Antiphospholipid syndrome is an autoimmune disorder characterized by either a history of vascular thrombosis (one or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ) or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The systemic features of the syndrome are characterized by large variability depending on the affected organ(s). Among them, neurological and behavioural disturbances, dermatological features as livedo reticularis and renal, ocular, liver or valvular heart manifestations have been reported in antiphospholipid syndrome patients. However, studies on the frequency and clinical presentation of the ocular manifestations as the prevailing (first) sign of antiphospholipid syndrome in patients suffering from “unexplained” ocular disease are missing.
There is unexplained ocular features from the anterior or posterior segment and unexplained neuro-ophthalmologic symptoms. Sign and symptom bilateral retinal occlusive disease, unilateral nonarteritic anterior ischemic optic neuropathy with macular oedema. Moderate to high levels of antiphospholipid antibodies were detected in all of them at baseline as well as 6 to 12 weeks after initial testing confirming the presence of antiphospholipid antibodies. Anticoagulant treatment with acenocoumarol was instituted resulting in stabilization and/or improvement of ocular signs in all of them.
Due to the important diagnostic and therapeutic implications of antiphospholipid syndrome, the possibility of ocular features as the first clinical manifestation of antiphospholipid syndrome should be kept in mind of the physicians particularly in patients with no evident risk factors for ocular disease. Anticoagulant treatment and close follow-up seem to be essential for vision salvation and stabilization
Antiphospholipid syndrome or
antiphospholipid antibody syndrome (APS or APLS or), often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids that provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, 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 however also occurs in the context of other autoimmune diseases, such as systemic lupus erythematosus (SLE), in which case the term “secondary antiphospholipid syndrome” is used. In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed “catastrophic antiphospholipid syndrome” (CAPS) and is associated with a high risk of death.
Antiphospholipid syndrome is diagnosed with blood tests. It often requires treatment with anticoagulant medication such as warfarin or heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy.
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).
Antiphospholipid syndrome can cause (arterial/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 (blood clot of the deep veins of the legs) and the most common arterial event is stroke. In pregnant women affected by APS, miscarriage can occur prior to 20 week of gestation, while pre-eclampsia is reported to occur after that time. Placental infarctions, early deliveries and stillbirth are also reported in women with APS. 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 thrombocytopenia (low platelet count), heart valve disease, and livedo reticularis (a skin condition). Some patients report headaches, migraines, and oscillopsia.
Very few patients with primary APS go on to develop SLE.
Risk factors for developing antiphospholipid syndrome include:
genetic marker HLA-DR7
SLE or other autoimmune disorders
Genetic markers: HLA-B8, HLA-DR2, HLA-DR3
Race: Blacks, Hispanics, Asians, and Native Americans
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.
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 (by degradating activated factor V).
LAC 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, which 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 (>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.
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. Presence of genetic thrombophilia may determine the need for anticoagulation therapy. 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.
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 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 (e.g.: 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 factors (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 iu/dl (35%) whereas a specific factor antibody will rarely give a result higher than 10 iu/dl (10%). Monitoring IV anticoagulant therapy by the APTT 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.
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.
Classification with APS requires evidence of both one or more specific, documented clinical events (either a vascular thrombosis and/or adverse obstetric event) and the confirmed presence of a repeated aPL. The Sapporo APS classification criteria (1998, published in 1999) were replaced by the Sydney criteria in 2006. Based on the most recent criteria, classification with APS requires one clinical and one laboratory manifestation:
A documented episode of arterial, venous, or small vessel thrombosis—other than superficial venous thrombosis in any tissue or organ by objective validated criteria with no significant evidence of inflammation in the vessel wall and/or
1 or more unexplained deaths of a morphologically normal fetus (documented by ultrasound or direct examination of the fetus) at or beyond the 10th week of gestation and/or 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded or at least 1 premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia or severe pre-eclampsia according to standard definitions, or recognized features of placental insufficiency plus
Anti-cardiolipin IgG and/or IgM measured by standardized, non-cofactor dependent ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (i.e., > 40 GPL or MPL, or > the 99th percentile) and/or
Anti-β2 glycoprotein I IgG and/or IgM measured by standardized ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (> the 99th percentile) and/or
Lupus anticoagulant detected on 2 occasions not less than 12 weeks apart according to the guidelines of the International Society of Thrombosis and Hemostasis.
There are 3 distinct APS disease entities: primary (the absence of any comorbidity), secondary (when there is a pre-existing autoimmune condition, most frequently systemic lupus erythematosus, SLE), and catastrophic (when there is simultaneous multi-organ failure with small vessel occlusion).
According to a 2006 consensus statement, it is advisable to classify APS into one of the following categories for research purposes:
I: more than one laboratory criterion present in any combination;
IIa: lupus anticoagulant present alone
IIb: anti-cardiolipin IgG and/or IgM present alone in medium or high titers
IIc: anti-β2 glycoprotein I IgG and/or IgM present alone in a titer greater than 99th percentile
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.
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