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Antiphospholipid Antibody
Syndrome
- Maria Gerosa, M.D, Piersandro Riboldi, M.D., Pier Luigi Meroni, M.D.
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Allergy, Clinical Immunology & Rheumatology Unit
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Department of Internal Medicine, University of
Milan
- IRCCS Istituto Auxologico Italiano
- Via
G. Spagnoletto, 3 20149 Milan (Italy),
-
Phone +39-02-61911-2553
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Fax +39-02-61911-2559
What it is
Antiphospholipid Syndrome (APS) is a new systemic
autoimmune disease, characterized by the association of recurrent
arterial/venous thrombosis and/or foetal losses in the presence of the
so-called anti-phospholipid autoantibodies (aPL) in the serum.
The disease may present with a variety of clinical
manifestations depending on the site of the clot formation (thrombosis)
in the venous or in the arterial circulation. Clotting does occur in the
absence of other causes known to be responsible for thrombosis.
Venous thrombosis affects lower legs most
frequently, and is complicated by pulmonary embolism (clot is released
and reaches pulmonary vessels where it causes blood flow arrest -
pulmonary infarction). Arterial thrombosis can occurr at any site, but
is most frequent in the brain circulation, causing strokes or transient
ischemic attacks. Clinical signs depend on the involved brain areas,
i.e. movement deficits, visual disturbances. Repeated cerebral ischemic
events may end into cognitive impairment or vascular dementia. Moreover,
there is sound suggestion that aPL are associated with epilepsy.
Antibodies are also associated with thrombosis in coronary arteries
(myocardial infarction); repeated small thrombotic events may cause
cardiac valve thickening/damage with the risk of releasing clots into
the arterial circulation (arterial embolism). Patients with APS may also
display a reduced number of platelets, and skin involvement with
mottled purplish discoloration (livedo
reticularis) or ulcers.
The obstetrical presentation includes early and late
foetal loss, intrauterine growth retardation, and pre-eclampsia (charactherized
by high blood pressure and the presence of protein in the urine during
pregnancy). Anti-phospholipid antibodies are now accepted as the major
cause for recurrent fetal losses and pregnancy complications in the
absence of other known causes.
Patients may present both thrombosis and foetal
losses or just one.
In few cases, repeated thrombotic events may take
place in a short time leading to a progressive damage of several organs
(the so called thrombotic storm). This is an acute and lifethreatening
condition called catastrophic APS.
Fast facts
·
Anti-phospholipid antibodies accounts
for 15-20% of all episodes of deep vein thrombosis, one third of new
strokes occurring in patients under the age of 50 and 10-15% of women
with recurrent fetal loss.
·
The disease can be isolated (primary
APS) or associated to other autoimmune diseases, mainly Systemic Lupus
Erythematosus (SLE).
·
Once the disease is diagnosed, an
adequate therapy can prevent in most cases the recurrence of the
symptoms.
Who gets it
APS is a disease of young
women, with a female:male ratio of 5:1 and it is frequently diagnosed
between 30 and 40 years of age. Up to 40% of patients with SLE are
positive for aPL, but just half of them develop thrombosis and/or foetal
losses.
Like most of autoimmune
disorders, APS has a genetic component, although there is not a direct
transmission from parent to offspring.
What causes it
APS can be defined as an
autoantibody-mediated disease. The reason(s) why patients develop these
autoantibodies has not been yet completely understood. There is some
evidence that environmental factors, such as infections, in the presence
of a genetic predisposing background, can play a role in triggering aPL
production.
When these autoantibodies are
in the circulation, they are able to interfere with some mechanisms of
the coagulation cascade so favoring clot formation (venous and/or
arterial thrombosis). Thrombosis is also partially responsible for
foetal losses. In fact, thrombosis at the placental level impairs blood
exchange between mother and foetus ending in fetal growth retardation or
death. Moreover, aPL may also affect placenta development directly
without clotting (i.e. inhibit proliferation and growth of the placenta
tissues and their firm adhesion to the uterus).
Anti-phospholipid antibodies
can be present in the circulation for a long time, but thrombotic events
do occur only occasionally. It has been suggested that aPL represent a
necessary but not sufficient factor to induce clotting. Conditions of
increased venous stasis (prolonged immobilization, surgery, pregnancy
etc.) or other risk factors for venous/arterial thrombosis including
congenital defects (Factor II or V mutation, Antithrombin III
deficiency, defective protein C/S anticoagulant activity),
hyperhomocysteinemia, hypertension, smoking, atherosclerosis, use of
estrogens, infectious episodes are required to trigger clotting.
How it’s diagnosed
The diagnosis of APS is
formally made by the demonstration of aPL in the patient’s serum in the
presence of the clinical features (i.e. thrombosis and/or miscarriage).
Anti-phospholipid antibodies
should be screened by using a clotting functional assay (the Lupus
Anticoagulant test) or by solid-phase assays: the anti-cardiolipin and
the anti-b2
glycoprotein I antibody tests. Different tests are required because of
the heterogeneity of the aPL population. Actually, each single test
cannot detect all the possible autoantibodies and their combined use
garantees that any positivity is not missed. At least one of the
above-mentioned assays should test positive and must be confirmed in two
occasions at least 12 weeks apart to rule out transient positivities
not associated with the clinical manifestations.
How
it’s treated
The most common situation is
the detection of aPL after a thrombotic event or after recurrent fetal
losses; thus the main target is prevention of recurrences, being the
persistent presence of aPL a strong risk factor for new manifestations.
Vascular events.
Acute thrombotic events (both
arterial and venous) are treated in a conventional way independently on
the presence of aPL (anticoagulation by heparin infusion and then by
oral anticoagulant drugs; in some cases clot dissolution by fibrinolytic
agents).
For venous events, oral
anticoagulation is required to avoid recurrences, possibly continued for
years. Stronger anticoagulation is suggested in peculiar cases with
additional risk factors for thrombosis (i.e. an associated systemic
disease – such as a lupus disease – or the presence of other coagulation
abnormalities).
For arterial events, the
prevention of recurrences is performed with drugs that inhibit platelet
function and only in severe cases with oral anticoagulation.
Obstetrical manifestations
Subcutaneous heparin and low
dose aspirin are the standard therapy for preventing new fetal losses.
The therapy is started at the beginning of the pregnancy and prolonged
also in the period immediately after the delivery. Such a therapeutical
approach has been shown to be effective in the majority of the cases
with a positive pregnancy outcome in more than 80% of the patients.
Pregnant women who experienced previous thrombotic events are treated
with higher dose of heparin to avoid new thrombotic manifestations
favored by the pregnancy itself.
The therapy with heparin and
aspirin has been shown to be safe for both the mother and the baby in
the majority of the cases.
Another frequent situation is
the detection of aPL in subjects with no prior thrombotic events or
pregnancies. Still debated is the need of a primary prevention of
thrombosis or to treat the first pregnancy: in these situations the
advisability of therapy is evaluated in each patient.
Broader health impacts:
Thrombosis per se is a
devastating consequence in APS patients and it may affect any organ in
the body. The recurrence of thrombosis and miscarriages in patients
with aPL is high and combined with high morbidity calls for an adequate
treatment. In addition, the disease is associated with a significant
socio-economical impact, often involving long-term disability and costly
treatments.
Living with the illness
The need of a long-term oral
anticoagulant therapy significantly affects the life style of the
patients: need of regular controls for the anticoagulation effect,
special attention to the diet and to situations at risk of bleeding.
Correction of conventional risk factors for thrombosis (diabetes,
hypertension, hypercholesterolemia, obesity, smoking and
contraceptive/substitutive estrogen therapy) is mandatory in APS
patients and significantly impacts the life style.
Present treatment for the
prevention of the obsterical manifestations is quite effective and the
majority of the women can have healthy babies eventually. Still there
are non responsive cases for which alternative therapies (i.e.
intravenous immunoglobulin infusions) may help.
Point to remember
§
The presence of aPL represent an important
risk factor for recurrent thrombosis and miscarriages.
§
The mainstay of the therapeutic intervention
is the prevention of clinical manifestations through oral
anticoagulation or anti-platelet drugs. Correction of concomitant other
risk factors for thrombosis is mandatory.
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