Antiphospholipid Syndrome (Antiphospholipid Antibody Syndrome, APS, APLS)

Article Author:
Jean Bustamante
Article Editor:
Steve Bhimji
Updated:
3/5/2018 5:40:10 PM
PubMed Link:
Antiphospholipid Syndrome (Antiphospholipid Antibody Syndrome, APS, APLS)

Introduction

Antiphospholipid antibodies are autoantibodies directed against phospholipid-binding proteins. Among these group of antibodies, lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) prolong phospholipid-dependent coagulation assays. Antiphospholipid syndrome (APLS) comprises the identification of antiphospholipid antibodies in the setting of arterial and venous thrombus and /or pregnancy loss. The most common sites of venous and arterial thrombosis are the lower limbs and the cerebral arterial circulation respectively, but any organ can be affected.

Etiology

APLS can be primary when no evidence of autoimmune disease is found, or secondary to autoimmune processes like systemic lupus erythematosus (SLE) in 40% of the cases. Genetic risk factors heighten the risk of antiphospholipid antibody (aPL)-associated thrombosis, such as coagulation factor mutations.

Epidemiology

One percent to 5% of healthy young patients has anticardiolipin antibodies and lupus anticoagulant antibodies. The prevalence of other antibodies increases with age and chronic diseases. Forty percent of patients with APLS have SLE. The prevalence of anticardiolipin antibodies in SLE is from 12% to 30%, and lupus anticoagulant is found in 15% to 34%. In 50% to 70% of the patients with SLE and antiphospholipid antibodies, their conditions progress to APLS.

Pathophysiology

Several thrombotic mechanisms exist in antiphospholipid syndrome. When oxidative stress is increased, Beta-2 glycoprotein I undergo posttranslational redox modifications and become immunogenic by forming disulfide bonds between cysteine 288 and cysteine 326 at the domain V and between cysteine 32 and cysteine 60. According to preclinical models, the oxidation of beta-2 glycoprotein I critical antiphospholipid syndrome unmasks B-cell epitope, leading to the formation of autoantibodies. 

A “two-hit” thrombosis model is proposed to explain thrombi formation in patients with antiphospholipid syndrome. A “first hit” injury to the endothelium needs to happen to have a “second hit” that potentiates the thrombus formation. Beta-2 glycoprotein I do not bind unstimulated endothelium in vivo. One of the postulates, when non-identifiable causes of endothelial injury are obvious, is a redox balance disturbance in the vascular beds that may prime the endothelium. Patients with antiphospholipid syndrome have lower levels of the reduced, protective, and non-immunogenic beta-2 glycoprotein I. Annexin A2 is an endothelial cell surface receptor that is up-regulated with oxidative stress. Smoking can lead to endothelial injury and increase the pro-thrombotic susceptibilities in patients with positivity for lupus anticoagulant.

Nitrite plasma levels are decreased in patients with APLS when compared with healthy controls. The decreased expression and activity of endothelial nitric oxide synthase results in the generation of peroxynitrite and superoxide. Preclinical models have shown how the domain I of beta-2 glycoprotein I autoantibodies antagonize the activity of endothelial nitric oxide synthase with resultant monocyte adhesion and inhibition of nitric oxide-dependent arterial relaxation.

Tissue factor expression is upregulated by antiphospholipid antibodies through some intracellular signaling pathways after binding the anti-beta 2 glycoprotein I autoantibodies to the monocytes' surface and endothelial cells' multiprotein complexes. Autoantibodies from patients with APLS disrupt the mitochondrial function of neutrophils and monocytes and increase the production of reactive species of oxygen, resulting in the subsequent expression of tissue factor.

Higher levels of factor XI have also been described in APLS patients.

Beta-2 glycoprotein I interact with von Willebrand factor receptor glycoprotein Ib-alpha and ApoE receptor 2, enabling anti-beta 2 glycoprotein I autoantibodies to crosslink these receptors and activate platelets.

History and Physical

The diagnosis of antiphospholipid syndrome includes clinical and laboratory criteria. Obstetric medical history is an important element of the anamnesis if APLS is suspected, and detail must be obtained. A history of arterial and venous thrombosis also are typical manifestations of APLS, and if repetitive, must be investigated. There are no pathognomonic physical exam findings to diagnose APLS, however certain skin changes like livedo reticularis and livedo racemose can be seen. Gangrene, ischemic limb changes, and signs of deep venous thrombosis can help diagnose the disease as well. Neurological signs and symptoms can guide clinicians to suspect stroke-like manifestations secondary to a prothrombotic state.

Aortic and mitral valve abnormalities also have been frequent findings in APLS if rheumatic fever is excluded. Stenosis and/or regurgitation can be present and must be documented. The described valvular abnormalities are valves that are thickened more than 3 mm, thickening of the proximal or middle portion of the leaflets, and the presence of irregular nodules on the atrial face of the edge of the mitral valve and/or the vascular face of the aortic valve.

APLS associated nephropathy has also been described when coexistent with thrombotic microangiopathy of the glomerular capillaries and both arterioles. Other histopathological findings are fibrous intimal hyperplasia with organized thrombi with or without recanalization, focal cortical atrophy, arterial and arteriolar fibrous or fibrocellular occlusions, eosinophilic casts formation contained inside atrophic tubules. Certain entities such as thrombotic thrombocytopenic purpura, vasculitis hemolytic uremic syndrome and malignant hypertension must be excluded to deem these changes associated to APLS.

Evaluation

The initial diagnostic criteria called Sapporo classification was published in 1999, but in 2006 a revised version for the definitive diagnosis of APLS was published in Sydney, Australia. This classification was called the updated Sapporo APS Classification or Sydney Classification. To diagnose APLS, at least one laboratory and one clinical criterion should be met.

Clinical Criteria

One of the following clinical findings should be confirmed to diagnose antiphospholipid antibody syndrome.

Vascular Thrombosis

  • On or more episodes of arterial, venous, or small-vessel thrombosis of any organ. Vascular events must be confirmed with appropriate imaging or histologically.
  • When tissue diagnosis is made, no significant inflammation should be present in the vessel wall.

Pregnancy Morbidity 

  • One or more fetal deaths of morphologically normal fetuses at 10 weeks of gestation or beyond.
  • One or more premature births of morphologically normal neonates before the 34th week of gestation. Prematurity must be secondary to eclampsia, severe preeclampsia, or placental insufficiency.
  • Three or more consecutive spontaneous abortions before the 10th week of gestation after ruling out any maternal anatomic or hormonal abnormalities and parental chromosomal causes.

Laboratory Criteria

  • One of the following laboratory findings should be confirmed to diagnose antiphospholipid antibody syndrome.
  • Detection of lupus anticoagulant in plasma on two or more occasions, 12 or more weeks apart.
  • Detection of IgG or IgM subtype of anticardiolipin antibodies in serum or plasma measured by standard ELISA on two or more occasions, twelve or more weeks apart.
  • Detection of Anti-b2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma measured by standard ELISA, on two or more occasions, 12 or more weeks apart.

If less than 12 weeks or more than 5 years separate clinical manifestations and positive laboratory tests, avoid an antiphospholipid syndrome diagnosis.

Treatment / Management

Management

The treatment of patients with antiphospholipid antibody syndrome depends on their risk of thrombosis and obstetric morbidity.

  • Patients who are not pregnant and have no history of thrombosis or prior pregnancy loss do not require treatment.
  • Patients who are pregnant and have prior pregnancy loss satisfying criteria for APLS but do not have a history of thrombosis are treated with prophylactic unfractionated heparin or low molecular weight heparin at prophylactic dosing with aspirin (81 mg/day).
  • Patients who have venous thrombosis and a prior history of thrombosis are treated with warfarin with INR goal of 2 to 3 and proper breaching with heparin or low molecular weight heparin.

Non-Cerebral

  • Patients who are non-cardiac require long-term warfarin therapy with an INR goal of 2 to 3.
  • Patients with cardiac conditions should be treated with aspirin plus clopidogrel +/- stents according to cardiologist evaluation and acute coronary syndrome guidelines.

Cerebral

  • Patients who have had a cardioembolic event are treated with warfarin with INR goal of 2-3.
  • Patients who have not had a cardioembolic event are treated with warfarin with INR goal of 2 to 3, clopidogrel, or aspirin +/- dipyridamole.
  • Recurrent arterial or venous thrombosis despite proper warfarin anticoagulation will require high dose warfarin plus aspirin and/or IVC filter.

The addition of aspirin or an increase in warfarin intensity anticoagulation or a switch to high dose unfractionated heparin or therapeutic doses of low molecular weight heparin may be needed, especially if INR is unstable.

  • To date, there is no indication for the use of novel oral anticoagulants.
  • Cardiovascular risk factors should be addressed in all patients with APLS.
  • In high-risk situations such as surgery, prolonged immobilization, and puerperium, warrant prophylaxis with low molecular weight heparin.
  • Patients with APLS and SLE benefit from low-dose aspirin therapy which reduces the risk of thrombosis.

Duration of treatment

  • Indefinite therapy is required for patients with definite APLS and thrombosis.
  • Three to 6 months is the usual treatment period for patients with a first-time venous thrombosis and non-diagnostic APLS profile.

Prognosis

Some European studies have observed a 90% to 94% survival over 10 years. Overall the prognosis of both primary and secondary APLS is similar, but in the latter, the morbidity may be increased as a result of any underlying rheumatic or autoimmune disorder.

Finally, in lupus patients with antiphospholipid antibodies, there is a higher risk of neuropsychiatric disorders and are a major predictor of irreversible organ injury.

Pearls and Other Issues

  • In a patient with systemic lupus erythematosus and APLS, it is recommended that one use hydroxychloroquine as it has been shown to have intrinsic antithrombotic properties.
  • Patients who have hyperlipidemia should be managed with statins.
  • Risk factors like smoking, oral contraceptives, hyperlipidemia or hypertension have to be eliminated.
  • All patients undergoing elective surgery need anticoagulant prophylaxis.
  • Note that during pregnancy, warfarin is contraindicated, but breastfeeding women may be prescribed warfarin or heparin.
  • The use of corticosteroids has not been proven to be effective in the management of patients with primary APLS and may, in fact, increase maternal morbidity and increase rates of premature birth. Despite all the current treatments, complications still occur in at least thirst of APLS pregnancies.
  • In patients with recurrent DVT, one should consider deployment of an inferior vena cava filter.