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The APS may occur in the absence of other associated diseases (primary APS) or in combination of other diseases (secondary APS) such as SLE. A more uncommon variant of APS is known as "catastrophic APS", which involves multiple organ thromboses and dysfunction. Clinical features of the APS are diverse, with the most prominent one being thrombotic events, as well as pregnancy complications. The "1 in 5 Rule" applies regarding the prevalence of APS; 1 in 5 of all young strokes, 1 in 5 recurrent miscarriages, 1 in 5 deep vein thromboses.2
A study by Cervera et al on 1000 patients with APS revealed that during the 5-year study period, 20% of patients developed APS-related manifestations.3 16% of patients had recurrent thrombotic events, with stroke being the most common (2.4%). The mortality rate was described as 5% during the period of the study. Among pregnant subjects, the most common foetal complications were found to be early pregnancy loss (17.7% of pregnancies) and premature births (35% of live births). A total of 53 patients (5.3%) in the cohort died, with the most common causes of death being bacterial infections (21% of death), myocardial infarction (19%), and stroke (13%).
The exact cause of the syndrome is not known, but a number of hypotheses regarding the mechanism of pathogenesis exist, which centre on immunological abnormalities, specifically the presence of the antiphospholipid antibodies. Little is known of the immune response which results in the production of the antiphospholipid antibodies.
Antiphospholipid antibodies (aPL) are a heterogenous group of antibodies that target a variety of antigens, including phospholipid binding proteins such as Î²2 glycoprotein I, phospholipid-protein complexes as well as the phospholipids themselves. There are various aPL antibodies, but those that are more commonly tested for clinically may be broadly categorised into lupus anticoagulants (LA), which are those that prolong phospholipid-dependent coagulation assays, and anticardiolipin antibodies (aCL), which are antibodies directed against cardiolipin (CL). Other antibodies that are possibly associated with the APS include antibodies to the components of protein C pathway (anti-protein C, anti-protein S, antithrombomodulin). Protein C is a plasma glycoprotein which plays a crucial role as an anticoagulant.
LA are detected by coagulation assays, and the most commonly used assays are the aPTT (activated Partial Prothrombin Time), the dRVVT (dilute Russell's Viper Venom Time), and KCT (Kaolin Clotting Time). Enzyme linked immunosorbant assays (ELISA), which are employed in the detection of aCL antibodies, assess the binding of a CL-coated plate by diluted patient serum, in the presence of bovine serum. However, some patients possess antibodies that bind only to human but not to bovine Î²2GPI, therefore the ELISA might potentially miss these patients. Human Î²2GPI is thus currently used in some assays.4 A patient has to be persistently positive for at least 12 weeks on either one of the assays to satisfy the APS laboratory classification criteria.
APS is commonly diagnosed using the updated Sapporo APS classification.5 To fulfil a diagnosis of APS, a combination of at least one clinical (vascular thrombosis and pregnancy morbidity) and one laboratory criterion is required.
The most commonly characterised target antigen for aPL antibodies is the phospholipid binding protein Î²2 glycoprotein I (Î²2GP I), to which the antibodies preferentially bind.6 Some of the potential effects of the antibodies on phospholipid binding proteins are summarised in Table 1.7
1. Direct inhibition of antigen enzymatic or cofactor function
2. Binding of fluid-phase antigens and causing a decrease in the plasma antigen levels by clearing the immune complexes
3. Forming immune complexes with antigens, which are deposited in vessel walls, resulting in inflammation and tissue injury
4. Cross-linking of membrane-bound antigen, causing dysregulation of antigen-phospholipid binding
5. Cross-linking of cell surface-bound antigens, triggering cell-mediated events
Table 1: Some potential effects of antiphospholipid antibodies on phospholipid binding proteins. 7
Patients with APS have an increased risk of venous and arterial thrombosis, recurrent pregnancy loss, and/or thrombocytopenia. Studies have shown that non-SLE patients with antiphospholipid antibodies are at a greater risk for venous thromboembolism than patients without these antibodies. A meta-analysis of the risk of venous thrombosis in patients without previous thrombosis or any underlying autoimmune disease found that patients with LA were at more than 10 times greater risk for venous thrombosis than patients without LA.8 It was also found that patients with high titres IgG aCL were at three times greater risk than patients without these antibodies. Several mechanisms of thrombosis brought on by the aPL antibodies have been proposed. One mechanism involves the inhibition of the phospholipid binding protein Î²2GP I. Î²2GP I has anticoagulant properties, which are displayed through the inhibition of the following: ADP-induced platelet aggregation, the intrinsic coagulation pathways, prothrombinase activity of platelets, as well as the activation of protein C in the presence of phospholipids. Inhibition of this protein results in the inhibition of its anticoagulant properties, and subsequently leading to an increase risk of thrombus formation. Other possible mechanisms include the inhibition of the protein C pathway, the inhibition of antithrombin activity, and displacement of annexin V, a potent anticoagulant protein.9
Park et al found that the prevalence of antiphospholipid antibodies in 81 women who had had recurrent spontaneous abortion (3 or more fetal losses) to be 16%, which was significantly higher than in 88 women whose pregnancies were successful (7%), and 64 women who had never been pregnant (3%).10 This suggests that elevated aPL plays an important role in pregnancy morbidity. Fetal loss in patients with APS is due to thrombosis forming at sites where fetal cells are exposed to maternal blood as well as at sites where vascular endothelial cells come into contact with circulating blood. Thrombosis formation at these sites are related to the reduction of surface-bound annexin V by aPL antibodies.11 Non-thrombotic mechanisms may also be involved, for example, the binding of the aPL antibodies to the trophoblast. The aPL antibodies may also play a role in other pregnancy complications, such as placental insufficiency and early severe pre-eclampsia.
Thrombocytopenia is frequently present in APS patients. A study shows a prevalence of thrombocytopenia of 23.4% in APS.12 However, the relation between aPL antibodies and thrombocytopenia is unclear. The study also found that miscarriages were more frequent in APS patients with thrombocytopenia.
Treatment for APS is generally tailored for each patient, depending on risk assessment. The main treatment for patients who are tested positive for aPL antibodies is anticoagulation or antiplatelet therapy, and the major drugs used in the treatment of APS are aspirin, heparin, and warfarin. Asymptomatic individuals who are tested positive for aPL antibodies do not require any specific treatment.
Aspirin is used as a prophylactic treatment in pregnancy in APS patients who have had a previous miscarriage. Aspirin is used either alone, or in combination with subcutaneous heparin. It is usually given in a low dose of between 75 to 100 mg. Aspirin has been shown to improve the rate of live birth in one study where it was found that prior to therapy, the rate of live births was 6.1% and after therapy, it was improved to 90.5%.13 A systematic review however reported three trials that showed no significant reduction in foetal loss when aspirin was given alone.14
Aspirin is safe to be used in pregnancy; however it is not without some adverse effects. The most common side effect experienced by patients on aspirin is gastrointestinal irritation, however with low dose aspirin, the risk is rather minimal. The risk for major bleeding also increased with the use of aspirin, however the increase is rather small.15 Aspirin shouldn't be used in individuals with a history of hypersensitivity to it or any other non-steroidal anti-inflammatory drugs. It may also delay the onset and increase duration of labour in pregnant women, thus it should be used with caution during pregnancy, especially during the third trimester.16
Patients who are pregnant and have had a previous thrombosis are commenced on treatment with the anticoagulant heparin, and it is useful as first-line treatment prior to changing to warfarin post-partum. Heparin is also used prophylactically in combination with aspirin in APS patients who have not had a thrombotic event previously. Treatment with heparin not only increases foetal survival, it might also play a role in protecting pregnancies by reducing the binding of antiphospholipid antibodies, reducing inflammation, facilitating implantation and inhibiting complement activation.17,18
Due to it not being orally absorbed, heparin is given as a twice-daily subcutaneous injection. Although it is a relatively safe drug (hence the reason why it is used in pregnancy in place of warfarin), heparin is associated with heparin-induced thrombocytopenia as well as osteoporosis on long-term use.19 Low molecular weight heparin has largely replaced standard heparin in APS pregnancy, as it has a lower risk of heparin-induced thrombocytopenia and osteoporosis.
The oral anticoagulant warfarin is used in more severe cases of APS where patients have had one or more thrombosis. Intensity and duration of treatment are determined on an individual basis, however warfarin therapy is usually instituted with a target international normalized ratio (INR) of 2.0-3.0. Warfarin has been shown to reduce the risk of recurrent venous thrombosis by 80-90% compared with placebo, irrespective of the presence of antiphospholipid antibodies.20 For long-term therapy, high-intensity warfarin (INR adjusted to more than 3.0) has been suggested to be more effective than low-intensity (INR of 2.0-3.0).21
Although effective, therapy with warfarin is not risk free. Warfarin is mainly associated with increased bleeding, especially at higher levels of anticoagulation that might be used in certain patients. On average, the risk of major bleeding in patients on treatment with warfarin is 3% per year, and about 20% of it is fatal.22 Warfarin is also teratogenic, as it is able to cross the placenta and cause abnormalities in the foetus, and may also cause fatal haemorrhage in the foetus, thus it is contraindicated especially in the first and third trimester of pregnancy. Low molecular weight heparin is used instead in cases where warfarin is unsuitable, e.g. in pregnancy.
Clopidogrel is similar to aspirin in its antiplatelet activity. It is used in combination with aspirin in non-cerebral arterial thrombosis. It is used as an alternative when aspirin is contraindicated, for example in those who are intolerant to aspirin despite treatment with a proton pump inhibitor, or in those with aspirin hypersensitivity. It does not have the irritant effects on the stomach that aspirin has. However, clopidogrel is costly, thus from a cost-effectiveness perspective it is currently not the obvious choice of drug to be prescribed unless patients are ineligible for aspirin.23 Clopidogrel may cause some adverse effects such as abdominal pain, diarrhoea, headache, and dizziness.
Hydroxychloroquine is an antimalarial drug that is also useful in the treatment of lupus, Sjögren's Syndrome, and in reducing inflammation in rheumatoid arthritis. It possesses a mild anti-clotting property, thus is beneficial in preventing thrombosis. Edwards et al have shown that hydroxychloroquine was able to significantly diminished both thrombus size and total time of thrombus formation in mice previously injected with IgG-APS.24 Other studies have reported that hydroxychloroquine has a protective effect on thrombosis in lupus patients, and is able to restore the anticoagulant effect of annexin V, which is known to be markedly reduced when aPL antibodies are present.25 Its use in antiphospholipid syndrome however is yet to be validated by well-conducted clinical trials.
Hydroxychloroquine may cause some side effects such as gastrointestinal disturbances, headache, and skin reactions.
Intravenous Immunoglobulin (IVIG)
IVIG is a blood product consisting of an intravenous preparation of pooled IgG extracted from a large number of donors. Its effect may last between 2 weeks and 3 months. It is currently being used in three major categories: immune deficiencies, inflammatory and autoimmune diseases, and acute infections such as Kawasaki disease and Guillain-Barre syndrome. Some off-label uses include the treatment of SLE, multiple sclerosis.
There is evidence that IVIG may be beneficial in obstetric complications of APS. Successful deliveries of healthy infants were observed in APS patients with previous unsuccessful pregnancies in a study by Spinnato et al.26 No pregnancy complications such as foetal intrauterine growth retardation or preeclampsia were observed. The therapy also did not cause any major side effects in the patients.
IVIG therapy is extremely expensive, and patients receiving it might experience some minor side effects such as headache and dermatitis, however despite these limitations, it has a good safety record.
Immunosuppressives such as azathioprine and cyclophosphamide were used to treat lupus and APS patients in the early 1980s; however the results proved to be disappointing.2 Newer biologics immunosuppressives such as rituximab might be helpful in certain resistant APS cases.27
Fig. 1. Treatment algorithm for APS. Adapted from Giannakopoulos et al 28
Clinical Scenario: A 32 year old female with antiphospholipid syndrome
A treatment recommendation for APS should be based on the individual, the history of symptoms the individual is presented with (e.g. prior thrombosis, previous miscarriage), and if the patient is a female of child-bearing age, whether she is currently pregnant or is trying to conceive. For a patient with positive tests who has not had a prior thrombosis, and is not pregnant, antithrombotic therapy is usually not indicated, unless at times of high risk, such as during surgical procedures.
In this clinical scenario, assuming that the patient is not currently pregnant, and has had a thrombotic event, the most suitable treatment recommendation for her is warfarin therapy. APS patients with prior thrombosis are at risk of recurrence, thus anticoagulant therapy is indicated for this group of patients.29 Subsequent thrombotic events tend to occur at the same site as the original event; venous thrombosis generally precedes recurrent venous events, while recurrent arterial events would occur after a first arterial thrombosis.29
Warfarin may have a better antithrombotic protection than aspirin, and seems to be the better choice in the prevention of recurrent thrombosis. A study has shown that warfarin (high intensity, producing an INR >3) was found to have the lowest recurrence rates per patient-year, compared to low intensity warfarin (producing an INR <3) and treatment with aspirin alone (recurrence rates: 0.013, 0.18, 0.23 respectively).21 Another study also presented similar results, with which it was concluded that intermediate- to high-intensity warfarin therapy may have a better antithrombotic protection than low- to intermediate-intensity warfarin therapy or aspirin therapy.29
Warfarin is also superior to aspirin in preventing cerebral thromboembolic event after an acute coronary syndrome. In a randomised multicenter trial, it was found that warfarin, given alone or in combination with aspirin, was better in reducing incidence of composite events after an acute myocardial infarction compared to aspirin alone, albeit a higher risk of bleeding.30 3630 patients were randomised to one of three treatments: warfarin alone (in a dose intended to produce an INR of 2.8-4.2), aspirin alone (160 mg daily), or warfarin (dose intended to produce an INR of 2.0-2.5) in combination with aspirin (75 mg daily). The trial was carried out over four years, and the primary outcome measured was a composite of death, nonfatal reinfarction, or thromboembolic cerebral stroke. The incidence of composite events was observed in 20% of patients receiving aspirin alone, 16.7% in patients receiving warfarin alone, and 15% of patients receiving warfarin in combination with aspirin. There was no statistically significant difference between the two groups receiving warfarin.
In terms of the intensity of the warfarin treatment, some studies advocate the use of high-intensity warfarin to prevent recurrent thrombosis, aiming at an INR of more than 3.0. However, two randomised trials have shown that moderate-intensity (producing an INR of <3.0) was better than high-intensity warfarin. In the first study, 114 APS patients were randomised to receive either high-intensity warfarin or moderate-intensity warfarin.31 It was found that 10.7% of patients receiving high-intensity warfarin had recurrent thrombosis, which was higher than those who received moderate-intensity warfarin (3.4%). In the second study, 109 APS patients with previous thrombosis were assigned either to high-intensity warfarin or standard antithrombotic therapy (moderate-intensity warfarin or aspirin 100 mg/day).32 Of those patients receiving high intensity warfarin, 11.1% had recurrent thrombosis, compared to only 5.5% in those on conventional treatment. Both trials aimed at proving that high-intensity warfarin therapy was better than moderate-intensity warfarin, however the results contradicted the objective. It can thus be concluded from both trials that moderate-intensity warfarin is appropriate to prevent recurrent thrombosis in APS patients. Major and minor bleeding were observed in these trials, with an excess of minor bleeding occurring with high-intensity warfarin therapy.
The optimal duration of anticoagulation in APS patients is generally tailored for each patient. It is recommended in the guidelines 33 that for venous thrombosis that occurs in the presence of reversible risk factors (e.g. pregnancy, cigarette smoking, immobilisation, use of oral contraceptives, and surgery), treatment for up to 6 months with management of the risk factors at target INR between 2.0-3.0 is appropriate. Other studies however, suggest that long-term anticoagulation might be beneficial in APS patients. Schulman et al showed that in patients with antiphospholipid antibodies, the risk of recurrence of venous thromboembolism was higher than in those without (29% vs 14%).34 The study also went on to show that in patients who received anticoagulant therapy indefinitely, there were no recurrences of the episode, compared to 20% of the patients who received anticoagulant therapy for only 6 months. The results of another study also seemed to support long term anticoagulation for prevention of recurrent thromboembolism.35 In this study, patients who had completed 3 months of anticoagulant therapy were randomised to either placebo or to continue receiving warfarin for a further 24 months. The placebo group had higher recurrence compared to the warfarin-treated group (27.4% vs 1.3% per patient-year).
Thus, based on the evidence presented by various clinical trials, it is recommended that the patient in this clinical scenario be commenced on a long-term, moderate-intensity warfarin therapy, aiming for a target INR of 2.0-3.0.
However, since the patient is of a child-bearing age, we cannot exclude the possibility of pregnancy. Should this patient becomes pregnant, or plans to conceive, it is recommended that she switches to low molecular weight heparin when trying to conceive or upon confirmation of pregnancy, as warfarin is known to be teratogenic, and heparin may improve the rates of live birth in patients with positive aPL antibodies.36 Patient's platelet count should be closely monitored throughout the duration of treatment with heparin, and recommencement of warfarin should be initiated post-partum.