Antiphospholipid Syndrome and Pregnancy Workup
- Author: Teresa G Berg, MD, FACOG; Chief Editor: Thomas Chih Cheng Peng, MD more...
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] :
Anticardiolipin antibodies - Anticardiolipin (aCL) IgG or IgM antibodies present at moderate or high levels (ie, >40 GPL or MPL or >99th percentile) in the blood on 2 or more occasions at least 12 weeks apart
Lupus anticoagulant - LAC detected in the blood on 2 or more occasions at least 12 weeks apart, according to the guidelines of the International Society on Thrombosis and Hemostasis
Anti-beta 2 -glycoprotein I antibodies IgG or IgM - In titer above the 99th percentile for normal as defined by the laboratory performing the test, on 2 or more occasions at least 12 weeks apart
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.
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, aCL, anti-b2GPI, and aPS/PT studies
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.
Hematologic and serologic characteristics of APS
All studies need to be repeated in at least 12 weeks for confirmation before the diagnosis of APS is appropriate.
Prolonged clotting times occur with any of the following:
Kaolin clotting time
Dilute Russell viper venom time
Plasma clotting time
These prolongations should be confirmed with one of the following:
Mixing studies with normal plasma, clotting time will remain prolonged with LA
Platelet neutralization test (recommended by some authorities)
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.
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):
Class I - Normal glomeruli observed with light microscopy; may show deposits with immunofluorescence or electron microscopy
Class II - Mesangial lesions
Class III - Focal proliferative glomerulonephritis
Class IV - Diffuse proliferative glomerulonephritis
Class V - Membranous glomerulonephritis
Class VI - Diffuse glomerular sclerosis
Fischer-Betz R, Specker C, Brinks R, Schneider M. Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischaemic events: an observational study. Lupus. 2012 Oct. 21(11):1183-9. [Medline].
Alijotas-Reig J, Ferrer-Oliveras R, Ruffatti A, et al. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 247 consecutive cases. Autoimmun Rev. 2015 May. 14(5):387-395. [Medline].
Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G, et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood. 2014 Jan 16. 123(3):404-13. [Medline].
Asherson RA, Khamashta MA, Ordi-Ros J, et al. The "primary" antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore). 1989 Nov. 68(6):366-74. [Medline].
Kochenour NK, Branch DW, Rote NS, Scott JR. A new postpartum syndrome associated with antiphospholipid antibodies. Obstet Gynecol. 1987 Mar. 69(3 Pt 2):460-8. [Medline].
Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol. 1992 May. 166(5):1318-23. [Medline].
Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999 Jul. 42(7):1309-11. [Medline].
[Guideline] Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb. 4(2):295-306. [Medline].
[Guideline] The American College of Obstetricians and Gynecologists. Antiphospholipid Syndrome. ACOG Practice Bulletin. January/2011. 118:1-8. [Full Text].
Sciascia S, Murru V, Sanna G, Roccatello D, Khamashta MA, Bertolaccini ML. Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: evaluation of 23 possible combinations of antiphospholipid antibody specificities. J Thromb Haemost. 2012 Dec. 10(12):2512-8. [Medline].
|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 supplementation
|Optimal 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|