one of the most feared
complications of the antiphospholipid syndrome (APS). The most common neurological complications
are ischemic stroke and transient ischemic attacks. The underlying pathology of
most of the neurologic complications is a thrombotic occlusion of cerebral
vessels without evidence of vasculitis. Other neurological complications
are also associated to APS, e.g.
cerebral venous thrombosis, movement disorders, epilepsy, migraine and multiple
sclerosis.
Patients
with APS are at increased risk of recurrent thromboembolism.
Despite the
increasing understanding of the mechanisms and clinical manifestations of APS,
thrombotic complications are unpredictable and the “triggering factors” can not
be identified in the majority of cases.
This study
is a prospective, consecutive European multicentre multi-centre
investigation which aimed to follow a
cohort of patients with ischemic cerebral manifestations of APS.
1. To
evaluate prospectively the predictive value of hs-CRP in patients with the presentation of ischemic cerebral manifestations of the APS.
2. To analyse the relation of the follow-up to the
titer of aCL antibodies or LA.
The
Diagnosis of APS is based on International Consensus Criteria (Arthritis Rheum
1999;42:1309-1311). Testing of aPL should be confirmed on two occasions.
Patients may have a primary or secondary form of APS.
The
diagnosis of neurological manifestation of the APS should be confirmed by a
neurologist and neuroimaging investigations (CT and/or MRI imaging) should be
made in order to document the extent of the disease.
hs-CRP-level
should be measured at the onset of the disease.
Data will
be collected during 3 years.
We expect
200 cases with a good European participation.
Following
possible difficulties should be considered:
CRP usually
is measured in clinical laboratories by either immunoephelometric or
immunoturbidimetric assays. Most of the studies which have examined the
clinical utility of CRP in predicting future arteriosclerotic or thrombotic
disease have used a high-sensitive CRP (hs-CRP) ELISA.
We
measured hs-CRP levels by a particle
enhanced turbidometric immunoassay
(Dade Behring) with a detection limit of 0.05 mg/dl.
The
registered CRP level should be measured by a high-sensitive method and the
cut-off level should be marked in order
to compare the different sensibility of the laboratory methods.
As
inflammatory processes may increase
hs-CRP levels, this should be excluded in patients before including it into
this study.
We
request of following clinical and laboratory data:
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Patients
characteristics and current medication
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Interval
between stroke and initial measurement of hs-CRP
(Did any accompanying disease occur
during this interval?)
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Anamnesis:
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Other
manifestations of APS
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Other
accompanying diseases, e.g. systemic inflammatory conditions or infections
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Primary
or secondary APS
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Time
of follow-up
- Levels
of the antiphospholipid antibodies
(Please note the type of lupus
anticoagulans and/or anticardiolipin ELISA)
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Level
of hs-CRP at admission and during follow-up
(Please note the type of reagens
and the cut-off level)
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Manifestation
of the ischemic stroke
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Result
of the neuroimaging study (cortical, sub-cortical, volume)
- Result
of the follow-up investigation
Please use a standardised scheme with the
following four categories:
§
complete
remission
§
residual
symptoms (please note the symptoms)
§
death
(please note the cause of death, result of obduction if possible)
§
recurrent
ischemic cerebral symptoms (please note the exact clinical symptoms)
Please also note if the patient suffered from
other aPL-related manifestations during the follow-up time.
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Therapy
(e.g. close monitoring of INR, statins)
Manifest
inflammatory diseases should be excluded.
Thank you
Thank you
very much for your help to register clinical and laboratory characteristics of
patients with neurological manifestations of APS and the documentation of the
follow-up.
We hope
that in future it may be possible to identify
a group of patients with high risk of residual or recurrent cerebral symptoms.
These
patients may benefit from a more careful follow-up and a more intensive
antithrombotic therapy.
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Last updated: 30 December 2004 |
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[1] (50
patients came from the Department of
Neurology Darmstadt and 10 patients came
from the University Hospital Frankfurt, Germany).