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Antiphospholipid Antibody Syndrome: Lupus Anticoagulants and Anticardiolipin Antibodies

The two most important clinical types of antiphospholipid-protein antibodies are traditionally called lupus anticoagulant (LA) and anticardiolipin (aCL) antibodies. These antibodies are associated in some patients, but not in others with clinical illness of varying severity. Individual patients may manifest arterial or venous thromboembolic disease, thrombocytopenia, recurrent pregnancy loss, and neurologic and skin abnormalities. The clinical importance, particularly of the lupus anticoagulant or higher titer aCL antibodies, has been increasingly recognized; these antibodies or their functional consequences are found in approximately 10% of patients with venous thromboembolic events. Although "lupus inhibitors" were initially noted in patients with bleeding disorders.

Synonyms for LA and aCL antibodies include antiphospholipid (aPL) antibodies, antiphospholipid-protein antibodies (APA), and autoantibodies to phospholipid-binding plasma proteins. The associated clinical manifestations including thrombophilia are variously called the LA syndrome, antiphospholipid syndrome (APS), or antiphospholipid-protein syndrome. These semantic choices are discussed in a recent review, but they are used less often than LA and aCL at the bedside.

Clinical Associations

LA and aCL antibodies have been reported in a variety of clinical disorders, including SLE, other autoimmune and connective tissue diseases, and in disorders that are unrelated to systemic lupus erythematosus. As with all associative relations, the degree to which a pathophysiologic condition contributes to clinically significant symptoms

Interpretation of estimates of APA frequency must consider the sensitivity of the diverse assay systems that have been used by investigators. Different LA assay systems have been tested with plasma samples from a rigorously defined group of patients with the antiphospholipid-protein syndrome,


Clinical Diagnoses Associated with Antiphospholipid-Protein Antibodies
Primary antiphospholipid-protein syndrome (PAPS): an autoimmune disorder with no apparent cause
Secondary autoimmune disorders
   Systemic lupus erythematosus; other autoimmune and connective tissue diseases; drug-induced: procainamide, hydralazine, quinidine, phenothiazines, penicillin
Malignancies: leukemia, lymphoproliferative and plasmacytic disorders, solid tumors
   Infections: viral, bacterial, protozoal, fungal
Neurologic disorders
Liver disease
Valvular heart disease
Peripheral arterial disease
Chronic renal failure
Sickle cell disease
EDTA-dependent pseudothrombocytopenia
No apparent disease

confirming the importance of variables such as the concentration and composition of phospholipids used in the assay , phospholipid reagent conformation, and so on. Laboratory aspects of antiphospholipid-antibody testing are discussed in the text that follows.

In a large series of internal medicine patients, 7% were APA positive and 2% fulfilled the criteria of antiphospholipid-antibody syndrome. The most commonly associated diseases were cancer and chronic or acute

Clinical Manifestations

Although lupus anticoagulants are immunologically distinct from anticardiolipin antibodies, clinical manifestations associated with each antibody appear to be similar. Clinical experience suggests that venous thrombosis is more likely associated with the LA, and arterial thrombosis is more likely associated with high-titer aCL antibodies. The antiphospholipid-antibody syndrome is characterized by the triad of fetal loss, thromboembolic disease (arterial or venous), and/or

TABLE 69-9 -- Criteria for Diagnosis of the Antiphospholipid-Antibody Syndrome
Clinical event Laboratory abnormality
Venous thrombosis Positive lupus anticoagulant test
or or
Arterial thrombosis Positive anticardiolipin antibody test
or (moderate-titer or high-titer IgG)
Immune thrombocytopenia The laboratory abnormality should persist for at least 2 months
or
Recurrent miscarriage
The diagnosis of antiphospholipid antibody syndrome requires a clinical event (left column) and an abnormal laboratory test result indicative of an LA, or a moderate- or high-titer of lgG anticardiolipin antibodies (right column). Ideally, the abnormal laboratory test should persist.

immune thrombocytopenia, but a wide variety of clinical features may be seen with APA. However, many patients with APA are asymptomatic. A proportion of asymptomatic patients will develop SLE  or other disorders.
Arterial and Venous Thromboembolic Disease.

The most common clinical presentation of patients with LA and/or aCL antibodies is arterial or venous thromboembolism, affecting up to 70% of patients in some series but averaging about 30 to 40% of patients in most studies. The most common site of thrombosis is extremity deep vein thrombosis, but occasionally unusual sites are involved, such as the axillary, retinal, hepatic veins, and cerebral venous sinus thrombosis. Cerebral thrombosis, often heralded by repeated transient ischemic attacks.

Thrombocytopenia.

Moderate thrombocytopenia is noted in approximately 50% of patients with lupus inhibitors, but in many cases it apparently is the result of the underlying disorder. Thrombocytopenia may be the result of platelet sensitization by antibodies attached to membrane phospholipids and/or glycoproteins.

Clinical Manifestations of Antiphospholipid Antibodies
Asymptomatic
Arterial and venous thromboembolism
   Avascular osteonecrosis
Hematologic
   Cytopenias: thrombocytopenia, autoimmune hemolytic anemia, leukopenia
   Coagulopathy: platelet dysfunction; prothrombin deficiency
Neurologic
   Acute ischemia (cerebrovascular accident, transient ischemic attack, encephalopathy); severe migraine; multiple infarct dementia; seizures; peripheral neuropathy; myasthenia gravis
Dermatologic
   Livedo reticularis; acrocyanosis (distal cutaneous ischemia, ulceration, gangrene); widespread cutaneous necrosis; pyoderma gangrenosum-like skin lesions; anetoderma in HIV-1 disease
Cardiopulmonary
   Marantic endocarditis; myocardial ischemia and infarction; intracardiac thrombotic mass; peripheral arterial disease; thromboembolic and nonthrombotic pulmonary hypertension
Obstetric
   Recurrent spontaneous abortion; intrauterine growth retardation; preeclampsia; chorea gravidarum; low Apgar scores
Catastrophic antiphospholipid syndrome

thrombocytopenia of obscure etiology, including those with ITP-like syndromes, probably should be screened for
Neurologic Syndromes

Various neurologic disorders have been linked with APA, including dementia, migraines, chorea, seizures, transverse myelopathy, Guillain-Barre syndrome, mononeuritis multiplex, transient global amnesia, and myasthenia gravis.

Dermatologic Disorders.

A variety of ischemic-dermatologic syndromes have been associated with aCL antibodies, including livedo reticularis, acrocyanosis (distal cutaneous ischemia, ulceration, gangrene), widespread cutaneous necrosis, and pyoderma gangrenosum-like skin lesions. Men with PAPS, in particular, may experience dermatologic problems.

Cardiac Disorders.

A high incidence of APA is seen in patients with peripheral arterial disease who experience an associated increased risk of early graft thrombosis. This may justify routine testing for APA before reconstructive vascular surgery.

Pulmonary Disorders.

Ischemic and thrombotic pulmonary disease is linked to APA, including pulmonary embolism, pulmonary hypertension, intra-alveolar pulmonary hemorrhage, and adult respiratory distress syndrome. The latter syndrome has been reported in patients with catastrophic antiphospholipid-antibody syndrome.

Obstetric Aspects.

APA are associated with obstetric complications, including intrauterine growth retardation, preeclampsia, chorea gravidarum, and primarily, recurrent spontaneous fetal loss (RSFL). Pregnancy losses in women with antiphospholipid antibodies are often caused by fetal death, despite normal fetal karyotypes. Spontaneous fetal loss is perhaps most common in the first trimester, but paradoxically, early first-trimester pregnancy losses.

It is generally considered not appropriate to screen for APA in asymptomatic pregnancies without a prior history of RSFL. APA were identified at the first prenatal visit in almost 25% of healthy pregnant women.

Although the mechanism by which APA cause recurrent pregnancy loss has not been fully explained, these antibodies may induce intervillous thrombosis, intravillous infarctions, and decidual vasculopathy.

Catastrophic Antiphospholipid-Antibody Syndrome.

Some patients with APA develop an acute, severe multiorgan illness characterized by diffuse small vessel ischemia and occlusion with extensive tissue damage, including myocardial infarction, limb ischemia, disseminated intravascular coagulation.

Laboratory Diagnosis of Antiphospholipid-Protein Antibodies

LA and high-titer aCL antibodies have similar clinical implications, although some studies suggest a higher thrombotic risk in patients with the LA. The laboratory should perform both fibrin-based coagulation assays.

Treatment of Antiphospholipid-Protein Antibodies Syndrome

The optimal treatment of patients with APA syndrome has not been defined. Depending on the clinical symptoms, patients with APA may need no treatment, or may need anticoagulant or immunosuppressive therapy.

Obstetric Treatment.

Since the risk of pregnancy loss in women with antiphospholipid syndrome and prior pregnancy loss may exceed 60%, a history of recurrent fetal loss is an indication for treatment during pregnancy. Antiplatelet agents such as aspirin 80 mg/day, low-dose immunosuppressive agents such as prednisone 15 to 30 mg/day.