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ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) is a term used to describe
the association between recurrent clinical events such as thrombosis (arterial
or venous), thrombocytopenia, or fetal loss and the presence of a persistent
antiphospholipid antibody 1-3. Other clinical
conditions associated with the syndrome include stroke, transient ischemic
attack, livedo reticularis, migraine, epilepsy, and heart valve disease4.
The syndrome is termed "primary" if there is no accompanying autoimmune
disease and "secondary" if the patient also has systemic lupus erythematosus
(SLE) or an autoimmune disorder1,2,5. Certain
infectious diseases and drugs may also result in the formation of antiphospholipid
antibodies which do not appear to be associated with clinical complications
and do not require therapy1,3,5.
The clinical course in those patients diagnosed with antiphospholipid
antibody syndrome ranges from asymptomatic to catastrophic5.
Treatment options vary depending on the site of the first thrombotic event,
the persistence of the antiphospholipid antibody, and other coincident
risk factors for rethrombosis2. When indicated,
treatment may include immunosuppressive therapy, antiplatelet, and/or anticoagulant
drugs1-5. Most studies indicate that the
incidence of recurrent thrombosis is reduced by warfarin therapy, but the
duration and intensity of warfarin therapy remains illdefined. The role
of aspirin is undefined1.
ANTIBODY FORMATION:
Antiphospholipid antibodies are a family of related but distinct autoimmune
and alloimmune immunoglobulins (IgG, IgM, IgA, or mixtures) that are directed
against the anionic phospholipids contained in the membranes of cells3,5,6.
Of the anionic phospholipids, phosphatidylserine seems to be the most antigenic.
Phosphatidylserine is normally on the interior surface of the platelet
and endothelial cell membranes. When the cell is activated, phosphatidylserine
is redistributed to the cell surface and participates in clot formation7.
Cellular damage may result in inappropriate phosphatidylserine expression
on the cell surface giving rise to antibody formation. Therefore, antibodies
against phosphatidylserine are a more physiologically relevant antibody
group.
LABORATORY DIAGNOSIS:
Antiphospholipid antibodies are detected by using two different testing
techniques, clotting tests and enzyme-linked immunoassay system (ELISA)
procedures which measures specific phospholipid antibodies. The antibodies
which interfere with phospholipid dependent clotting assays are referred
to as Lupus Anticoagulant (LA). Originally identified in association
with SLE and named after that disease, the lupus anticoagulant occurs in
the absence of the disease in a large number of cases1,2,5.
Those antibodies detected by ELISA are either anticardiolipin (aCL)
or antiphosphatidylserine (aPS) antibodies. Studies have indicated
that the presence of both anticardiolipin and antiphosphatidylserine antibodies
is more likely to be associated with clinical complications than either
antibody alone7.
There is no single laboratory test that is 100% sensitive and specific for detection of LA. According to the standards of the Lupus Anticoagulant/Phospholipid Dependent Antibodies Scientific Subcommittee of the ISTH, the diagnosis of Lupus Anticoagulant should meet the following guidelines8:
1. Use two or more screening tests to demonstrate an abnormal phospholipid dependent clotting test, such as the APTT and DRVVT tests.
2. Prove the abnormal screening test is due to the presence of a circulating inhibitor by mixing with normal plasma.
3. Prove the inhibitor is phospholipid dependent, such as the Platelet Neutralization Procedure.
4. Rule out other coagulopathies.
Anticardiolipin antibodies (aCL) are measured using an ELISA system.
There are at least nine commercial kits on the market for measurement of
these antibodies that vary greatly in their sensitivity and specificity9.
HEMEX Laboratories uses a specific test system (not a screening test) that
reports results in GPL and MPL, units that are directly traceable to the
standards of the Phospholipid Standardization Laboratory at the University
of Louisville10.
Antiphosphatidylserine antibodies (aPS) are also measured an ELISA test
system. The diluent contains 2-glycoprotein which is a serum cofactor necessary
for the binding of antiphosphatidylserine in the patient's serum to the
phosphatidylserine coating the test system wells7.
Both IgG and IgM antibodies are measured as GPS and MPS respectively.
Antiphospholipid Antibody Syndrome is diagnosed by both
Lupus Anticoagulant and ELISA testing. The laboratory diagnosis
of antiphospholipid antibody syndrome is positive when either
the Lupus Anticoagulant or anticardiolipin/antiphosphatidylserine
antibody is positive or when both tests are positive.
HEMEX Laboratories follows an organized, sequential approach for laboratory
diagnosis of anti-phospholipid antibody syndrome. All reagents and test
procedures have been chosen to meet national guidelines for testing and
identification of antiphospholipid antibodies, not just screening. HEMEX
can provide clincial consultation, if desired, to help determine the best
clinical testing protocol or most cost effective screening tests.
SPECIMEN REQUIREMENTS for ANTIPHOSPHOLIPID testing:
Lupus Anticoagulant: 3 ml frozen citrated plasma. Plasma must be platelet free. Double spin or filter the specimen to ensure that all platelets have been removed. Any remaining platelets in the specimen may contribute enough phospholipid to result in a false negative test for LA.
Anticardiolipin Antibodies: 1 ml frozen serum.
Antiphosphatidylserine Antibodies: 1 ml frozen serum.
Hexagonal Phase Lupus Anticoagulant: 1 ml frozen plasma platelet
free as above for LA.
For more information, call HEMEX Laboratories at 997-9161 or
1-800-999-CLOT
(2568).
REFERENCES:
1. Lockshin MD. Answers to the antiphospholipid antibody syndrome. NEJM 1995;332(15):1025-7.
2. Khamashta MA, Cuadrado MJ., Mujic F, Taub NA, Hunt BJ, Hughes, GRV. The management of thrombosis in the antiphospholipid-antibody syndrome. NEJM 1995;332(15):993-997.
3. Smith JB, Cowchock FS. Antiphospholipid Antibodies: Clinical and laboratory considerations, pathophysiology, and treatment. Autoimmunity in Reproduction. Immunology and Allergy Clinics of North America 1994;14(4):821-831.
4. Hughes GRV. The antiphospholipid syndrome: ten years on. The Lancet 1993;342:341-344.
5. Triplett D. Antiphospholipid-protein antibodies: Laboratory detection and clinical relevance. Thrombosis Research 1995;78(1):1-31.
6. Rosove MH, Brewer PMC. Antiphospholipid thromobosis: Clinical course after the first thrombotic event in 70 patients. Ann Int Med 1992;117(4):303-308.
7. Package Insert. REAADS Anti-Phosphatidylserine Semi-Quantitative Test Kit. REAADS Medical Products, Inc. Westminster, CO. February 1996.
8. Brandt JT, Triplett DA., Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: An update. Thrombosis and Haemostasis 1995;74(4):1185-1190.
9. Reber G., Arvieux J, Comby E, Degenne D, deMoerloose P, Sanmarco M, Potron G. Multicenter evaluation of nine commercial kits for the quantitation of anticardiolipin antibodies. Thrombosis and Haemostasis 1995;73(3):
444-452.
10. Package Insert. REAADS Anti-Cardiolipin Semi-Quantitative Test Kit. REAADS Medical Products, Inc. Westminster, CO. April 1995.