Anti-Phospholipid Syndrome

Also known as: Anticardiolipin (ACL) syndrome, APL or APS for antiphospholipid syndrome, Hughes Syndrome

ICD-9 Code: 289.81
ICD-10 Code: D68.61

What is it?

APL syndrome refers to a constellation of clinical findings, including vascular thrombosis, fetal wastage, and thrombocytopenia, that are seen in association with certain autoantibodies. These autoantibodies include ACL or APL antibodies; functional hematologic tests, including the lupus anticoagulant test and the Russell Viper venom time, assess the impact of these antibodies on clotting assays.

What causes it?

The etiology of APL syndrome is unknown. Patients with a variety of infections, cancers, and other conditions may develop ACL antibodies, but fewer develop clinical APL syndrome. ACL antibodies may be found in as many as half of patients with systemic lupus erythematosus (SLE). Clinical APL syndrome occurs only in a minority of those with the antibody. The prcise pathogenesis of the APL syndrome is unknown. It is hypothesized that antibodies to negatively-charged phospholipids, such as cardiolipin, alter the normal anticoagulant function of the vascular endothelium. Alternatively, ACL and other APL antibodies may potentiate platelet activation, resulting in thrombosis.

Who gets it?

APL syndrome occurs most commonly among young women, but all ages and both sexes may develop this condition. APL antibodies without clinical symptoms are not infrequently observed, e.g. among SLE patients, and the presence of the antibodies by themselves is insufficient to diagnose the syndrome.

What are the symptoms?

Clinical characteristics of APL syndrome are shown in the Table. Recurrent venous or arterial thromboses are the most prominent feature. A history of thrombosis in a patient thought to be otherwise at low risk of such an event often prompts the search for APL syndrome. Other common presentations include recurrent spontaneous abortions and thrombocytopenia.

Complications: APL syndrome is responsible for 20% all cases of DVT, 20% of MI under age 45 years and 20% of all cerebrovascular accidents (CVA).  Among lupus patients with antiphospholipid antibodies, up to half may develop the antiphospholipid syndrome;  but very few (5%) APL patients will develop SLE.

– APL syndrome may also cause leg ulcers, transverse myelitis, valvular disease, hemolytic anemia, pulmonary hypertension and livedo reticularis,

Catastrophic APL syndrome refers to fulminant organ failure from widespread thromboses. Precipitating events often include infection, surgery, trauma, anticoagulant cessation, pregnancy, or the use of estrogen-containing compounds. A thrombotic microangiopathy usually affects the kidney, gut, heart, lungs, and brain but may also affect the skin, adrenals, and pancreas. This may result in renal, pulmonary or adrenal failure, alveolar hemorrhage, and bowel infarction, among others complications. This may be confused with thrombotic thrombocytopenic purpura (TTP) or disseminated intravascular coagulation (DIC) because these patients may also have thrombocytopenia, DIC, schistocytes, and severe anemia. Mortality is high, and treatment may require various types of modalities, including immunomodulatory agents and anticoagulants.

Table: Characteristics of the Antiphopholipid Antibody Syndrome
Venous thrombosis (e.g., pulmonary embolus, deep venous thrombosis, retinal vein thrombosis, Budd-Chiari syndrome)
Arterial thrombosis (e.g., cerebrovascular accident, myocardial infarction)
Recurrent fetal loss
Less common
Livedo reticularis
Cutaneous ulceration
Hemolytic anemia
Endocardial/cardiac valvular vegetations (Libman-Sacks endocarditis)
Chorea, myelopathy

How is it diagnosed?

Diagnosis of APL syndrome depends on two distinct types of laboratory tests: functional hematologic tests (the lupus anticoagulant test) or assays for specific antibodies (e.g., ACL antibody test). Although many patients with APL syndrome may have abnormal results in both types of test, others may manifest only one abnormal test result. Although they are not exactly the same, the terms APL and ACL are often used interchangeably.

There are several laboratory tests that define the presence of a lupus anticoagulant. A prolonged partial thromboplastin time (PTT) with a normal prothrombin time is suggestive. If the PTT does not correct with a 1:1 dilution with normal serum, as would be expected if the prolonged PTT were owing to a deficiency of clotting factors, the presence of an inhibitor such as the lupus anti-coagulant is suggested. The dilute Russell viper venom time and the kaolin clot time are clotting tests that depend on phospholipids and are thus interfered with when APL antibodies are present. Finally, correction of a prolonged PTT by addition of excess phospholipids, as is done in the platelet neutralization test and the hexagonal phospholipid test, suggests that a lupus anticoagulant is present.

Enzyme-linked immunosorbent assay (ELISA) is used to identify antibodies that bind to negatively charged phospholipids, including cardiolipin, phosphatidylcholine, and others. Although several antibody isotypes (e.g., IgG, IgA, IgM) may have ACL activity, high-titer IgG ACL correlates most strongly with the clinical syndrome of APL syndrome. Recently, it has been demonstrated that most pathogenic ACL antibodies have binding activity only in the presence of another serum protein, beta2-glycoprotein-I.

Differential Diagnosis: Other considerations for recurrent thrombotic events might include protein C, protein S, antithrombin III or factor V Leiden deficiency, dysfibrinogenemias, hyperhomocystinemia, nephrotic syndrome, malignancies, Behçet’s syndrome, paroxysmal nocturnal hemoglobinuria, TTP, Buerger’s diseases, sickle-cell anemia, hyperlipidemia, severe diabetes, or hypertension. Interestingly, APL syndrome is unique in that it causes both venous and arterial thromboses; while venous thromboses will result from disorders involving antithrombin III, protein C or S.   Recurrent fetal loss may also be associated with anti-Ro antibodies, coexistent infection or inflammatory diseases, or anatomic abnormalities of the female reproductive tract.

Keys to Diagnosis: An international consensus conference concluded that APL syndrome is defined by at least one clinical criterion (vascular thrombosis, pregnancy complications) and one laboratory testing criterion (lupus anticoagulant, ACL antibodies).

How is it treated?

Treatment of APL syndrome depends to some extent on the occurrence and severity of the clinical manifestations. Acutely, patients with severe thromboembolic events (e.g., pulmonary embolism) are treated with anticoagulation in the same manner as those without APL syndrome. Because patients with APL syndrome are prone to recurrent thromboses, many physicians recommend that patients with a single serious clotting event be treated with long-term oral anticoagulation, typically with warfarin. Patients with recurrent events should receive anticoagulation unless there are compelling reasons not to do so. Treatment that achieves an international normalized ratio >2 appears to be more efficacious than less intense anticoagulation. When anticoagulation is not feasible, low doses of aspirin are commonly used as adjunctive therapy, although data supporting the efficacy of this approach are lacking. In some circumstances (e.g., pregnancy), warfarin is contraindicated because it crosses the placenta. Daily treatment with heparin is an alternative. Low molecular weight heparin therapy has also been successfully used in female patients with APL syndrome who wish to carry the pregnancy to full-term.  The role of clopidogrel and newer oral anticoagulants remains to be defined. Because APL syndrome relates to antibody production, corticosteroids and other immunomodulatory agents have been tried for some patients. However, good data supporting this approach are lacking.

Adapted from: RheumaKnowledgy


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