Antiphospholipid syndrome


Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.
The diagnostic criteria require one clinical event and two positive blood test results spaced at least three months apart that detect lupus anticoagulant, anti-apolipoprotein antibodies, or anti-cardiolipin antibodies.
Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such as systemic lupus erythematosus. In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed "catastrophic antiphospholipid syndrome" and is associated with a high risk of death.
Antiphospholipid syndrome often requires treatment with anticoagulant medication such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin is not used during pregnancy because it can cross the placenta, unlike heparin, and is teratogenic.

Signs and symptoms

The presence of antiphospholipid antibodies in the absence of blood clots or pregnancy-related complications does not indicate APS.
Antiphospholipid syndrome can cause arterial or venous blood clots, in any organ system, or pregnancy-related complications. In APS patients, the most common venous event is deep vein thrombosis of the lower extremities, and the most common arterial event is stroke. In pregnant women affected by APS, there is an increased risk of recurrent miscarriage, intrauterine growth restriction, and preterm birth. A frequent cause of such complications is placental infarctions.
In some cases, APS seems to be the leading cause of mental and/or development retardation in the newborn, due to an aPL-induced inhibition of trophoblast differentiation. The antiphospholipid syndrome responsible for most of the miscarriages in later trimesters seen in concomitant systemic lupus erythematosus and pregnancy.
Other common findings, although not part of the APS classification criteria, are low platelet count, heart valve disease, and livedo reticularis. There are also associations between antiphospholipid antibodies and headaches, migraines, and oscillopsia. Some studies have shown the presence of antiphospholipid antibodies in the blood and spinal fluid of patients with psychological symptoms.

Risk factors

Risk factors for developing antiphospholipid syndrome include:
There is an additional elevated risk of adrenal gland bleeds leading to Waterhouse–Friderichsen syndrome. This will require adrenal steroid replacement treatment for life.

Pathogenesis

Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies" 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 are associated with thrombosis and vascular disease. The syndrome can be divided into primary and secondary forms.
Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH, which in turn inhibits Protein C, a glycoprotein with regulatory function upon the common pathway of coagulation.
Lupus anticoagulant antibodies bind to prothrombin, thus increasing its cleavage to thrombin, its active form.
In APS there are also antibodies binding to Protein S, which is a co-factor of protein C. Thus, anti-protein S antibodies decrease protein C efficiency.
Annexin A5 forms a shield around negatively charged phospholipid molecules, thus reducing their availability for coagulation. Thus, anti-annexin A5 antibodies increase phospholipid-dependent coagulation steps.
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.
Patients with both Lupus anticoagulant antibodies and moderate/high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone.
The increased risks of recurrent miscarriage, intrauterine growth restriction and preterm birth by antiphospholipid antibodies, as supported by in vitro studies, include decreased trophoblast viability, syncytialization and invasion, deranged production of hormones and signalling molecules by trophoblasts, as well as activation of coagulation and complement pathways.

Diagnosis

Antiphospholipid syndrome is diagnosed using either liquid-phase coagulation assays to detect lupus anticoagulant or solid phase ELISA assays to detect anti-cardiolipin antibodies or anti-apolipoprotein antibodies.
Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some patients with APS. Presence of genetic thrombophilia may determine the need for anticoagulation therapy. Thus genetic thrombophilia screening can consist of:
The use of testing for antibodies specific for individual targets of aPL such as β2 glycoprotein 1 and phosphatidylserine is currently under debate, as testing for anticardiolipin antibodies currently appears to be sensitive and specific for diagnosis of APS, even though cardiolipin is not a known target for antiphospholipid antibodies in vivo.

Lupus anticoagulant

This is tested for by using a minimum of two coagulation tests that are phospholipid-sensitive, due to the heterogeneous nature of the lupus anticoagulant antibodies. The patient on initial screening will typically have been found to have a prolonged partial thromboplastin time that does not correct in an 80:20 mixture with normal human plasma. The PTT, dilute Russell's viper venom time, kaolin clotting time, dilute thromboplastin time, silica clotting time and prothrombin time 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 being diagnosed as positive.
Distinguishing a lupus antibody from a specific coagulation factor inhibitor 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 factors. Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iu/dl whereas a specific factor antibody will rarely give a result higher than 10 iu/dl.
Monitoring IV anticoagulant therapy by the PTT ratio 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

can be detected using an enzyme-linked immunosorbent assay immunological test, which screens for the presence of β2glycoprotein 1 dependent anticardiolipin antibodies.A low platelet count and positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.

Criteria

Classification with APS requires evidence of both one or more specific, documented clinical events and the confirmed presence of a repeated aPL. The Sapporo APS classification criteria were replaced by the Sydney criteria in 2006. Based on the most recent criteria, classification with APS requires one clinical and one laboratory manifestation:
There are 3 distinct APS disease entities: primary, secondary, and catastrophic.
According to a 2006 consensus statement, it is advisable to classify APS into one of the following categories for research purposes:
The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement, Definite CAPS diagnosis requires:
VDRL, which detects antibodies against syphilis, may have a false positive result in aPL-positive patients, although the more specific test for syphilis, FTA-Abs, that use recombinant antigens will not have a false-positive result.

Treatment

Often, this disease is treated by giving aspirin to inhibit platelet activation, and/or warfarin as an anticoagulant. The goal of the prophylactic treatment with warfarin is to maintain the patient's INR between 2.0 and 3.0. It is not usually done in patients who have had no thrombotic symptoms.
Anticoagulation appears to prevent miscarriage in pregnant women. In pregnancy, low molecular weight heparin and low-dose aspirin are used instead of warfarin because of 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. In refractory cases plasmapheresis may be used.

Prognosis

The long-term prognosis for APS is determined mainly by recurrent thrombosis, which may occur in up to 29% of patients, sometimes despite antithrombotic therapy.

History

Antiphospholipid syndrome was described in full in the 1980s, by E. Nigel Harris and Aziz Gharavi. They published the first papers in 1983. The syndrome was referred to as "Hughes syndrome" among colleagues after the rheumatologist Graham R.V. Hughes, who brought together the team.

Research

APS ACTION, is the first-ever international research network that has been created to design and conduct large-scale, multicenter clinical trials in persistently antiphospholipid antibody positive patients. The network consists of a multidisciplinary group of physicians and investigators from around the world who are interested in antiphospholipid syndrome research. The primary mission of APS ACTION is to prevent, treat, and cure antiphospholipid antibody associated clinical manifestations through high quality, multicenter, and multidisciplinary clinical research.