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Antiphospholipid Antibody Syndrome & Pregnancy Loss: Management In Primary Care Settings

Objectives: The purpose of this article is to educate nurse practitioners about antibody-mediated thrombosis, and particularly to develop their skills for early diagnosis of this disorder. After reading this article, the nurse practitioner should be able to:

  • Define antiphospholipid antibody symdrome and list its risk factors, presenting symptoms and associated diagnostic tests;
  • List the differential diagnoses for APS;
  • Discuss the effect of APS on pregnancy; and
  • Describe management strategies for APS during pregnancy.

Antibody-mediated thrombosis occurs when antiphospholipid antibodies form and act against phospholipids on plasma membranes and phospholipid-containing circulating proteins involved in clotting, leading to a clinical condition called antiphosholipid antibody syndrome (APS). The ensuing arterial and venous thrombosis, particularly within the placenta and its blood vessels, may lead to repeated pregnancy loss. Recent discoveries about autoimmunity in health and disease, improved testing and early antibody detection methods, along with the development of specific therapeutic modalities, now offer better strategies for preventing recurrent pregnancy loss associated with APS.

Because not all women with antiphospholipid antibodies exhibit clinical manifestations, NPs must be familiar with APS and its presentation so they can provide early diagnosis and treatment to significantly improve pregnancy outcomes.

Background and Definitions
Antiphospholipid antibodies are a family of immunoglobulins that act against phospholipids on plasma membranes and normal plasma proteins, bind to circulating phospholipids involved in coagulation pathways, and bring about APS, a serious hypercoagulability condition (Table 1). APS can lead to arterial or venous thrombosis, thrombocytopenia, cerebral ischemia, myocardial infarction, multiorgan failure and recurrent fetal loss.1,2

APS-related thrombosis can occur in almost all body systems. Table 2 summarizes the most common clinical symptoms of APS.

Lupus anticoagulant and anticardiolipin antibodies often are associated with APS.3 The term lupus anticoagulant refers to antiphospholipid antibodies detected by functional clotting assays (activated partial thromboplastin time, or APTT), while the term anticardiolipin antibodies refers to antiphospholipid antibodies detected by anti-cardiolipin enzyme-linked immunosorbent assay testing. In contrast, the term antiphospholipid antibodies refers to antibodies that are detected by both of these tests plus the false-positive venereal disease research laboratory (VDRL) test. Although the term "anticoagulant" suggests bleeding tendencies, few APS patients experience bleeding.

APS can occur in primary and secondary forms. Primary APS is diagnosed in the absence of associated systemic diseases, and comprises about 50% of cases. The remainder of cases occur in the presence of autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus (SLE).

Epidemiology of APS
APS frequently affects people with autoimmune diseases. Approximately 2% of the population (men and women) have antiphospholipid antibodies circulating in their bloodstreams, and 30% to 50% of people with SLE may have antiphospholipid antibodies.1,3 As is the case with other autoimmune disorders, familial association is a likely culprit.

Ten percent of women with unexplained recurrent pregnancy loss test positive for antiphospholipid antibodies, and after three spontaneous abortions, the likelihood increases to 41%.4 Additionally, 16% to 38% of women with early onset pre-eclampsia and 25% to 33% of women with placental abruption also test positive for antiphospholipid antibodies.5,6 A study of 100 APS patients found that 53% of women with antiphospholipid antibodies had thrombosis, 52% had thrombocytopenia, and 60% had pregnancy losses.7

Because antiphospholipid antibodies do not produce symptoms in many cases, NPs must be alert to all signs of APS in pregnant women. When symptoms suggest APS, test for antiphospholipid antibodies immediately. Prompt diagnosis and early treatment significantly improve pregnancy outcomes.

Immunopathophysiology of APS
In APS, antiphospholipid antibodies are produced by Ig gamma (IgG), Ig mu (IgM) and Ig alpha (IgA) or any mixture of the three as a response to a "non-self tissue" by the B and T cells of the immune system. Once formed, antibodies can attack any phospholipid-bound cells in a targeted organ, including the white matter of the brain, the heart, the kidneys, lining of the joints, red blood cells, platelets and circulating plasma proteins. Factors that may influence the formation of antiphospholipid antibodies in APS are described here.

Phospholipids (phosphorous-containing lipids): These lipids are fundamental parts of cell membranes and the membranes of the intracellular organelles, such as the mitochondria. For example, phosphatidylserine, phosphatidic acid and phosphatidylinositol, against which antiphospholipid antibodies can be formed, all are present on cell membranes (Table 1).8 Cardiolipin, a phospholipid abundant in the cardiac mitochondrial membrane, can trigger antibodies in APS.9 In addition, plasma proteins involved in clotting pathways contain phospholipids. Thromboplastin, which is essential to initiation of the extrinsic clotting pathway, is composed of a phospholipid called cephalins. When antibodies attack phospholipid-containing plasma proteins, clotting mechanisms are significantly altered.

Co-factors: Investigators have determined that antiphospholipid antibodies detected by ELISA do not often target the phospholipid cardiolipin itself, but a plasma protein identified as ß2 glycoprotein, which has affinity for phospholipid surfaces. Therefore, when these ß2 glycoproteins bind to negatively charged cardiolipin and prothrombin (also bound to negatively charged phospholipids), the ß2 GPI glycoproteins then attract the antiphospholipid antibodies to this new complex, causing alterations in phospholipid-dependent interactions. Similarly, antiphospholipid antibodies may interfere with several endothelial antithrombotic functions, such as activation of platelets, the protein C pathway and the synthesis of prostaglandin I2.10 Research shows that with the assistance of ß2 glycoprotein, antiphospholipid antibodies interfere with the activation of protein C, thereby creating a procoagulant state.11 Table 3 lists the major proteins targeted by the antiphospholipid antibodies.

Lipoprotein-a: More than 90% of the lipids in plasma are in the form of lipoproteins. Lipoprotein-a is similar to low-density lipoproteins, consisting of a core of cholesterol esters, a surface layer of phospholipids and free cholesterol, and a molecule of a lipoprotein-b 100. This property confers an atherogenic potential, and makes the presence of lipoprotein-a an independent risk factor for cardiovascular diseases. High levels of lipoprotein a is a marker for APS, since its presence correlates with arterial and venous thrombosis.12

Serum Adhesion Molecules: Serum adhesion molecules, released after injury from endothelial cells that line blood vessels, may be responsible for the hypercoagulable state in APS.10 These adhesion molecules are elevated in the serum of patients with severe thrombotic profiles and among those with primary and secondary APS.

Genetic Factors: A common genetic variation for prothrombin is associated with elevated plasma prothrombin levels and a twofold higher risk for thrombosis.13 The exact sequence of events that leads to the thrombogenic state remains unknown, however.

Research has soundly established that the presence of antiphospholipid antibodies correlates with thrombus formation. Antibodies produced by IgG appear to be more closely associated with recurrent venous and arterial thrombosis and recurrent fetal loss than those produced by IgA and IgM. In a study of 72 primary APS patients, 10% were negative for any antibodies, but 40.3% were positive for IgG, 20% for IgG and IgM, and 15.3% for an IgG, IgM and IgA mixture. The rest were positive for varying mixtures of anticardiolipin antibodies for IgG.14 More significantly, the incidence of IgG alone or in combination with IgM or IgA was high among women who had primary APS and had experienced fetal loss.

Mechanism of Pregnancy Loss
The impact of pregnancy on normal physiology, including coagulation, is profound. Fibrin and plasma fibrinogen levels increase throughout the course of pregnancy (possibly as much as 50%), creating a hypercoagulable state.15 Although clotting time is not altered during pregnancy, the essential coagulating blood factors VII, VIII, IX and X are increased. Additionally, the female reproductive tract is the second richest site for kininogen, a plasma protein that is a common target of antiphospholipid antibodies.8

Two mechanisms appear to prevent maternal rejection of the fetus: some degree of suppression of the cellular immunity induced by progesterone and human chorionic gonad-otropin hormones in the placenta, and the prevention of antibody formation by the cell coating of the trophoblastic tissue, the outer cells of the fertilized ovum that render these tissues immunologically inert.15

At the time of implantation, the trophoblastic layer of the blastocyst attaches itself to the surface of the endometrium. The thickened endometrium under the implanted blastocyst, now referred to as the decidua basalis, develops into the maternal portion of the placenta. It is the decidua basalis that may be most threatened by coagulation pathologies, including APS.

The chorionic villi, which come in direct contact with the decidua basalis, form the fetal portion of the placenta. The outer layer of the trophoblastic tissue becomes the syncytium, which covers the chorionic villi of the fetal portion of the placenta. This syncytium is the functional layer of the placenta, which comes in direct contact with maternal blood in the intervillous spaces and allows for exchange of nutrients, gases and metabolic wastes.15 Any interference with the blood flow in this compartment, which may be the case in APS, jeopardizes the health of the fetus. In a normal pregnancy, syncytial knots may occur and normally degenerate without producing pathology. Pregnancy loss associated with APS is linked to placental thrombosis, spiral artery vasculopathy and syncytial abnormal knot formation.2 Functional annexin V binding sites are essential for the maintenance of placental blood flow, and annexin V has a 1,000-fold higher affinity for anionic phospholipids than blood clotting factors.16 The presence of anti-annexin V autoantibodies contributes to placental thrombosis, necrosis and fetal loss. Hypoxia, secondary to spiral artery vasculopathy, may be the underlying cause of obstetric complication in APS.17

Although recurrent pregnancy loss often occurs with APS, fertility is not affected. Once pregnancy occurs, however, women with APS experience higher than average rates of first and second trimester spontaneous abortions and fetal deaths, pregnancy-induced hypertension, intrauterine growth retardation and, in women who are anti-Ro-positive, fetal heart block. Research shows that earlier pregnancy losses are frequently associated with antiphosphatidylethanolamine antibodies, an antibody to neutral phospholipids (Table 1).8 Kininogen-dependent IgG antibodies may augment thrombin-induced platelet aggregation, which may be responsible for early pregnancy losses. In addition, several investigators have reported that the presence of cofactor ß2 GPI-dependent anticardiolipin antibodies and lupus anticoagulant may be predictive of miscarriages.18

The diagnosis of APS is based on patient history and laboratory tests. At least one clinical and one laboratory feature of APS must be present.19 Table 2 summarizes the clinical manifestations of APS.

Three major serologic tests are widely used to detect antibodies associated with APS: lupus anticoagulant, anticardiolipin antibodies and VDRL. The lupus anticoagulant and anticardiolipin antibodies are considered the gold standards for serologic diagnosis. In one study of women with recurrent pregnancy loss, the serologic distribution of antiphospholipid antibodies was as follows: 62% were positive for lupus anticoagulant, 15% positive for IgG anticardiolipin antibodies, 14% were positive for lupus anticoagulant and one other anticardiolipin antibody, and 9% were positive for IgM.6 Researchers have proposed laboratory criteria for the diagnosis of APS that are gaining acceptance among clinicians (Table 4).20

Interpretation of Test Results
Lupus Anticoagulant Testing: The identification of lupus anticoagulant is based on a series of three tests that includes the partial thromboplastin time, Russel viper venom time and the Kaolin clotting time. These tests are not specific to antiphospholipids; they detect clotting deficiencies.19 You may order further confirmatory tests to distinguish clotting deficiencies from antiphospholipid antibodies. Russel viper venom time is more sensitive to lupus anticoagulant in women who have had recurrent miscarriages.6

Anticardiolipin Antibodies: This test compares immunoglobulins and phospholipids in the patient's serum. IgG is the most common immunoglobulin in the serum of patients with thrombotic episodes and recurrent pregnancy loss. In a study of primary APS patients with thrombosis and fetal loss, only 10% tested negative for any antibodies and IgG was present in more than 76% of patients alone or in combination with other immunoglobulins.14 Moreover, among women with repeated pregnancy loss, the presence of three anticardiolipin antibodies isotypes with positive lupus anticoagulant can lead to more pregnancy losses. The test can also determine the titer of antiphospholipid antibodies (low, medium or high positive). Generally, patients with moderate or high levels of antiphospholipid antibodies are more susceptible to thrombotic complications.

Antiphospholipid Panel and the ß2 GPI: The ß2 GPI is now considered the best predictor of thrombotic events, although the sensitivity of the test ranges from 40% to 90%. Experts recommend always testing for the presence of ß2 GPI antibodies in patients with APS.20

Clinical Manifestations in Pregnancy
In general, the risk of thrombosis is five times higher among pregnant women than nonpregnant women of similar age.21 The hypercoagulability associated with pregnancy results in thromboembolic complications, and pulmonary embolism is a major cause of maternal mortality. APS further increases this pregnancy-induced tendency for clot formation, making thrombosis the most common manifestation of the disease. Women who test positive for antiphospholipid antibodies late in the first trimester have a significantly increased risk for preeclamsia or intrauterine death.

In addition, women with ß2 GPI-dependent IgG antibody-to-cardiolipin or antibody-to-ß2 GPI itself are at risk for fetal loss.5 More significantly, women with ß2 GPI-dependent IgG antibody-to-cardiolipin at 10 weeks' gestation have an approximately 20-fold higher relative risk for intrauterine growth retardation and preeclamsia than unaffected women.6

Two other symptoms commonly associated with APS are livedo reticularis and amaurosis fugax. Livedo reticularis manifests as reddish-blue discoloration on the extremities that intensifies with exposure to cold. Amaurosis fugax is characterized by transient, short-term, monocular visual deficits that may signal small-vessel thrombosis, thromboembolism or spasm.

Management of APS in Pregnancy
Nurse practitioners are essential to the early diagnosis of APS, as well as to appropriate consultation and referral. A team approach to management is critical and should encompass the patient, her family, a perinatologist, a rheumatologist, her primary care provider and social services.

Differential diagnoses of repeated pregnancy loss other than APS include: chromosomal abnormalities (60% to 70% of early spontaneous abortions); uterine anomalies (5% to 10% of recurrent first trimester abortions); and luteal phase defect (25% of recurrent pregnancy losses).3

Chromosomal studies on the abortus should be performed to rule out abnormalities, and when positive, follow-up genetic counseling and testing of the parents is indicated. Pelvic ultrasound, magnetic resonance imaging, hysteroscopy and hysterosalpingograms should be performed to rule out structural uterine anomalies that may result in pregnancy loss. Luteal phase defects that require testing include inadequate progesterone production in the luteal phase, hyperprolactinemia and thyroid dysfunction (hyper- or hypothyroidism).

In previously undiagnosed women for whom none of the more common causes of recurrent pregnancy loss are identified, APS testing is warranted if they have a history of unexplained fetal death or recurrent pregnancy loss or they develop pregnancy-induced hypertension prior to 34 weeks' gestation.

The primary pharmacologic treatment for APS during pregnancy is heparin, and it has been associated with live birth in 71% to 90% of treated patients.2,19,22 Because heparin is cleared more rapidly in pregnancy, it is critical to monitor the International Normalized Ratio level and maintain it at 1.5 to two times the control level. The dosage of standard, unfractionated heparin may range between 5,000 and 20,000 units subcutaneously every 8 to 12 hours, with the higher doses prescribed for patients with prior histories of fetal death, thrombosis or stroke.

Treatment with anticoagulants should continue for at least 6 weeks following delivery because of the increased risk for embolic formation. Warfarin may be substituted during this time, regardless of whether the mother is breastfeeding. Heparin does not cross the placenta, so fetal anomalies are not associated with it. However, bone loss and thrombocytopenia can occur in the mother. To decrease osteoporosis risk, supplementation with calcium (1,500 mg calcium carbonate) and vitamin D is recommended, along with aerobic weight-bearing exercise such as walking. Use of low-molecular-weight heparin (20 mg/d of enoxaparin) appears to be effective in pregnancy and is associated with less bone loss than conventional-weight heparin. Because low-molecular-weight heparin does not affect the partial thromboplastin time, its efficacy requires monitoring of factor Xa levels. The use of low-molecular-weight heparin in pregnancy prohibits the use of epidural analgesia in labor.

Low-dose aspirin therapy (75 mg/day to 100 mg/day), alone or in conjunction with heparin or prednisone, provides effective management of APS, research shows.2,22 However, aspirin is a category D during the third trimester because it can delay labor onset due to prostaglandin suppression, increase risk for bleeding at delivery, and increase risk for neonatal jaundice and premature closure of the ductus arteriosus in the fetus. Therefore, its use is not recommended beyond 34 weeks' gestation. Steroids and gammaglobulin have also been tested to prevent fetal complications among women with repeated pregnancy loss and produced mixed results. Prednisone suppresses antiphospholipid antibodies in pregnancy and is associated with a 20% to 100% occurrence of live births. Since prednisone increases blood pressure and blood glucose levels, accelerates bone loss and produces outcomes comparable to or less favorable than the aforementioned treatments, it is generally not recommended as the first-line therapy.2,19

Treatment with intravenous IgG is still considered experimental. The therapy has been associated with 100% perinatal survival, but, because of the high cost ($4,000 per month) and the risk of hypertension and congestive heart failure associated with the high protein load, it is generally reserved for patients with severe thrombocytopenia.2,5,19

Monitoring of maternal and fetal well-being includes serial ultrasounds and biophysical profiles beginning at 20 weeks' gestation to evaluate fetal growth. Doppler flow studies can identify abnormal uteroplacental flow. In anti-Ro-positive women, careful auscultation of the fetal heart or serial fetal echocardiograms should begin at 16 to 18 weeks' gestation to assess for possible heart block.23

Your Challenge: Early Diagnosis
APS is a significant risk for pregnancy complications and repeated pregnancy loss. For primary care practitioners, the challenge lies in early diagnosis. Screen every woman with an autoimmune disorder, a history of recurrent pregnancy loss or early pregnancy-induced hypertension. Laboratory tests for APS should include, as part of the antiphospholipid panel, anticardiolipin antibodies, lupus anticoagulant and ß2 GPI. Positive results for lupus anticoagulant and anticardiolipin antibodies have the greatest predictive value for pregnancy loss.

Because these tests are not specific to APS, it is important to carefully evaluate the patient's history to rule out other conditions associated with positive test results before initiating heparin treatment. Once the diagnosis is established, numerous effective treatment modalities can improve pregnancy outcomes. In an educational bulletin dedicated to this topic, the American College of Obstetricians and Gynecologists states that the importance of identifying APS lies not so much in its prevalence, but in its implications for the individual patient and its status as a potentially treatable cause of pregnancy loss.24 *

Ayhan Aytekin Lash has a doctorate in higher education and is an associate professor at Northern Illinois University in DeKalb. She is a fellow of the American Academy of Nursing. Diana Mertens is a certified nurse-midwife with a doctorate in public health and is a member of the nursing faculty at Northern Illinois University. Hulya Okumus has a doctorate in nursing and is a member of the nursing faculty at Dokuz Eylul University in Izmir, Turkey.

Table 1: Antiphospholipid Protein Antibodies
Antibody Comments
Lupus anticoagulants Antibodies to phospholipids increase clotting
Anticardiolipin antibodies Antibody to phospholipid cardiolipin increases clotting
Reagin Antibody responsible for positive serologic test for syphilis
Specific antibodies to anionic phospholipids
  • Antiphosphotidylserine
  • Antiphosphatidic Acid         Cell membrane phospholipids
  • Antiphosphatidylinositol
  • Specific antibodies to neutral phospholipids
  • Antiphosphosphatidylethanolamine      Cell membrane phospholipid

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    Table 2: Selected Clinical Manifestations of APS
    Thrombocytemia, autoimmune hemolytic anemia, arterial and venous clots
    Pregnancy loss, intrauterine growth retardation, oligohydramnios
    Pulmonary emboli and pulmonary hypertension
    Angina, myocardial infarction, coronary vasculopathy, cardiac valvular vegetation, Lipman-Sacks endocarditis
    Transient ischemic attacks, stroke, migraines, cerebral vascular thrombosis
    Skin and Musculoskeletal
    Livedo reticularis, avascular necrosis of bone
    Retinal vein and artery occlusions, amaurosis fugax, retinopathy, ischemic optic neuropathy

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    Table 3: Antiphospholipid Antibody Target Proteins
    Protein Targets Comments
    ß2 Glycoprotein I Co-factor for antiphospholipids
    Annexin V Placental anticoagulant protein
    Complement factor H Inflammatory mediator
    High-molecular weight kininogen
    Low-molecular weight kininogen
    Intrinsic pathway clotting factors
    Prothrombin Clotting factor (inactivated by LA)
    Protein C Clotting factor (counteracts clotting)
    Protein S Clotting factor
    Factor X Clotting factor

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    Table 4: Serologic Tests for the Diagnosis of APS
    Clinical Manifestations Serologic Tests
  • Venous thrombosis
  • Antiphospholipid ELISAs
          Positive anticardiolipin antibody profile:
              IgG, IgM and IgA isotypes with
              IgG anticardiolipin antibody > 20 GPL* units
  • Arterial thrombosis
  • IgM, anticardiolipin antibody > 10 MPL**
    plus positive lupus anticoagulant test measured by:
          partial thromboplastin time
          Russel viper venom time
          Kaolin clotting time

    Anti-beta-ß2 GPI ELISA
          IgG anti-beta-ß2 I
          IgM anti-beta-ß2 I

    Also recommended:
    Antiphospholipid panel (any or all of the following):

          Antiphosphatidic acid
          Antiphosphatidylethanolamine       Antiphosphatidylcholine

  • Recurrent pregnancy loss
  • Pregnancy loss
  • Three or more spontaneous
    miscarriages or one unexplained
  • Second or third trimester fetal demise
  • Positive lupus anticoagulant test
    Thrombocytopenia Platelet count (not a serologic test)
    *GPL: G phospholipid units **MPL: M phospholipid units
    GPL and MPL units correspond to the binding activity of 1mg/mL of purified anticardiolipin antibody

    Antiphospholipid Antibody Syndrome & Pregnancy Loss: Management In Primary Care Settings

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