Antiphospholipid syndrome: causes and pathogenesis

The causes of antiphospholipid syndrome are not known. The most common antiphospholipid syndrome develops with rheumatic and autoimmune diseases, mainly in systemic lupus erythematosus. An increase in the level of antibodies to phospholipids is also observed in bacterial and viral infections (streptococci and staphylococci, mycobacterium tuberculosis, HIV, cytomegalovirus, Epstein-Barr viruses, hepatitis C and B and other microorganisms, although thromboses rarely develop in such patients), malignant neoplasms some drugs (hydralazine, isoniazid, oral contraceptives, interferons).

Antibodies to phospholipids are a heterogeneous population of antibodies to antigenic determinants of negatively charged (anionic) phospholipids and / or to phospholipid-binding (cofactor) plasma proteins. To the family of antibodies to phospholipids include antibodies, which determine the false positive reaction of Wasserman; lupus anticoagulant (antibodies that prolong in vitro clotting time in phospholipid-dependent coagulation tests); antibodies reacting with cardiolipin AFL and other phospholipids.

Interaction of antibodies with phospholipids is a complex process, in which the central role is assigned to cofactor proteins. Of the cofactor plasma proteins binding phospholipids, the most known beta _2- glycoprotein 1 (beta ₂ GP-I), which has anticoagulant properties. During the interaction of beta ₂ GP-I with phospholipids of membranes of endothelial cells and platelets, the formation of "neoantigens" occurs, with which circulating antibodies to phospholipids react, resulting in platelet activation, damage to the vascular endothelium with loss of antithrombogenicity, disruption of fibrinolysis and suppression of the activity of proteins of the system of natural anticoagulants (proteins C and S). Thus, in patients with antiphospholipid syndrome, persistent activation of the hemostasis system is observed, which develops as a result of increased prothrombotic and depression activity of antithrombotic mechanisms and leads to recurrent thrombogenesis.

To explain the cause of thrombosis in patients with antiphospholipid syndrome, the hypothesis of a "double stroke" has now been proposed. In accordance with this, circulating antibodies to phospholipids (the "first stroke") promote hypercoagulation, creating the prerequisites for the development of thrombosis, and the induction of thrombogenesis occurs as a result of the action of additional factors ("second stroke"), which are regarded as local trshternye mechanisms.

[1], [2], [3], [4], [5], [6], [7]

Pathomorphology of antiphospholipid syndrome

The morphological picture of nephropathy associated with antiphospholipid syndrome is characterized by a combination of acute and chronic vasocclusive changes.

• Acute changes are represented by thrombotic microangiopathy with fibrin clots in glomerular capillaries and preglomerular vessels, which is noted in only 30% of renal biopsy specimens of patients with nephropathy associated with antiphospholipid syndrome.
• These or other signs of chronic changes are found in almost all biopsies. These include arteriosclerosis and arteriosclerosis of the intracranial vessels, fibrotic hyperplasia of the intima of the interlobular arteries and their branches due to the proliferation of myofibroblasts acquiring the appearance of "bulbous husks", organizing thrombi with signs of recanalization or without it (see "Thrombotic microangiopathies"). The combination of acute and chronic changes in the kidney biopsy reflects the recurrence of thrombus formation in the vascular bed of the kidneys and suggests the possibility of the development of acute thrombotic microangiopathy in patients with chronic vasocclusive pathology.

The main morphological changes in nephropathy associated with antiphospholipid syndrome

Localization	Sharp changes	Chronic changes
Glomeruli	Expansion of mesangium Mesangiolysis Collapse of capillary loops Shrinking of basal membranes The two-contouring of membranes Sub-endothelial deposits Intracapillary thrombosis Heart Attack	Thickening of the basement membrane Retraction of the capillary bundle Expansion of Bowman's capsule space Ischaemia of capillary loops Segmental or global glomerulosclerosis
Arteries, arterioles	Fresh occlusive thrombi Edema and degeneration of the endothelium Mucoid swelling of the subendothelium Necrosis	Organized thrombi Recanalization of blood clots Microaneurysms Subendothelial fibrosis Concentric hyperplasia of the intima and the muscular layer Proliferation of myofibroblasts Diffuse fibrosis

As a result of the progression of thrombotic microangiopathy, fibrotic occlusion of affected vessels develops with the appearance of foci of ischemic atrophy of the cortex in the basin of these vessels in the most severe cases. In the foci of cortical ischemia, a whole complex of changes in all elements of the renal parenchyma is revealed: massive interstitial fibrosis, tubular atrophy, vascular occlusion due to intimal fibrotic hyperplasia and / or organized thrombi (less often fresh blood clots). The glomeruli are reduced in size, sclerotized, assembled into groups or, on the contrary, are cystically enlarged, devoid of capillary loops or have a pronounced retraction of the capillary bundle. A feature of the morphological picture of nephropathy associated with the antiphospholipid syndrome is the presence in one biopsy of sclerosed and "pseudocystic" glomeruli.

The combination of arteriosclerosis, fibrotic intimal vascular hyperplasia and focal atrophy of the cortex, as well as interstitial fibrosis with tubular atrophy, regardless of the presence or absence of thrombotic microangiopathy, makes it possible to assume a diagnosis of nephropathy associated with antiphospholipid syndrome. Thus, thrombotic microangiopathy is only a morphological equivalent of the acute course of the thrombotic process in the intra-venous vessels. The term "nephropathy associated with an antiphospholipid syndrome includes thrombotic microangiopathy, but is not limited to it.

Along with vaso-occlusive changes in kidney biopsies with antiphospholipid syndrome, the double-contour of the basal membrane of the glomerular capillaries is often noted, sometimes the picture of focal glomerulosclerosis. Immunohistochemical examination in the walls of vessels and glomeruli reveals deposits of fibrin, in some cases combined with deposits of the C3-component of complement and IgM in the intima of the arteries.