Antiphospholipid syndrome - Causes and pathogenesis

The causes of antiphospholipid syndrome are unknown. Most often, antiphospholipid syndrome develops in rheumatic and autoimmune diseases, mainly in systemic lupus erythematosus. Increased levels of antibodies to phospholipids are 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 thrombosis in such patients rarely develops), malignant neoplasms, and the use of certain medications (hydralazine, isoniazid, oral contraceptives, interferons).

Anti-phospholipid antibodies are a heterogeneous population of antibodies to antigenic determinants of negatively charged (anionic) phospholipids and/or to phospholipid-binding (cofactor) plasma proteins. The family of anti-phospholipid antibodies includes antibodies that cause a false-positive Wasserman reaction; lupus anticoagulant (antibodies that prolong in vitro blood clotting time in phospholipid-dependent coagulation tests); antibodies that react with cardiolipin aPL and other phospholipids.

The interaction of antibodies with phospholipids is a complex process in which cofactor proteins play a central role. Of the plasma cofactor proteins that bind phospholipids, the best known is beta ₂ -glycoprotein 1 (beta ₂ GP-I), which has anticoagulant properties. During the interaction of beta ₂ GP-I with phospholipids of endothelial cell membranes and platelets, "neoantigens" are formed, with which circulating antibodies to phospholipids react, resulting in platelet activation, damage to the vascular endothelium with the loss of its antithrombogenic properties, disruption of fibrinolysis processes, and suppression of the activity of proteins of the natural anticoagulant system (proteins C and S). Thus, in patients with antiphospholipid syndrome, persistent activation of the hemostasis system is noted, developing due to increased activity of prothrombotic and depression of antithrombotic mechanisms and leading to recurrent thrombosis.

To explain the cause of thrombosis development in patients with antiphospholipid syndrome, the "double strike" hypothesis has been proposed. According to it, circulating antibodies to phospholipids ("first strike") promote hypercoagulation, creating prerequisites for thrombosis development, and thrombus formation is induced by additional factors ("second strike"), which are considered as local thrombotic mechanisms.

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Pathomorphology of antiphospholipid syndrome

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

• Acute changes are represented by thrombotic microangiopathy with fibrin thrombi in the glomerular capillaries and preglomerular vessels, which is observed in only 30% of kidney biopsies of patients with nephropathy associated with antiphospholipid syndrome.
• Some signs of chronic changes are found in almost all biopsies. These include arteriosclerosis and arteriolosclerosis of intrarenal vessels, fibrous hyperplasia of the intima of interlobular arteries and their branches due to the proliferation of myofibroblasts, which acquire the appearance of an "onion peel", organizing thrombi with or without signs of recanalization (see "Thrombotic microangiopathy"). The combination of acute and chronic changes in a renal biopsy reflects the recurrence of thrombus formation in the vascular bed of the kidneys and indicates the possibility of developing acute thrombotic microangiopathy in patients with chronic vaso-occlusive pathology.

Main morphological changes in nephropathy associated with antiphospholipid syndrome

Localization	Sharp changes	Chronic changes
Balls of Balls	Expansion of the mesangium Mesangiolysis Collapse of capillary loops Wrinkling of basement membranes Double-loop membranes Subendothelial deposits Intracapillary thrombosis Heart attack	Thickening of the basement membrane Capillary bundle retraction Expansion of the Bowman's capsule space Capillary loop ischemia Segmental or global glomerulosclerosis
Arteries, arterioles	Fresh occlusive thrombi Edema and endothelial degeneration Mucoid swelling of the subendothelium Necrosis	Organizing thrombi Recanalization of thrombi Microaneurysms Subendothelial fibrosis Concentric hyperplasia of the intima and muscular layer Myofibroblast proliferation Diffuse fibrosis

As a result of thrombotic microangiopathy progression, fibrous occlusion of the affected vessels develops with the appearance in the most severe cases of foci of ischemic atrophy of the cortex in the basin of these vessels. 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 fibrous hyperplasia of the intima and/or organizing thrombi (less often fresh thrombi). The glomeruli are reduced in size, sclerotic, collected in groups or, on the contrary, cystically enlarged, devoid of capillary loops or have pronounced retraction of the capillary bundle. A feature of the morphological picture of nephropathy associated with antiphospholipid syndrome is the presence of sclerotic and "pseudocystic" glomeruli in one biopsy.

The combination of arteriosclerosis, fibrous hyperplasia of the vascular intima and focal atrophy of the cortex, as well as interstitial fibrosis with tubular atrophy, regardless of the presence or absence of thrombotic microangiopathy, allows one to assume with a high probability the 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 intrarenal vessels. The concept of "nephropathy associated with antiphospholipid syndrome" includes thrombotic microangiopathy, but is not limited to it.

Along with vaso-occlusive changes in renal biopsy specimens with antiphospholipid syndrome, double contouring of the glomerular capillary basement membrane is often observed, sometimes - a picture of focal glomerulosclerosis. Immunohistochemical examination reveals fibrin deposits in the vessel walls and glomeruli, in some cases combined with deposits of the C3 component of complement and IgM in the intima of the arteries.