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Antiphospholipid antibody syndrome.

The antiphospholipid antibody syndrome (APS) is defined by thrombotic events and/or obstetric complications and the presence of antiphospholipid antibodies (APAs) detected in patient plasma. Antiphospholipid antibodies are acquired autoantibodies directed against phospholipid-protein complexes. Currently recognized laboratory criteria for APS include lupus anticoagulant (LA), immunoglobulin (Ig) G or IgM anticardiolipin (aCL) antibodies, or IgG or IgM anti-beta-2 glycoprotein I antibodies (anti-B2GPI). (1) Lupus anticoagulants are identified by clot-based coagulation tests, whereas aCL and anti-B2GPI antibodies are identified by enzyme-linked immunosorbent assay (ELISA). An important caveat with respect to diagnosing APS is the need to exclude transient antibodies by retesting the patient at least 12 weeks following initial positive laboratory results. (1-3) The mechanism of thrombosis in APS patients is still unknown, although several mechanisms have been postulated. (4) These include APA interference with endogenous anticoagulant mechanisms (disruption of the annexin A5 anticoagulant shield, (5) inhibition of the protein C pathway, inhibition of antithrombin), binding and activation of platelets, interactions with endothelial cells inducing expression of adhesion molecules and tissue factor, and activation of the complement cascade.

The term lupus anticoagulant is a misnomer because most patients with laboratory findings of LA do not have systemic lupus erythematosus (SLE). (6) Lupus anticoagulant activity was first described in 1952 by Conley and Hartmann, (7) who reported a laboratory clotting defect in the plasma of 2 patients with SLE. It became apparent that approximately 15% of patients with active SLE have a false-positive Venereal Disease Research Laboratory test. (8) This is explained by the presence of cardiolipin (phospholipid) in the Venereal Disease Research Laboratory test reagent. The term lupus anticoagulant was first coined in 1972 by Feinstein and Rapaport. (9) Following that, several major advances have occurred in the understanding of LAs. In 1991, the Lupus Anticoagulant/Antiphospholipid Antibody Subcommittee of the International Society on Thrombosis and Haemostasis published recommendations for LA testing. (10) These recommendations were updated in 1995 (11) and again in 2009. (3)

CLINICAL FEATURES

Despite the prolongation in clotting times in patients with LA antibodies, APS predominantly presents as a prothrombotic disorder with either vascular thrombosis or pregnancy complications. Bleeding is quite uncommon and, when present, is usually secondary to significant thrombocytopenia, dysfunctional platelets, hypoprothrombinemia, or an underlying disease. (12)

As per the revised clinical criteria for APS, vascular thrombosis is defined by 1 or more objectively confirmed episodes of arterial, venous, or small vessel thrombosis occurring in any tissue or organ. (1) Venous thromboembolism is the most common clinical presentation and affects between 30% and 70% of APS patients. (13,14) The deep veins of the extremities are most commonly affected, followed by axillary, retinal, hepatic, and cerebral venous sinus thrombosis. (15) Pregnancy morbidity includes 1 or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation; 1 or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, preeclampsia, or placental insufficiency; or 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation. (1) Clinical studies have linked LA positivity with an increased risk for ischemic stroke. (16) In addition, APAs are also linked with various neurologic disorders like dementia, migraines, chorea, seizures, transverse myelopathy, mononeuritis multiplex, and myasthenia gravis. (17)

[FIGURE 1 OMITTED]

Thrombocytopenia (platelets 100-150 x [10.sup.3] [mu]) is found in approximately 20% of patients with APS and is found in more than 40% of patients with an underlying autoimmune disease. (18) Autoantibodies directed against platelet glycoproteins have been implicated as a cause for thrombocytopenia in patients with APS.

Among APAs, LA positivity is recognized as the strongest risk factor for thromboembolic events or pregnancy morbidity. (19) Anticardiolipin antibodies show clinically significant association only at moderate to high titers, and the IgG isotype appears to carry more clinical significance than the IgM isotype for both aCL and antiB2GPI antibodies. (20) Patients with "triple positivity" are at highest risk.

Antiphospholipid antibodies are seen in conjunction with autoimmune diseases like SLE, rheumatoid arthritis, and Behcet syndrome. (12) Antiphospholipid antibodies are also identified in patients with hematolymphoid malignancies, (21) monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, and liver disease. Certain infections such as hepatitis C, (22) human immunodeficiency virus syndrome, (23) HTLV-1 associated spastic paraparesis, Q fever, and malaria (24) may also be associated with APAs.

The term primary antiphospholipid syndrome has been used when APS occurs in the absence of an underlying disease. In conjunction with other medical illnesses, the term secondary antiphospholipid syndrome has been used. (25) However, the most recent international consensus statement on classification criteria for APS advise against this terminology because the clinical consequences in both groups appears to be the same. (1)

In rare cases, APS leads to rapid multiorgan failure due to generalized thrombosis. If the patient experiences clinical involvement of at least 3 different organ systems with histologic evidence of thrombosis, it is termed catastrophic antiphospholipid syndrome. (18,26)

LABORATORY FINDINGS

To establish a diagnosis of APS, in addition to the clinical findings there should be a positive laboratory test result indicating the presence of APAs (positive LA, aCL, or anti-B2GPI antibodies). Enzyme-linked immunosorbent assays for other APA specificities (including IgA B2GPI antibody, IgA cardiolipin antibody, prothrombin antibodies, phosphatidylserine antibodies, and phosphatidylcholine antibodies) are also available but are not currently recommended due to uncertain clinical significance (1) (refer to Figure 1 for a laboratory algorithm outlining APS testing). Laboratory testing should be limited to patients who have a significant probability of having APS. Lupus anticoagulant testing is also often performed in patients who have an unexplained prolonged activated partial thromboplastin time. The International Society on Thrombosis and Haemostasis subcommittee recommends categorizing patients according to clinical characteristics into low, moderate, and high priority for LA testing to minimize the risk of a false positive as follows: low, venous or arterial thromboembolism in elderly patients; moderate, accidentally found prolonged activated partial thromboplastin time in asymptomatic subjects, recurrent spontaneous early pregnancy loss, unprovoked venous thromboembolism in young patients; and high, unprovoked venous thromboembolism and unexplained arterial thrombosis in young patients (<50 years), thrombosis at unusual sites, late pregnancy loss, any thrombosis or pregnancy morbidity in patients with autoimmune diseases (SLE, rheumatoid arthritis, autoimmune thrombocytopenia, autoimmune hemolytic anemia). (3) Any positive laboratory test needs to be repeated 12 or more weeks following the initial positive laboratory result. This helps to exclude transient APAs, which are often secondary to intercurrent infection or other acute illness. (1,2)

For LA detection, careful attention must be paid to blood collection and processing. Double centrifugation is recommended to ensure that the plasma is platelet-poor because contaminating platelets can neutralize the antibodies, resulting in a false-negative result. Plasma filtration introduces variables such as loss of von Willebrand factor and is not recommended. To prevent the loss of coagulation factors, the plasma should be tested or frozen as quickly as possible following collection. The sample should be thawed at 37 [degrees] C for 5 minutes to avoid formation of cryoprecipitate and mixed thoroughly before testing. (3)

Lupus anticoagulants prolong phospholipid-dependent coagulation tests due to antagonism of reagent phospholipids. The prolongation of clotting times is a laboratory phenomenon due to limited phospholipid in the test reagents. No single test will identify all LAs, and it is recommended to perform at least 2 screening assays, based on different methods, before excluding an LA due to differences in reagent sensitivity. (1,3) The risk of false-positive results may be increased to an unacceptable level if more than 2 screening tests are performed. (3) The most commonly used screening assays include the activated partial thromboplastin time and dilute Russell viper venom time. Activated partial thromboplastin time reagents with reduced levels of phospholipid and silica as an activator are thought to be most sensitive to LA effects. (3) Kaolin as an activator is not recommended because of its problematic behavior in automated coagulometers. (3) The prothrombin time is not usually prolonged because of the large amount of phospholipid in the thromboplastin reagent.

The results of screening tests are considered suggestive of LA when clotting times are longer than the local cut-off value. (3) A positive screen is followed by a mixing study. Lupus anticoagulants demonstrate an inhibitor pattern in mixing studies wherein the prolonged coagulation time fails to correct by mixing patient and pooled normal plasma. The presence of an LA is confirmed by demonstrating shortening of the prolonged coagulation time on addition of excess phospholipids. Although general guidelines exist, many different test methods, reagents, and algorithms can be used for LA identification. There is no gold standard test and no perfect algorithm, and laboratories must be attuned to variables that affect the testing to maximize sensitivity and specificity (an example algorithm for LA testing is shown in Figure 2).

Anticoagulant medications such as heparin, direct thrombin inhibitors, and vitamin K antagonists (warfarin) can interfere with LA testing due to their effects on coagulation assays. Heparin and direct thrombin inhibitors are of particular concern because they prolong phospholipid-dependent coagulation tests and behave as inhibitors in mixing studies, potentially mimicking an LA. A thrombin time, or other means of identifying heparin, should be routinely performed on test plasma to identify the presence of heparin or direct thrombin inhibitors. The commercial dilute Russell viper venom time reagents used for LA testing contain heparin neutralizers; however, if the content of heparin in the test plasma exceeds the reagent neutralization capacity (typically greater than 0.8-1.0 U/mL), it can give rise to a false-positive LA test result. (3) Activated partial thromboplastin time reagents generally do not neutralize heparin. Low-molecular-weight heparin has less effect on LA testing than unfractionated heparin. (3) In general, blood for LA testing should be collected before starting anticoagulant drugs or after their discontinuation. For vitamin K antagonists, wait 1 to 2 weeks after discontinuation or until the international normalized ratio is less than 1.5. (3)

Testing for aCL and anti-B2GPI antibodies (IgG and IgM) by ELISA should be performed concurrently with LA testing if APS is suspected. (3) Anticardiolipin results are considered positive if present in moderate to high titer, whereas anti-B2GPI results are positive in titer greater than the 99th percentile. (1) Cardiolipin is a negatively charged phospholipid, and aCL antibodies in APS typically require a protein cofactor (such as B2GPI) to create the antigenic target (phospholipid-protein complex). Thus, B2GPI-dependent aCL assays are recommended. (27) Transient aCL antibodies have been identified during infections; these characteristically do not have a B2GPI cofactor requirement and are often low-titer IgM. (12) In the B2GPI ELISA, B2GPI is bound directly to the ELISA plate. In general, the aCL assay is more sensitive for APS, whereas the B2GPI assay is more specific. (27) Similar to LA testing, APA ELISA assays lack standardization and have imperfect sensitivity and specificity.

TREATMENT AND PROGNOSIS

Patients with APS may be treated in an outpatient setting. Patients with catastrophic antiphospholipid syndrome require intense observation and treatment, often in an intensive care unit. The specific therapy for catastrophic antiphospholipid syndrome includes the use of intravenous heparin, corticosteroids, and possibly plasma exchange with or without intravenous immunoglobulin. In general, treatment regimens for APS must be individualized according to the patient's current clinical status and history of thrombotic events. Asymptomatic individuals who have positive laboratory tests do not meet APS criteria and do not require specific treatment. Patients with significant thrombotic events or obstetric complications are treated with anticoagulant therapy. Even if the venous or arterial occlusion occurred many years previously, long-term treatment with oral anticoagulant therapy is often used. (28) Low-dose aspirin is used widely in this setting as well; however, its effectiveness remains unproven. Hydroxychloroquine, with its intrinsic antithrombotic properties, might be useful in some patients. Steroids or intravenous immunoglobulin has proved beneficial in LA patients with hypoprothrombinemia syndrome (LA antibodies directed against prothrombin) who either have bleeding or need surgery. (29) Immunosuppressive medications, such as cyclophosphamide, are effective in reducing elevated antibody levels; however, the antibody titers rise significantly following discontinuation. (12) Patients with catastrophic antiphospholipid syndrome need intensive treatment with corticosteroids, immunosuppression, intravenous IgG, and/or plasma exchange. (26) Pregnant APS patients with no history of thrombosis benefit from low-dose heparin; however, those with a history of thrombosis need therapeutic anticoagulation with low-molecular-weight heparin. Planned pregnancy enables change from long-term warfarin to aspirin and heparin before pregnancy is attempted. (30)

[FIGURE 2 OMITTED]

CONCLUSIONS

Antiphospholipid antibody syndrome is a heterogeneous syndrome, both clinically and in the laboratory. Correct diagnosis is critical to ensure optimal patient management. However, laboratory testing in this arena challenges both pathologists and clinicians due to lack of standardization and variable sensitivity and specificity of the tests. Improved test standardization is needed, as are more data correlating laboratory tests with clinical features.

References

(1.) 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;4(2):295-306.

(2.) Triplett DA. Antiphospholipid antibodies. Arch Pathol Lab Med. 2002; 126(11):1424-1429.

(3.) Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7(10):1737-1740.

(4.) Pierangeli SS, Chen PP, Raschi E, Et A. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenetic mechanisms. Semin Thromb Hemost. 2008;34(3):236-250.

(5.) Rand JH, Wu XX, Quinn AS, Taatjes DJ. Resistance to annexin A5 anticoagulant activity: a thrombogenic mechanism for the antiphospholipid syndrome. Lupus. 2008;17(10):922-930.

(6.) Jude B, Goudemand J, Dolle I, Author C. Lupus anticoagulant: a clinical and laboratory study of 100 cases. Clin Lab Haematol. 1988;10:41-51.

(7.) Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest. 1952;152:621-622.

(8.) Moore JE, Lutz WB. The natural history of systemic erythematosus: an approach to its study through chronic biologic false-positive reactors. J Chronic Dis. 1955;1(3):297-316.

(9.) Feinstein DI, Rapaport SI. Acquired inhibitors of coagulation. Prog Hemost Thromb. 1972;1:75-95.

(10.) Guidelines on testing for the lupus anticoagulant. Lupus Anticoagulant Working Party on behalf of the BCSH Haemostasis and Thrombosis Task Force. J Clin Pathol. 1991;44(11):885-889.

(11.) Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost. 1995;74(4):1185-1190.

(12.) Greer JP, Foerester J, Rodgers GM, Glader B, eds. Wintrobe's clinical hematology. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.

(13.) Gastineau DA, Kazmier FJ, Nichols Wl, Bowie EJ. Lupus anticoagulant: an analysis of the clinical and laboratory features of 219 cases. Am J Hematol. 1985; 19(3):265-275.

(14.) Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med. 1980;92(2, pt 1):156-159.

(15.) Boggild MD, Sedhev RV, Fraser D, Heron JR. Cerebral venous sinus thrombosis and antiphospholipid antibodies. Postgrad Med J. 1995;71(838):487-489.

(16.) Saidi S, Mahjoub T, Almawi WY. Lupus anticoagulants and antiphospholipid antibodies as risk factors for a first episode of ischemic stroke. J Thromb Haemost. 2009;7(7):1075-1080.

(17.) Brey RL, Chapman J, Levine SR, et al. Stroke and the antiphospholipid syndrome: consensus meeting Taormina 2002. Lupus. 2003;12(7):508-513.

(18.) Lim W. Antiphospholipid antibody syndrome. Hematology Am Soc Hematol Educ Program. 2009:233-239.

(19.) Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003; 101(5):1827-1832.

(20.) Galli M. The antiphospholipid triangle. J Thromb Haemost. 2010;8(2): 234-236.

(21.) Stasi R, Stipa E, Masi M, et al. Antiphospholipid antibodies: prevalence, clinical significance and correlation to cytokine levels in acute myeloid leukemia and non-Hodgkin's lymphoma. Thromb Haemost. 1993;70(4):568-572.

(22.) Prieto J, Yuste JR, Beloqui O, et al. Anticardiolipin antibodies in chronic hepatitis C: implication of hepatitis C virus as the cause of the antiphospholipid syndrome. Hepatology. 1996;23(2):199-204.

(23.) Bloom EJ, Abrams DI, Rodgers G. Lupus anticoagulant in the acquired immunodeficiency syndrome. JAMA. 1986;256(4):491-493.

(24.) Facer CA, Agiostratidou G. High levels of anti-phospholipid antibodies in uncomplicated and severe Plasmodium falciparum and in P. vivax malaria. Clin Exp Immunol. 1994;95(2):304-309.

(25.) Day HM, Thiagarajan P, Ahn C, Reveille JD, Tinker KF, Arnett FC. Autoantibodies to beta2-glycoprotein I in systemic lupus erythematosus and primary antiphospholipid antibody syndrome: clinical correlations in comparison with other antiphospholipid antibody tests. J Rheumatol. 1998;25(4):667-674.

(26.) Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clinical and laboratory features of 50 patients. Medicine (Baltimore). 1998;77(3):195-207.

(27.) Wong RC, Favaloro EJ. A consensus approach to the formulation of guidelines for laboratory testing and reporting of antiphospholipid antibody assays. Semin Thromb Hemost. 2008;34(4):361-372.

(28.) Ordi-Ros J, Perez-Peman P, Monasterio J. Clinical and therapeutic aspects associated to phospholipid binding antibodies (lupus anticoagulant and anticardiolipin antibodies). Haemostasis. 1994;24(3):165-174.

(29.) Pernod G, Arvieux J, Carpentier PH, Mossuz P, Bosson JL, Polack B. Successful treatment of lupus anticoagulant-hypoprothrombinemia syndrome using intravenous immunoglobulins. Thromb Haemost. 1997;78(2):969-970.

(30.) Branch DW, Khamashta MA. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol. 2003;101(6): 1333-1344.

Nikhil A. Sangle, MD, FRCPath; Kristi J. Smock, MD

Accepted for publication September 1, 2010.

From the Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, and ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Nikhil Sangle, MD, FRCPath, Department of Pathology, 50 N Medical Dr, University of Utah Health Sciences Center, Salt Lake City, Utah 84132 (e-mail: nikhil_sangle@yahoo.com).
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Author:Sangle, Nikhil A.; Smock, Kristi J.
Publication:Archives of Pathology & Laboratory Medicine
Date:Sep 1, 2011
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