Antiphospholipid Syndrome

Essentials of Diagnosis

• Hypercoagulability, with recurrent thromboses in either the venous or arterial circulation

• Thrombocytopenia is common

• Recurrent fetal loss

• Because recurrent events are common and often serious, lifelong anticoagulation with warfarin is recommended for patients with antiphospholipid syndrome (APS)

General Considerations

• Primary APS is diagnosed in patients who have

  • Venous or arterial occlusions

  • Pregnancy complications

    • 3 or more first trimester miscarriages

    • Unexplained fetal death and premature birth before 34 weeks of gestation attributable to severe preeclampsia, eclampsia, or placental insufficiency

  • Diagnostic antiphospholipid antibodies but no other features of systemic lupus erythematosus (SLE)

• Catastrophic APS

  • Occurs in < 1% of patients with antiphospholipid antibodies

  • Leads to diffuse thromboses, thrombotic microangiopathy, and multiorgan system failure

Symptoms and Signs

• Often asymptomatic until a thrombotic event or a pregnancy loss occurs

• Thrombotic events may occur in either the arterial or venous circulations and include

  • Deep venous thromboses

  • Pulmonary emboli

  • Cerebrovascular accidents

  • Budd-Chiari syndrome

  • Cerebral sinus vein thrombosis

  • Myocardial infarction

  • Digital infarction

  • Hemorrhagic infarction of the adrenal glands (due to adrenal vein thrombosis)

  • Other thrombotic events

• Other symptoms and signs often attributed to the APS include

  • Mental status changes

  • Livedo reticularis

  • Skin ulcers

  • Microangiopathic nephropathy

  • Cardiac valvular thickening or vegetations

• Pregnancy losses associated with APS include

  • Three or more unexplained consecutive spontaneous abortions prior to 10 weeks' gestation

  • One or more unexplained deaths of a morphologically normal fetus after 10 weeks' gestation

  • Preterm delivery at less than 34 weeks' gestation due to preeclampsia or placental insufficiency

Differential Diagnosis

• Exclusion of SLE and other autoimmune disorders is essential because these disorders may be associated with additional complications requiring alternative treatments

• Other genetic or acquired conditions associated with hypercoagulability must be excluded including

  • Activated protein C resistance/Factor V

  • Protein C deficiency

  • Protein S deficiency

  • Antithrombin deficiency

  • Hyperprothrombinemia (prothrombin gene G20210A mutation)

  • Increased Factor VIII activity

  • Hyperhomocysteinemia

• Catastrophic APS has a broad differential diagnosis, including

  • Sepsis

  • Pulmonary-renal syndromes

  • Systemic vasculitis

  • Disseminated intravascular coagulation

  • Thrombotic thrombocytopenic purpura

Laboratory Findings

• Laboratory criteria include the identification of at least one of the following three antiphospholipid antibodies

  • Anti-cardiolipin antibodies

    • Anti-cardiolipin IgG or IgM antibodies are typically measured with enzyme immunoassays

  • A "lupus anticoagulant" that prolongs the partial thromboplastin time test in vitro

    • Although the lupus anticoagulant is detected by a prolongation of the partial thromboplastin time in vitro, paradoxically it is associated with a thrombotic tendency rather than a bleeding risk

    • The Russell viper venom time (RVVT) is more sensitive test for the lupus anticoagulant

    • The RVVT is prolonged in the presence of the lupus anticoagulant

    • It does not correct with mixing studies but does with the addition of excess phospholipid

  • An antibody causing a "biologic false-positive test" for syphilis

    • In the "biologic false positive" variant of the antiphospholipid antibody, the rapid plasma reagin (RPR) is (falsely) positive, but specific anti-treponemal assays are negative

• In pregnancy

  • At least one of the following antiphospholipid antibodies is detectable

    • Lupus anticoagulant

    • Anticardiolipin antibodies

    • Anti-beta-2-glycoprotein 1 antibodies

• The diagnosis of APS requires two positive antiphospholipid antibody test results at least 12 weeks apart since transient positive results can occur

• Treat nonpregnant patients with APS with warfarin to maintain an INR of 2.0–3.0

• Patients who have recurrent thrombotic events at this level of anticoagulation may require higher doses of warfarin aiming for INRs > 3.0, but bleeding risk increases substantially

• Patients with APS should receive lifelong anticoagulation therapy

• Treatment of APS in pregnancy

  • Warfarin is teratogenic and is not used

  • Optimal treatment is unclear but generally involves administration of a heparin compound (unfractionated or low-molecular-weight heparin [LMWH]) in prophylactic amounts (5000–10,000 units subcutaneously twice per day for the former) and low-dose aspirin (81 mg)

  • Although anticoagulation is particularly prudent in women with a history of thrombosis, there is also evidence that this management reduces the risk for spontaneous abortion in women with recurrent pregnancy loss from APS

  • Treatment is typically continued through pregnancy and the early postpartum period for thromboprophylaxis, although it is unclear whether this approach decreases the risk of stillbirth or placental dysfunction

  • LMWH is also commonly used for this indication (30–40 mg subcutaneously once per day); however, it is not clear that LMWH has the same effect on reducing the risk of recurrent abortion as unfractionated heparin

  • The use of corticosteroids and intravenous immunoglobulin are of unclear benefit in these patients, and neither treatment is recommended

• In patients with catastrophic APS, a three-pronged approach is taken in the acute setting:

  • Intravenous heparin

  • High doses of corticosteroids

  • Either intravenous immune globulin or plasmapheresis