Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent episodes of thrombosis in the arterial or venous circulatory system and / or maternal complications. It combines a persistent elevation in anti-phospholipid antibodies (aPL), including lupus anticoagulant (LA), anti-β2-glycoprotein I (anti-β2GPI) and / or anti-cardiolipin (aCL).1 APS is probably the most acquired thrombophilia, affecting approximately 2% of the general population, with thrombotic events occurring mainly in the deep venous network of the lower extremities and the cerebral arteries. Thrombi can also form in unusual locations such as the visceral or hepatic veins and the cerebral venous circulation. aPLs are a heterogeneous group of antibodies, which act against negatively charged phospholipids or phospholipid-protein complexes of the cell membrane, resulting in the clinical manifestations of the syndrome.

APS is distinguished on the basis of its etiology as primary and secondary. Primary APS is assumed in patients with clinical and laboratory evidence of the syndrome but no other systemic disease, while secondary APS occurs in the setting of another systemic disease. The most common cause of secondary APS is systemic lupus erythematosus (SLE). A percentage of 15%-35% of patients with SLE are positive for aPL, but only 50% of them will experience clinical manifestations of the syndrome. Every so often, secondary APS can be attributed to autoimmune disease (rheumatoid arthritis, scleroderma, Sjogren syndrome), malignancies (lung-breast cancer, leukemia, lymphoma, myeloproliferative disorders), vasculitis, inflammatory bowel disease, hemolytic anemia, infections (AIDS, malaria, syphilis, bacterial infections), even after drug administration.2,3

The incidence of APS is estimated at 5 of 100.000 person-years.4 aPLs are detected in 1%-5% of the general population, but only a minority of those have clinical manifestations of the syndrome.5

On the other hand, aPLs are detected in 13% of patients hospitalized for ischemic cerebral infarction (stroke), 11% of patients with acute myocardial infraction (AMI), 9,5% of patients with deep vein thrombosis (DVT) and 6% of women with maternal morbidity. Transiently increased aPL titers are also found in infectious states, malignancies, chronic inflammation and advanced age, without correlation with the clinical aspects of the syndrome.6,7

APS is the underlying aetiology in 20% of patients with DVT, more common than practitioners generally believe. Also one out of five adult patients aged under 45 years old that present with an ischemic stroke without any known cause are diagnosed with APS. What this syndrome is most notorious for, are unprovoked miscarriages. Indeed, it is the most common cause and according to the consensus statement for APS 1 out of 5 miscarriages can be attributed to.1

APS is commonly diagnosed in young and middle-aged adults with the median age being 31 years old. There are, nevertheless, case reports in children and elderly people. There seems to be a predilection for females, with them being affected five fold than men. This might be due to the higher prevalence of SLE and collagen disease in women. Up to date, it is unknown why or which patient will develop arterial or venous thrombosis. According to an international European pediatric registry, younger patients with primary APS were more prone to arterial thrombosis, while venous thrombosis occurred in older children with APS secondary to collagen disease.8

For an accurate diagnosis of APS, one must rely on both clinical criteria and laboratory data. In particular, a clinical criterion (thrombosis or maternal morbidity) and the detection of an APS specific antibody (LA, aCL or anti β2-GPI) must co-exist in a patient to establish the diagnosis.9 Thrombosis is defined as one or more episodes of arterial/venous or small vessel occlusion in any part of the human body, detected by histopathologic or imaging methods. Accordingly, maternal morbidity is defined as: a) spontaneous miscarriage in the first trimester (threeor more otherwise unexplained fetal deaths before the 10th week of gestation) when other anomalies like chromosomal mutations have been ruled out b) premature birth of a morphologically normal neonate before the 34th week of gestation due to severe pro/eclampsia or placental insufficiency and c) one or more unexplained deaths of an anatomically normal fetus after the 10th week of gestation. As pertained to laboratory criteria, one or more of the antibodies in the plasma or serum must be detected: LA, medium or high titers of aCL (IgG or IgM) or anti-β2 GPI (IgG or IgM) in at least two contiguous measurements 12weeks apart.1 These criteria are derived from the 2006 consensus statement of the classification criteria for definite APS and are valid to date. (Fig 1)

Special attention must be paid to a serious manifestation of APS, known as catastrophic APS (CAPS), which is a rapidly progressing and life-threatening disease, characterized by microvascular thrombosis with multiple organ involvement and a morbidity of 50% of the patients affected.10

aPLs are an heterogenous group of antibodies with multiple antigenic targets. Their main target is β2-GPI plasma protein. Other known antigenic targets seem to be annexin V and prothrombin.11 Remarkably, aPLs exhibit an interesting paradox. In vitro, they bind with phospholipids of the prothrombinase complex, hindering thrombin's formation and prolonging clotting assays, while in vivo they prepossess thrombosis. Their origin is not well known, with many theories advocating genetic and environmental factor interactions.12,13

Thrombotic predisposition in APS has been attributed to multiple factors, such as the accretion of adhesion molecules of endothelial cells, the activation of platelets that produce thromboxane and the excretion of proinflammatory cytokines. The endothelium malfunction is also through the aPL induced NO synthetase inhibition. Lastly, complement peptides C3, C5a and C5b also play an integral part in the activation of endothelial cells and hence the propagation of thrombosis.14

Cardiovascular manifestations of APS are relatively frequent, with the most common being valvulopathies (33% of patients with primary and 40%-50% of patients with secondary APS) and coronary artery disease (15% of patients with primary and 30% of patients with secondary APS). Uncommon manifestations include endocardial thrombi and pulmonary arterial hypertension.15

APS correlates with a high risk of thromboembolism. Data from observational studies conclude that subjects with high aPL titers are on a higher thrombotic risk.15 The importance of searching for correlation between APS and aPL in subjects with acute coronary syndrome (ACS) has been demonstrated through aplenty of studies and has occupied the interest of the scientific community in the last decades. Subjects with APS have a higher prevalence of microvascular disease and atherosclerosis than general population, albeit similar risk factors for cardiovascular disease. It is noteworthy that patients diagnosed with APS have a 2,8% chance of ACS in young age.15,16

For this review we searched and found more than 100 case reports and a systematic review of ACS in patients with APS. Most of these studies are related to young patients and it is now known that ACS might be the first presentation of this syndrome.17,18 Women are more predisposed, with ACS occurring mainly in the fourth decade of life.19 It stands to reason that APS patients with coronary syndromes are at a high mortality risk. ACS was the cause of death in 19% of 1000 APS patients in a European registry with a five-year observation period.20,21