Antiphospholipid syndrome is characterised by a variety of clinical and immunological manifestations. The clinical hallmarks of this syndrome are thrombosis and poor obstetric outcomes, including miscarriages, fetal loss and severe pre-eclampsia. The main antiphospholipid antibodies include lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I. The combination of aspirin and heparin is considered the standard of care for women with antiphospholipid syndrome and embryo–fetal losses; however, aspirin in monotherapy may have a place in women with recurrent early miscarriage. A good benefit–risk ratio of low-molecular-weight heparin in pregnancy thrombosis treatment has been reported. Warfarin must be avoided if possible throughout the first trimester of pregnancy. Adequate pregnancy management of women with antiphospholipid syndrome should include co-ordinated medical-obstetrical care, a close follow-up protocol and a good neonatal unit. Close blood pressure control and early detection of proteinuria, together with Doppler studies of the utero–placental circulation should be included in the management protocol.
Introduction
Antiphospholipid syndrome (APS) is an autoimmune disease affecting mainly young adults, and is characterised by the presence of recurrent arterial or venous thrombosis and adverse obstetric outcomes, such as miscarriages, fetal loss and severe pre-eclampsia. Antiphospholipid antibodies are its most typical laboratory findings, and a mild-to-moderate thrombocytopenia is frequently present. In this review, we look at the pathogenesis, epidemiology, clinical manifestations, classification criteria, therapeutic management and follow up of this syndrome.
Epidemiology
Antiphospholipid antibodies can be detected in 1–5% of healthy women. The prevalence of positive antiphospholipid antibodies increases to 15% in women with recurrent first trimester losses and up to 20% in women suffering a stroke at or before the age of 50 years. Around 40% of women with lupus have antiphospholipid antibodies; it is estimated that less than 40% of them will eventually develop thrombotic events. The prevalence of APS is unknown, but it has been estimated to be 0.5% in the general population.
In a large 5-year prospective cohort study, the mean age at diagnosis was 34 years. The female to male ratio was 3.5:1 for the primary form of the disease and 7:1 for APS associated to systemic lupus erythematosus. The mortality rate was around 5%.
Sporadic spontaneous abortion occurs in up to 15% of all recognised pregnancies, and recurrent miscarriage occurs in about 1% of women of reproductive age. They can be caused by chromosomal, anatomic, hormonal (progesterone, oestrogens, diabetes or thyroid disease), coagulation or platelet abnormalities. Taking into account all possible causes, APS could be responsible for 10–15% of recurrent miscarriages, whereas antiphospholipid antibodies could be identified in 5–20% of these women. This is consistent with the findings from Rai et al. that nearly 10% of 500 women with three or more miscarriages had persistently positive lupus anticoagulant. These frequencies may be biased because studies were conducted before the updated classification criteria.
Fetal death occurs in up to 5% of unselected pregnancies, being less likely as pregnancy advances. The overall contribution of APS in this setting is still unclear. Pre-eclampsia and other hypertensive disorders affect 2–8% of all pregnancies, which is a major contributor to maternal mortality worldwide. About one-third of untreated women with APS may develop pre-eclampsia during pregnancy, and more than 10% of these women will deliver small for gestational age infants.
Epidemiology
Antiphospholipid antibodies can be detected in 1–5% of healthy women. The prevalence of positive antiphospholipid antibodies increases to 15% in women with recurrent first trimester losses and up to 20% in women suffering a stroke at or before the age of 50 years. Around 40% of women with lupus have antiphospholipid antibodies; it is estimated that less than 40% of them will eventually develop thrombotic events. The prevalence of APS is unknown, but it has been estimated to be 0.5% in the general population.
In a large 5-year prospective cohort study, the mean age at diagnosis was 34 years. The female to male ratio was 3.5:1 for the primary form of the disease and 7:1 for APS associated to systemic lupus erythematosus. The mortality rate was around 5%.
Sporadic spontaneous abortion occurs in up to 15% of all recognised pregnancies, and recurrent miscarriage occurs in about 1% of women of reproductive age. They can be caused by chromosomal, anatomic, hormonal (progesterone, oestrogens, diabetes or thyroid disease), coagulation or platelet abnormalities. Taking into account all possible causes, APS could be responsible for 10–15% of recurrent miscarriages, whereas antiphospholipid antibodies could be identified in 5–20% of these women. This is consistent with the findings from Rai et al. that nearly 10% of 500 women with three or more miscarriages had persistently positive lupus anticoagulant. These frequencies may be biased because studies were conducted before the updated classification criteria.
Fetal death occurs in up to 5% of unselected pregnancies, being less likely as pregnancy advances. The overall contribution of APS in this setting is still unclear. Pre-eclampsia and other hypertensive disorders affect 2–8% of all pregnancies, which is a major contributor to maternal mortality worldwide. About one-third of untreated women with APS may develop pre-eclampsia during pregnancy, and more than 10% of these women will deliver small for gestational age infants.
Pathogenesis
Antiphospholipid syndrome was first identified as an autoantibody-induced thrombophilia. The hallmarks of this syndrome are vascular thrombosis involving both the venous and arterial beds, as well as placental circulation. Thrombosis in the placental vasculature may lead to infarctions and placental insufficiency. This is not exclusively seen in APS, and may also occur in pre-eclampsia. On the other hand, it has been observed that in many women with obstetric APS there is no evidence of placental thrombosis, infarctions or vasculopathy; instead, inflammatory signs are seen. This finding has contributed to the redefinition of the concept of APS as an inflammatory disorder.
In-vitro and in-vivo studies have proved the important role played by endothelial cells, neutrophils, monocytes, platelets, cytokines and complement in the induction of thrombosis and fetal death in APS. Maternal endothelial cell activation may play a role in defective placentation. Antiphospholipid antibodies bind to negatively charged phospholipids, protein-binding phospholipids, or both, triggering the activation of endothelial cells, monocytes and platelets. In addition, antiphospholipid antibody complexes, mainly formed by β2 glycoprotein I and anti-β2 glycoprotein I, activate the classical and alternative complement pathways. Therefore, complement deficiency or inhibition of complement activation proved a protective effect against pregnancy loss and thrombosis in a murine model. This fact could explain the benefits of low-dose heparin, owing to its capacity of complement inactivation rather than by its antithrombotic effects.
Activated endothelial cells express adhesion molecules and, along with monocytes, upregulate the production of tissue factor. Tissue factor is the major initiator of the coagulation cascade in vivo , playing an important role in thrombosis and inflammation. Growing evidence suggests that antiphospholipid antibodies-dependent induction of tissue-factor activity on circulating monocytes is an important mechanism of hypercoagulability in APS. Complement can also contribute significantly to thrombosis by increasing tissue-factor expression in various cell types. Tissue factor, acting as a proinflammatory molecule, enhances neutrophil activity causing trophoblastic injury, placental dysfunction and damage in the developing placenta and embryo. In addition, antiphospholipid antibodies seem to cause direct trophoblastic dysfunction, resulting in impaired transplacental exchange between the mother and the fetus, which can lead to early miscarriage, pre-eclampsia, intrauterine fetal growth restriction or even intrauterine fetal death.
The disruption of the annexin A5 shield also plays an important role in the pathogenesis of APS. Annexin A5 is a potent vascular and placental anticoagulant protein, which has high affinity for negatively charged phospholipids. It is highly expressed on the apical membranes of placental villous syncytiotrophoblast, at the interface between the fetus and the placenta. Its anticoagulant effect results from the capacity to crystallise over phospholipid bilayers, blocking their availability for coagulation reactions. Antiphospholipid antibodies interfere with annexin A5 function, leading to accelerated coagulation reactions, and probably contributing to pregnancy loss and to the thrombogenic effects of these antibodies. Rand et al. proved that the antimalarial drug hydroxychloroquine reduces the binding of antiphospholipid antibodies to phospholipid bilayers, reversing the effects of antiphospholipid antibodies on annexin A5 and restoring its activity. This is consistent with the antithrombotic effect of hydroxychloroquine suggested by many studies, particularly in women with systemic lupus erythematosus and antiphospholipid antibodies carriers.
Clinical features, laboratory assessment and classification criteria
Classification criteria were first proposed in Sapporo, Japan, in 1998, and recently updated in 2006 in Sydney, Australia. At least one clinical manifestation, such as vascular thrombosis or pregnancy morbidity, together with positive laboratory tests, including lupus anticoagulant, anticardiolipin (aCL) and anti-β2-glycoprotein I antibodies (anti-β2GPI), detected at least twice12 weeks apart, are necessary to fulfil the classification criteria ( Table 1 ).
| Clinical criteria | Laboratory criteria |
|---|---|
|
|
Pregnancy morbidity a
|
a In studies of populations of women who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of women according to a, b, c as listed.
Antiphospholipid syndrome can occur in isolation in over 50% of women or is associated with other systemic autoimmune diseases, mainly systemic lupus erythematosus.
Deep-vein thrombosis and pulmonary embolism are the most frequent manifestations of APS. Unlike thrombosis associated with congenital thrombophilias, however, arterial territories can also be involved. Arterial thrombosis affects preferably cerebral circulation, presenting as strokes or transient ischemic attacks. APS can also affect coronary, retinal, renal and glomerular circulation. Thromboses are typically recurrent and frequently affect the same territory in subsequent thrombotic events.
Obstetric morbidity includes fetal and maternal complications. In a multicentre prospective cohort of 1000 women with antiphospholipid syndrome, the most frequent fetal complications were miscarriage, followed by fetal loss and premature birth, whereas the most common maternal manifestations were pre-eclampsia, followed by eclampsia and abruptio placentae.
Classification criteria include three or more consecutive and spontaneous early miscarriages before 10 weeks of gestation, after chromosomal or anatomic defects have been excluded; at least one unexplained fetal death after the 10th week of gestation of a morphologically normal fetus; or a premature birth before the 34th week of gestation of a normal neonate due to eclampsia or severe pre-eclampsia or placental insufficiency.
Therefore, women with APS are at increased risk of both miscarriage and thrombosis, which can coexist in around 2.5–5% of cases.
Antiphospholipid syndrome may also present with other frequent clinical manifestations (more than 20% of cases) that are not included in the classification criteria, such as thrombocytopenia, migraine and livedo reticularis. Other less common manifestations are heart valve disease, haemolytic anaemia, coronary artery disease and the haemolysis, elevated liver enzymes and low platelet count syndrome (HELLP). Clinicians should be aware that these features might be the presenting manifestations of APS.
As discussed above, clinical manifestations must be accompanied by one or more persistently positive antiphospholipid antibodies detected by coagulation, immunological tests, or both. Lupus anticoagulant is detected by functional assays based on a combination of several clotting tests, including dilute Russell Viper Venom Time. aCL and anti-β2GPI are detected by enzyme-linked immunosorbent assays. Unfortunately, standardisation among these tests is poor, requiring careful interpretation of their results. To fulfil classification criteria, titres of aCL must be higher than 40 G phospholipid units (GPL) or M phospholipid units (MPL), whereas anti-β2GPI titres must be above the 99th percentile. Only immunoglobulin G (IgG) or immunoglobulin M (IgM) are considered in those criteria. Neither immunoglobulin A isotypes, nor other antiphospholipid antibodies (antiprothrombin and phosphatidylserine-prothrombin complex antibodies) are included in the criteria, although their pathogenic potential cannot be completely excluded.
Lupus antibody is the most powerful predictor of thrombosis and recurrent miscarriages. In a meta-analysis including 25 studies designed to assess the association between antiphospholipid antibodies and recurrent fetal loss, lupus anticoagulant showed the strongest association with recurrent fetal losses before 24 weeks of gestation (odds ratio [OR] 7.79, 95% confidence interval [CI] 2.30 to 26.45). It was not possible to analyse the association of lupus anticoagulant with early miscarriage (before 13 weeks). IgG aCL were associated with early (OR 3.56, 95% CI 1.48 to 8.59) and late recurrent fetal losses (OR 3.57, 95% CI 2.26 to 5.65). Considering women with moderate to high titres increased the rate of association (OR 4.68, 95% CI 2.96 to 7.40). Meanwhile, immunoglobulin M aCL were associated with late recurrent fetal losses (OR 5.61, 95% CI 1.26 to 25.03). No relationship was found between anti-β2GP1 and recurrent miscarriages (OR 2.12, 95% CI 0.69 to 6.53). Ruffatti et al. also found that lupus anticoagulant is the antiphospholipid antibody that most strongly influences pregnancy outcome. Moreover, those women with more than one positive test for antiphospholipid antibodies had poorer outcomes; those women who were positive for all three tests, called ‘triple positive’, had a significantly higher incidence of pregnancy loss compared with women who had one or two positive tests for antiphospholipid antibodies.
The neonatal outcome of newborn babies to mothers with APS was recently studied in a retrospective analysis by the same group. They found a significant association between lupus anticoagulant, women with the triple antiphospholipid positivity and poor infant outcomes. Women with the triple antiphospholipid positivity and a thrombosis profile of the antiphospholipid syndrome seem to have higher probability of poor neonatal outcome, characterised by a higher rate of respiratory distress syndrome, infections, bronchopulmonary dysplasia, among other complications. By contrast, women with pregnancy morbidity alone and given conventional treatment were likely to have better neonatal outcomes than the previous group. Similar results were found in a study by Bramham et al., showing that a history of thrombosis worsens the obstetric prognosis in women with APS.
In summary, classification criteria are useful for research purposes, but clinical practice should go further. Different clinical and immunological profiles have clear prognostic significance and are an extremely important tool for guiding clinical decisions. Moreover, frequent clinical manifestations of APS are not included in the criteria, and great variability still exists among the different tests used to detect antiphospholipid antibodies. Therefore, it is important to highlight that, in many clinical scenarios, strict criteria may prove difficult to apply, which results in the need for a careful balance between classification criteria and clinical sense.
Clinical management
Early recognition and diagnosis of APS helps prevent thrombosis and obstetric morbidity. All women with systemic lupus erythematosus, and maybe with any systemic autoimmune disease, who want to become pregnant, should be tested for antiphospholipid antibodies. Women who have suffered intrauterine growth restriction, stillbirth, severe pre-eclampsia (particularly before 34 weeks of gestational age), eclampsia, or HELLP syndrome, and in all cases with additional clinical features of APS, should be tested too. On the other hand, it is not advised to test women who have had only one miscarriage ( Table 2 ). Treatments for thrombotic and obstetric manifestations of APS are discussed below.
| Systemic autoimmune diseases carriers |
| Women who have a history of: |
| recurrent miscarriage |
| intrauterine growth restriction |
| stillbirth |
| hypertension, severe pre-eclampsia or eclampsia (<34 weeks of gestational age) |
| abruptio placentae |
| preterm newborns (<34 weeks of gestational age) |
| haemolysis, elevated liver enzymes, low platelets syndrome |
Treatment of thrombosis in antiphospholipid syndrome
The treatment of thrombotic manifestations of APS has been widely updated, and it is not the purpose of this review. It is important to highlight that women with antiphospholipid antibodies, especially those with lupus or with a high-risk antibodies profile, are candidates for long-term primary thromboprophylaxis with low-dose aspirin.
In women with APS and thrombosis, the current standard of care is long-term secondary prophylaxis with oral warfarin, maintaining the international normalised ratio (INR) between 2.0 and 3.0 for the first venous thromboembolic event. Recommendations for the treatment of arterial events are not as standardised, and either maintaining INR over 3.0 or between 2.0 and 3.0 combined with antiaggregant therapy could be possible options. Increasing the intensity of INR is also recommended for women with recurrent venous events. Hydroxychloroquine can also play a role in preventing thrombosis. This has been seen in women with lupus ; however, given the excellent safety profile, its use could also be extended to women with primary APS.
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