Introduction

Antiphospholipid syndrome (APS) is a systemic auto-immune disorder characterised by recurrent arterial and/or venous thrombosis, pregnancy losses and by the presence of elevated and persistent levels of antiphospholipid antibodies (aPLs), a group of antibodies directed against phospholipids or phospholipid-binding proteins. This entity was first described in the 1980s in patients with systemic lupus erythematosus (SLE) while cases of patients with recurrent abortions, thrombosis and aPL had been reported in previous years .

In the following years, it became more evident that cases with features of APS without manifestations of other connective tissue diseases (CTDs) existed . The first classification criteria for APS patients, also called ‘Sapporo criteria’, were defined in 1999 . They suggested a diagnosis of APS in presence of one of both the classical clinical manifestations (thrombosis or pregnancy complication) and the persistent high-titre positivity of anti-cardiolipin antibodies (aCLs) or lupus anticoagulant (LAC). An update was made in 2004 , which implied the introduction of anti-β2-glycoprotein I (anti-β2GPI) as an independent laboratory criterion for the definition of APS. Currently, according to the revised criteria, a diagnosis of APS can be made when at least one clinical criterion (one or more episode of vascular thrombosis or obstetrical complication) and one laboratory criterion (LAC, aCL or anti-β2GPI confirmed positivity) are fulfilled.

Although APS was initially considered an auto-immune coagulopathy, it is now clear that this disorder is a more complex and systemic disease than expected, so that the label of ‘systemic disease’ can be applied to it as for other CTDs . As a matter of fact, even if the more frequent manifestations remain the classical events included in the classification criteria, a large number of less common manifestations in different organs and tissues have been described in APS patients. The systemic nature of APS has been attributed to the ubiquitous presence of their target autoantigens, which potentially makes every cell in the human body susceptible to the effects of aPL, or to the different pathogenic autoantibodies and pathogenic mechanisms described in APS .

The ‘Classical’ APS

Venous, arterial or small vessel thrombosis is the distinctive characteristic of APS and the first cause of death in these patients , with vessels of any size and in any site possibly being involved. According to the current criteria , the thrombotic episode must be confirmed by objective methods, such as imaging studies or histopathology, with the latter considered diagnostic for APS only if no evidence of inflammation in the vessel wall is found. The most frequent events reported in the literature are deep vein thromboses, pulmonary embolism and strokes . A high rate of recurrence is described in APS patients, particularly if untreated, whereas a reduction (but not a complete abolition) of this risk is reported in patients receiving an anti-thrombotic prophylaxis .

The other main clinical feature of APS is obstetrical morbidity that includes foetal losses and preterm deliveries. The most specific event is intrauterine foetal death (at or after the 10th week of gestation). A normal foetal morphology, documented by ultrasound or by direct examination of the foetus, is required for the loss being attributable to aPL. In addition, recurrent spontaneous abortions (before the 10th week of gestation) are included in classification criteria for APS. As early pregnancy losses are a frequent event also in the general population , only three or more consecutive spontaneous abortions, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded, are considered diagnostic. Finally, APS patients can experience premature birth (before 34th week of gestation) because of eclampsia, severe pre-eclampsia or placental insufficiency. This last criterion includes abnormal or non-reassuring foetal surveillance tests, abnormal Doppler flow velocimetry, oligohydramnios or postnatal birth weight less than the 10th percentile for the gestational age (i.e., intrauterine growth restriction).

Despite this being the most typical clinical picture of APS, there are many other features, not included in the criteria, associated with the syndrome. In fact, cardiac, pulmonary, neurological, renal, cutaneous, haematological, gastrointestinal, bone, ocular and endocrinologic manifestations have been described in APS patients. Many of these events are directly related to thrombosis, but different pathophysiologic mechanisms can be involved.

The ‘Classical’ APS

Venous, arterial or small vessel thrombosis is the distinctive characteristic of APS and the first cause of death in these patients , with vessels of any size and in any site possibly being involved. According to the current criteria , the thrombotic episode must be confirmed by objective methods, such as imaging studies or histopathology, with the latter considered diagnostic for APS only if no evidence of inflammation in the vessel wall is found. The most frequent events reported in the literature are deep vein thromboses, pulmonary embolism and strokes . A high rate of recurrence is described in APS patients, particularly if untreated, whereas a reduction (but not a complete abolition) of this risk is reported in patients receiving an anti-thrombotic prophylaxis .

The other main clinical feature of APS is obstetrical morbidity that includes foetal losses and preterm deliveries. The most specific event is intrauterine foetal death (at or after the 10th week of gestation). A normal foetal morphology, documented by ultrasound or by direct examination of the foetus, is required for the loss being attributable to aPL. In addition, recurrent spontaneous abortions (before the 10th week of gestation) are included in classification criteria for APS. As early pregnancy losses are a frequent event also in the general population , only three or more consecutive spontaneous abortions, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded, are considered diagnostic. Finally, APS patients can experience premature birth (before 34th week of gestation) because of eclampsia, severe pre-eclampsia or placental insufficiency. This last criterion includes abnormal or non-reassuring foetal surveillance tests, abnormal Doppler flow velocimetry, oligohydramnios or postnatal birth weight less than the 10th percentile for the gestational age (i.e., intrauterine growth restriction).

Despite this being the most typical clinical picture of APS, there are many other features, not included in the criteria, associated with the syndrome. In fact, cardiac, pulmonary, neurological, renal, cutaneous, haematological, gastrointestinal, bone, ocular and endocrinologic manifestations have been described in APS patients. Many of these events are directly related to thrombosis, but different pathophysiologic mechanisms can be involved.

The cardiac involvement in APS

Cardiac disease occurs frequently in APS and can be very etherogeneous. Acute myocardial infarction can be the consequence of coronary artery (thrombotic or embolic) occlusion . The aPLs can predispose to this event by accelerating the atherosclerotic process; this explains the early onset of cardiac ischaemic disease and the increased risk of restenosis of coronary arteries after angioplasty in APS patients .

Interestingly in APS patients acute myocardial infarction can also occur in the absence of coronary artery lesions (as a direct consequence of aPL-related thrombosis), especially in pre-menopausal women or in patients without classical risk factors for atherosclerosis .

Apart from coronary heart disease that fulfils the criterion of thrombosis, heart valve lesions are frequent abnormalities in APS, being described in up to 30–50% of patients . They can be defined when aPLs are associated to the presence of lesions and/or regurgitation and/or stenosis of mitral and/or aortic valve and are considered to be due to adherent platelet–fibrin thrombi on the endocardial surface of valves (non-bacterial thrombotic endocarditis) . Because infective endocarditis and rheumatic fever can produce similar alterations, a history of those diseases has to be excluded. Valvular (focal or diffuse) thickening is the most common alteration, particularly affecting the mitral valve followed by aortic valve . Less often solitary or multiple vegetations, usually irregular, are seen in these patients . A significant haemodynamic abnormality is reported in only a minority of patients . Valve alterations seem to be more frequent in patients with APS associated to another CTD than in primary APS (PAPS) .

In APS patients also left ventricular systolic dysfunction, attributed to ischaemia, increased aortic stiffness, pulmonary hypertension or reduced left ventricular preload, has been described in Ref. .

Cardiac thrombo-embolism is also a possible risk in APS patients, because both valve lesions/vegetations and in situ thrombi (produced as a consequence of intracardiac stasis) can produce embolic material with the possibility of systemic (particularly cerebrovascular) events .

For all these reasons, echocardiographic follow-up is recommended in APS patients.

The pulmonary involvement in APS

Acute pulmonary embolism (PE) is one of the most frequent thrombotic manifestations of APS ; it is frequently associated with deep venous thrombosis of the extremities and it is often the first manifestation of the disease. Leaving aside classical thrombotic manifestations, other pulmonary manifestations can occur in APS patients.

First of all, pulmonary hypertension (PH), defined according to guidelines as a mean pulmonary arterial pressure (PAP) ≥25 mmHg at rest as assessed by right heart catheterisation, can be observed in 1.8–3.5% of these patients as a consequence of different processes . It can be the outcome of a previous PE, as the result of the following remodelling events that lead to permanent pulmonary vascular changes (chronic thrombo-embolic pulmonary hypertension), but interestingly this complication can be observed also in APS patients without a clear history of PE . For this reason, the study of the pulmonary circulation in APS patients with pulmonary hypertension (by ventilation–perfusion scintigraphy and/or computed tomography angiography) can be helpful in excluding the presence of chronic thrombo-embolism. However, PH in APS patients could also be due to a left heart disease, especially in the case of significant mitral or aortic valvulopathy. Finally, idiopathic arterial PH due to a progressive pulmonary vasculopathy, as observed in various CTDs, is described in association with APS. The role of aPL in the pathogenesis of this last form of PH is not completely clear, but the activation of platelets, the interaction with endothelial cells and the induction of the expression of endothelin-1 by these antibodies have been proposed as possible mechanisms .

Another rare pulmonary manifestation of APS, generally observed in cases of catastrophic APS (CAPS), is acute respiratory distress syndrome (ARDS), a clinical condition characterised by bilateral alveolar pulmonary infiltrates with a partial pressure arterial oxygen/fraction of inspired oxygen ratio less than 200 . This condition represents a form of non-cardiogenic pulmonary oedema, which has been hypothesised to be related to aPL, previously described also in the bronchoalveolar lavage (BAL) fluid, or to inflammatory cytokine cascade seen in CAPS .

Finally rare cases of diffuse alveolar haemorrhage, a clinical condition characterised by dyspnoea, cough, fever and haemoptysis associated with diffuse alveolar infiltrates, has been described in APS patients . The absence of haemoptysis in one-third of cases can make diagnosis not so easy. BAL fluid analysis will show also in these atypical cases a haemorrhagic pattern.

The neurological involvement in APS

Central nervous system (CNS) involvement is a common feature of APS and has been attributed to both vascular thrombosis and direct injury to neuronal tissue induced by aPL .

Stroke and transient ischaemic attack are the most common arterial thrombotic events, with the first event being one of the most serious and disabling complication of the disease . Stroke in APS is particularly serious considering that it often occurs in young patients and has a tendency to recur without an adequate therapy . In addition to local thrombosis also, vascular heart disease can explain cerebrovascular manifestations as a possible source of emboli reaching cerebral vessels . In APS patients also, the so-called Sneddon’s syndrome has been described . This condition is characterised by the association between cerebrovascular disease and widespread livedo reticularis, and it is considered the result of a non-inflammatory occlusive arteriopathy of small/medium-sized arteries of the skin and the brain . In patients affected by this syndrome, a prevalence of aPL of 41% has been reported suggesting that these antibodies can contribute to this disorder .

Cognitive dysfunction, such as memory loss, difficulty in concentrating or in keeping attention for a long time, has been associated to the presence of aPL-related microvasculopathy . This hypothesis is supported by the observation of behavioural changes in aPL-injected mice or of learning disabilities in children born to APS patients and by the anecdotal observation that cognitive alterations in APS patients can improve during anticoagulation therapy taken for other reasons . The risk of cognitive dysfunction in APS patients seems to be increased in the presence of white matter lesions on cerebral magnetic resonance (MR) .

Even if epileptic seizures are more common in APS associated to SLE than in PAPS, their association with aPL has been demonstrated . In most cases, seizures are supposed to be the consequence of ischaemic damage, but an interference of aPL with neuronal function has also been suggested .

Many APS patients complain of headache, which can vary from intermittent to persistent episodes and can be unresponsive to analgesics . Even if there is no clear association with aPL, reduction of this symptom in some patients treated with anticoagulants suggests a possible relationship, as for cognitive dysfunction .

Multifocal white matter lesions on brain MR are a common finding in APS patients . As similar lesions can be found in multiple sclerosis (MS) patients and as some neurological APS manifestations, such as transverse myelitis, optic neuritis and sensory problems, can be very similar to those of MS (MS-like syndrome), an accurate differential diagnosis is needed . Static and subcortical lesions rather than dynamic, periventricular and ovoid-shaped ones suggest an APS instead of an MS .

Movement disorders have been rarely described in APS. Chorea, although rare in APS (1.3% of patients) , has been strongly correlated to aPL presence . In a case series, chorea was often triggered by hormonal events (such as oestrogen-containing oral contraceptives, pregnancy and the post-partum period) and in one-third of cases cerebral infarcts were found at brain MR .

Finally, transverse myelitis is also a rare complication of APS (less than 1%), strongly associated with aPL . The pathogenesis of this manifestation in APS is not clear, but ischaemia and aPL’s direct effects on the spinal cord are considered possible .

The renal involvement in APS

Antiphospholipid-mediated thrombosis in renal vasculature can cause different consequences depending on the size, type and site of the vessel.

The involvement of the renal artery and its main branches can cause systemic hypertension that can also be severe presenting in some cases as malignant hypertension . As this condition can be reversed with therapy, the ecocolordoppler study of renal arteries is essential to exclude a stenosis. In other cases, the same lesion can produce different events ranging from acute to chronic slowly progressive ischaemic renal failure . For these lesions, in addition to thrombosis, accelerated atherosclerosis and endothelin-induced vasoconstriction are considered possible pathogenetic mechanisms

In case of occlusive lesions of arterial intraparenchymal vessels, for in situ thrombosis or embolisation from heart lesions, renal infarction can take place . Its manifestations are marked hypertension, renal dysfunction and pain .

Further, lesions in smaller vessels, such as glomeruli, arterioles and interlobular arteries, are possible in APS realising a thrombotic microangiopathy. This condition is clinically characterised by hypertension, renal failure and proteinuria and should be investigated by renal biopsy having distinctive histological features .

Finally, renal vein thrombosis has been described in APS patients. It can be the first manifestation of the disease and should be excluded by ecocolordoppler study of renal veins in cases of nephrotic syndrome

The cutaneous involvement in APS

Dermatologic manifestations in APS patients are common and vary from minor to life-threatening conditions . The most frequent is livedo reticularis, a red or bluish alteration of the skin with a net-like pattern due to the blood stasis in capillaries and venules. In contrast to cutis marmorata, a similar lesion observable in healthy people, it is usually widespread and persistent. More rare are skin ulcerations that can be post-phlebitic (ulcer in a leg with previous venous thrombosis accompanied by oedema and erythema) or caused by a circumscribed skin necrosis (small painful ulcer surrounded by a purplish-brown halo and often preceded by purpura). In the second case, a biopsy generally shows a thrombosis of dermal vessels. If stenosis or occlusion involves larger vessels, digital gangrene can occur. Finally, as in other thrombo-embolic conditions, also in APS subungual splinter haemorrhages can appear.

The haematologic involvement in APS

The most frequent haematologic alteration in APS patients (20–40% of cases) is thrombocytopaenia . This condition is usually moderate (>50 × 10 ⁹ l ⁻¹ ) and, except in rare cases, is not associated with haemorrhagic events. The reduction of platelets can be due to their destruction or activation/aggregation .

Auto-immune haemolytic anaemia is another characteristic of APS even if it is less frequent (6–10% of patients) than thrombocytopaenia . In some cases, this alteration is present together with auto-immune thrombocytopaenia in the so-called ‘Evans syndrome’ .

In very rare cases, especially in the context of a widespread systemic thrombosis, a bone marrow necrosis with the destruction of haematopoietic tissue occurs in APS. .

The gastrointestinal involvement in APS

A wide range of abdominal manifestations has been reported in the context of APS, even if hepatic involvement is the most common .

The Budd–Chiari syndrome is a consequence of the obstruction of the outflow of hepatic venous blood. The classical picture is characterised by abdominal pain, hepatomegaly and ascites, but the clinical expression of this condition can vary from asymptomatic to fulminant liver failure . Hepatic infarction, compared with other organs, is a rare condition because of the dual blood supply to the liver, but rare cases have been described in APS patients .

Among intestinal manifestations the most relevant is bowel infarction, due to the thrombosis of mesenteric (venous, arterial or both venous/arterial) vessels. The typical clinical manifestation is an intestinal angina, but if this condition is not recognised it can evolve into an acute abdomen .

Finally few cases of splenic infarction, acute non-inflammatory pancreatitis and other liver non-thrombotic disease (i.e., nodular regenerative hyperplasia, portal hypertension and so on) have been described in APS patients .

The ocular involvement in APS

An extremely variable percentage of patients with APS (8–88%) have an ocular involvement during its clinical history . As this can be the presenting manifestation, aPL detection should be strongly considered in patients (especially young) with visual symptoms suspicious for vaso-occlusive disease.

The most common site of ocular involvement in APS is the posterior segment, with a wide range of complications . Among them, central retinal vein/artery or branched retinal vein/artery occlusion are the most classical, even if diverse retinal, choroidal, vitreal and scleral changes can be observed. Usually patients report visual symptoms, such as blurred vision, amaurosis, scotoma or visual field defects, but ophthalmic disease may be asymptomatic. For this reason, in APS patients routine ophthalmological examination is recommended .

Optic neuropathy is another common feature of APS, and it represents the major cause of blindness in these patients . In PAPS patients, a non-arteritic unilateral optic neuritis due to a thrombotic event involving the ciliary vasculature is more frequent, whereas in APS patients associated to SLE an arteritic bilateral optic neuritis tends to prevail.