Antiphospholipid Syndrome (APS)

Patients diagnosed with antiphospholipid syndrome suffer from a variety of
conditions.  The more commonly seen clinical conditions of
antiphospholipid syndrome (APS) include recurrent venous thrombosis,
recurrent arterial thrombosis, thrombocytopenia and recurrent fetal loss.  
Neurological, dermatological, hematological, and cardiopulmonary
complications associated with APS are also widely reported.

1.        Venous thrombosis occurs most frequently in deep veins.  Venous
thrombosis in other vascular beds such as the renal veins and the hepatic
portal vein have also been reported.  
2.        Arterial thrombosis occurs less frequently than venous thrombosis.  
Transient ischemic attack (mini-stroke) is a common arterial presentation.  
3.        Thrombocytopenia (low platelet count) occurs in about 15% to 20 % of
patients with APS.  
4.        Obstetric complications include recurrent spontaneous abortion and
recurrent fetal loss.
5.        Neurological manifestations usually present as chorea, Guillain Barré
syndrome, or Sneddon’s syndrome.  
6.        Dermatological manifestations include livedo reticularis, leg ulcers,
necrotizing purpura, and peripheral gangrene.
7.        Other hematological manifestations include hemolytic anemia and
leukopenia.
8.        Cardiopulmonary complications include valvular lesion and
pulmonary hypertension.

APS can occur in patients with another underlying disease or without other
complications.  APS without any underlying disease is classified as primary
antiphospholipid syndrome while APS associated with other diseases, such
as systemic lupus erythematosus (SLE) or other autoimmune diseases, is
classified as secondary antiphospholipid syndrome.  Approximately 40 % of
SLE patients possess antiphospholipid antibodies.  Of these SLE patients
with aPL, about 40 % develop thrombosis.  In comparison, only 12 % of SLE
patients without aPL develop thrombosis.

In APS patients, anticardiolipin and lupus anticoagulant (LA) are the two
main clinical groups of antiphospholipid antibodies in blood circulation.  
They could be characterized by two different assay methods.  Anticardiolipin
is identified by enzyme-linked immunosorbent assay (ELISA and LA is
detected by clotting assays.  Although they are normally described as anti-
phospholipid antibodies, their binding to phospholipid is actually mediated
by protein cofactors.

Anticardiolipins are antibodies that react with cardiolipin-binding proteins.  
The major antigen for anticardiolipin was identified to be ß2-glycoprotein I
(ß2GPI) by three research groups independently in 1990.  Therefore,
anticardiolipins are actually anti-ß2GPI antibodies.  However, not all
anticardiolipin antibodies are directed against ß2GPI.  Other antigenic
targets of anticardiolipin and antiphospholipid antibodies have been
identified, albeit less commonly.  Most of these antigens share the
phospholipid-binding characteristic of ß2GPI and they include prothrombin,
protein C, protein S, annexin V, thrombomodulin, kininogen, thrombin-
antithrombin complex, C4b-binding protein, and lipopolysaccharide binding
protein.  Therefore, strictly speaking, anticardiolipin antibodies are a group of
protein-dependent antiphospholipid antibodies, which includes anti-ß2GPI.

LAs are antibodies that can prolong the clotting time of coagulation assays.  
The major coagulation antigen for LA was identified to be prothrombin.  LA
specific for ß2GPI have also been described.  This is known as
anticardiolipin-type A.  Anti-ß2GPI without LA activity is referred to as
anticardiolipin-type B.  Therefore, even though anticardiolipin, anti-ß2GPI, LA
and aPL are classified into different groups, they are closely related
antibodies whose activity may overlap.

Anticardiolipin antibodies are routinely detected by two different enzyme-
linked immunosorbent assays (ELISAs).  One has negatively charged
phospholipid, usually cardiolipin, coated to the ELISA plate, and uses fetal
calf serum that contains ß2-glycoprotein I (ß2GPI) as diluent of patient
plasma samples.  The other one has ß2GPI, one of the major target
antigens of anticardiolipin, directly coated to an oxidized ELISA plate.  The
former ELISA will detect antibodies specific for ß2GPI as well as other
phospholipid-binding serum proteins because of the use of fetal calf serum
as sample diluent.  In contrast, the latter ELISA can only detect antibodies
specific for ß2GPI.

Coagulation assays useful for detecting lupus anticoagulant (LA) include
activated partial thromboplastin time (APTT) sensitive to LA, kaolin clotting
time (KCT), and the dilute Russell’s viper venom time (dRVVT).  A prolonged
APTT clotting time suggests the presence of LA.  However, a mixing study (1:
1 mix of normal and patient’s plasma) needs to be performed to ensure that
the APTT prolongation is not caused by a coagulation factor deficiency.  The
presence of a putative LA has to be confirmed by the neutralization of its
inhibitory activity when phospholipid concentration is increased.  KCT and
dRVVT are also effective in detecting LA.  In addition, KCT is especially
sensitive in detecting prothrombin-specific LA while dRVVT is sensitive for
ß2GPI-specific LA.

APS can be treated by different therapy depending on the specific
conditions.  Anticoagulation therapy with long term use of warfarin to achieve
an International Normalized Ratio (INR) > 3 with or without low dose aspirin
(75 mg) was found to be effective in preventing recurrent venous and
recurrent arterial thrombosis.  Corticosteroid treatment is effective for
thrombocytopenia; however splenectomy may be necessary.  Low dose
aspirin and subcutaneous unfractionated heparin has proven to be effective
in preventing recurrent fetal loss.
Antiphospholipid Syndrome
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