Antiphospholipid antibody syndrome (APS) is an autoimmune thrombotic syndrome characterized by the presence of antiphospholipid antibodies (APAs) in association with either recurrent venous or arterial thromboembolic events or repeated fetal loss. The antiphospholipid antibodies are directed against phospholipid-binding plasma proteins and cause an increased risk of clot formation.
- Primary (50%): Occurs in patients without clinical evidence of another autoimmune disease
- Secondary: Occurs in association with another disease, most commonly systemic lupus erythematosus (SLE)
- Catastrophic APS (<1%):
- Differs from primary and secondary types in the caliber of vessels affected. Venous or arterial thrombosis of large vessels is less common, and patients present with acute thrombotic microangiopathy, the kidneys being the most commonly affected organ.
- DIC, which does not occur in primary or secondary forms, is seen in up to 25% of patients with the catastrophic type
- Has a high mortality, approaching 50% even with treatment
- Synonym(s): Hughes syndrome
Atherosclerosis and cancer are more frequent causes of thrombosis than is APS.
- Increased frequency of recurrent fetal loss
- Increased risk of premature delivery due to pregnancy-related hypertension and uteroplacental insufficiency
- No specific age or race predilection
- Equal frequency occurs among males and females for both primary and secondary forms in young pre-pubertal patients
- Female predilection for both primary and secondary forms because of the inclusion of pregnancy-related events in the classification criteria and because of the female predominance in autoimmune diseases such as SLE, respectively.
- 15% of women with recurrent pregnancy loss have APS
- 5–21% of all patients with DVT have APS
APAs are present in 1–15% of the general population and in up to 70% of those with SLE. Of those with SLE who have APAs, 50–70% may develop this syndrome.
The following may increase the likelihood of thrombosis in patients with APAs:
- Oral contraceptive use
Increased risk in relatives of individuals with APS, however, no specific genetic patterns isolated
- Modification of secondary risk factors for atherosclerosis includes control of HTN, diabetes, hyperlipidemia, and smoking cessation
- Avoidance of oral contraceptives in patients with known APA
APAs may promote thrombosis in any organ by the following hypotheses:
- Increased platelet adhesion and aggregation due to interactions of the antibodies with platelet membrane phospholipids
- Oxidant-mediated injury of vascular endothelium
- Interference with the phospholipid-binding proteins involved in the regulation of coagulation
- Mechanism by which APAs become generated is speculative, but may occur as a result of autoimmunity, as a response to inner membrane antigens exposed on apoptotic cells, or from cross-reactivity to exogenous antigens from infectious organisms
- The presence of APAs alone may not generate thrombosis, but the occurrence of a “second hit” via environmental factors or comorbidities may be required for activation
Commonly Associated Conditions
- SLE (most common rheumatic disease associated with APAs)
- Thrombotic thrombocytopenic purpura (TTP)
- Hemolytic-uremic syndrome (HUS)
- Malignant hypertension
- Acute renal failure
- Nephrotic syndrome
- HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count in association with pregnancy)
- DVT/pulmonary embolus (PE)
- Valvular disease
- Sneddon syndrome (APS variant syndrome in which livedo reticularis is associated with HTN and stroke)
- Malignant neoplasms
- Multiple bacterial, viral, and parasitic infections may result in transient increases in APAs
- Certain medications may be associated with APA production, including phenothiazines, hydralazine, procainamide, and phenytoin, but usually do not result in thrombotic events
- Sapporo criteria, revised 2006 (1):
- The presence of at least 1 of the following clinical criteria :
- Vascular thrombosis:
- ≥1 clinical episodes of arterial, venous, or small vessel thrombosis, occurring within any tissue or organ, confirmed by imaging studies, Doppler studies, or histopathology
- Complications of pregnancy:
- ≥1 unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation OR
- ≥1 premature births of morphologically normal neonates at or before the 34th week of pregnancy due to severe preeclampsia, eclampsia, or placental insufficiency OR
- ≥3 unexplained consecutive spontaneous abortions before the 10th week of pregnancy, unexplained by maternal or paternal chromosomal abnormalities or maternal anatomic or hormonal causes
- Vascular thrombosis:
- AND the presence of at least 1 of the following laboratory criteria on ≥2 occasions at least 12 weeks apart:
- Lupus anticoagulant antibodies detected in the blood
- Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood via a standardized ELISA
- Anti-B2 glycoprotein-I IgG or IgM antibodies in blood at a titer >99th percentile via a standardized ELISA
- Valid lab findings should occur no more than 5 years prior to clinical manifestations
- Personal history of thrombosis (DVT, PE, stroke)
- Obstetric history (especially pregnancy losses)
- Bleeding (from thrombocytopenia)
- Family history of rheumatologic illness
- Vaso-occlusive events can occur in any organ system, so perform thorough review of systems
- DVT of the legs (most common manifestation of APS)
- Skin exam may include findings of livedo reticularis (lacy, erythematous rash in net-like pattern, typically on wrists and knees), purpuric lesions, or ulcerations
- Insufficiency murmur of aortic or mitral valve
- Diverse neurologic symptoms: paresthesias, weakness, tremors, cognitive deficits, stroke/TIA
Diagnostic Tests & Interpretation
- May result in false-positive VDRL/RPR
- The risk of thrombosis may increase with the level of APA detected and the number of APA types present in one individual
- The clinical significance of other autoantibodies, including those directed against prothrombin, annexin V, phosphatidylserine, and phosphatidylinositol, remains unclear
“Lupus anticoagulant” (LA) is a misnomer since it results in an increased risk of thrombus, not an anticoagulant effect. The antibodies cause an increase in the aPTT in vitro, although they are associated with hypercoagulable state in vivo.
Initial lab tests
- Clotting test for lupus anticoagulant
- ELISA test for anticardiolipin antibodies
- ELISA test for anti-β2 glycoprotein-I antibodies
- CBC to determine if thrombocytopenia (platelet count usually 50,000–140,000/µL) or hemolytic anemia are present
Follow-Up & Special Considerations
LAs cannot be detected in patients treated with unfractionated heparin, but may be detected in patients on low molecular weight heparin or warfarin within therapeutic ranges
- Doppler ultrasonography of lower extremities to look for DVT
- If PE suspected, CT angiography or other diagnostic modalities
- Echocardiography may be helpful in some cases with cardiac involvement
- MRI may demonstrate CNS involvement, with high-intensity lesions suggestive of a vasculopathy
- Arteriography in patients with arterial thrombotic events
Biopsy of the affected organ system may be necessary in select cases to distinguish the vasculopathy of this syndrome from a vasculitis
- Usual finding is microangiopathic process with bland thrombosis and with minimal vascular or perivascular inflammation:
- Acute changes: Capillary congestion and noninflammatory fibrin thrombi
- Chronic changes: Ischemic hypoperfusion
- Atrophy and fibrosis
- Conditions that cause thrombotic microangiopathy, such as hemolytic-uremic syndrome or TTP
- Thrombophilic conditions, such as:
- Deficiency of protein C, protein S
- Deficiency of antithrombin III
- Mutation of factor V Leiden
- Prothrombin gene mutation
- Neoplastic and myeloproliferative disorders
- Hyperviscosity syndromes
- Embolic disease secondary to atrial fibrillation, marked LV dysfunction, endocarditis, cholesterol emboli
- Heparin-induced thrombocytopenia
Asymptomatic individuals with APAs and no other underlying illness are unlikely to benefit from low-dose ASA in the absence of other risk factors (2)[A]
- In symptomatic non-pregnant individuals with APS:
- Initial therapy with both unfractionated or LMW heparin and warfarin, then continuing on only warfarin once therapeutic
- Warfarin treatment of moderate intensity (to achieve INR between 2.0–3.0) significantly reduces the rate of recurrent thrombosis after an initial thromboembolic event (2)[A]
- Warfarin treatment may require higher intensity (to achieve INR 3.0–4.0) in patients with an initial arterial thromboembolic event or recurrent venous thromboembolic event despite anticoagulation, although further evidence-based studies are required to establish such a recommendation
- Lifelong treatment is recommended, although this remains heavily debated
- In patients with noncardioembolic stroke and a single APA result without other indications for anticoagulation, moderate intensity warfarin OR ASA (325 mg daily) may be administered (3)[A]
- Consider adding dipyridamole extended-release (200 mg twice daily) to aspirin (30 to 325 mg daily) as the combination has been shown to be superior to aspirin alone (4)[A]
- Clopidogrel (75 mg daily) alone may be used as an equivalent alternative to the combination of aspirin and dipyridamole (5)[A]
- In pregnant individuals with APS:
- For women with no prior history of thrombosis and ≥2 early pregnancy losses or ≥1 late pregnancy loss, consider ASA (81 mg daily) with attempted conception and add low-dose unfractionated heparin 5,000–10,000 units SC b.i.d. or LMWH (enoxaparin 40 mg sc daily) when a viable intrauterine pregnancy is documented (3)[A]
- Treatment should continue until at least the third trimester (rate of fetal loss may exceed 90% in untreated patients, while therapies such as aspirin and heparin can reduce the rate to 25%) and consider through delivery and for a few weeks postpartum (6)[B]
- For the catastrophic form, recommendation for aggressive therapy with steroids, anticoagulation, and plasma exchange (+/- IVIG)
Patients with thrombosis may require thrombectomy or an IVC filter for those with lower extremity DVT for whom anticoagulation is contraindicated
Patients with APS-related events should be considered for inpatient treatment in the following situations:
- Massive DVT, symptomatic PE, high risk of bleeding on anticoagulation therapy, comorbid conditions
Warfarin therapy is lifelong; patients need monitoring to maintain INR of 2.0–3.0. Pregnant patients on prolonged heparin (esp UFH) should be closely monitored for heparin-induced thrombocytopenia (HIT).
- Those on anticoagulation should maintain a consistent diet of foods containing vitamin K and avoid foods with anticoagulant properties
- Healthy diet to prevent obesity and dyslipidemia to decrease risk of atherothrombosis
Avoid use of oral hormonal contraceptives.
- Pulmonary HTN, neurologic involvement, myocardial ischemia, nephropathy, gangrene of extremities, and catastrophic APS are associated with a worse prognosis.
- Most patients experience recurrences months or years after the initial event.
- Mortality rate is ∼50% in patients presenting with the catastrophic type, and death is due to multiorgan system failure.
Discontinuation of warfarin results in increased risk of thrombosis (even death), particularly in the 1st 6 months after stopping treatment.
1. 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.
2. Erkan D, Lockshin MD. New approaches for managing antiphospholipid syndrome. Nat Clin Pract Rheumatol. 2009;5:160–70.
3. Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA. 2006;295:1050–7.
4. ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367:1665–73.
5. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238–51.
6. Ziakas PD, Pavlou M, Voulgarelis M, et al. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010;115:1256–62.
Derksen, RHWM and PG de Groot. Towards evidence-based treatment of thrombotic antiphospholipid syndrome. Lupus. 2010;19:470–474.
Giannakopoulos B, Krilis SA, et al. How I treat the antiphospholipid syndrome. Blood. 2009;114:2020–30.
- 289.81 Primary hypercoagulable state
- 289.82 Secondary hypercoagulable state
26843008 Antiphospholipid syndrome (disorder)
- APS can be of either the primary form or the secondary form associated with another underlying illness
- The diagnosis of APS requires both clinical and laboratory criteria
- Thrombosis is the most common clinical manifestation of APS; most common site of venous thrombosis are DVTS and the most common site of arterial thrombosis is the brain
- Treatment is usually with lifelong moderate-intensity warfarin, but may vary, depending on the underlying condition
- Patients with APS and recurrent fetal loss should be considered for combination heparin and ASA treatment during pregnancy