Antiphospholipid syndrome (APS) is an autoimmune disorder that is associated with pregnancy complications, including preeclampsia, thrombosis, autoimmune thrombocytopenia, fetal growth restriction, and fetal loss. (See Prognosis and Presentation.)
APS is classified as primary or secondary, depending on its association with other autoimmune disorders. Primary APS is diagnosed in patients demonstrating the clinical and laboratory criteria for the disease without other recognized autoimmune disease. Secondary APS is diagnosed in patients with other autoimmune disorders, such as systemic lupus erythematosus (SLE). (See Presentation and Workup.)
Women with the clinical features of APS should be tested for 3 antiphospholipid antibodies that have proven association with the diagnosis of APS: lupus anticoagulant (LAC), anticardiolipin (aCL) antibody, and anti-beta-2glycoprotein I antibody. (See Pathophysiology, Etiology, and Workup.)
These antibodies predispose to clotting in vivo, predominantly by interfering with the antithrombotic role of PLs. The antiphospholipid (aPL) autoantibodies bind moieties on negatively charged PLs or moieties formed by the interaction of negatively charged PLs with other lipids, PLs, or proteins. (See Pathophysiology, Etiology, Treatment, and Medication.)
Obstetric features of APS are as follows:
Nonobstetric features of APS are as follows:
Biologic effects mediated by the human aPL antibodies include the following:
In patients with primary APS, the presence of the 3 aCL isotypes plus LAC has been associated with a higher number of recurrent spontaneous abortions, compared with other possible combinations of aCL isotypes. (Human aCL antibodies cause placental necrosis in BALB/c mice.)
The association between aPL antibodies and particular human leukocyte antigen (HLA) alleles and HLA-linked epitopes has been reported in studies of patients with lupus erythematous (eg, HLA-DR7, HLA-DR4). The HLA-DR3 phenotypes seem to predispose to the formation of aCL antibodies and antinuclear antibodies (ANAs), but this has not been confirmed in patients, and particular HLA alleles associated with recurrent miscarriage have not been reported.
Animals immunized with aCL or with the cofactor beta-2 glycoprotein I (b2GPI) develop clinical manifestations of APS, including fetal loss, thrombocytopenia, and neurologic and behavioral dysfunction, along with elevated levels of aPL antibodies.
The aCL antibodies bind to b2GPI, or a complex formed by this b2GPI is a platelet adhesin glycoprotein and cardiolipin. Exposure of endothelial cells to anti-b2GPI antibodies and their corresponding peptides leads to the inhibition of endothelial cell activation, as shown by decreased expression of the adhesion molecules E-selectin, intercellular adhesion molecule, and vascular cell adhesion molecule and of monocyte adhesion.
In vivo infusion of each of the anti-b2GPI antibodies into BALB/c mice followed by administration of the corresponding specific peptides prevents the peptide-treated mice from developing experimental APS. These fascinating results suggest that the use of synthetic peptides that focus on neutralization of pathogenic anti-b2GPI antibodies represents a possible new therapeutic approach to APS.
Passive transfer into naive mice of inherently heterogeneous aPL antibody populations—from humans with APS or from autoimmune mice—either affinity-purified or as part of whole immunoglobulin fractions, has been shown to induce growth retardation and fetal loss.
Like other autoimmune disorders, APS does not have a known etiology, although it is known that the passive transfer of maternal antibodies mediates autoimmune disorders in the fetus and newborn. The mechanism of excess autoantibody production and immune complex formation is not well understood.
Certain genetic factors may be important, as indicated by a number of family and twin studies for SLE and the demonstration of an increased frequency of HLA-DR2, HLA-DR3, and HLA-DR4 null alleles in patients with SLE. As with other autoimmune disorders, women have a higher incidence than men and the diagnosis is more likely to be made in women of reproductive age.
PL molecules are ubiquitous in nature and are present in the inner surface of the cell (ie, on the inner or outer surface of the cell membrane or intracellular organelles) and in microorganisms. Therefore, during infectious disease processes, including viral (eg, HIV, Epstein-Barr virus [EBV], cytomegalovirus [CMV], adenoviruses), bacterial (eg, bacterial endocarditis, tuberculosis, Mycoplasma pneumonia), spirochetal (eg, syphilis, leptospirosis, Lyme disease), and parasitic (eg, malaria infection) infections, the disruption of cellular membranes may occur during cell damage. PLs are consequently released, stimulating aPL antibodies.
The SWISS PROT protein database revealed high homology between the hexapeptides that bind to ILA-1, ILA-3, and H-3 mAbs and the membrane particles of different bacteria and viruses. The sequence LKTPRV showed homology to 8 different bacteria (eg, Pseudomonas aeruginosa) and homologies to 5 types of viruses (ie, polyoma virus, human CMV, adenovirus).
The sequence TL-RVYK also shows homology to 8 different bacteria, including Haemophilus influenzae, Neisseria gonorrhoeae, and Shigella dysenteriae, and to viruses such as EBV and HIV. Therefore, data may support the theory predicting that epitope mimicry is involved in the propagation of the autoimmune status.
Women have been reported to account for approximately 80% of patients with APS. The aPL antibodies account for 65-70% of cases of venous thrombosis in women with venous thrombosis in unusual sites (eg, cerebral, portal, splenic, subclavian and mesenteric veins). The aPL antibodies are detected in approximately 2% of all patients with nontraumatic venous thrombosis.
Approximately 22% of women with APS have had venous thrombosis and 6.9% have had a cerebrovascular incident (over a median follow-up period of 60 mo); 24% of thrombotic events have been found to occur during pregnancy or the postpartum period. The rate for thrombosis or stroke is 5-12%. These observations suggest that women with documented APS should not take estrogen-progestin combination oral contraceptives.
Most cases of APS (80%) are in women. APS is predominantly diagnosed in reproductive-aged women (ie, 15-55 y). This is similar to other autoimmune states.
APS is one of the major causes of thrombosis and its complications in women, with arterial thrombosis, coronary artery occlusions, and venous thrombosis being reported in patients with this syndrome. Previous thrombosis in the face of a diagnosis of APS has been documented to have a recurrence rate of 25% per year in untreated patients.
A 2015 retrospective analysis by the European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS) found very good maternal-fetal outcomes in women whose obstetric APS [OAPS] was treated.[2]
Previous fetal loss appears to be a risk factor for fetal loss, preeclampsia, premature birth, and placenta-mediated complications in women with pure OAPS, according to a 2014 report from the Nîmes Obstetricians and Hematologists Antiphospholipid Syndrome (NOH-APS) study.[3] In addition, the incidence of such late-pregnancy complications were greater in the treated women with pure OAPS compared to nontreated women negative for antiphospholipid antibodies.
The investigators defined pure OAPS as pregnancy morbidity in women with no previous history of thrombosis (ie, repeated unexplained abortion < 10th gestational wk, unexplained fetal loss ≥ 10 gestational week, or premature birth < 34th gestational wk due to preeclampsia).[3] Treatment included low molecular weight heparin (LMWH) and low-dose aspirin (LDA).
Thrombosis, especially in patients with APS and a history of thrombosis, is a major concern. Morbidity may also be associated with anticoagulation in patients treated with heparin or low–molecular-weight heparins in pregnancy. Moreover, women with APS have an increased incidence of preeclampsia, which, when it occurs, frequently develops prior to 34 weeks’ gestation. The incidence of severe preeclampsia requiring premature delivery is also increased.
APS is also associated with infertility and pregnancy complications, such as spontaneous abortions, prematurity, and stillbirths.
Landry-Guillain-Barré-Strohl syndrome
Landry-Guillain-Barré-Strohl syndrome (LGBSS) of acute inflammatory demyelinating polyradiculoneuropathy, although exceedingly rare in pregnancy, can occur in patients with APS and lupus.
Patients usually present with progressive bilateral and symmetrical muscle weakness accompanied by mild sensory symptoms, including paresthesia, numbness, and tingling. The disease can progress to involve the respiratory muscles, resulting in respiratory failure. Two thirds of the patients have a history of viral-like infections 1-3 weeks prior to the onset of symptoms.
CMV infection has been incriminated as a potential etiologic agent in some pregnant patients presenting with LGBSS.
Acute inflammatory demyelinating polyradiculoneuropathy is a rare disease with an incidence of approximately 1-1.5 cases per 100,000 LGBSS cases per year.
Mortality rates during pregnancy are not well characterized. Multiorgan failure has been described during pregnancy by Asherson[4] and during postpartum by Kochenour.[5]
The aPL antibodies are found in 10-15% of women at high risk for fetal growth restriction. Neonatal morbidity and mortality may be influenced by indicated preterm delivery for maternal severe preeclampsia or fetal growth restriction.
Neonatal lupus dermatitis, a variety of systemic and hematologic abnormalities, and isolated congenital heart block have been associated with APS and SLE.
Fetal deaths at or beyond 20 weeks' gestation may be attributable to APS involvement. The rate of fetal loss may exceed 90% in untreated patients with APS. Therapy (including aspirin and heparin) can reduce the rate of fetal loss to 25%, as described by Cowchock et al.[6]
The “international consensus statement for the diagnosis of antiphospholipid syndrome,” published in 1999 by Wilson et al, serves as a set of criteria similar to that for the diagnosis of other autoimmune disorders. The criteria were updated in 2006 to reflect new insights into APS. The diagnosis requires that the patient have at least 1 clinical and 1 laboratory criterion.[7, 8]
Clinical criteria
The clinical criteria for APS include the following:
Criteria for laboratory testing, which are consistent with current clinical management guidelines from the American Congress of Obstetricians and Gynecologists, include the following[9] :
Findings in APS can also include the following:
The diagnosis of APS is based primarily on clinical history and laboratory data. Patients with secondary APS are more likely to have findings on physical examination, although some physical findings may be associated with primary APS. Thrombosis and stroke are possible residual neurologic findings in APS.
Cutaneous manifestations of APS can include the following:
As previously mentioned, the 1999 “international consensus statement for the diagnosis of antiphospholipid syndrome” provided a set of criteria for the diagnosis of APS. These were updated in 2006 to reflect new insights into the disease.
The diagnosis of APS requires that the patient have at least 1 clinical criterion and 1 laboratory criterion. The criteria for laboratory testing, which are consistent with current clinical management guidelines from the American Congress of Obstetricians and Gynecologists (ACOG), include the following[7, 8, 9] :
In a 3-year retrospective analysis by the European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS), the investigators indicated that all relevant laboratory studies should be obtained to avoid false-negative diagnoses and that levels may act as serologic markers for some cases.[2]
Appropriate neurologic or imaging studies should be performed based on clinical findings; ie, a computed tomography (CT) or magnetic resonance imaging (MRI) scan can be carried out in the presence of central nervous system (CNS) symptoms.
Antiphospholipid (aPL) antibodies are detected by conventional and specific solid-phase or enzyme-linked immunoassays. Results are measured as GPL (IgG aCL), MPL (IgM aCL), or aPL (IgA aCL) units and reported in semiquantitative terms such as negative, low positive, medium positive, or high positive.
Systemic lupus erythematosus (SLE) is associated with lower serum complement levels, measured either as total hemolytic complement activity CH50 or as levels of the third and fourth components of complement C3 and C4, respectively. Decreased levels of these are indicative of consumption by immune complexes. However, preeclampsia, however, is associated with an increased serum complement level.
LAC is detected by phospholipid (PL)-dependent clotting assays, without correction with normal plasma. Results are confirmed by demonstrating PL dependency. The activated partial thromboplastin time (aPTT) is prolonged. Sera are screened for anticoagulant activity by mixing them with platelet-pool normal sera and assaying the aPTT. Several laboratory measurements are available for the assessment of LAC.
For aCL or anti-beta2 -glycoprotein I antibodies, an IgG isotype greater than 12-20 GPL units (medium to high positive) detected in a standardized assay using standard serum calibrators is indicative.
Anti-beta2 -glycoprotein I IgG or IgM isotype in serum or plasma that is greater than the 99th percentile for a normal population as defined by the laboratory performing the test.
In a study of 230 patients with SLE, Sciascia et al determined that combining tests for LAC, anti-beta2 -glycoprotein I, and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies provided greater diagnostic accuracy for APS than did other combinations of laboratory tests. The investigators also found that patients in whom all 3 tests were positive were at greater risk for clinical events, such as thrombosis or pregnancy loss, than were patients in whom only 1 or 2 of the tests were positive.[10]
All studies need to be repeated in at least 12 weeks for confirmation before the diagnosis of APS is appropriate.
Lupus anticoagulant
Prolonged clotting times occur with any of the following:
These prolongations should be confirmed with one of the following:
Anticardiolipin antibodies
Many aCL antibodies correlate poorly with the clinical manifestations of APS. At present, only IgG and IgM in moderate and high levels are recommended to be used in the diagnosis of APS.
VDRL test
False-positive results from the venereal disease research laboratory (VDRL) test may occur.
As previously mentioned, clinical evidence of glomerulonephritis is found in more than 50% of cases of SLE. Histologically, the following 6 classes of lupus glomerulonephritis have been recognized by the World Health Organization (WHO):
Pregnant women with APS are considered high-risk obstetric patients, and medical care is instituted with this in mind.
In patients receiving or recently treated with corticosteroid therapy, administer supplementation to cover the labor or cesarean delivery.
Pregnancy in itself is not harmful to the mother or the baby unless added work related to the newborn, as well as emotional stress in the family, proves to be too much for a particular patient. Therapeutic abortions are generally not indicated in pregnant women with autoimmune disease.
Epidural anesthetic is not recommended if the mother has a marked drop in the maternal platelet count. The use of forceps or the vacuum extractor should be individualized.
No evidence indicates adverse effects related to breastfeeding, although breastfeeding is not recommended if high doses of cytotoxic or immunosuppressive agents are required.
Patients should be counseled in all cases regarding symptoms of thrombosis and thromboembolism and should be educated regarding, and examined frequently for, the signs or symptoms of thrombosis or thromboembolism, severe preeclampsia, or decreased fetal movement.
Ultrasonography is recommended every 3-4 weeks starting at 18-20 weeks’ gestation, in patients with a poor obstetric history, evidence of preeclampsia, or evidence of fetal growth restriction.
Human chorionic gonadotropin (hCG) values in the first trimester can be followed to evaluate the viability of the pregnancy. If hCG levels are increasing normally (ie, doubling every 2 days) in the first month of pregnancy, a successful outcome is predicted in 80-90% of cases. However, when the increases are abnormal (ie, slower), a poor outcome is predicted in 70-80% of cases.
In patients with uncomplicated APS, ultrasonography is recommended at 30-32 weeks’ gestation to assess fetal growth. Lagging fetal growth may reflect uteroplacental insufficiency in patients with APS.
Drugs such as chloroquine and cytotoxic agents are not recommended during pregnancy; patients should stop taking these drugs several months prior to becoming pregnant.
Splenectomy during the early second trimester or at the time of cesarean delivery may be considered in patients with thrombocytopenia refractory to glucocorticoid therapy.
Anticoagulation with heparin is recommended in APS and pregnancy with a history of a thromboembolic event. Low-molecular-weight heparin (LMWH) may be used in these patients.
Importantly, counsel the patient regarding potential adverse effects of heparin. Heparin-induced osteoporosis occurs in 1-2% of cases. Initiation of heparin in the face of a failing pregnancy should be undertaken with caution due to bleeding risks.
Bone density studies should be considered in patients receiving anticoagulation therapy with heparin or LMWH due to the risks of osteopenia. This may be most important in women who have been treated in a previous pregnancy or are planning pregnancy.
Warfarin may be substituted for heparin during the postpartum period to limit further risk of heparin-induced osteoporosis and bone fracture.
In women without a history of a thromboembolic event, optimal therapy is not as clear. Anticoagulation may decrease recurrent pregnancy loss in this group of women. Low-dose aspirin combined with prophylactic doses of heparin or LMWH appears to be superior to aspirin therapy alone or maternal steroids.
Lefkou et al studied 21 pregnant women with APS who developed preeclampsia and/or intrauterine growth restriction during treatment with low-dose aspirin plus low-molecular weight heparin (LDA+LMWH ) and found increased placental blood flow and improvement in preeclampsia features in the patients who received both pravastatin and LDA+LMWH.[11]
Infused immunoglobulins may modulate aCL antibodies levels by the following 3 mechanisms:
Immunosuppressive agents are recommended for patients with SLE with secondary APS. Thromboprophylaxis is also recommended. In addition, patients should be evaluated for renal disease, (glomerulonephritis, end-stage renal disease), anemia, and thrombocytopenia. (See the Table below.)
Table. Proposed Management for Women With aPL Antibodies
View Table | See Table |
Note the following:
Patients with APS, especially secondary APS, may require surgical interventions for long-standing complications of their autoimmune disorder.
Cardiac valvular surgery is recommended in patients with severe aortic regurgitation due to the noninfectious vegetations that are seen as a result of APS.
Splenectomy is recommended in patients with the chronic form of idiopathic thrombocytopenic purpura and is associated with remission in approximately 75% cases.
Thromboprophylaxis is recommended for any abdominal or orthopedic surgery. Manage thrombotic or hemorrhagic complications. Be aware of associated thrombocytopenia, and use laboratory methods of perioperative anticoagulation monitoring in the setting of prolonged clotting times.
The patient should be informed about potential maternal and obstetric problems, including fetal loss, thrombosis or stroke, PIH, fetal growth restriction, and preterm delivery. Consultation with specialists in Maternal-Fetal Medicine and Rheumatology should be considered.
In women with APS and 1 or more prior thrombotic events, lifelong anticoagulation with warfarin may be advisable to avoid recurrent thrombosis. An assessment by a rheumatologist or hematologist may also be helpful.
In 2020, the American College of Rheumatology published guidelines on the in patients with rheumatoid diseases, including patients who are positive for antiphospholipid antibodies (aPL).[12] Recommendations for aPL-positive pregnant patients included the following:
In women with well-recognized obstetric APS, anticoagulant prophylaxis is recommended during pregnancy and the postpartum period. Pregnant women with APS are considered at risk for thrombosis and pregnancy loss. Data suggest low-dose aspirin and heparin (either unfractionated heparin or LMWH) to be the treatments of choice for prevention of pregnancy loss in pregnant women with APS and previous pregnancy losses. Pregnant women with APS and a history of thrombosis but no pregnancy loss require only treatment with heparin. Treatment is optional for patients with no history of pregnancy loss or thrombosis.
Clinical Context: Heparin is indicated to decrease the risk of thrombosis and pregnancy loss in pregnant women with APS.
It augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. Heparin does not actively lyse but is able to inhibit further thrombogenesis. The drug prevents reaccumulation of clot after spontaneous fibrinolysis.
Clinical Context: Enoxaparin, an LMWH, is indicated to decrease the risk of thrombosis and pregnancy loss in pregnant women with APS. It prevents deep venous thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases the inhibition of factor Xa.
Clinical Context: Dalteparin is indicated for the prevention of DVT, which may lead to PE. It enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, dalteparin preferentially increases the inhibition of factor Xa. The average duration of treatment is 7-14 days.
Unfractionated intravenous (IV) heparin and fractionated subcutaneous (SC) LMWH are the 2 choices for initial anticoagulation therapy. Warfarin therapy may be initiated in the postpartum stage.
These are used in the treatment or prophylaxis of clinically evident intravascular thrombosis. Special precaution should be exercised in obstetrical emergencies or massive liver failure.
Similar to unfractionated heparin, LMWHs are a class of anticoagulants termed glycosaminoglycans. LMWHs are derived from unfractionated heparin but have smaller, more standard average masses than does heterogeneous unfractionated heparin.
Unlike standard heparin, LMWHs have higher specificity for factor Xa and have fewer effects on platelet activity. As a result, LMWH may cause bleeding less often, while still retaining anticoagulant effects. LMWHs may be associated with less risk of heparin-induced osteoporosis.
Clinical Context: Aspirin's antiplatelet effect is indicated to decrease the risk of thrombosis and pregnancy loss in pregnant women with APS. It inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2. Aspirin is used in low dose to inhibit platelet aggregation and to improve complications of venous stasis and thrombosis.
Randomized, controlled trials demonstrate improved fetal survival when pregnant women with APS and prior pregnancy losses are treated with low-dose aspirin plus heparin, compared with low-dose aspirin alone.
Feature Management Pregnant Nonpregnant APS with prior fetal death or recurrent pregnancy loss Heparin in prophylactic doses (15,000-20,000 U of unfractionated heparin or equivalent per day) administered subcutaneously in divided doses with low-dose aspirin daily
Calcium and vitamin D supplementationOptimal management uncertain; options include no treatment or daily treatment with low-dose aspirin APS with prior thrombosis or stroke Heparin to achieve full anticoagulation (does not cross the placenta) Warfarin administered daily in doses to maintain international normalized ratio of =3 APS without prior pregnancy loss or thrombosis No treatment or daily treatment with low-dose aspirin or daily treatment with prophylactic doses of heparin plus low-dose aspirin; optimal management uncertain No treatment or daily treatment with low-dose aspirin; optimal management uncertain LGBSS High-dose IVIG at 400-1500 mg/kg/day for several days IVIG at 400-1500 mg/kg/d for several days aPL Antibodies Without APS LAC or medium to high level of aCL IgG No treatment No treatment Low levels of aCL IgG, only aCL IgM, or only aCL IgA without LA, aPL, or aCL No treatment No treatment