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| SYMPOSIUM-RHEUMATOLOGY |
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| Year : 2014 | Volume
: 19
| Issue : 1 | Page : 19-27 |
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Antiphospholipid syndrome: A review
Varun Dhir, Benzeeta Pinto
Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| Date of Web Publication | 1-Feb-2014 |
Correspondence Address:
Varun Dhir
Department of Internal Medicine, Rheumatology Services, Postgraduate Institute of Medical Education and Research, Chandigarh-160 012
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0971-9903.126231
Antiphospholipid syndrome is being increasingly recognized as a disease with a myriad of clinical manifestations ranging from recurrent thrombosis and pregnancy morbidity to valvular lesions, transverse myelitis, thrombocytopenia and hemolytic anemia. It may be primary or secondary, i.e., associated with other autoimmune diseases. The latest classification criteria (Sydney 2006) recognize just three tests to define this syndrome-lupus anticoagulant, anticardiolipin antobodies and anti β2 glycoprotein 1 antibodies. Treatment of thrombotic events involves lifelong anticoagulation with vitamin K antagonists like warfarin. Antiphospholipid antibody syndrome (APS) with only pregnancy morbidity is treated with thromboprophylaxis using heparin during pregnancy and postpartum for 6 weeks. Catastrophic APS occurs in approximately 1% of APS, and is characterized by microvascular thrombosis (thrombotic storm) and organ dysfunction. In this review we discuss the pathogenesis, diagnosis, treatment and prognosis of the APS. Keywords: Antiphospholipid syndrome, autoimmune disease, treatment
How to cite this article:
Dhir V, Pinto B. Antiphospholipid syndrome: A review. J Mahatma Gandhi Inst Med Sci 2014;19:19-27 |
| Introduction | |  |
Antiphospholipid antibody syndrome (APS) is an autoimmune thrombophilic syndrome characterized by recurrent venous, arterial or small vessel thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies. APS may occur in association with other autoimmune disorders called secondary APS or may be primary in the absence of any underlying illness. The discovery of this syndrome can be traced back to the 1950s with the finding of prolonged activated partial thromboplastin time (aPTT) and even earlier with the biologic false positive syphilis test. Subsequently, in the 1980s with the detection of antibodies against cardiolipin, it was named the anticardiolipin syndrome, later revised to antiphospholipid syndrome. [1] This review synthesises the current information on this syndrome. The search strategy for this review included a search on Pubmed using the term "antiphospholipid" or "anticardiolipin" or "lupus anticoagulant".
| Pathogenesis of Antiphospholipid Syndrome | | |
As the name suggests - antiphospholipid syndrome is mediated through antibodies directed against phospholipids or proteins associated with phospholipids, the latter being more common. Although many antiphospholipid antibodies have been described, the three that are the best studied and are part of the diagnostic criteria are lupus anticoagulant, anticardiolipin and anti β2 glycoprotein 1. More than one antibody is associated with 'lupus anticoagulant' activity including antibodies to cardiolipin (ACL), β2GP1, prothrombin and annexin V. Several mechanism have been suggested to explain the prothrombotic state induced by antibodies to the aforementioned antigens. The primary mechanism has been thought to be activation of endothelial cells, monocytes and platelets by antiphospholipid antibodies. This leads to increased expression of adhesion molecules on endothelial cells and upregulation of tissue factor. Activated platelets also synthesize thromboxane A2 altering the prostacyclin-thromboxane balance to favour thrombosis. In addition, APL may also impair fibrinolysis and interefere with the thrombomodulin-protein C-protein S pathway. The pathogenesis of pregnancy loss in APS is more complex, and apart from the hypercoagulable state causing vasculopathy and thrombosis of spiral arteries of the placenta causing uteroplacental insufficiency, other mechanisms may also play a role. These include interference with annexin V (placental anticoagulant protein), complement activation, the action of antiphospholipid antibodies directly on the trophoblast affecting its differentiation and maturation and finally immunomodulation by activation of toll like receptor (TLR)4. [2],[3],[4],[5]
| Criteria for Diagnosis and Classification of Antiphospholipid Syndrome | | |
The diagnosis of APS is based on the occurrence of the clinical features of APS in the context of persistent positivity for antiphospholipid antibodies (APLA). Classification criteria were initially proposed in 1998 in Sapporo (Japan) and have been widely referred to as 'Sapporo criteria'. [6] These were subsequently revised in 2006 and are known as the revised or 'Sydney criteria'. [7] These were proposed to categorize patients for research purposes; however, they are also used to make a definite diagnosis. The presence of one clinical criterion and one laboratory criterion is essential. [Table 1] The revised criteria retain the fundamental features of the original Sapporo criteria, but are different in increasing the interval between repeat testing to 12 weeks and adding antiβ2GP1 as a laboratory criterion. | Table 1: Revised Sapporo or Sidney criteria for classification of antiphospholipid antibody syndrome
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| Clinical Features | | |
Like other autoimmune diseases, there is a female preponderance in APS as well (F:M = 4-5:1). APS has an onset in the middle aged, i.e 30-40 years old, although, the Euro-phospholipid cohort had around 10% patients who were older than 50 years and 2.5% below 15 years of age. Antiphopholipid syndrome can be a standalone entity (called 'primary APS') or it may be associated with other connective tissue diseases (called 'secondary APS'). Primary APS was most common (50%) followed by APS associated with systemic lupus erythematosus (SLE;around 35%) in a large cohort of patients with APS. [8] Thrombosis is characteristic of this syndrome with venous thrombosis being most common. Common manifestations (non-obstetric), at onset, in a large cohort of 1000 patients (Euro-phospholipid cohort) were deep venous thrombosis, thrombocytopenia, livedo reticularis, stroke, pulmonary embolism, fetal loss and hemolytic anemia. Less common but nonetheless important clinical features were pseudovasculitic skin lesions, skin ulcers, myocardial infarction and digital gangrene. [8] Among the cumulative manifestations during the evolution of the disease (initial 5-6 years) the most common was deep venous thrombosis (38.9%) [Table 2]. [8] | Table 2: Major manifestations of antiphospholipid syndrome as per the europhospholipid cohort study
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Obstetric and fetal complications include early and late pregnancy losses and pre-eclampsia. Other manifestations included premature births, abruptio placentae and postpartum cardiopulmonary syndrome. In the europhospholipid cohort, pre-eclampsia and early fetal loss were the most common complications [Table 2]. [8] This was also found in another cohort (EUROAPS) on 211 women with APS (530 pregnancies) which found the prevalence of early fetal loss and late fetal loss to be 43.3% and 32.4%, respectively. [9] 'Recurrent miscarriage syndrome' (RMS) which is defined as three or more consecutive miscarriages before mid second trimester, is an important manifestation of APS. RMS is not uncommon, occuring in 1 to 3% of women. Although, the most common cause of RMS is fetal chromosomal abnormalities, [10] APS is found in 10-15% of RMS making it an important correctable cause of the same. [11] APS is even more important for 2 nd and 3 rd trimester losses, due to the limited number of causes, and a study found lupus anticoagulant to be positive in 1/3 rd of the patients with pregnancy loss after 20 weeks. [12] APS also causes intrauterine growth retardation (IUGR) due to placental insufficiency and prematurity. Women with only obstetric manifestations of APS are also at risk for thrombotic events. In a prospective study, the risk of thrombosis during pregnancy was 5 percent among women with known APS (compared with 0.025 to 0.10 percent in the general). [13] The Nimes Obstetricians and Hematologists study on ladies with recurrent miscarriages (≥3 first trimester losses) or late miscarriages (2 nd and 3 rd trimester), also found higher annual incidence of deep vein thrombosis (1.46%) in the APLA positive women compared to 0.43% in others. [14]
A minority of patients have 'catastrophic APS; which is characterized by multiple simultaneous vascular occlusions occurring in a small span of time, first described by Asherson in 1992 and hence the eponym 'Ashersons syndrome'. [15] Manifestations are usually in the form of cutaneous (skin purpura, necrosis, splinter hemorrhages), renal failure (requiring dialysis in some), Pulmonary (ARDS) cardiac failure and neurologic (seizures and stroke) and gastrointestinal (mesenteric ischemia). Other unusual manifestations include focal hepatic necrosis, bone-marrow necrosis, adrenal, splenic infarctions and polyneuropathy. Large vessel involvement may also occur concomitantly. Laboratory findings include thrombocytopenia in a majority (3/4 th ) which is often mild to moderate (unlike the severe thrombocytopenia in thrombocytopenic thrombotic purpura), hemolytic anemia (1/4 th patients), disseminated intravascular coagulation (1/4 th ) and occasionally schistocytes. [15] An important clue in half the patients is the previous history (in the form of unexplained DVT etc) or diagnosis of the classical antiphospholipid syndrome before they present with the catastrophic variant of the same. The immediate precipitating factor in catastrophic antiphospholipid syndrome (CAPS) can be infections, surgery or sudden stoppage of anticoagulation. Upto 6% of CAPS seems to be associated with pregnancy and peupeurium; many starting as HELLP syndrome (defined as hemolysis, elevated aspartate aminotransferase and low platelets). In one series, more than half the pregnancies had fetal or neonatal demise. [16]
| Laboratory Findings in Anti-Phosholipid Syndrome | | |
General
Unlike other autoimmune disease, where even in the absence of autoantibodies, clinical features alone can be used to diagnose the disease (like antinuclear antibody negative SLE), anti-phospholipid syndrome requires the detection of autoantibodies. However, similar to other autoimmune diseases, even persistently positive antibodies are not diagnostic without clinical features. In a case control study in 73 such women who had persistently positive antibodies, there was no difference with respect to pregnancy outcomes compared to controls. [17] Indeed, positivity of antiphospholipid antibodies may reach upto 10% in some populations and 50% in SLE, most not manifesting the clinical features of the syndrome. [18]
The three tests included in the classification criteria are anticardiolipin antibody, anti-β2GP1 antibody and lupus anticoagulant. These tests are not equal, i.e., they have different connotations with respect to prognosis. A meta-analysis looked at the relationship of the test positivity and the risk of late (<24 weeks) and early (<13 weeks) recurrent fetal loss. They found that lupus anticoagulant had the strongest association with late recurrent fetal loss (odds ratio 7.8) followed by IgG anticardiolipin antibody (odds ratio 3.6). There was no association of fetal loss with anti-β2GP 1. [19]
Anticardiolipin antibody
The anticardiolipin antibody test is perhaps the most commonly performed test for the detection of this syndrome. It was first described in 1983 as a radioimmunoassay and the ELISA format was established in1985. [20],[21] It detects antibodies against cardiolipin (usually of bovine or human origin), and is usually done in an ELISA format. It is now believed that most of the antibodies that the assay actually detects are those against anti-β2GP1 (a protein bound to the cardiolipin) and not the cardiolipin itself. [22],[23] The β2GP1 protein is introduced during the procedure of the ELISA (washing with bovine serum albumin as a blocking agent). It is usually done for both the IgG and the IgM subtypes, although in some cases IgA is also done. The results are reported as GPL and MPL units, which have been standardized with regard to how much cardiolipin purified preparations of these antibodies, will bind. The general trend found in a large study (Europhospholipid cohort) is that of the total cases of antiphospholipid syndrome, approximately 90% are anticardiolipin positive, with 45% being IgG ACL alone, 30% being IgG and IgM ACL both positive and 15% being IgM positive alone. [8]
Before the Sydney criteria, [6] most laboratories would report results as low positive (<20 units MPL or GPL), medium titers (above 20 upto 40 units) and high titers (more than 40 units); with medium to high titers taken as positive. However, the Sydney criteria has tried to increase the specificity of the diagnosis by taking a cut off of positive of more than 40 units (both MPL and GPL). [7] However, at the same time, it is recommended that every laboratory performing this test, defines their own cutoffs using healthy samples. These tests are considered positive only if they are persistently found to be positive even after 12 weeks.
Lupus anticoagulant
The 'lupus anticoagulant' is both a phenomenon and a test! The phenomenon was the one first recognized in patients with systemic lupus erythematosus, when it was seen that they had increased aPTT values but a paradoxical thrombosis. The lupus anticoagulant effect is due to antibodies against a variety of phospholipids or phospholipid-protein complexex. The phospholipids these antibodies are directed against include β2GP1, cardiolipin, prothrombin, annexin V and others. Thus unlike the anticardiolipin assay and anti-β2GP1 assays which detect the antibodies directly using an immunoassay like ELISA, this test is a measure of the functional effect of the antibodies on coagulation tests. The usual trend in a large study was that 50% of all patients of antiphopholipid syndrome had lupus anticoagulant positivity; however, lupus anticoagulant was the sole positive test in only 10% of these. [8] A positive lupus anticoagulant as compared to a positive ACL is associated with the highest risk for thrombosis. Thus, despite having anti-cardiolipin positivity satisfying the diagnosis of APS, it is still essential to go ahead and do a LAC, as the chance of a recurrent thrombosis goes up substantially if the latter is also positive. [24]
The most common coagulation tests used to detect the Lupus anticoagulant are the dilute aPTT and the dilute Russel viper venom time. The blood sample of the patient should be taken in an anticoagulant (citrate) and then centrifuged with a high speed within 4 hours to get platelet poor plasma. If the coagulation time is prolonged, then a sequence of steps can help to confirm the presence of LAC [25],[26] [Table 3]. | Table 3: The various steps to confirm the presence of Lupus anticoagulant
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β2GP1 antibody test
The β2GP1 antibody test was a result of the realization that actually the antibodies against cardiolipin were recognizing a protein and not the phospholipid. [22],[27] This protein was β2 glycoprotein 1 (β2GP1) and hence as a corollary to this, efforts were made to develop tests which directly detected the specific antibody by coating this protein in ELISA plates. Like the ACL, here also both IgM and IgG subtypes are tested for and any of them if found to be positive on repeat testing (at 12 weeks) will constitute a criteria for this syndrome.
However, despite its initial promise, the test has not replaced the anticardiolipin antibody test. This is because of lack of standardization of the test and the realization that the anticardiolipin test actually was picking up many other pathogenic antibodies as well, e.g., those that recognized the protein-phospholipid complex. Indeed, it has been suggested that 25% of the cases are picked up extra by anticardiolipin antibodies that are not picked up using β2GP1 and LAC. [24]
Non-criteria antibodies
Testing for other antibodies against other phospholipids namely phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylethanolamine or against phospholipid-associated proteins namely annexin V, prothrombin etc is currently done in research laboratories and as of now are not recommended to diagnose APS in the clinic. Some authors refer to patients having clinical manifestations with non-standardized antibody test positive as 'seronegative APS'. [28]
| Treatment of Antiphospholipid syndrome | | |
The treatment of antiphospholipid syndrome is evolving. However, we will endeavour to give the current treatment protocols along with the evidence for them. It is important to differentiate a-priori patients with thrombotic manifestations (venous or arterial) from those with just obstetric manifestations of APS.
Treatment of a patient with venous or arterial thrombosis
The treatment strategy consists of anticoagulation of the patient for life. The patient is usually started on injection heparin (unfractionated or low molecular weight) for the initial few days (till oral anticoagulant starts working) followed by oral anticoagulant (warfarin or acenocoumarol) to achieve INR of 2-3 to be continued lifelong. It must be noted that usually the INR is not affected by APLA per se [Table 4]. This is true for both venous and arterial thrombosis. Unfractionated heparin can be given as an infusion or by subcutaneous injections. Low molecular weight heparin is often preferred, because of ease of administration, lack of requirement to adjust aPTT and less risk of heparin induced thrombocytopenia and osteoporosis.
The drug of choice for oral anticoagulation in APS till date remains warfarin with dose adjustment to achieve an INR of 2-3. There is as yet little evidence that targeting a higher INR leads to better results in the case of venous thrombosis. This was the subject of two randomized controlled trials which did not find targeting a higher INR (3-4) resulted in any better outcomes, paradoxically there was higher thrombotic episodes in the latter. [29] However, there has been a recommendation, based on limited evidence, that in the case of arterial APS, treatment with a higher INR (>3) be preferred. However, this remains controversial, with a difference of opinion among experts. [30] Similarly, the role of the newer anticoagulants like direct thrombin inhibitors (dabigatran etexilate) or direct Xa inhibitors (rivaroxaban, Apixaban and Edoxaban) which have been proven in most settings to be equal to warfarin, is still under scrutiny and as of now cannot replace warfarin in APS. [31] It is not certain that add-on low dose aspirin gives any benefit over anticoagulation, however, it has been recommended in the case of arterial thrombosis. [30] In patients with ischemic stroke, the APL and stroke study (APASS), looked at presence of antiphospholipid antibodies in patients with stroke (single time not repeated), and found in those with positive APLA, there was no difference between those treated with aspirin or warfarin. [32]
Unlike other autoimmune diseases immunomodulatory drugs have very little role in APS except in catastrophic APS. Basic research has shown that hydroxychloroquine reverses platelet activation and directly reduces the binding of antiphospholipid antibody-β2-glycoprotein I complexes to phospholipid bilayers. [33],[34] Observational studies have found that hydroxychloroquine use is protective in preventing thrombosis in SLE patients with aPL positivity. [35] However, its utility in primary APS is unclear. Another drug that deserves mention is rituximab, a chimeric monoclonal antibody directed against CD20, which has been used in APS not responding to conventional anticoagulation, thrombocytopenia associated with APS and in catastrophic APS. [36],[37] Finally, risk factor modification in patients with traditional cardiovascular risk factors should be undertaken. Statins may have a direct benefit in antiphospholipid syndrome by decreasing tissue factor production and endothelial adhesiveness induced by aPL antibodies, however, they are not currently part of the routine management. [38]
Treatment of antiphospholipid syndrome in pregnancy
In patients with just obstetric complications (never had thrombosis), the current recommendation is treatment with heparin and low dose aspirin for the duration of the pregnancy and postpartum till 6 weeks. Importantly, the dose used in this case is equivalent to the prophylactic doses of these agents. It has also been recommended that low dose aspirin be started pre-conceptionally in these women. Despite treatment, there remains a failure rate of 20-30%. [39],[40],[41] The major trials looking therapy in patients with just obstetric complications of APS have been the subject of some criticism. Rai et al., compared aspirin alone to aspirin with unfractionated heparin and found the latter to be better in leading to a successful pregnancy (71% versus 42%). However, a majority of patients in this study had recurrent fetal losses before 10 weeks (63%), and anticardiolipin positivity was low. [42] In contrast, Farquharson et al., did not find any difference in successful pregnancies comparing low dose aspirin alone compared to dalteparin (fractionated heparin) with low dose aspirin (72% versus 78%). [43] Studies that have just looked at aspirin monotherapy versus no therapy have found no benefit of aspirin alone. [44],[45]
In women who have already suffered a thrombotic event (with or without an obstetric complication), the therapeutic approach differs and includes full dose anticoagulation with heparin during pregnancy. [46] Warfarin although teratogenic has been tried in a small study in women between 15-34 weeks period of gestation without harm. [47] Another drug, which deserves a mention, is steroids, which currently has no role in the management of APS in pregnancy. Studies on oral steroids did not find them to be efficacious in addition to aspirin with or without heparin; on the contrary, they were associated with more prematurity and hypertension. [48],[49] However, some recent reports of low dose steroids have suggested benefit on use in first trimester in refractory obstetric APS. [50] Intravenous immunoglobulins have also been tried in refractory patients with antiphospholipid syndrome. [51] The role of newer anticoagulants like fondaparinux (pentasaccharide which inhibits Xa) is unclear.
Treatment of asymptomatic aPL carriers
The role of aspirin to prevent thrombosis in asymptomatic aPL positive patients and obstetric complications is controversial. Only one randomized trial examined the efficacy of aspirin in asymptomatic APS carriers. This study used 81 mg of aspirin and after a mean duration of followup of 2.30 ± 0.95 years found no benefit of aspirin. However, a recent meta-analysis which included 11 studies (10 observational and 1 interventional) with 1208 patients found that low dose aspirin reduced the risk of first thrombosis in aPL positive asymptomatic subjects and those with SLE. [52] It may be prudent to prescribe aspirin to those with high risk such as patients with triple positivity and with additional cardiovascular risk factors.
Treatment of the catastrophic antiphospoholipid syndrome
The catastrophic antiphospholipid syndrome requires a multi-pronged strategy that deals with the inciting event (antibiotics for any infection), removal of the plasma mediators of inflammation as well as antiphospholipid antibodies (plasma exchange), pharmacologic control of inflammatory cascade (pulse steroids or intravenous immunoglobulins ± other immunosuppressants like cyclophosphamide especially in case of associated systemic lupus), and finally anticoagulation. The removal of necrotic tissues (like finger/toe amputations) may help to quell thrombotic storm. Plasma exchange (daily) is widely considered to be the most effective treatment. In one study, the survival of patients using the multimodal therapy was 70%, indicating that early aggressive intervention may lead to reasonable outcomes. [15]
| Prognosis | | |
Most patients of APS with thrombosis do well on anticoagulation. In the five year follow up of the europhosholipid cohort in which patients were on oral anticoagulation, only 2.1% developed new DVT, 2.4% developed new strokes and 2.3% developed new transient ischemic attacks. [53] However, untreated, a majority of patients with APS will have recurrent thrombosis in the next 5 years. The prognosis of patients with pregnancy morbidity was also fairly good in the europhospholipid cohort with 74% having successful pregnancies at study entry which increased to 81.8% in the five year follow-up. The overall mortality was 5.3%. [53]
| Conclusions | | |
The antiphospholipid syndrome is an enigmatic autoimmune disease with newer manifestations being recognized on an ongoing basis. The current classification criteria (Sydney 2006) which require the presence of one clinical and one laboratory criteria are used in diagnosis. Treatment includes lifelong anticoagulation in a case of thrombosis, whereas for isolated obstetric APS, prophylactic heparin is given in pregnancy. Low dose aspirin is often added to both regimens. APS remains an exciting area for research and encompasses all areas of medicine - presenting as young stroke to a neurologist, venous thrombosis to an internist, poor obstetric history to an obstetrician, valvular disease or myocardial infarctions to a cardiologist.
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[Table 1], [Table 2], [Table 3], [Table 4]
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