The geoepidemiology of the antiphospholipid antibody syndrome
Introduction
The antiphospholipid syndrome (APS) is a systemic autoimmune disease defined by the occurrence of recurrent thromboembolic events and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Antiphospholipid antibodies are formally detected by functional coagulation assay (the so called lupus anticoagulant – LAC) and/or by solid phase assays: anti-cardiolipin (aCL), or anti-β2 glycoprotein I (anti-β2GPI) antibody tests.
Classification criteria for APS have been developed at the Sapporo antiphospholipid meeting and then recently updated [1]. APS is defined by the presence of at least one of the clinical criteria and one of the laboratory criteria. The criteria define patients with “primary” APS (PAPS) as those with the diagnosis in the absence of any underlying autoimmune disease, and patients with “secondary” APS (SAPS) as those with autoimmune disorders, aPL and the clinical manifestations of the syndrome [1].
A variant of APS characterized by acute thrombotic microangiopathy with subsequent multiorgan failure and high mortality rate has been also identified: the so called catastrophic APS (CAPS) [2]. Probable and microangiopathic APS are additional disease subsets that have been suggested but not yet formally accepted [2].
The present chapter will address the aPL prevalence in the formal clinical manifestations of the syndrome both in adults and in the paediatric populations as well as their occurrence in association with other systemic autoimmune conditions. The occurrence (and prevalence) of aPL in asymptomatic subjects or in association with other non-autoimmune conditions will also be evaluated.
Section snippets
aPL and arterial thrombosis
The cumulative retrospective literature analysis indicates that approximately 30% to 40% of patients with aPL have a history of thrombosis and that 30% of the events are arterial [3].
Cerebral circulation is the most commonly affected arterial district while coronary arteries and additional arterial anatomical localizations are less frequently reported [4].
The Euro-Phospholipid Group analyzed the prevalence of the most relevant clinical and immunological features in a cohort of 1000 APS patients
aPL and venous thrombosis
Venous thrombosis (VT) is the most common APS clinical manifestation, usually deep vein thrombosis (DVT), and occurs in more than 30% of patients [5].
Frequencies of aPL in venous thrombosis have been reported to range from 5.2% to 30% for any aPL, 0.6–16% for LA, and 4–24% for aCL [7].
Galli et al. performed a meta-analysis of case–control, cross-sectional, and ambispective studies to calculate the OR with 95% confidence interval (CI) of LAC and IgG/IgM aCL for venous thrombosis. All the studies
aPL and pregnancy morbidity
Multiple cross-sectional studies reported an association between aCL and/or LAC and recurrent foetal loss, with a frequency ranging from 10% to 19%; however some studies failed to confirm such a finding [7]. Foetal losses can occur in any trimester of pregnancy, although their frequency was higher before the 10th week of gestation than after (35.4% vs. 16.9% respectively) in the Euro-phospholipid series. The specificity of recurrent early abortion is still discussed because of the difficulty in
aPL and non-classification criterial clinical manifestations
According to the 2006 International consensus statement for classification of definite APS, the following manifestations are not included in the updated criteria: heart valve disease (vegetations, valve thickening and dysfunction), livedo reticularis (LR), nephropathy, neurological manifestations (cognitive dysfunction, migraine, multiple sclerosis, transverse myelopathy, and epilepsy), and thrombocytopenia. Although undoubtedly frequent the above mentioned features are not thought to be
aPL and systemic autoimmune diseases
The antiphospholipid syndrome can occur in association with other systemic autoimmune diseases and in particular with SLE: 37% of the patients of the Europhospholipid series was suffering from full blown SLE, while 4% was associated with lupus-like disease [5].
The prevalence of aPL among patients with SLE ranges from 12% to 44% for aCL, from 15% to 34% for LAC, and from 10% to 19% for anti-β2GPI [7]. It has been suggested that fluctuations of the antibody titers because of disease activity
aPL in the general population and in other pathological conditions
Antiphospholipid antibodies can be found in apparently healthy control subjects with a prevalence ranging from 1 to 5% for both aCL and LAC. In most of the cases the antibodies displayed low titres [7]. An increased prevalence of the antibodies detectable with all the assays has been reported with ageing. The highest values were reported in healthy centenarians but without a clear association with the APS clinical manifestations [30].
Since the association of aPL and syphilis was first
aPL in the paediatric antiphospholipid syndrome
Antiphospholipid antibodies can be found in a high percentage of children without any underlying disorder, with an estimated frequency that ranges from 3 to 28% for aCL and from 3 to 7% for anti-β2GPI. The reason of such frequent occurrence in comparison with the adults has been related to the frequent infectious processes taking place during childhood [36]. Increased prevalence of anti-β2GPI antibodies (up to 42%) was also detected in children suffering from atopic dermatitis with no APS
aPL and the ethnicity
Environmental and genetic factors contribute to ethnic variation and susceptibility to APS and thus interethnic differences in disease patterns may be due to environmental or genetic factors, or both [38].
Genetic factors are important in the development of APS. This is demonstrated by animal models, by the familial occurrence of this syndrome, and by its association with various HLA alleles. Some HLA alleles carry the risk to produce aPL, and this is independent on the clinical context. In
Take-home messages
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aPL can be detected in asymptomatic healthy controls (prevalence 1–5%). aPL can be induced by infections, malignancies, vaccinations and drugs. In these cases the autoantibodies are usually transient, at low titre, and with a weak association with the APS clinical manifestations.
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Arterial thrombosis displays a strong association with LAC and anti-β2GPI. Cerebral circulation is the most commonly affected arterial district in APS patients.
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Venous thrombosis is the most frequent APS clinical
References (57)
- et al.
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)
J Thromb Haemost
(2006) New subsets of the antiphospholipid syndrome in 2006: “PRE-APS” (probable APS) and microangiopathic antiphospholipid syndromes (“MAPS”)
Autoimmun Rev
(2006)Lessons from the “Euro-phospholipid” project
Autoimmun Rev
(2008)- et al.
Anti-beta 2 glycoprotein I antibodies and the risk of myocardial infarction in young premenopausal women
J Thromb Haemost
(2007) - et al.
Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature
Blood
(2003) - et al.
Antibeta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome
Blood
(2003) - et al.
Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy
Am J Med
(1998) - et al.
The presence of IgG antibodies against anti-B2-glycoprotein I predicts the risk of thrombosis in patients with the lupus anticoagulant
J Thromb Haemost
(2005) - et al.
Anticardiolipin and anti-B2-glycoprotein I antibodies in preeclampsia
Obstet Gynecol
(2003) - et al.
Anti-beta 2 glycoprotein I antibodies in general obstetric population: preliminary results on the prevalence and correlation with pregnancy outcome. Anti-beta2 glycoprotein I antibodies are associated with some obstetrical complications, mainly preeclampsia–eclampsia
Eur J Obstet Gynecol Reprod Biol
(1997)