INTRODUCTION	Section 2 of 10
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Background: Antiphospholipid syndrome (APS) is a recently recognized autoimmune condition that may manifest with fetal loss, thrombosis, or autoimmune thrombocytopenia. Women with these clinical features should be tested for lupus anticoagulant (LAC) and anticardiolipin (aCL) antibodies; most patients with APS have both LAC and aCL immunoglobulin G (IgG) antibodies. The diagnosis of APS requires the presence of both clinical and biological features.

Systemic lupus erythematosus (SLE) is a chronic systemic disease with diverse clinical and laboratory manifestations. LAC (and aCL) predisposes to clotting in vivo, predominantly by interfering with the antithrombotic role of phospholipids (PLs); therefore, it is associated with clinical thrombosis, not bleeding. 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.

aPL antibodies belong to the large family of antibodies that react with negatively charged PLs, including cardiolipin, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylcholine, and phosphatidic acid.

Pathophysiology: The biologic effects mediated by the human aPL antibodies include (1) reactivity with endothelial structures, which disturbs the balance of prostaglandin E2/thromboxane production; (2) interaction with platelet PLs, with consequent up-regulation of platelet aggregation; (3) dysregulation of complement activation; and (4) interaction of aPL with phosphatidylserine exposed during trophoblast syncytium formation, which raises the possibility of a more direct effect of these autoantibodies on placental structures.

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.

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. However, 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 neurological and behavioral dysfunction, along with elevated levels of aPL antibodies.

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 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, either affinity-purified or as part of whole immunoglobulin fractions, from humans with APS or autoimmune mice has been shown to induce growth retardation and fetal loss.

Frequency:

• In the US: SLE occurs in approximately 120 cases per 100,000 population and causes pregnancy complications in approximately 45 cases per 100,000 pregnant population. 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 mesenteric veins), aPL antibodies are detected in approximately 2% of patients with nontraumatic venous thrombosis. This is a rate similar to that of several inherited conditions of hypercoagulability such as antithrombin III deficiency and protein C deficiency. 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 occurred 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.

Mortality/Morbidity:

• APS increases the risk for maternal and fetal morbidity and fetal mortality in pregnancy. The rate of fetal loss may exceed 90% in untreated patients who have APS. Therapy (including aspirin and heparin) can reduce the rate of fetal loss to 25%, as described by Cowchock et al.

• APS is one of the major causes of thrombosis and its complications in women. SLE, transient serologic abnormalities, skin lesions, and congenital heart block are affected by APS. The true neonatal lupus dermatitis, a variety of systemic and hematologic abnormalities, and isolated congenital heart block are associated with APS.

• APS is also associated with infertility and pregnancy complications such as spontaneous abortions, prematurity, and stillbirths. Fetal deaths at or beyond 20 weeks' gestation may be attributed to APS involvement, and aPL antibodies are found in 10-15% of women at high risk for fetal growth restriction.

Sex: The female-to-male ratio is 9:1.

Age: Newborns of women with SLE may develop lupus syndrome. This predominantly affects reproductive-aged women (ie, 15-55 y).

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Physical:

• Obstetric complications related to APS include the following:

• Sporadic miscarriage

• Recurrent pregnancy loss: Positive test results for IgG or immunoglobulin M (IgM) aCL antibodies may be found in up to 20% of women with the antibodies, but many positive results are of low level or only the IgM isotype and therefore are not diagnostic of APS.

• Recurrent embryonic pregnancy loss or death of the fetus at or beyond 10 weeks' gestation

• Pregnancy-induced hypertension (PIH) with high risk for preterm delivery

• Preterm birth

• Uteroplacental insufficiency

• LAC and medium-to-high positive levels of aCL antibodies (IgG or IgM): These may be found in 2-4% of otherwise healthy individuals.

• Clinical evidence of glomerulonephritis is found in more than 50% of cases. However, if biopsies are performed on all patients, the incidence of some nephritis may be as high as 90%. SLE is associated with encephalopathy and seizures, to a lesser degree with ischemic stroke, and, rarely, with subarachnoid hemorrhage.

• Clinical criteria for the diagnosis of APS are as follows:

• Fetal loss: This criterion is defined as 3 or more spontaneous abortions with no more than one live birth or unexplained second or third trimester fetal death.

• Thrombosis or stroke: This is unexplained venous or arterial thrombosis, including stroke and arterial insufficiency due to arterial thrombosis.

• Autoimmune thrombocytopenia: Other causes of thrombocytopenia must be excluded.

• Cutaneous manifestations
  • These may include digital cyanosis, livedo reticularis, digital gangrene, and leg ulcers. The cause of these features remains otherwise unexplained.

  • Other features related to cutaneous manifestations, with a cause that remains unexplained, include transient ischemic attacks or amaurosis fugax, positive result from the Coombs test, hemolytic anemia, chorea, and chorea gravidarum.

  • Discoid rash (ie, erythematous raised patch with keratotic scaling and follicular plugging) is a criterion. Older lesions may be atrophic. Again, the cause remains unexplained.

  • Photosensitivity with an unexplained cause is another criterion.

• Arthritis: Patients may have nonerosive arthritis involving 2 or more peripheral joints, and the cause cannot otherwise be determined.

• Serositis: This may be (1) pleuritis or pleural effusion or (2) pericarditis or pericardial effusion, the cause of which cannot be explained.

• Renal disorder: Proteinuria of 0.5 g/d or the presence of cellular casts, without another cause, is a criterion for APS.

• Neurologic disorder: Criteria include seizures in the absence of other causes or psychosis in the absence of other causes.

• Hematologic disorder: Features, without an otherwise explainable cause, include (1) hemolytic anemia with reticulocytosis, (2) leukopenia of less than 4000 cells/mm³ on at least 2 occasions, (3) lymphopenia of less than 1500 cells/mm³, or (4) thrombocytopenia of less than 100,000 cells/mm³.

• Immunologic disorder: Again, the cause remains unexplained.

• The clinical manifestations of SLE include the following:

• Skin lesions - 84-71%

• Arthritis - 63-95%

• Nephritis - 46-77%

• Raynaud phenomenon - 10-58%

• Neuropsychiatric features - 0-59%

• Lymphadenopathy - 0-58%

• Pleurisy - 37-56%

• Mucous membrane ulceration - 7-54%

• Pericarditis - 29-45%

• Splenomegaly - 9-18%

• Aseptic necrosis - 0-10%

Causes: Passive transfer of maternal antibodies mediate autoimmune disorders in the fetus and newborn. The mechanism of excess autoantibody production and immune complex formation is not well understood, although current investigation is focused on abnormal regulator functions and the possibility of a slow virus infection. In addition, 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.

Significant controversy still exists regarding the role of oral contraceptives in inducing SLE. ANA associated with LP were reverted to negative when the drug was discontinued. Some patients using the intrauterine device complain of dysmenorrhea and recurrent infections, especially those taking prednisone and cytotoxic drugs. Although the incidence of SLE in families was initially believed to be no greater than in the general population, this is no longer thought to be true.

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), the disruption of cellular membranes may occur during cell damage. PLs release and stimulate 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 shows homology to 8 different bacteria, including Haemophilus influenzae, Neisseria gonorrhoeae, and Shigella dysenteriae, and to viruses such as EBV and HIV. Therefore, data might support the theory predicting that epitope mimicry is involved in the propagation of the autoimmune status.

• Autoantibodies include the following:

• Antiphospholipid

• Anticardiolipin

• Antiphosphatidylinositol

• Antiphosphatidylserine

• Antiphosphatidylcholine

• Anti–beta-2 glycoprotein I

• Antinuclear antibody

• Anti-DNA (double- or single-stranded)

• Anti-Sjögren syndrome A antibody (Ro)

• Anti-Sjögren syndrome B antibody (Ia)

• Antibodies against microorganism(s) associated with infection or vaccination include the following:

• Antibacterial PL

• Antibacterial protein

• Antiviral glycoprotein

• Anti-Sjögren syndrome A antibody (Ro) and anti-Sjögren syndrome B antibody (Ia): These are associated with neonatal lupus erythematosus, including congenital complete heart block. These antibodies are usually present in patients with Sjögren syndrome.