Antiphospholipid syndrome

The antiphospholipid syndrome, named APS is one of the most common autoimmune diseases. At her ill two to five percent of the population, primarily women ( Gynäkotropie ). Other names for the disease are Stovin Hughes syndrome, Hughes Syndrome, cardiolipin antibody syndrome, antiphospholipid antibody syndrome, APA 's syndrome and lupus anticoagulant.

Typical clinical symptoms that may indicate a GSP, are thrombosis, recurrent miscarriages and intrauterine death. In addition, there are many other non-specific symptoms that can complicate the diagnosis of APS. Laboratory tests, various antiphospholipid antibodies detected, but these are not specific, but are also common in other rheumatic diseases also in healthy subjects.

Basics

In antiphospholipid syndrome, there are specific antibodies against various phospholipids ( cardiolipin, prothrombin, etc.) and phospholipidbindende proteins such as beta-2- glycoprotein I. This so-called antiphospholipid antibodies, it is an increased coagulability ( hypercoagulability ) of the blood and consequently to increased thrombosis.

We distinguish the primary APS ( PAPS ), which occurs independently of other diseases, from secondary APS ( SAPS). The secondary APS, which is by far the more common form of the two, is found particularly in the context of autoimmune diseases. The most common underlying disease systemic lupus erythematosus is (SLE). Very much less frequently occurs secondary to APS in the context of other diseases such as malignant tumors, HIV, infections or medication side effect. From a clinical perspective, the division into PAPS and SAPS today is no longer meaningful.

Was first described the syndrome in 1959 by JP Hughes and Stovin PGI. In 1983 the antiphospholipid syndrome was seen by the British rheumatologist Robert Graham Vivian Hughes as an independent disease, independent of other autoimmune diseases occur when autoantibodies against phospholipids.

But this phospholipid antibodies can also be detected in the secondary connection with autoimmune diseases such as lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome. As can be detected only in about 1 to 5% phospholipid antibodies in healthy individuals, they come in 16 to 35 % before the lupus patients.

In 8-14 % of patients in whom a venous thrombosis was re- occurred, phospholipid antibodies were also found, indicating that the disease is much more common than believed for a long time.

Symptoms

• Frequent miscarriages and early abortions
• Increased incidence of venous and arterial thrombosis and embolism
• Thus caused diseases such as pulmonary embolism, heart attacks, strokes, renal infarcts, etc.
• Consumption of platelets ( platelets ) characterized paradoxical bleeding, especially in the skin ( purpura)
• Skin bleeding, ulcers

Causes and pathomechanisms

About the pathogenic mechanism of antiphospholipid syndrome has so far been little known. It is now known that phospholipid antibodies - other than it leaves the name suggests - not directly to phospholipids, but bind to their associated proteins. These include, for example, beta-2- glycoprotein I, prothrombin, protein C, protein S, annexin V, or coagulation factor XII.

With the emergence of the APS, the beta- 2-glycoprotein I plays a crucial role. Usually beta-2- glycoprotein I is circulated as a soluble monomeric protein in blood plasma. Its physiological function is not yet known. 5 about the domain of the polypeptide it binds to anionic phospholipids in the cell membrane of various endothelial cells, including monocytes and platelets, which play a role in blood coagulation.

By binding to the phospholipids, the beta-2- glycoprotein I undergoes a conformational change whereby the binding site for the phospholipid antibodies in the domain 1 is accessible. The antibody binding results in the formation of stable beta-2- glycoprotein I dimers bind to different receptors in the cell membrane. These are thereby activated and set certain processes in the cell in transition, in platelets about their activation.

Also annexin V appears to play a role in the development of thrombosis in the course of APS. Antibodies block in vitro in the serum of patients with APS, the binding of annexin V to phospholipids and the anticoagulant effect of annexin V.

Despite intensive research, there are still many questions unanswered. For various other proteins such as Protein S and Protein C, and other phospholipids such as phosphatidylethanolamine, a connection with the APS is suspected. Whether there is a genetic correlation with the APS, is not yet fully understood.

Diagnosis of APS

The clinical symptoms of APS alone do not allow a clear diagnosis of the disease, since they are not specific enough. Therefore laboratory tests in the diagnosis of disease play a very important role.

Since the formulation of the international preliminary classification criteria of the antiphospholipid syndrome numerous basic research and numerous clinical trials have been published, which led to the revision of this so-called Sapporo criteria. In 2005, an expert committee formulated in a workshop before the Eleventh International Congress on Antiphospholipid Antibodies the then-current classification criteria.

Clinical criteria

First occurrence of vascular thrombosis without obvious signs of inflammation on the vessel walls.

Second pregnancy complications such as

• Intrauterine fetal death before 10 weeks of gestation in an otherwise normal fetus,

• Preterm birth before 34 weeks of gestation due to eclampsia (a sudden serious illness in the last trimester of pregnancy, characterized by convulsions), or a severe placental insufficiency (insufficient function of the placenta ),

• Three or more unexplained consecutive spontaneous abortions before the 10th week of pregnancy.

Laboratory parameters

• Detection of lupus anticoagulant in the plasma, twice at an interval of twelve weeks, according to the guidelines of the International Society on Thrombosis and Hemostasis (Scientific Subcommittee on Lupus Anticoagulants / Phospholipid - Dependent Antibodies ).
• Increased anti-cardiolipin titers (IgG and / or IgM) in the blood. The values ​​must be determined on two separate occasions that are at least twelve weeks apart. It must be standardized ELISA test systems are used for beta-2- glycoprotein I dependent anticardiolipin antibodies.
• Increased beta-2- glycoprotein I antibody titers (IgG and / or IgM). The values ​​must be determined on two separate occasions that are at least twelve weeks apart. The detection is carried out with a standard ELISA assay.

The diagnosis of APS is considered verified if at least one clinical criterion and one laboratory criterion are met.

Laboratory tests for the diagnosis of APS

In accordance with the diagnosis criteria, there are two different ways to determine the phospholipid antibodies: antibodies against cardiolipin (CL ), or beta- 2-glycoprotein I are detected by specific ELISA assays. The so-called lupus anticoagulants (LA ) are determined with blood clotting tests.

In general, the assay for lupus anticoagulants is specific, while cardiolipin and beta- 2-glycoprotein I- ELISA assays are more sensitive. APS patients may have antibodies against cardiolipin and beta- 2-glycoprotein I, and lupus anticoagulant, but it can also be present only antibodies from one of the two groups. It is therefore necessary, in the case of disease suspicion always perform both tests.

An ongoing therapy with anticoagulants may affect LA tests. Such tests will be carried out by the diagnostic criteria for clinical monitoring and the diagnosis to be confirmed after twelve weeks, as required by the diagnostic criteria. The cardiolipin and beta- 2-glycoprotein I- ELISAs other hand, are not affected by anticoagulant drugs and are therefore preferable to monitor patients in the further course.

A disadvantage of all APS evidence has long been the wide variation between different laboratories and the individual tests of the different manufacturers. Each laboratory should use high quality ELISA systems. Meanwhile, there are for all immunoglobulin classes defined standard sera with which the anti-cardiolipin and anti -beta 2-glycoprotein I- ELISAs can be calibrated.

Lupus Anticoagulant

The detection of lupus anticoagulant (LA ) is important for the diagnosis of APS. It is based on the principle that antibodies against thrombin and beta-2- glycoprotein I to anionic phospholipids compete with vitamin K-dependent clotting factors to the binding sites and thereby increase the clotting time of the blood in vitro.

First, a screening test is performed to demonstrate the extension of the phospholipid-dependent clotting time: When LA- proof a step- by-step approach is recommended. In the second step is followed by a displacement assay in which the sample is mixed with normal plasma. It aims to prevent blood clotting disorder is caused by the lack of a clotting factor. A third test finally confirmed by other means again that the inhibition of blood coagulation is actually phospholipid - dependent and not due to a specific coagulation factor.

Anti- cardiolipin

The observation that sera from SLE patients showed in a test based on the binding of cardiolipin for syphilis regularly false positive results, led to the discovery of cardiolipin antibodies and the development of the first anti -cardiolipin ELISAs.

Studies in the 1990s, then showed that there are two different types of anti-cardiolipin antibodies: those that directly bind to cardiolipin and those that interact only in the presence of the plasma protein beta-2- glycoprotein I to cardiolipin. Only this combination of antibodies specific for the APS or systemic lupus erythematosus (SLE).

Anti -cardiolipin ELISAs (short: Anti -CL) measure the content of cardiolipin antibodies in diluted blood plasma, usually in the presence of bovine serum as a source of beta- 2-glycoprotein I. But since not all anti-cardiolipin antibodies from human plasma samples also bind the bovine (ie derived from cattle) beta- 2-glycoprotein I, the performance of these tests may be affected. Therefore, modern anti-cardiolipin ELISAs always containing human beta-2- glycoprotein I as so-called coenzyme. This ensures that these tests demonstrate both the antibodies that bind cardiolipin alone, as well as all antibodies to cardiolipin in complex with beta- 2-glycoprotein I.

Direct cardiolipin antibodies are found only in patients with infectious diseases such as syphilis, malaria, infectious mononucleosis, tuberculosis or hepatitis A. Their binding to cardiolipin can be inhibited by the presence of beta-2- glycoprotein I even.

Except in the diagnosis of antiphospholipid syndrome may contribute cardiolipin antibodies also in the clinical differentiation of patients after thrombosis or embolism ( blood vessel blockage ). For example, patients with positive anti-cardiolipin test after completion of therapy with warfarin for the treatment of thrombosis have a significantly increased risk for recurrence ( relapse ).

Anti -beta -2- glycoprotein I

Beta- 2-glycoprotein I is a plasma glycoprotein, the polypeptide comprising five different domains. Domain V at one end contains the binding site for anionic phospholipids in the cell membrane, to which beta-2- glycoprotein I anneal. Domain I, on the other end is preferred recognized by the beta- 2-glycoprotein I antibodies, which play a role in the antiphospholipid syndrome. They are directly related to the development of thrombosis.

The risk of thrombosis or pregnancy complications increases with the number of positive evidence for phospholipid antibodies. It is at its highest when all three tests are positive, lupus anticoagulant, anti- cardiolipin and anti -beta- 2-glycoprotein I.

Other antibodies

Other antibodies, eg against annexin V, prothrombin, phosphatidylserine, phosphatidylcholine, phosphatidic acid or phosphatidylethanolamine have compared with anti- cardiolipin and anti -beta 2- glycoprotein I only limited diagnostic value and therefore play a less prominent role. Important is their determination in anti-cardiolipin and anti -beta 2-glycoprotein I- negative patients, as they can also occur alone.

Initial investigations suggest that a determination of the full autoantibody profile in relation to the type or site of the thrombosis or embolism, and other risk factors (eg, pregnancy, genetic thrombophilia ) may be useful in the clinical differentiation of patients. The determination of the complete Phospholipidantikörper spectrum, thus improving the diagnostic specificity. There is also evidence that indicate antibodies against phosphatidylserine at an increased risk of stroke.

Therapy and Treatment Strategies

The treatment of asymptomatic patients who phospholipid antibodies were detected, consists of a thrombosis. Aspirin has here proved to be effective in some cases. In patients with lupus and secondary APS hydroxychloroquine also provides protection against thrombosis.

After a thrombotic event effective anticoagulant therapy over a longer period should be maintained. The possible, for example by administration of phenprocoumon. In patients with complications of pregnancy, in which a history of thrombosis were not yet occurred, several clinical studies have shown that administration of aspirin and heparin may be beneficial to the further course of pregnancy.

For pregnant women with elevated levels of phospholipid antibodies, but without thrombosis or miscarriages in the history, a close clinical monitoring and low-dose aspirin or heparin is recommended.

Particularly critical is the treatment of patients who develop a so-called catastrophic APS after surgery or after childbirth. This leads to multiple thrombosis in many smaller blood vessels, such as the kidney and thus acute renal failure or multiple lung embolism.

Due to the increased risk of thrombosis anticoagulation ( anticoagulation ) with acetylsalicylic acid ( ASA), heparin, or with a possibly severe thrombocytopenia with phenprocoumon (eg, warfarin ) are required. In symptomatic patients, this should be life-long with otherwise asymptomatic patients only in situations where an increased risk of thrombosis (e.g., operations). In particularly critical situations, the antibodies can be removed by plasmapheresis from the blood, the further formation can be suppressed by cytostatic agents such as mycophenolate mofetil.

A treatment-related decrease of antiphospholipid antibodies was observed during treatment with methotrexate.

View

When APS clinical manifestations also occur in the brain. These include headaches, migraines, balance problems, seizures, transient ischemic attacks or infarcts, especially among young people under 45 years. The infarcts may be manifested in imaging as changes in the marrow bearing. Histologically, these represent lacunar infarcts as autopsies and bleeding all vessels dar.

These events can be attributed in large part to the reduced perfusion of the brain and the increased clotting tendency. Increasingly, however, are increasing also evidence of a direct effect of Phospholipidantikörper in the brain.