Antiphospholipid syndrome

Overview
Antiphospholipid syndrome (APS or APLS) or antiphospholipid antibody syndrome is a disorder of coagulation, which causes blood clots (thrombosis) in both arteries and veins, as well as pregnancy-related complications such as miscarriage, preterm delivery, or severe preeclampsia. The syndrome occurs due to the autoimmune production of antibodies against phospholipid (aPL), a cell membrane substance. In particular, the disease is characterised by antibodies against cardiolipin (anti-cardiolipin antibodies) and β2 glycoprotein I.

The term "primary antiphospholipid syndrome" is used when APS occurs in the absence of any other related disease. APS is commonly seen in conjunction with other autoimmune diseases; the term "secondary antiphospholipid syndrome" is used when APS coexists with other diseases such as systemic lupus erythematosus (SLE). In rare cases, APS leads to rapid organ failure due to generalised thrombosis and a high risk of death; this is termed "catastrophic antiphospholipid syndrome".

Antiphospholipid syndrome is sometimes referred to as Hughes syndrome after the rheumatologist Dr. Graham R.V. Hughes (St. Thomas' Hospital, London, United Kingdom) who worked at the Louise Coote Lupus Unit at St Thomas' Hospital in London.

Pathogenesis
Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies" (Anticardiolipin antibodies and Lupus anticoagulant) react against proteins that bind to anionic phospholipids on plasma membranes. Like many autoimmune diseases, it is more common in women than in men. The exact cause is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies (those that arise as a result of the autoimmune process) are associated with thrombosis and vascular disease. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms. The main target of anti-cardiolipin antibodies is apolipoprotein H (commonly referred to as β2Glycoprotein 1) and the main target of Lupus anticoagulant is prothrombin. Other targets of anti-phospholipid antibodies are protein S, protein C and annexin A5.

The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β2glycoprotein 1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to high titres (>40 GPLU or MPLU). Patients with both Lupus anticoagulant antibodies and moderate/high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone.

Usual Antiphospholipid Antibody Syndrome

 * Patients with antiphopholipid antibody syndrome and a history of clot have a recurrence rate as high as 0.2 events per year.
 * There is an association between the antiphospholipid syndrome and systemic rheumatic disease, though overall more patients do not have systemic rheumatic disease than do. The most common association is with SLE (termed secondary anti-phospholipid antibody syndrome, and occurs in about 10-40% of SLE patients).  There is also association with cancer, leukemia, idiopathic/immune thrombocytopenic purpura (ITP), human immunodeficiency virus (HIV), rheumatoid arthritis (RA), Sjogren’s, Behcet’s, and some drugs (chlorpromazine, dilantin, hydralazine, quinidine, procainamide, interferon, pyrimethamine, etc).
 * The target of both antibodies may be phospholipid bound to a cofactor.
 * Beta2-glycoprotein-I is likely the cofactor in patients with anti-cardiolipin antibodies, and may also be important in patients with a lupus anticoagulant.
 * Prothrombin is an important cofactor in patients with lupus anticoagulant.
 * Beta2-glycoprotein-I usually binds negatively charged phospholipids and inhibits contact activation of the clotting cascade and platelet activation. In this syndrome, anitphospholipid antibodies may facilitate thrombosis by inhibiting the anticoagulant effects of beta2-glycoprotein-I.  In the future, a test for antibodies to beta2-glycoprotein-I may be used clinically.
 * The vascular disease of the antiphospholipid antibody syndrome is not due to vasculitis. The characteristic histopathologic finding is thrombotic microangiopathy.
 * Anticardiolipin antibody
 * The antibody is directed against beta2-glycoprotein-I and cardiolipin, a phospholipid component of cell membranes, also used as an antigen in the assay for syphilis (why syphilis elicits an antibody response to cardiolipin is not clear).
 * Patients with anticardiolipin antibody are more likely to have arterial clots than those with lupus anticoagulant. These patients are also at increased risk for early coronary artery bypass graft (CABG) graft occlusion, precocious coronary artery disease (CAD), and valvular heart disease.
 * Lupus Anticoagulant
 * Lupus anticoagulant is a misnomer: it’s actually a pro-coagulant in vivo, and is often seen in patients without lupus. It usually (not always) elevates the lab reading of the partial thromboplastin time (PTT).
 * Lupus anticoagulant is also directed against the phospholipid membrane, and requires the cofactor prothrombin.

Catastrophic Antiphospholipid Antibody Syndrome

 * A subset of patients with antiphospholipid antibody syndrome develop a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.
 * Though specific diagnostic criteria have not been established, some have suggested that criteria include documented thrombosis in 3 or more organs.
 * Commonly involved organs include the central nervous system (CNS), kidney and distal extremities with acral necrosis. Hypertension is also commonly present, and may be malignant.
 * CNS manifestations may be quite heterogeneous, including confusion, focal signs, and/or seizures.
 * Acute Respiratory Distress Syndrome (ARDS) may be present
 * Signficant cardiac necrosis has been described
 * Adrenal hemorrhage has been described
 * Liver and gastrointestinal tract infarctions have been described
 * Oliguria and rapidly deteriorating renal function may be observed.
 * Histopathology shows evidence of multiple small and/or large vessel occlusions.
 * Frequently no specific etiology is identifiable, and patients present quite suddenly without any obvious precipiting factors.

Diagnosis
Antiphospholipid syndrome is tested for in the laboratory using both liquid phase coagulation assays (lupus anticoagulant) and solid phase ELISA assays (anti-cardiolipin antibodies).

Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Thus genetic thrombophilia screening can consist of:
 * Further studies for Factor V Leiden variant and the prothrombin mutation, Factor VIII levels, MTHFR mutation.
 * Levels of protein C, free and total protein S, Factor VIII, antithrombin, plasminogen, tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1)

The testing of antibodies to the possible individual targets of aPL such as β2 Glycoprotein 1 and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin is not considered an in vivo target for antiphospholipid antibodies.

Signs and symptoms
The presence of antiphospholipid antibodies (aPL) in the absence of blood clots or pregnancy-related complications does not indicate APS (see below for the diagnosis of APS).

Antiphosphilipid syndrome can cause (arterial/venous) blood clots (in any organ system) or pregnancy-related complications (especially miscarriage in the second or third trimester). In APS patients, the most common venous event is deep vein thrombosis of the lower extremities (blood clot of the deep veins of the legs) and the most common arterial event is stroke.

Other common findings, although not part of the APS Classification Criteria, are thrombocytopenia (low platelet count), heart valve disease, and livedo reticularis (a skin condition). Some patients report headaches and migraines. Antiphospholipid syndrome can rarely mimic multiple sclerosis with an estimated 10% of patients misdiagnosed.

Very few patients with primary APS go on to develop SLE.

Usual Antiphospholipid Antibody Syndrome

 * Associated sign and symptoms may include:
 * Major Features:
 * Venous thrombosis
 * Arterial thrombosis
 * Thrombocytopenia
 * Recurrent fetal loss
 * Minor Features:
 * Migraine
 * Livedo reticularis
 * Endocardial valvular vegetations
 * Transverse myelopathy
 * Chorea
 * Leg ulcers
 * Other signs and symptoms include:
 * Myocardial Infarction
 * Stroke
 * Pulmonary embolism
 * Amaurosis fugax
 * Retinal infarct
 * Other visceral infarct
 * Peripheral or deep venous occlusion
 * Raynaud’s syndrome
 * Pulmonary hypertension
 * Avascular necrosis
 * Recurrent fetal loss (especially in the 2nd or 3rd trimester)
 * Pre-eclampsia
 * Adrenal insufficiency
 * Coomb’s positive hemolysis
 * Sudden multi-systemic occlusion (the Catastropic antiphospholipid-antibody syndrome).

Lupus anticoagulant
This is tested for by using a minimum of two coagulation tests that are phospholipid sensitive this is due to the heterogeneous nature of the lupus anticoagulant antibodies. The patient on initial screening will typically have been found to have a prolonged APTT that does not correct in an 80:20 mixture with normal human plasma (50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80:20 mix), dilute Russell's viper venom time (DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time (TDT/DTT) or Prothrombin time (using a lupus sensitive thromboplastin) are the principal tests used for the detection of lupus anticoagulant. These tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positivity to allow a diagnosis of antiphospholipid syndrome. This is to prevent patients with transient positive tests (due to infection etc) being diagnosed as positive.

Distinguishing a lupus antibody from a specific coagulation factor inhibitor (eg: Factor VIII). This is normally achieved by differentiating the effects of a lupus anticoagulant on factor assays from the effects of a specific coagulation factor antibody. The lupus anticoagulant will inhibit all the contact activation pathway antibodies (Factor VIII, Factor IX, Factor XI and Factor XII). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iudl (35%) where as a specific factor antibody will rarely give a result higher than 10iudl (10%). Monitoring IV anticoagulant therapy by the APTR is compromised due to the effects of the lupus anticoagulant and in these situations is generally best performed using a chromogenic assay based on the inhibition of Factor Xa by Antithrombin in the presence of Heparin.

Anticardiolipin antibodies
These can be detected using an enzyme-linked immunosorbent assay (ELISA) immunological test, which screens for the presence of β2glycoprotein 1 dependent anticardiolipin antibodies (ACA).

A Low platelet count and positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.

Diagnostic Criteria
The diagnosis of APS is made in case of a clinical event (vascular thrombosis or pregnancy event) and repeated positive tests of aPL performed 12 weeks apart (repeat aPL testing is necessary due to the naturally occurring presence of transient low levels of aPL following infections).

The Updated Sapporo APS Classification Criteria are commonly used for APS diagnosis. Based on these criteria, APS diagnosis requires:
 * a) Vascular Thrombosis (blood clots) in any organ or tissue or Pregnancy Event (one or more miscarriages after 10th week of gestation, three or more miscarriages before 10th week of gestation, or one or more premature births before 34th week of gestation due to eclampsia) and
 * b) Persistenly (12 weeks apart) Positive aPL (lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies, or moderate-to-high titer β2-glycoprotein-I antibodies).

The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement, Definite CAPS diagnosis requires:
 * a) Vascular Thrombosis in three or more organs or tissues and
 * b) Development of manifestations simultaneously or in less than a week 'and
 * c) Evidence of small vessel thrombosis in at least one organ or tissue and
 * d) Laboratory confirmation of the presence of aPL.

Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative.

Differential Diagnosis

 * Hemolytic uremic syndrome-Thrombotic thrombocytopenic purpura (HUS-TTP)
 * Disseminated Intravascular Coagulation (DIC)
 * Vasculitis
 * Embolic disease
 * Cryoglobulinemia
 * Calciphylaxis

Treatment
The cornerstone of therapy for symptomatic antiphospholipid syndrome hinges on platelet inhibition with or without anticoagulation. Platelet inhibition is often achieved with aspirin, while warfarin and heparin are the mainstays of anticoagulation. Generally there is no indication for primary prophylaxis. Immunosuppression, the use of intravenous immunoglobulin, and plasmapheresis have also been used with modest success.

Anticoagulation
When anticoagulation with warfarin is pursued, some authors recommend a goal INR of 3.0-4.0. However, the current standard of care targets a therapeutic INR of 2.0-3.0 following initial venous thromboembolism, and an INR >3.0 for an arterial event or venous thrombosis refractory to anticoagulation. Khamashta et al in a study of 147 patients with usual antiphopholipid antibody syndrome showed a low rate of recurrent thrombosis in patients with INR >3, with a risk of 7.1% bleeding complications per patient year (a third of which were serious).

Anticoagulation in pregnancy
During pregnancy, low molecular weight heparin and low-dose aspirin are used to avoid warfarin's teratogenicity. Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin treatment after missing a menstrual cycle.

Platelet inhibition
Aspirin is frequently added to a regimen of chronic anticoagulation, particularly when patients experience recurrent thrombosis despite therapeutic aticoagulation. However data demonstrating additive benefit are lacking.

Immunosuppression
It is not clear that immunosuppression is beneficial, particularly in patients who do not have an underlying autoimmune process. Nevertheless, immunosuppression is often tried in patients who have failed usual anticoagulation. Steroids, for example prednisone 1 mg/kg (or equivalent), has been used with moderate success. Pulse solumedrol IV 1 g/d for 3 days is an alternative regimen. Cyclophosphamide, either oral or pulse IV, has demonstrated modest utility.

Other, more desperate interventions include intravenous immunoglobulin and plasmapheresis. The latter has been shown via case reports to have efficacy in patients who have failed other interventions.

Treatment of catastrophic disease
Optimal treatment has not been clearly defined in this condition. We are limited to data from small case report studies. These patients often display a fulminant course with rapid multiorgan system failure, so multiple interventions are often desperately tried in hopes that the patient might respond to something and survive.