Antiphospholipid Syndrome

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Classification according to ICD-10
D68.6 Other thrombophilia
ICD-10 online (WHO version 2019)

The antiphospholipid syndrome ( APS ) is the most common autoimmune diseases . Two to five percent of the population, primarily women, suffer from it ( gynecotropia ). Other names for the disease are cardiolipin antibody syndrome, antiphospholipid antibody syndrome, and (rarely) APA syndrome.

Typical clinical symptoms that may indicate APS are thrombosis , recurrent miscarriages, and intrauterine fetal death. However, there are many other non-specific symptoms that can make diagnosing APS difficult. Various antiphospholipid antibodies can be detected in laboratory chemistry, but these are not specific, but are also found more frequently in diseases of the rheumatic type , as well as in healthy people.

Basics

The antiphospholipid syndrome contains specific antibodies against various phospholipids ( cardiolipin, etc.) and phospholipid-binding proteins such as prothrombin and beta-2-glycoprotein I. These so-called antiphospholipid antibodies (APA) lead to increased coagulability of the blood and consequently to increased thrombosis .

A distinction is made between primary APS (PAPS), which occurs independently of other diseases, and secondary APS (SAPS). The secondary APS, which is the far more common form of the two, is found particularly in the context of autoimmune diseases . The most common underlying disease is systemic lupus erythematosus (SLE). Secondary APS occurs much less often in the context of other diseases such as malignant tumors , HIV , infections or as a drug side effect. From a clinical point of view, the division into PAPS and SAPS no longer makes sense today.

The clinical picture was first described in 1959 by JP Hughes and PGI Stovin. In 1983, the English rheumatologist Graham Robert Vivian Hughes viewed the antiphospholipid syndrome as an independent clinical picture in which autoantibodies against phospholipids occur independently of other autoimmune diseases.

These antiphospholipid antibodies can also be detected secondarily in connection with autoimmune diseases such as lupus erythematosus , rheumatoid arthritis or Sjögren's syndrome . While phospholipid antibodies can only be detected in about 1 to 5% of healthy people, they occur in 16 to 35% of lupus patients.

Phospholipid antibodies were also found in 8–14% of patients who had newly developed venous thrombosis, indicating that the disease is significantly more common than previously assumed.

Symptoms

Causes and Pathomechanism

Little is known about the pathomechanism of the antiphospholipid syndrome. Today we know that phospholipid antibodies - contrary to what the name suggests - do not bind directly to phospholipids, but to proteins associated with them. These include, for example, beta-2-glycoprotein I, prothrombin , protein C , protein S , annexin V or coagulation factor XII.

The beta-2-glycoprotein I plays a crucial role in the development of APS. Normally, beta-2-glycoprotein I circulates in the blood as a soluble monomeric plasma protein. Its physiological function is not yet known. Via domain 5 of the polypeptide chain, it binds to anionic phospholipids in the cell membrane of various endothelial cells, including monocytes and platelets , which play a role in blood clotting.

By binding to the phospholipids, the beta-2-glycoprotein I undergoes a conformational change, whereby the binding site for the phospholipid antibodies in domain 1 becomes accessible. Antibody binding leads to the formation of stable beta-2-glycoprotein I dimers, which bind to various receptors in the cell membrane. This activates them and sets certain processes in motion in the cell, such as their activation in blood platelets .

Annexin V also appears to play a role in the development of thrombosis in the course of APS. In vitro antibodies in the serum of APS patients block the binding of annexin V to phospholipids and the anticoagulant effect of annexin V.

Despite intensive research, many questions remain unanswered. For various other proteins such as protein S or protein C and other phospholipids, e.g. B. Phosphatidylethanolamine , a connection with the APS is suspected. Whether there is a genetic correlation with the APS has not yet been conclusively clarified.

Diagnostics of the APS

The clinical symptoms of APS alone do not allow a clear diagnosis of the disease because they are not specific enough. That is why laboratory tests play a very important role in diagnosing the disease.

Since the formulation of the preliminary international classification criteria for the antiphospholipid syndrome, numerous fundamental research papers and numerous clinical studies have been published, which led to the revision of these so-called Sapporo criteria. In 2005 a panel of experts formulated the currently applicable classification criteria in a workshop before the Eleventh International Congress on Antiphospholipid Antibodies .

Clinical Criteria

1. Occurrence of vascular thrombosis with no obvious signs of inflammation on the vessel walls.

2. Pregnancy complications such as

• intrauterine fetal death in or after the 10th week of pregnancy of an otherwise normal fetus,

• Premature birth before the 34th week of pregnancy due to eclampsia (a sudden serious illness in the last trimester of pregnancy, characterized by seizures) or severe placental insufficiency (insufficient function of the placenta ),

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

Laboratory parameters

  • Detection of lupus anticoagulant in 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. Values ​​must be determined on two separate occasions, at least twelve weeks apart. Standardized ELISA test systems for beta-2-glycoprotein I-dependent cardiolipin antibodies must be used.
  • Increased beta-2-glycoprotein I antibody titers (IgG and / or IgM). Values ​​must be determined on two separate occasions, at least twelve weeks apart. Evidence is provided with a standardized ELISA test.

The diagnosis of APS is confirmed when at least one clinical criterion and one laboratory criterion are met.

Laboratory tests to diagnose APS

According to the diagnostic criteria, there are two different ways of determining the phospholipid antibodies: Antibodies against cardiolipin (CL) or beta-2-glycoprotein I are detected with specific ELISA test systems . The so-called lupus anticoagulants (LA) are determined with blood coagulation tests.

In general, the test for lupus anticoagulant is more specific, while the cardiolipin and beta-2-glycoprotein I ELISAs are more sensitive. APS patients may have antibodies against cardiolipin or beta-2-glycoprotein I and lupus anticoagulant, but antibodies from one of the two groups can also be present. It is therefore necessary to always carry out both tests if you are suspected of being sick.

Ongoing anticoagulant therapy can interfere with LA testing. Such tests are carried out by the diagnostic criteria to monitor the progress or to confirm the diagnosis after twelve weeks, as required by the diagnostic criteria. The cardiolipin and beta-2-glycoprotein I ELISAs, on the other hand, are not affected by anticoagulant drugs and are therefore preferable for monitoring the patient in the further course.

For a long time, a disadvantage of all APS certificates was the wide range of fluctuations between different laboratories and the individual tests from different manufacturers. Every laboratory should therefore use high quality ELISA test systems. There are now defined standard sera for all immunoglobulin classes with which the anti-cardiolipin and anti-beta-2-glycoprotein I ELISAs can be calibrated.

Lupus anticoagulant

The detection of the 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 compete with vitamin K-dependent blood coagulation factors for binding sites on anionic phospholipids and thereby prolong the clotting time of the blood in vitro .

A step-by-step procedure is recommended for the detection of LA: First, a screening test is carried out to detect the prolongation of the phospholipid-dependent clotting time. The second step is a displacement test in which the sample is mixed with normal plasma. He should rule out that the bleeding disorder is caused by the lack of a clotting factor. A third test finally confirms once again in another way that the inhibition of blood coagulation is actually phospholipid-dependent and is not based on a specific coagulation factor.

Anti-cardiolipin

The observation that sera from SLE patients regularly showed false positive results in a test based on the binding of cardiolipin for syphilis , 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 cardiolipin antibodies: those that bind directly to cardiolipin and those that only interact with cardiolipin in the presence of the plasma protein beta-2-glycoprotein I. Only these combination antibodies are specific for APS or systemic lupus erythematosus (SLE).

Anti-Cardiolipin-ELISAs (short: Anti-CL) measure the content of cardiolipin antibodies in diluted blood plasma, mostly in the presence of bovine serum as a source of beta-2-glycoprotein I. But since not all cardiolipin antibodies from human plasma samples are also measured bind the bovine (i.e., derived from cattle) beta-2-glycoprotein I, the performance of these tests may be impaired. That is why modern anti-cardiolipin ELISAs always contain human beta-2-glycoprotein I as a so-called coenzyme . This ensures that these tests detect both the antibodies that bind cardiolipin alone and all antibodies against cardiolipin in complex with beta-2-glycoprotein I.

The 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 even be inhibited by the presence of beta-2-glycoprotein I.

In addition to the diagnosis of the antiphospholipid syndrome, cardiolipin antibodies can also contribute to the clinical differentiation of patients after a thrombosis or an embolism (blood vessel occlusion ). For example, patients with a positive anti-cardiolipin test after the end of therapy with warfarin for the treatment of thrombosis have a significantly increased risk of a relapse (relapse).

Anti-beta-2 glycoprotein I.

Beta-2-glycoprotein I is a plasma glycoprotein whose polypeptide chain has 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 attaches. Domain I, at the other end, is preferably 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 results for phospholipid antibodies. It is highest when all three tests are positive, lupus anticoagulant, anti-cardiolipin, and anti-beta-2 glycoprotein I.

Other antibodies

Other antibodies, e.g. B. against annexin V, prothrombin, phosphatidylserine , phosphatidylcholine , phosphatidic acid or phosphatidylethanolamine have only a limited diagnostic value compared to anti-cardiolipin or anti-beta-2-glycoprotein I and therefore play a less prominent role. Their determination is important in anti-cardiolipin- or anti-beta-2-glycoprotein I-negative patients, since they can also occur alone.

Initial studies indicate that determining the full autoantibody profile in connection with the type or location of the thrombosis or embolism and other risk factors (e.g. pregnancy, genetic thrombophilia ) could be helpful in the clinical differentiation of patients. The determination of the complete spectrum of phospholipid antibodies improves the diagnostic specificity. There is also evidence that antibodies to phosphatidylserine indicate an increased risk of stroke.

Studies published in 2014 with an Immuno-Dot for the simultaneous determination of ten different phospholipid-binding proteins or phospholipids show a new, promising approach for the determination of risk factors in patients with anti-phospholipid syndrome. Anti-cardiolipin, anti-β2-GP1, phosphatidylinositol, phosphatidylserine, phosphatidylcholine, phosphatidylethiolamine, phosphatidylglycerol, phosphatidic acid, annexin V and prothrombin in the serum (IgG and / or IgM) are measured simultaneously in a sample using a new hydrophobic membrane. Initial trials show a promising new tool that is recommended for examining the relevance of aPL profiles as risk factors for APS.

The above results with a line immuno dot were confirmed by an international multi-center study and published in Arthritis Research & Therapy (2016) 18: 111 "Antiphospholipid antibodies detected by line immunassay differentiate among patients with antiphospholipid syndrome, with infections and asmptomatic carries" published. In summary, the data show: good agreement for the determination of APL in APS patients, but also shows differences in APS patients with infections and asymptomatic carriers. And the results also show good values ​​in determining the risk of arterial and venous thrombosis.

Therapy and treatment strategies

The treatment of asymptomatic patients in whom phospholipid antibodies have been detected consists of thrombosis prophylaxis. In some cases, acetylsalicylic acid has proven to be effective here. Hydroxychloroquine also offers protection against thrombosis in patients with lupus and secondary APS .

After a thrombotic event, more effective anticoagulant therapy must be maintained for an extended period of time. This is achieved, for example, by giving phenprocoumon . In patients with pregnancy complications who had no history of thrombosis, several clinical studies have shown that the administration of aspirin and heparin can have beneficial effects on the further course of the pregnancy.

Close clinical monitoring and low-dose aspirin or heparin is recommended for pregnant women with elevated levels of phospholipid antibodies but no history of thrombosis or miscarriage.

The treatment of patients who develop what is known as catastrophic APS after an operation or after delivery is particularly critical. This leads to multiple thromboses in numerous smaller blood vessels, e.g. B. the kidney and thus acute kidney failure or multiple pulmonary embolisms.

Due to the increased tendency to thrombosis, anticoagulation with acetylsalicylic acid (ASA), heparin or, in the event of severe thrombocytopenia, with phenprocoumon (e.g. Marcumar) is necessary. In symptomatic patients, this should be carried out for life, in otherwise asymptomatic patients only in situations with an increased risk of thrombosis (e.g. operations). In particularly critical situations, the antibodies can be removed from the blood by plasmapheresis , the further development can be suppressed by cytostatics such as mycophenolate mofetil .

A therapy-related decrease in antiphospholipid antibodies was observed during therapy with methotrexate . In kidney transplants in patients with the antiphospholipid syndrome, the use of the mTOR inhibitor sirolimus was able to increase the rate of transplant survival in a very small study group .

outlook

In APS, clinical manifestations also occur in the brain. These include headaches, migraines , balance disorders, epileptic seizures, transient ischemic attacks or heart attacks, especially in young people under 45 years of age. The infarcts may manifest as changes in the medullary bed on the imaging . Histologically, autopsies present these as lacunar infarcts and hemorrhages in all vessels.

These events can be largely attributed to the reduced blood flow to the brain and the increased tendency to clot. Increasingly, however, there are also indications of a direct effect of phospholipid antibodies in the brain.

Individual evidence

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