Definition

Autoimmune hypercoagulable state resulting from antibody recognition of cell membrane components including cardiolipin and β2-glycoprotein. Commonly seen in lupus, patients with APLS will often have a history of miscarriage and/or unexplained thrombosis.

Evaluation

In order to make the definitive diagnosis of APLS, the patient must meet at least one clinical criteria and at least one laboratory criteria.

Clinical criteria

• Vascular thrombosis: arterial, venous, or small-vessel thrombus in any organ.
• Complication of pregnancy: >1 unexplained fetus death(s) after 10 weeks with a morphologically normal fetus, >1 premature birth(s) before 34 weeks with a morphologically normal fetus, or >3 unexplained consecutive spontaneous abortions before 10 weeks of gestation.

Laboratory criteria (modified Sapporo criteria)

• Anticardiolipin IgM or IgG antibodies (moderately or highly positive on two or more occasions, at least 12 weeks apart).
• Anti-beta2-glycoprotein IgM or IgG antibodies (moderately or highly positive on two or more occasions, at least 12 weeks apart).
• Lupus anticoagulant antibodies (positive on two or more occasions, at least 12 weeks apart).
• NOTE: antiphospholipid antibodies may be transiently positive during acute thrombosis. Initial testing best delayed for a few weeks after initial episode of thrombosis.
• Making the laboratory diagnosis of lupus anticoagulant: while the cornerstone of laboratory diagnosis is antibody testing, the expense of antibody testing has led to guidelines that recommend assessing lupus anticoagulant activity before proceeding to antibody tests.
  • Step 1: is the PTT elevated?
    • If yes, proceed directly to mixing study (step 2).
    • If no, check dilute Russell viper venom time (RVVT). RVVT is more specific to the part of the coagulation cascade that requires phospholipids, and thus a more sensitive test for APLS.
    • If the RVVT is normal, STOP. The patient most likely does not have APLS.
    • If the RVVT is prolonged (abnormal), proceed to the mixing study (step 2).
  • Step 2: does a mixing study correct the prolonged PTT (or RVVT)? 
    • If yes, the problem is most likely a factor deficiency. Run an “incubated” mixing study. If the PTT remains corrected, the problem is a factor deficiency. If the PTT (or RVVT) begins to prolong again, proceed to step 3.
    • If no, the problem is either APLS or a factor inhibitor. Proceed to step 3.
  • Step 3: does the PTT (or RVVT) correct with addition of excess phospholipids?
    • If yes, you have your diagnosis: antiphospholipid syndrome. 
  • At USCF we also send a lupus hexa test that uses hexagonal phospholipid which is more potent at reversing inhibition by an anti-phospholipid antibody. About 1/2 of patients with APLS will be positive for both dRVVT and Hexa, 1/4 positive for dRVVT alone, and 1/4 positive for Hexa based on UCSF experience.

Management

• Patients with APLS usually require indefinite therapeutic anticoagulation with warfarin to achieve an INR of 2-3 unless strong contraindications exist. DOACs are not currently recommended.
• When PTT is prolonged by APLS, monitor degree of anticoagulation with anti-Xa level when bridging to warfarin with heparin.
• If PT is also elevated at baseline, consider presence of an anti-prothrombin antibody which may increase risk of bleeding. In this case, anticoagulation (even with warfarin) needs to be monitored with a chromogenic factor-Xa assay. 

Key Points

• In rare cases, APLS can lead to multi-organ dysfunction through the accumulation of clots in a multiple locations; this is referred to catastrophic APLS, and has a very poor prognosis.
• PTT is prolonged by APLS, often resulting in a need to monitor degree of anticoagulation with anti-Xa level when bridging to warfarin with heparin – sometimes anti-Xa is monitored even with a normal PTT – consult with Hematology.

Crowther MA, Ginsberg JS, Julian J et al, A comparison of two intensities of warfarin for the prevention  of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349(12):1133-8.

Levine JS, Branch DW, Rauch J.  The antiphospholipid syndrome. N Engl J Med 2002;346:752-763.

Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.

Pengo V, Tripodi A, Reber G et al. Update of the guidelines for lupus anticoagulant detection. J Thromb  Haemost. 2009 7:1737-40.

Win K, Rodgers GM. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. Am J Hematol. 2014 Oct;89(10):1017.