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Antiphospholipid syndrome (APS)

Antiphospholipid syndrome (APS) is a syndrome characterized by venous and/or arterial thrombosis, obstetric pathology (miscarriage in I and II trimesters of pregnancy, premature birth), less thrombocytopenia, and other (cardiovascular, neurological, skin, etc.) manifestations, associated with hyperproduction of antiphospholipid antibodies.

Antiphospholipid antibodies (APLA)

Antiphospholipid antibodies (APLA) are a serological marker and risk factor for development of thrombotic complications in antiphospholipid syndrome. They are a family of antibodies that recognize antigenic determinants of anionic and neutral phospholipids, and complex epitopes formed during the interaction of phospholipids and phospholipid binding proteins.

The process of clot formation involves the interaction of autoantibodies with phospholipids membranes of platelets, endothelium and phospholipid binding plasma proteins.

Autoantibodies can be generated to various negatively or neutral charged phospholipid membranes of platelets and endothelium - cardiolipin (CL), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidic acid (P

There are the following forms of antiphospholipid syndrome:

  • antiphospholipid syndrome in patients with reliable diagnosis of SLE (secondary APS);
  • antiphospholipid syndrome in patients with lupus-like manifestations;
  • primary antiphospholipid syndrome;
  • "catastrophic" antiphospholipid syndrome (acute disseminated coagulopathy/vasculopathy) with acute multiorgan thrombosis;
  • other microangiopathic syndromes (thrombotic thrombocytopenic purpura/hemolyticuremic syndrome); HELLP syndrome (hemolysis, increased liver enzymes, decreased platelet count); DIC; hypoprothrombinemia syndrome;
  • seronegative antiphospholipid syndrome.

Spectrum of clinical manifestations of the antiphospholipid syndrome are extremely diverse, as potentially can affect vessels of any caliber and localization, including the aorta. In the context of antiphospholipid syndrome is described pathology of the central nervous system, cardiovascular system, kidney function, endocrine glands, gastrointestinal tract.

The most typical manifestation of antiphospholipid syndrome is obstetrical pathology. Obstetric complications associated with presence of antiphospholipid syndrome (APS) include:

  • recurrent pregnancy loss (two or more spontaneous abortion or non-developing pregnancy in the I and II trimesters)
  • antenatal death of the fetus
  • premature birth
  • severe forms of gestosis
  • intrauterine growth retardation in combination and without symptoms of preeclampsia
  • severe complications of the postpartum period

Pathogenetic reason for the development of obstetric complications in antiphospholipid syndrome is a placental decidual vasculopathy, is caused by impaired production of prostacyclin, thrombosis, and infarctions of the placenta and disrupt the process of implantation.

The frequency of antiphospholipid antibodies (APLA) detection is increased in patients with inflammatory, autoimmune and infectious diseases (HIV, hepatitis C, etc.), malignancies, in patients receiving medications (oral contraceptives, psychotropic drugs, etc.).

According to preliminary international criteria mandatory methods for the laboratory diagnosis of antiphospholipid syndrome include identification of antibodies to cardiolipin class IgG and IgM using ELISA and detection of lupus anticoagulant (LA) in the phospholipid-dependent coagulation tests.

For diagnosis of antiphospholipid syndrome requires the presence of at least one clinical and one laboratory sign; IgG/IgM antibodies to cardiolipin must be determined in the serum in medium or high titers on 2 or more studies with an interval of at least 6 weeks using standard ELISA, allowing detection of β2-glycoprotein I-dependent antibodies to cardiolipin. Lupus anticoagulant should be determined in plasma in 2 or more studies with an interval of at least 6 weeks standard method.

 

Lupus anticoagulant

Lupus anticoagulant - is a collective term, implying only factors present in plasma, causing elongation in vitro phospholipid-dependent coagulation tests, and clinically cause hypercoagulation.

Diagnosis of lupus anticoagulant consists of three stages:

  1. Screening tests, based on the elongation of the phospholipid-dependent coagulation tests (APTT, kaolin test, test with Russell's Viper venom, the prothrombin time, texturename time).
  2. Correctional sample, implying a clarification of the genesis of lengthening the screening tests.
  3. Confirming test, the purpose of which is to elucidate the nature of the inhibitor (specific or nonspecific).

 

Antibodies to phospholipids

The term "antibodies to phospholipids" refers to antibodies to negatively charged phospholipids, lose weight in as cardiolipin, (CL), phosphatidylinositol (IGF), phosphatidylserine (f), phosphatidyl acid (FC). Using a screening test, a link has been observed between the presence of IgG and APLA, as well as the development of thrombosis in patients; and the presence of IgG FC, IgG IGF, IgG and f with thrombocytopenia.

 

Antibodies to cardiolipin

Antibodies to cardiolipin are a major fraction of antibodies to phospholipids. These antibodies are detected in various autoimmune diseases. Their presence in patients with SLE is associated with development of thrombosis and thrombocytopenia. The presence of cardiolipin antibodies observed in patients with neurological disorders, such as epilepsy and chorea.

In the treatment of antiphospholipid syndrome (APS) concentration of antibodies to cardiolipin may vary, and may remain at the same level.

 

Antibodies to other phospholipids

Recently, there is evidence indicating the need to consider the full spectrum of antiphospholipid antibodies in pregnant women with preeclampsia: preeclampsia is accompanied by impaired placentation, reduced placental perfusion, endothelial cell dysfunction and systemic vasospasm.

Preeclampsia in the presence of antiphospholipid antibodies (APLA) is characterized by severe and atypical course, the onset of symptoms at the end of II – beginning of III trimester, early development of the asymmetric form of the intrauterine development of the fetus.

Found that most often with preeclampsia and intrauterine fetal malnutrition are found autoantibodies to cardiolipin (CL) (IgM - 46%, IgG - 22%), phosphatidylserine (PS) (IgM - 37%, IgG - 16%) and phosphatidylcholine (IgM - 42%, IgG - 23%). Level AFLA in preeclampsia correlates with the severity of the disease.

 

Cofactors for antiphospholipid antibodies

Plasma proteins associated with phospholipids of cell membranes, prothrombin, ß2-glycoprotein I, annexin V, high molecular weight kininogen, protein C and S and the number of other — serve as cofactors in the presence of phospholipids which are associated with autoantibodies.

The discovery of cofactor-dependent antiphospholipid antibodies (APLA) — the most reliable sign of involvement APLA to the antiphospholipid syndrome (APS), while the cofactor-independent AFLA referred to as nonspecific signs of infection. In particular, APLA can be detected in patients with syphilis, acute and chronic viral infections. In these cases antiphospholipid antibodies do not interact with phospholipid-bound proteins.

On the contrary, when the false positive Wasserman reaction in patients suffering from systemic and hematological diseases, detection of antiphospholipid antibodies (APLA) associated with prothrombin or ß2-glycoprotein I, indicates their association with antiphospholipid syndrome.

 

Antibodies to ß2-glycoprotein I (ß2-GP I)

It is assumed that a particularly important role in the process of interaction APLA and endothelial cells plays a ß2-glycoprotein I. ß2-glycoprotein I with a molecular weight of 50 kDa present in normal plasma at a concentration of about 200 μg/ml, circulates in association with lipoproteins and possesses natural anticoagulant activity.

Antibodies present in the sera of patients with antiphospholipid syndrome, actually do not recognize the antigenic determinants of cardiolipin and conformational epitopes, formed during the interaction of ß2-glycoprotein I to cardiolipin.

 

Antibodies to annexin V

The cause of miscarriage in the later stages with the progression of antiphospholipid syndrome is the development of thrombotic vasculopathy of the spiral arteries of the placenta. Proved the role of annexin V in the genesisgenesis of fetal loss syndrome in patients with antiphospholipid syndrome, reduction of which on the surface of the villi leads to the development of thromboses and infarcts of the placenta.

Annexin V, also known as placental anticoagulant protein (PAP I), belongs to the family of calcium-dependent proteins that bind phospholipids. Annexin V is presented in many tissues, mainly endothelial cells and placenta.

At low concentrations of annexin V is present in platelets, in the higher - in leukocytes and erythrocytes. It has a pronounced anticoagulant properties. This is due to the properties of high affinity to anionic phospholipids and the ability to inhibit activated coagulation factors bind to the cell membrane phospholipids.

Annexin V covers the phospholipids according to the type of carpet, providing a local anticoagulant effect. During physiological pregnancy at the expense of long-term location of annexin V on the surface of the trophoblast does not happen thrombosis. In patients with antiphospholipid syndrome, including on the background infectious process, the possible production of autoantibodies to this protein. Antibodies displace annexin V from the surface of endothelial cells and trophoblast cells, which leads to hypercoagulability and pregnancy loss.

With increasing gestational age thrombus formation processes in the vessels of the placenta becoming increasingly important.

 

Antibodies to prothrombin

Prothrombin (coagulation factor II) is a vitamin K-dependent glycoprotein, synthesized in the liver and involved in blood coagulation. Prothrombin turning into thrombin on the membrane of damaged cells, provides the activation of factors VIII and V, the transition of fibrinogen to fibrin.

Antibodies to prothrombin are pathogenic: directly inhibit the coagulation factors, which leads to prolonged phospholipid-dependent coagulation tests.

It is shown that lupus antibodies causing prolonged phospholipid-dependent coagulation tests, that require the presence of plasma proteins like ß2-glycoprotein I or prothrombin.

The presence of autoantibodies to prothrombin is one of the main causes of thrombosis in patients with SLE and antiphospholipid syndrome. High levels of antibodies to prothrombin are associated with risk of deep vein thrombosis the thigh, and pulmonary embolism. In addition, increasing the concentration of antibodies to prothrombin is a prognostic risk factor for myocardial infarction.