Antiphospholipid syndrome is an autoimmune disorder characterized by venous and arterial thrombosis or pregnancy complications (eg, recurrent miscarriage) and persistent autoantibodies to phospholipid-bound proteins. The pathophysiology is not precisely known. Diagnosis is by blood tests. Anticoagulation is often used for prevention and treatment.
(See also Overview of Thrombotic Disorders.)
The antiphospholipid syndrome (APS) is an autoimmune disorder that is characterized by arterial, venous, or microvascular thrombosis or recurrent pregnancy loss caused by antibodies directed against one or more phospholipid-bound proteins (eg, beta-2 glycoprotein 1, prothrombin, annexin A5). In the clinical laboratory, antiphospholipid syndrome is associated with anticardiolipin antibodies, beta-2 glycoprotein 1 antibodies, and the lupus anticoagulant (or lupus inhibitor) which causes prolongation of phospholipid-dependent coagulation assays such as the PTT or dilute Russell viper venom time (dRVVT). The antibodies that cause prolongation of coagulation tests were originally called lupus anticoagulants because they were initially identified in patients with systemic lupus erythematosus (SLE). However, this terminology is no longer used because these antibodies can also occur in patients without SLE (as occurs in primary APS).
The pathogenesis of thrombosis in APS is unclear. Beta-2 glycoprotein 1 in plasma binds to phospholipid-rich surfaces. Antibodies to beta-2 glycoprotein 1 upregulate cellular adhesion proteins, such as E selectin, and procoagulant proteins, such as tissue factor. Tissue factor is a receptor and cofactor for factor VII and is expressed on epithelial cells to help form a hemostatic barrier. In addition, antibodies to beta-2 glycoprotein 1 downregulate expression of tissue factor pathway inhibitor, an endogenous anticoagulant protein. Antiphospholipid antibodies also activate neutrophils and monocytes, which activate tissue factor, as well as platelets and complement. Each of these derangements may contribute to the hypercoagulable state associated with antiphospholipid syndrome.
Clinical manifestations of APS include arterial or venous thrombosis, recurrent pregnancy loss, thrombocytopenia, hemolytic anemia, or thrombotic microangiopathy, which can cause renal or neurologic dysfunction.
Catastrophic antiphospholipid syndrome
In a small proportion of patients with APS, widespread thromboses occur in small vessels supplying multiple organs, often including the brain (causing neurologic defects). This syndrome is called catastrophic APS (CAPS) and can be confused with disseminated intravascular coagulation (DIC), (HIT), and thrombotic microangiopathy (TMA).
The diagnosis of CAPS should be considered in patients with multiorgan failure (dysfunction of three or more organs) who have positive laboratory test results for APS. Acute kidney injury, encephalopathy, adrenal hemorrhage (due to thrombosis), skin necrosis, and diffuse alveolar hemorrhage are known manifestations.
Diagnosis of Antiphospholipid Syndrome
Laboratory testing, beginning with partial thromboplastin time (PTT) and the dilute Russell viper venom time (DRVVT)
In patients with clinical events (thrombosis or pregnancy loss) that suggest APS, laboratory testing should be done to confirm the diagnosis.
In the presence of antiphospholipid antibodies, the PTT is prolonged and does not correct with 1:1 or 4:1 mixing with normal plasma. Correction of the PTT after adding excess purified phospholipids is consistent with the presence of an antiphospholipid antibody.
The dilute Russell viper venom time (DRVVT) is another assay to detect the lupus inhibitor. It is more sensitive than the PTT to the presence of antiphospholipid antibodies. The venom causes coagulation by activating factor X. The presence of lupus anticoagulant prolongs the clotting process. Normal plasma has no effect on the clotting time, but addition of excess phospholipid reverses the prolongation.
Immunoassays for IgG and IgM antibodies against cardiolipin and beta-2 glycoprotein 1 are also done. It is important to do both immunoassays and coagulation assays when diagnosing APS because some patients will only have positive results for one test.
To confirm the diagnosis, the positive tests should be repeated 12 weeks after initial testing to confirm abnormal results.
Treatment of Antiphospholipid Syndrome
Anticoagulation
1). Higher rates of recurrent thromboembolism with DOACs have been noted, so these medications should not be used for treatment of thrombotic APS.
aspirin is used during pregnancy to prevent recurrent pregnancy losses in women with APS. After delivery, unfractionated heparin or low molecular weight heparin is continued for 6 weeks for thromboprophylaxis.
Treatment reference
1. Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018;378(21):2010-2021. doi:10.1056/NEJMra1705454
