(See also Overview of Thrombotic Disorders Overview of Thrombotic Disorders In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more .)
The antiphospholipid syndrome (APS) is an autoimmune disorder Autoimmune Disorders In autoimmune disorders, the immune system produces antibodies to an endogenous antigen (autoantigen). The following types of hypersensitivity reactions may be involved: Type II: Antibody-coated... read more 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 Overview of Thrombotic Disorders In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more , recurrent pregnancy loss, Recurrent Pregnancy Loss Recurrent pregnancy loss is ≥ 2 to 3 spontaneous abortions. Determining the cause may require extensive evaluation of both parents. Some causes can be treated. Causes of recurrent pregnancy... read more thrombocytopenia Overview of Platelet Disorders Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more 
, hemolytic anemia Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more 
, 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 Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC), heparin-induced thrombocytopenia Heparin-induced thrombocytopenia Platelet destruction can develop because of immunologic causes (viral infection, drugs, connective tissue or lymphoproliferative disorders, blood transfusions) or nonimmunologic causes (sepsis... read more (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 Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage is persistent or recurrent pulmonary hemorrhage that originates from the lung parenchyma (ie, the alveoli) as opposed to the airways. There are numerous causes, but... read more 
are known manifestations.
Treatment includes high-dose corticosteroids, anticoagulation, plasmapheresis, and sometimes rituximab (an anti-CD20 monoclonal antibody) or eculizumab (an anti-complement component C5 monoclonal antibody).
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
In patients with thrombotic APS, indefinite treatment with warfarin is the standard approach (1 Treatment reference Antiphospholipid syndrome is an autoimmune disorder characterized by venous and arterial thrombosis or pregnancy complications (eg, recurrent miscarriage) and persistent autoantibodies to phospholipid-bound... read more ). Higher rates of recurrent thromboembolism with DOACs have been noted, so these medications should not be used for treatment of thrombotic APS.
Unfractionated heparin or low molecular weight heparin plus low-dose 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
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
heparin |
Hepflush-10 , Hep-Lock, Hep-Lock U/P, Monoject Prefill Advanced Heparin Lock Flush, SASH Normal Saline and Heparin |
rituximab |
RIABNI, Rituxan, RUXIENCE, truxima |
eculizumab |
Soliris |
warfarin |
Coumadin, Jantoven |
