Antiphospholipid Syndrome

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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