Antiphospholipid Syndrome - Pathology

Antiphospholipid Syndrome 1
Antiphospholipid
Syndrome
Feature
Disease Facts
Roger S. Riley, M.D., Ph.D.
April, 2005
Synonyms
Antiphospholipid antibody syndrome, Hughes syndrome.
Epidemiology
The incidence of patients with asymptomatic APS is unknown. Antiphosphlipid antibodies
(lupus anticoagulants and anticardiolipin antibodies) are present in 1-5% of the
general population, and in about 50% of patients with systemic lupus erythrmatosus
(SLE) and other autoimmune diseases. Approximately 40,000 new patients develop
arterial or venous thrombosis per year in the United States from primary or secondary
APS. The median age of new patients is approximately 30 years, with a male:female
ratio of about 1:3.
Etiology &
Pathogenesis
Since the initial description of APS more than 20 years ago, numerous associations of
antiphospholipid antibodies with various infectious diseases, drugs, and autoimmune
diseases lead to many conflicting theories of its etiology. Although anionic phospholipids
were long believed to be the antigenic targets for antiphospholipid antibodies, it
has became apparent in recent years that the actual target is 2-glycoprotein I (2-
GPI), a plasma protein with strong affinity for negatively charged macromolecules
such as anionic phospholipids. Very recently, the discovery of shared peptide sequences
between 2-GPI and some microorganisms, particularly Saccharomyces cervisiae,
has lead to the hypothesis that at least some cases of APS may not be of primary
autoimmune origin, but due to molecular mimicry. 2-GPI has complex interactions
with the coagulation system that are poorly understood at present.
Clinical
Presentation
APS is clinically defined by the presence of one or more antiphospholipid antibodies
(lupus anticoagulant, anticardiolipin antibody) and/or a biologic-false positive test for
syphilis (FPTS) accompanied by the simultaneous or subsequent development of any
one or more of a number of APA-affiliated clinical manifestations. These include venous
thrombosis, arterial thrombosis, obstetrical complications, thrombocytopenia, bleeding,
neurological disease (transient ischemic attacks (TIA's) and stroke, early-onset
dementia, amaurosis fugax and retinal venous or arterial thrombosis, etc.), skin lesions
(livedo reticularis, etc.), cardiac valve vegetations and mitral regurgitation, myocardial
dysfunction, primary pulmonary hypertension, and adrenal insufficiency.
Primary APAS is thrombosis and or obstetrical complications in association with antiphospholipid
antibodies, but without signs of connective tissue disease, while secondary
APAS refers to those patients with systemic lupus erythematosus (SLE) who also
have an APA. Before a definitive diagnosis of primary APAS can be made, at least two
years of careful clinical observation are necessary to rule out early SLE, and one of the
tests for APA should be positive on two occasions at least three months apart. Overall,
autoimmune disease is present, or subsequently identified, in approximately 20% of
patients with APAs.
APAs develop in patients receiving certain drugs, and in a miscellaneous group of patients
with a variety of diseases, including malignancy, HIV and other viral infections.
Therapeutically administered drugs affiliated with APAs include phenytoin, chlorpromazine,
dilantin, quinidine, procainamide, and some antibiotics.

Antiphospholipid Syndrome 2
Feature
Disease Facts
Clinical
Presentation
(Cont’d)
Rare APA patients present with acute multi-organ involvement, including signs and
symptoms of encephalopathy, seizures, livedo reticularis, renal insufficiency, pulmonary
failure, and multiple thrombi involving both large and small vessel occlusions.
The term “catastrophic APA syndrome” and “Asherson syndrome” has been applied to
this disease, which is associated with high-titered APAs and a high mortality rate.
Laboratory
Features
The laboratory diagnosis of a LA is based on the initial finding of an abnormal
phospholipid-dependent clotting assay, followed by confirmation that a clotting inhibitor
is present, and that the inhibitor is dependent on phospholipid. Unfortunately, the
heterogeneous nature of LAs limits the sensitivity and specificity of individual coagulation
assays for LA detection and analysis; multiple assays are usually required and
there is no standard method of approach. However, the initial laboratory evaluation
will usually show a prolonged activated partial thromboplastin time (aPTT) with a normal
to slightly prolonged prothrombin time (PT). An aPTT mixing study is necessary to
identify the cause of the elevated aPTT and establish the presence of an inhibitor.
The Russell Viper Venom Time (RVVT) is the most widely used clinical laboratory assay
for confirmation of the presence of a phospholipid-dependent antibody. Russell’s viper
(Vipera russellii) is a large venomous snake native to India and Southeast Asia. Russell’s
viper venom (RVV) causes massive thrombosis when injected in vivo. The coagulant
protein of RVV is an enzyme (serine protease) which directly activates factor X in
the presence of Ca ++ , bypassing the intrinsic and extrinsic pathways. The activated
factor X then activates prothrombin in the presence of factor V and phospholipid.
The dilute Russell Viper Venom Time (dRVVT) uses a “diluted” venom concentration
and minimal phospholipid concentration to give a clotting time of 23 to 27 seconds
with normal serum. Under these circumstances, the clotting time becomes very sensitive
to the presence of phospholipid. LAs bind the available phospholipid, block the activation
of factor II, and lead to a prolongation of the clotting time. The dRVVT is more
specific for LA than the aPTT since it is not influenced by deficiencies of the contact or
intrinsic pathway factors or antibodies to factors VIII, IX, or XI. The dRVVT can be
used to detect LA in patient samples with a normal aPTT since phospholipid dilution
increases the sensitivity of the assay. A commercially available dRVVT test reagent,
(DVVtest, American Diagnostica, Inc., Greenwich, CT) combines RVV, plant phospholipid,
and calcium into a single reagent. A second reagent, containing RVV, extra
plant phospholipid, and calcium is usually available to “confirm” a positive result. The
extra phospholipid in the confirm reagent corrects a prolonged dRVVT time in a manner
analogous to platelet addition in the aPTT-based platelet neutralization procedure.
Other confirmatory assays for phospholipids-dependent antibodies include the hexagonal
phospholipid assay , PNP, tissue thromboplastin inhibition (TTI) assay, textarin
tine, kaolin clotting time (KCT). Because of individual variability in laboratory results, a
positive findings in at least two assays is recommended for diagnostic confirmation.
Anti-cardiolipin antibodies are detected by ELISA assays utilizing microliter plates
coated with dried cardiolipin. Bovine albumin or fetal calf serum is added to block nonspecific
binding sites, serum specimens are incubated in the microtiter wells, followed
by washing to remove serum and unbound immunoglobulin, and incubation with
monospecific or polyvalent enzyme-labeled anti-human immunoglobulin. Affinitypurified,
isotype specific ACAs and a series of international workshops in the 1980’s
resulted in standardized methodology and the definition of standard units of anticardiolipin
activity (GPL and MPL). One GPL or MPL unit is equivalent to one mg/mL of an
affinity-purified standard IgG or IgM sample obtained from specified individuals. Later
assays utilized negatively-charged phospholipids instead of cardiolipin.

Antiphospholipid Syndrome 3
Feature
Treatment
Disease Facts
The treatment of APS is based on the severity of clinical manifestations, particularly
thrombosis, and whether the patient has the primary or secondary form of the disease.
Aspirin is the cornerstone of treatment in patients without a history of thrombosis,
with hydroxychloroquine added in patients with SLE. Patients with a single episode
of thrombosis are at a high risk of recurrent thrombotic disease, and require lifelong
anticoagulation, currently with warfarin. Pregnant women with APS are usually treated
with heparin or low molecular weight heparin to prevent pregnancy loss. Other forms
of treatment may include corticosteroids or intravenous immunoglobulin.
Treatment
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Antiphospholipid Syndrome 4
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