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Review
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Antiphospholipid Syndrome
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Timothy
P. Collins, MD
The
lupus anticoagulants, anticardiolipin antibodies and anti-beta2
glycoprotein I antibodies are autoimmune antibodies against
phospholipids or plasma proteins bound to anionic phospholipids
and comprise a clinical paradox of thromboembolic disease
called the antiphospholipid syndrome (APS). Classically,
it is a reflex lab test ordered as a part of any hypercoagulable
work-up. In this review, I hope to simplify this complex
autoimmune phenomenon to the basic epidemiology, clinical
manifestations, treatment and the diagnostic criteria as
recently proposed by the International Consensus and American
College of Hematology.
It
has been reported that antiphospholipid antibodies are found
among young, apparently healthy individuals at a prevalence
of 1 to 5% for both anticardiolipin antibodies and the lupus
anticoagulant (Petri et al.). As with other autoimmune phenomenon,
the presence of antiphospholipid antibodies increases with
age and with coexistent chronic disease. Not surprisingly,
the prevalence of antiphospholipid antibodies is considerably
higher in patients with systemic lupus erythematosus (SLE)
(Avcin et al.).
Several
theories exist in an attempt to explain the cellular and
molecular mechanisms by which antiphospholipid antibodies
promote thrombosis: activated endothelial cells, oxidant-mediated
injury to the vascular endothelium, direct interference
in the phospholipid mediated regulation of coagulation and
a mechanism similar to the paradoxical thrombosis of heparin
induced thrombocytopenia (Levine et al.). The common pathology,
however, is a characteristic thrombotic microangiopathy
with minimal vascular or perivascular inflammation. This
change in the architecture of both small and large arteries
(also present in other disorders such as hemolytic-uremic
syndrome and scleroderma) is the nidus for in situ thrombosis
from which emboli can originate and/or lodge. The
clinical and laboratory diagnostic criteria as proposed
by the International Consensus Statement are as follows:
(Levine et al.)
Clinical Criteria
- Vascular Thrombosis. One or more clinical episodes
of arterial, venous or small vessel thrombosis occurring
in any tissue or organ.
- Complications
of Pregnancy. One or more unexplained death of morphologically
normal fetuses at or after the 10th week of gestation;
or one or more premature births of morphologically normal
neonates at or before the 34th week of gestation;
or three or more unexplained consecutive spontaneous
abortions before the 10th week of gestation.
Laboratory Criteria
- Anticardiolipin antibodies. IgG or IgM antibodies
present in moderate or high levels in the blood in two
or more occasions at least 6 weeks apart.
- Lupus
anticoagulant antibodies. Lupus anticoagulant antibodies
detected in the blood on two or more occasions at least
6 weeks apart, according to the guidelines of the International
Society on Thrombosis and Hemostasis.
Thrombosis can occur in virtually any vascular bed in the
body, thus making the clinical manifestations and differential
diagnosis extremely broad. Patients can present with evidence
of vascular insult to any organ. Venous thromboses
are more common than arterial thromboses in the antiphospholipid
syndrome. In fact, deep venous thrombosis (DVT) is the presenting
clinical manifestation in 32% of people diagnosed with APS
and antiphospholipid antibodies can be detected in 10% of
all patients with a venous thrombosis (Ginsberg et al).
The most common site of DVT is the calf, but renal, hepatic,
axillary, subclavian, or retinal veins or the vena cava
can be involved. The most common site of arterial thrombosis
is the cerebral vessels, but coronary, renal and mesenteric
arteries have been noted.
There
is some evidence that correlates the levels and coexistence
of antiphospholipid antibodies with incidence of events.
For example, one moderately large-scale study found that
venous thrombosis occurred in 44% of patients with high
titers of anticardiolipin antibodies, 29% with low titers
and 10% in those without the antibodies. Patients with SLE
and anticardiolipin antibodies also have an increased incidence
of thromboses as evidenced by a study of 1400 lupus patients
(Cervera et al.). A small subset of patients, estimated
at 0.8%, fall into the unfortunate category of catastrophic
antiphospholipid syndrome. Widespread thrombotic disease,
with visceral damage was the initial manifestation in three
quarters of patients studied. When present, this disorder
is fatal almost 50% of the time, even with anticoagulant
treatment (Levine et al.).
Standard
therapy for thrombosis in patients with APS consists of
heparin followed by warfarin. The treatment of pregnant
patients remains controversial but usually consists of a
combination of heparin and aspirin. It has been well documented
in clinical trials that an INR between 2.6 and 3.0 reduced
the incidence of thrombotic events by up to 75% whereas
low intensity warfarin or aspirin alone proved no benefit
(Cervera et al). Prophylactic therapy in patients who are
known to have antiphospholipid antibodies but no episodes
of thromboses is an important related treatment issue. Therapy
in this patient population is not generally recommended
unless there is a noted high level of anticardiolipin antibodies
or the patient has another risk factor for thrombosis such
as SLE. In the latter group of patients, hematologists usually
recommend aspirin 81mg per day (Petri et al.).
In
conclusion, it is obvious that APS is a potentially lethal
yet commonly occurring autoimmune phenomenon. Close attention
to clinical evidence for thromboembolic disease in conjunction
with the proposed diagnostic guidelines can hopefully prevent
significant morbidity and mortality on the wards and in
the ambulatory setting.
References
- Avcin, T. et al. Recent Advances in Antiphospholipid
Syndrome. Lupus 2002; 11:4
- Petri, M. Pathogenesis and Treatment of the
Antiphospholipid Syndrome. Med Clin North Am
1997; 81:151
- Cervera, R. et al. Antiphospholipid Syndrome:
clinical and immunologic manifestations and patterns
of disease expression in a cohort of 1000 patients.
Arthritis Rheum 2002; 46:1019
- Ginsberg, JS, et al. Antiphospholipid antibodies
and venous thromboembolism. Blood 1995; 86:3685
- Levine, LS, et al. The Antiphospholipid Syndrome.
N Engl J Med 2002; 346:752.
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