Rheumatology

Antiphospholipid Syndrome

Does this patient have antiphospholipid syndrome?

Antiphospholipidsyndrome (APS or APLS) is an autoimmune, hypercoagulable state caused by antibodies against phospholipids that produces thrombosis (arterial or venous) as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, or severe preeclampsia.

The syndrome is thought to be due to the production of autoantibodies against phospholipids (aPL). In particular, the disease is characterized by antibodies against cardiolipin (anti-cardiolipin antibodies) and β2-glycoprotein I.

There are 3 types of APS: primary (the absence of any other autoimmune disease), secondary (associated with another autoimmune condition, most frequently systemic lupus erythematosus, SLE), and catastrophic (with simultaneous multi-organ failure and small vessel occlusion).

Classification with APS requires evidence of both one or more specific, documented clinical events (either a vascular thrombosis and/or adverse obstetric event) and the confirmed presence of a repeated aPL. The Sapporo APS classification criteria (1998, published in 1999) were replaced by the Sydney criteria in 2006. Based on the most recent criteria, classification with APS requires one clinical and one laboratory manifestation.

Clinical manifestations

A clotting event, a documented episode of arterial, venous, or small vessel thrombosis—other than superficial venous thrombosis in any tissue or organ by objective validated criteria with no significant evidence of inflammation in the vessel wall, and/or:

Pregnancy pathology

  • One or more unexplained deaths of a morphologically normal fetus(documented by ultrasound or direct examination of the fetus) at or beyond the 10th week of gestation, and/or:

  • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, without maternal anatomic or hormonal abnormalities and without paternal and maternal chromosomal causes, or:

  • At least one premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia or severe pre-eclampsia according to standard definitions, or recognized features of placental insufficiency.

The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement, Definite CAPS diagnosis requires:

  • Vascular thrombosis in three or more organs or tissues.

  • Development of manifestations simultaneously or in less than a week.

  • Evidence of small vessel thrombosis in at least one organ or tissue.

  • Laboratory confirmation of the presence of APL.

What tests to perform?

Laboratory

  • Anti-cardiolipin IgG and/or IgM measured by standardized, non-cofactor dependent ELISA on two or more occasions, not less than 12 weeks apart; medium or high titre (i.e., > 40 GPL or MPL, or > the 99th percentile), and/or:

  • Anti-beta 2-glycoprotein I IgG and/or IgM measured by standardized ELISA on two or more occasions, not less than 12 weeks apart; medium or high titre (> the 99th percentile), and/or:

  • Lupus anticoagulant detected on two occasions not less than 12 weeks apart according to the guidelines of the International Society of Thrombosis and Hemostasis.

  • False positive VDRL; the VDRL may be positive in aPL-positive patients (aPLs bind to the lipids in the test and produce the positive result) although more specific tests for syphilis, such as the FTA-ABS that use recombinant antigens will be negative.

  • Although IgA anti-phospholipid antibodies have been shown to be pathogenic in animal models, their clinical significance is unclear. However, clinical events can occur in patients with isolated ACL-IgA or IgA anti-beta 2 GPI antibodies. These antibodies may identify additional patients with APS who do not meet current diagnostic criteria.

  • Patients with APS can also have other causes of hypercoagulability and overlap with inherited thrombophilias can occur.

How should patients with antiphospholipid syndrome be managed?

Patients with high titer APL-antibodies are at risk of developing a thrombotic event. The highest risk is associated with the presence of LAC.

Primary thrombosis prevention

Primary thrombosis prevention in persistently aPL-positive individuals requires a risk-stratified approach; elimination of reversible thrombosis risk factors and aggressive prophylaxis during high-risk periods is crucial.

The APLASA study showed that asymptomatic, persistently aPL-positive individuals do not benefit from low-dose aspirin for primary thrombosis prophylaxis and have a low annual incidence rate (less than 2.75 per 100 patient-years) of acute thrombosis, and develop vascular events when additional thrombosis risk factors are present. However, due to the low risk associated with low dose ASA (81 mg) many physicians continue to prescribe it.

Initial thrombosis

Treatment of the initial thrombosis in patients with the APS does not differ from treatment of patients without APLs. Anticoagulation with heparin and subsequent oral anticoagulation is initiated. The intensity of anti-coagulation is not clearly defined. The duration of anticoagulation in patients without the APS is 6 months.

In patients with APS, the risk of recurrence is relatively high for both arterial and venous thrombotic events; as a result, patients are generally started on life-long oral anticoagulation.

Secondary prevention

For the secondary prevention of thrombosis in persistently aPL-positive individuals, the current recommendation is life-long warfarin; however, determining the intensity and duration of warfarin treatment, as well as the role of alternative anticoagulants, requires further research.

The effectiveness of high-intensity anticoagulation in patients with antiphospholipid syndrome (APS) and vascular involvement is not supported by data from prospective, controlled studies. The role of medications generally used in autoimmune disorders to try and control the immune system is limited. The primary role of these medications in patients who have secondary antiphospholipid antibody syndrome is to control the associated systemic auto-immune disease.

Anti-platelet drugs, such as aspirin and Plavix are also used in addition to oral anticoagulation in patients who failed oral regimens. Low-molecular-weight heparins can also be used in patients who fail oral anti-coagulation.

Long-term anticoagulation has a 3% yearly risk of a major hemorrhage, of which approximately 1/5 are fatal. Beginning long-term anticoagulation is influenced by the patient's overall risk of recurrent thrombosis balanced against the risks associated with long-term anticoagulation on an individual basis.

The newly approved oral anti-coagulant Pradaxa has a lower risk of hemorrhagic complications but has not been studied in patients with APS. Patients with baseline prolonged PTT due to the presence of LAC requiring treatment with unfractionated heparin need to be monitored using factor Xa levels. Including a hematologist in the management team is encouraged.

Catastrophic APS

Patients with catastrophic APS usually receive a combination of anticoagulants, corticosteroids, intravenous immunoglobulin and plasma exchange; however, despite this aggressive approach, the mortality rate remains high. The role of the anti-CD20 antibody in the treatment of CAPS remains to be determined.

Pregnancy and the antiphospholipid antibody syndrome

As mentioned above, the antiphospholipid antibody syndrome is associated with pregnancy complications. These complications include miscarriages, preterm labor, low birth-weight and preeclampsia. For women with known antiphospholipid antibody syndrome, it is recommended that pre-pregnancy counseling is obtained. This allows the patient to be monitored closely from the beginning of the pregnancy.

Treatments during pregnancy are a subject of active investigation at this time. Several studies have examined the use of heparin along with low-dose aspirin (81 mg, or baby aspirin) throughout the pregnancy and have demonstrated improved fetal outcomes.

Other regimens that have been examined include the use of aspirin and prednisone. The studies of aspirin and prednisone combinations suggested that complications associated with prednisone use, in most cases, outweigh the benefits and thus prednisone is not a commonly used agent in addition to aspirin.

While there is also concern about the risk for maternal thrombotic events in APL positive pregnancies there are no evidence based recommendations for the management of such pregnancies.

Healthy women or women with SLE that had one or two pregnancy losses may be treated with low dose ASA but require close materno-fetal monitoring. ASA should be initiated pre-conception or at the time of a positive pregnancy test.

Women that meet criteria for obstetric APS should be treated with mini or moderate dose unfractionated heparin or prophylactic dose low molecular weight heparin (LMWH).

Women that have had a previous thrombotic event and are on long-term oral anti-coagulation should be treated with adjusted-dose unfractionated heparin or LMWH.

See Table I.

Table I.

Heparin Dosing
UH mini-dose -5,000 units SQ q 12 hr.
moderate dose-SQ q 12 hr, adjusted to target anti-factor Xa level of 0.1-0.3 IU/ml.
adjusted dose - SQ q 12 hr, target mid-interval APTT (or, if LAC is present, an anti-factor Xa level) into therapeutic range.
LMWH prophylactic dose – Dalteparin 2,500 or 5,000 units SQ q 24 hr. Enoxaparin 20 or 40 mg SQ q 24 hr. Any once-daily LMWH adjusted to target a peak anti-factor Xa level of 0.2-0.6 IU/ml.
adjusted dose - weight-adjusted, full treatment doses .Dalteparin, 200 units/kg SQ in 1 or 2 injections orEnoxaparin 1 mg/kg SQ q 12 hr or 1.5 mg/kg SQ q 24

Heparin should be initiated at the time of a positive pregnancy test or detection of fetal heart activity. In addition to anticoagulation, calcium (1200mg/day) and vitamin D (400-800 IU/day) should be given for prophylaxis of heparin induced osteoporosis.

Heparin has several effects that may help prevent thromboembolic events and pregnancy loss: anti-thrombin effect, inhibition of factor Xa, platelet aggregation, and complement activation (which plays a role in the pathogenesis of APS).

Like unfractionated heparin, low molecular weight heparins (LMWH) inactivate factor Xa, but have a lesser effect on thrombin. As a result, LMWHs do not prolong the APTT. Potential advantages of LMWH over unfractionated heparin are once daily dosing and lower risks of hemorrhage, thrombocytopenia, and osteoporosis.

Postpartum management of women with APS is controversial. However, these women are probably at increased risk of developing pregnancy-related venous thrombosis and should receive postpartum anticoagulation.

In women who received heparin or LMWH antepartum, we continue anticoagulation postpartum. Unfractionated heparin (5000 units every 12 hours) is administered beginning 12 hours post-cesarean delivery and 4-6 hours post-vaginal birth if there is no significant bleeding, and either continued or replaced with warfarin (stopping the heparin when the INR is therapeutic) for 4-6 weeks. We also continue low dose ASA postpartum for 4-6 weeks.

Women with obstetric APS are at risk from other thrombotic events.

What happens to patients with antiphospholipid syndrome?

There is limited data on the long-term outcomes of patients with APS; the presence of aPL in the serum of patients with SLE has been identified as an independent risk factor for premature death.

How to utilize team care?

APS patients should be cared for by a rheumatologist and a hematologist to evaluate other non-autoimmune causes of thrombophilia and manage anti-coagulation. In addition, patients with obstetric APS should be under the care of a high risk obstetrician.

Are there clinical practice guidelines to inform decision making?

American College of Chest Physicians (ACCP) recommendations for anticoagulation of pregnant women with antiphospholipid antibodies.

What is the evidence?

Miyakis, S, Lockshin, MD, Atsumi, T, Branch, DC, Brey, RL, Cervera, R. "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)". J Thromb Haemost. 2006. pp. 4295-306.306.

Asherson, RA, Cervera, R, de Groot, PG. "Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines". Lupus. vol. 12. 2003. pp. 530-4.

Kumar, S, Papalardo, E, Sunkureddi, P, Najam, S, González, EB, Pierangeli, SS. "Isolated elevation of IgA anti-beta2glycoprotein I antibodies with manifestations of antiphospholipid syndrome: a case series of five patients". Lupus. vol. 18. 2009 Oct. pp. 1011-4.

Chopra, N, Koren, S, Greer, WL, Fortin, PR, Rauch, J, Fortin, I, Senécal, JL, Docherty, P, Hanly, JG. "Factor V Leiden, prothrombin gene mutation, and thrombosis risk in patients with antiphospholipid antibodies". J Rheumatol. vol. 29. 2002 Aug. pp. 1683-8.

Erkan, D, Harrison, MJ, Levy, R, Peterson, M, Petri, M, Sammaritano, L, Unalp-Arida, A, Vilela, V, Yazici, Y, Lockshin, MD. "Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody–positive individuals". A&R. vol. 56. pp. 2382-91.

Erkan, D, Lockshin, MD. "New approaches for managing antiphospholipid syndrome". Nat Clin Pract Rheumatol. vol. 5. 2009 Mar. pp. 160-70.

Andreoli, L, Fredi, M, Nalli, C, Reggia, R, Lojacono, A, Motta, M, Tincani, A. "Pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome". J Autoimmun. 2011 Dec 26.

Bates, SM, Greer, IA, Pabinger, I. "Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. vol. 133. 2008. pp. 844S.

Girardi, G, Redecha, P, Salmon, JE. "Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation". Nat Med. vol. 10. 2004. pp. 1222.

Gris, JC, Bouvier, S, Molinari, N, Galanaud, JP, Cochery-Nouvellon, E, Mercier, E, Fabbro-Peray, P, Balducchi, JP, Marès, P, Quéré, I, Dauzat, M,. "Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study". Blood. 2011 Dec 6.

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