Thrombotic microangiopathy: causes and pathogenesis

The causes of thrombotic microangiopathy are diverse. Isolate infectious forms of hemolytic-uremic syndrome and are not associated with infection, sporadic. Most cases of infectious hemolytic-uremic syndrome (90% in children and about 50% in adults) have intestinal prodrome-a typical associated with diarrhea or post-diarrheal hemolytic-uremic syndrome. The most frequent pathogen in this form of hemolytic uraemic syndrome is E. coli, producing verotoxin (also known as shiga-like toxin for its structural and functional similarity to type I Shigella dysenteriae toxin , also causing hemolytic-uremic syndrome). Almost 90% of patients with diarrhea + haemolytic uremic syndrome in the economically developed countries are allocated E. Coli serotype 0157: H, but at least 10 more serotypes of this pathogen associated with the development of thrombotic microangiopathy are known. In developing countries, along with E. Coli, the causative agent of the disease is often Shigella dysenteriae I type.

Post-diarrheal hemolytic-uremic syndrome is the most common cause of acute renal failure in children. The incidence of diarrhea + hemolytic-uremic syndrome averages 1.5-2.1 cases per 100 000 children's population per year with a maximum frequency in children under 5 years (6/100 000 per year). In adults aged 20-49 years, the incidence is reduced to 1 / 100,000, reaching a minimum of 0.5 / 100,000 in persons over 50 years of age. Postdiarrheal haemolytic-uremic syndrome is widespread throughout the world, at times its outbreaks are epidemic, registering most often in children's institutions and nursing homes. Morbidity is characterized by seasonal fluctuations, its peak falls on the summer months. The natural reservoir of pathogens of diarrhea + hemolytic-uremic syndrome is livestock. Bacterial contamination of foods, especially meat and milk, as well as water, can lead to the development of hemorrhagic colitis, which is complicated by hemolytic-uremic syndrome in 5-10% of cases. The most frequent cases are children aged 9 months to 4 years, with equal probability boys and girls.

10% of hemolytic-uremic syndrome in children and more than 50% in adults occurs without diarrheal prodrome (so-called atypical, not associated with diarrhea, D-HUS). Although in some cases it can be of an infectious nature (it develops after a viral infection, an infection caused by pneumococcus, producing neuraminidase, AIDS), this form of hemolytic-uremic syndrome with infection is usually unrelated. Most cases of D-HUS are idiopathic, some are hereditary.

Thrombotic thrombocytopenic purpura is much less common than hemolytic-uremic syndrome (0.1-0.37 per 100 000), predominantly in adult women. The peak incidence falls on the 3-4th decade of life. Thrombotic thrombocytopenic purpura can develop de novo, without previous factors (idiopathic or classical thrombotic thrombocytopenic purpura), but there is also a family form of the disease. In most patients with this form, the disease becomes chronic recurrent, with frequent exacerbations.

Along with hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura, secondary forms of thrombotic microangiopathy are isolated. Symptomocomplex, similar in morphological and clinical signs with HUS / TTP, can develop in women during pregnancy and after childbirth, with malignant hypertension and systemic diseases - systemic lupus erythematosus and systemic scleroderma, AIDS. At the end of the 20th century, his appearance began to be associated with the antiphospholipid syndrome. The development of thrombotic microangiopathy is possible in patients with malignant neoplasms (in 50% of cases, metastatic adenocarcinoma of the stomach is detected, rarely - colon cancer, breast cancer, small cell lung cancer), in bone marrow, heart, liver, kidney transplant recipients. Recently, more and more often describe thrombotic microangiopathy in the use of drugs, the list of which is constantly expanding. Most often, oral contraceptives, antitumor drugs (mitomycin, bleomycin, cisplatin), calcium ionine inhibitors (cyclosporin, tacrolimus), ticlopidine, clopidogrel, interferon alfa, quinine lead to the development of HUS / TTP.

Pathogenesis of thrombotic microangiopathy

Thrombotic microangiopathy is a condition common to numerous diseases with various pathogenetic mechanisms. However, regardless of whether thrombotic microangiopathy develops primarily or secondary, the central link in pathogenesis is the damage to the vascular endothelium in the target organs, mainly in the kidneys. Trigger mechanisms of activation of endothelial cells are different: bacterial exo- and endotoxins in typical forms of hemolytic-uremic syndrome, the effect of antibodies or immune complexes in systemic diseases, drugs.

The most well studied pathogenesis of the post-diarrheal hemolytic-uremic syndrome. With this form of the disease, the causative agent of which in most cases is the E. Coli of serotype 0157: H7, damage to the endothelium of microvessels in the kidney induces verotoxin. Verotoxin consists of a subunit A having a cytotoxic effect and 5 subunits B that bind to specific glycolipid receptors of the cell membrane, allowing the subunit A to enter the cell. After internalization, subunit A inhibits protein synthesis, leading to cell death. Receptors for verotoxin are determined on membranes of the endothelium of microvessels, including capillary capillaries, mainly in childhood. With age, the number of them decreases, which explains the primary incidence of hemolytic-uremic syndrome in children. When ingested with infected food or water, the E. Coli verotoxin-producing strains bind to specific receptors on the colonic mucosa, produce exo- and endotoxins, multiply and cause damage and cell death, leading to the development of colitis, often hemorrhagic. Entering the systemic circulation, verotoxin causes damage to target organs, manifested in the vast majority of cases by clinical symptoms of hemolytic-uremic syndrome, less often - thrombotic thrombocytopenic purpura.

Bacterial lipopolysaccharide (endotoxin) can act synergistically with verotoxin, exacerbating damage to endothelial cells by inducing local synthesis of pro-inflammatory cytokines-tumor necrosis factor-a (TNF-a), interleukin-1p (IL-ip). In turn, the increase in production of TNF-a contributes to the enhancement of endothelial damage, stimulating the activation of neutrophils in the damaged portion of the vessel, followed by the release of toxic mediators for the vascular wall. The synergistic effect of verotoxin and bacterial endotoxin on local renal enhancement of TNFα synthesis, demonstrated in the experiment, partially explains the severity of kidney damage in a typical hemolytic-uremic syndrome.

A key link in the pathogenesis of thrombotic thrombocytopenic purpura is currently believed to be the presence in the blood of super-large Willebrand factor (WF) multimers, whose massive release from endothelial cells in thrombotic microangiopathy is considered an important mechanism for increased platelet aggregation, since these super-large multimers are more effective than conventional , bind receptors on the platelet membrane, leading to rapid thrombus formation in the microcirculatory bed. Superlarge multimers. B. Are determined in the bloodstream of patients with thrombotic thrombocytopenic purpura and disappear after recovery, probably as a result of the fact that their excess amount in the acute period of the disease exceeds the possibilities of proteolysis. The persistence of superlarge multimers. B. With thrombotic thrombocytopenic purpura is associated with a deficiency of the protease that cleaves them. In family cases of the disease, this defect is hereditary and permanent, with the acquired forms of thrombotic thrombocytopenic purpura - transient, caused by the presence of inhibitory antibodies.

The consequence of endothelial damage, regardless of the cause, is the loss of natural thrombore resistance, which is maintained by a number of biologically active substances produced by intact endothelial cells (thrombomodulin, tissue plasminogen activator, prostacyclin, nitric oxide). Their action prevents the aggregation of platelets and the formation of clots of fibrin. Activated endothelium, on the contrary, produces mediators with a pronounced procoagulant and proaggregant effect: von Willebrand factor, inhibitor of plasminogen activator, tissue factor. In response to damage to the vascular endothelium with thrombotic microangiopathy, in addition to the excessive release of f. B., there is a decrease in the production of prostacyclin and nitric oxide, which are powerful antiplatelet agents, which also contributes to thrombus formation. In addition to strengthening the function of platelets in the pathogenesis of thrombotic microangiopathy, disruption of the plasma linkage of coagulation and fibrinolysis is of great importance. This leads to increased expression on the surface of endothelial cells of the tissue factor, followed by local activation of coagulation in areas of endothelial damage with enhanced formation and deposition of fibrin. Fibrin formation is also facilitated by reduced production of a tissue factor inhibitor, the endogenous anticoagulant protein belonging to the family of serine proteases. In addition, thrombotic microangiopathy is characterized by local inhibition of fibrinolysis in areas of microvascular injury by increasing the production of an inhibitor of the plasminogen activator. Thus, the damage to the vascular endothelium with thrombotic microangiopathy leads to a pronounced imbalance between the anti- and procoagulant mechanisms with a predominance of the latter, which is completed by increased thrombus formation in the microcirculatory bed of various organs, but mainly the kidneys and the central nervous system.

The pathogenesis of D-HUS is less well understood. Most of its cases are associated with exposure to drugs or other factors leading to endothelial damage or increased microvascular thrombosis. In family forms of the disease, a low level of the complementary C3 component is detected in the blood plasma, which is a consequence of the deficiency of the H-protein factor regulating the alternative way of complement activation. The cause of this defect are numerous mutations in the gene of factor H. As a result of loss of the regulatory effect of factor H, constant complement activation occurs, leading to damage to the endothelium and microthrombogenesis.

The main symptoms of HUS / TTP: thrombocytopenia, hemolytic anemia, renal failure - are directly related to intrasopharyngeal thrombosis. Thrombocytopenia is a consequence of activation with subsequent consumption of platelets in areas of damaged vascular endothelium, hemolytic anemia - damage to erythrocytes in contact with thrombi filling the microcirculatory bed. Impaired renal function is associated with their ischemic lesion, due to a decrease in perfusion due to thrombotic occlusion of the intrarenal vessels.

Pathomorphology of thrombotic microangiopathy

Regardless of the cause and underlying pathogenetic mechanisms, the morphological pattern for all forms of thrombotic microangiopathy is the same. Vascular renal pathology, characteristic of thrombotic microangiopathy, is characterized by damage to the endothelium and thrombosis of small-caliber vessels, primary damage to arterioles and glomerular ischemia. The main morphological features of thrombotic microangiopathy are edema of endothelial cells with their detachment from the basal membrane, expansion of the subendothelial space with the accumulation of a newly formed membrane-like material in it. Thrombotic microangiopathy is a special type of vascular lesion in which thrombosis and necrosis of the renal arteries and arterioles are not accompanied by cellular infiltration of the vascular wall.

The histological picture of the hemolytic-uremic syndrome depends on its shape and the age of the patients. There are 2 main types of pathology that can be crossed. D + HUS in children under 2 years is characterized mainly by glomerular lesions. In the early phase of the disease, thrombi predominate in the glomerular capillaries without or with minimal damage to the arterioles. After a few months, in most glomeruli, the changes practically disappear, but some of the glomeruli are sclerosed. In the most clinically severe cases, focal cortical necrosis is noted. Diffuse cortical necrosis, described in 1955 by S. Gasser, is now extremely rare.

In older children, adults and atypical hemolytic-uremic syndrome, the predominantly arteriolar type of lesion develops with the most frequent localization of the microangiopathic process in the afferent arterioles. In acute lesions of arterioles, edema and proliferation of myointimal cells are noted leading to narrowing or obliteration of the lumen of the vessel. Segmental necrosis of the vascular wall or thrombosis of arterioles with deposition in places of fibrin damage is possible. The chronic course of the process is characterized by the accumulation of collagen fibers in the vessel wall, stretching and hyperplasia of myointimal cells, which acquire a peculiar concentric arrangement resembling "onion shell", which causes fibrous occlusion of the lumen of the vessel. These changes lead to secondary glomerular ischemia with collapse of the glomeruli, manifested by retraction of the capillary loops, thickening and wrinkling of the capillary wall. With complete obliteration of the arteriolar lumen, glomerular necrosis develops. Severe ischemic damage to the glomeruli can lead to focal cortical necrosis. Morphological signs of glomerular ischemia, as a rule, are combined in patients with atypical hemolytic-uremic syndrome with thrombosis of glomerular capillaries. In the arteriolar type of lesion, changes also develop in the arterial and interlobar arteries.

Thrombotic thrombocytopenic purpura is characterized by the defeat of the microcirculatory bed of not only the kidneys, but also the brain, heart, pancreas, adrenals. Morphological changes in the kidneys with thrombotic thrombocytopenic purpura are similar to those in the arteriolar type of lesions within the hemolytic-uremic syndrome.

With all forms of thrombotic microangiopathy, the glomerular lesion is focal in nature, and as a rule only certain segments of the glomeruli are affected. Important signs of thrombotic microangiopathy are the thickening and double-contour of the basal glomeruli membranes, which can simulate a picture of mesangiocapillary glomerulonephritis. Mesangiolysis and aneurysmal expansion of capillaries of glomeruli and arterioles are noted in renal biopsy specimens in a small number of patients with thrombotic microangiopathy. Immunohistochemical study in all types of thrombotic microangiopathy reveals deposits of fibrin in the capillaries of the glomeruli and arterioles, thrombotic thrombocytopenic purpura can reveal IgG deposits, with hemolytic-uremic syndrome - IgM and C3 along the capillary wall. After the transferred acute form of thrombotic microangiopathy, the development of focal segmental glomerulosclerosis is possible, which is usually detected in patients with persistent arterial hypertension.

Classification of thrombotic microangiopathies

I. Primary forms:

• Hemolytic-uremic syndrome
  • Typical
  • Atypical
  • Hereditary
• Thrombotic thrombocytopenic purpura
  • Sharp
  • Chronic recurrent
  • Hereditary

II. Secondary forms associated with: pregnancy and childbirth (pre-eclampsia-eclampsia, HELLP-syndrome)

• malignant hypertension
• systemic diseases (systemic lupus erythematosus, systemic scleroderma)
• antiphospholipid syndrome
• malignant tumors
• organ and tissue transplantation
• HIV infection
• drug therapy
• other diseases and conditions (pancreatitis, glomerulonephritis,
• aortocoronary bypass, artificial heart valves)

[1], [2], [3], [4]