Thrombotic microangiopathy - Causes and pathogenesis

The causes of thrombotic microangiopathy are varied. There are infectious forms of hemolytic-uremic syndrome and those not associated with infection, sporadic ones. Most cases of infectious hemolytic-uremic syndrome (90% in children and about 50% in adults) have an intestinal prodrome - typical, associated with diarrhea or postdiarrheal hemolytic-uremic syndrome. The most common pathogen in this form of hemolytic-uremic syndrome is E. coli, which produces verotoxin (also known as shiga-like toxin for its structural and functional similarity to the toxin of Shigella dysenteriae type I, which also causes hemolytic-uremic syndrome). Almost 90% of patients with diarrhea + hemolytic uremic syndrome in economically developed countries are infected with 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 pathogen is often Shigella dysenteriae type I.

Postdiarrheal 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 per year with the highest incidence in children under 5 years of age (6/100,000 per year). In adults aged 20-49 years, the incidence decreases to 1/100,000, reaching a minimum of 0.5/100,000 in people over 50 years of age. Postdiarrheal hemolytic uremic syndrome is widespread throughout the world, with outbreaks sometimes occurring in epidemic proportions, most often in children's institutions and nursing homes. The incidence is characterized by seasonal fluctuations, with its peak occurring in the summer months. Livestock is a natural reservoir of diarrhea + hemolytic uremic syndrome pathogens. Bacterial contamination of food products, especially meat and dairy products, as well as water, can lead to the development of hemorrhagic colitis, which is complicated by hemolytic uremic syndrome in 5-10% of cases. Children aged 9 months to 4 years are most often affected, with equal probability for boys and girls.

10% of hemolytic uremic syndrome in children and more than 50% in adults occurs without a diarrheal prodrome (the so-called atypical, not associated with diarrhea, D-HUS). Although in some cases it can be of an infectious nature (develops after a viral infection, infection caused by pneumococcus producing neuraminidase, AIDS), usually this form of hemolytic uremic syndrome is not associated with infection. 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 cases per 100,000), mainly in adult women. The peak incidence occurs in the 3rd-4th decades of life. Thrombotic thrombocytopenic purpura can develop de novo, without previous factors (idiopathic or classic thrombotic thrombocytopenic purpura), but there is also a familial form of the disease. In most patients with this form, the disease becomes chronic and recurrent with frequent exacerbations.

Along with hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, secondary forms of thrombotic microangiopathy are distinguished. A symptom complex similar in morphological and clinical signs to HUS/TTP can develop in women during pregnancy and after childbirth, with malignant arterial hypertension and systemic diseases - systemic lupus erythematosus and systemic scleroderma, AIDS. At the end of the 20th century, its occurrence was also associated with 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, less often - colon cancer, breast cancer, small cell lung cancer), in recipients of bone marrow, heart, liver, kidney transplants. Recently, thrombotic microangiopathy has been increasingly described with the use of drugs, the list of which is constantly expanding. The most common agents that lead to the development of HUS/TTP are oral contraceptives, antitumor drugs (mitomycin, bleomycin, cisplatin), calcineurin inhibitors (cyclosporine, tacrolimus), ticlopidine, clopidogrel, interferon alpha, and quinine.

Pathogenesis of thrombotic microangiopathy

Thrombotic microangiopathy is a condition common to numerous diseases with different pathogenetic mechanisms. However, regardless of whether thrombotic microangiopathy develops primarily or secondarily, the central link in the pathogenesis is damage to the vascular endothelium in target organs, mainly in the kidneys. At the same time, the trigger mechanisms for 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 pathogenesis of postdiarrheal hemolytic-uremic syndrome has been studied most thoroughly. In this form of the disease, the causative agent of which is Escherichia coli serotype 0157:H7 in most cases, damage to the endothelium of microvessels in the kidney induces verotoxin. Verotoxin consists of subunit A, which has a cytotoxic effect, and 5 subunits B, which bind to specific glycolipid receptors of the cell membrane, allowing subunit A to penetrate the cell. After internalization, subunit A inhibits protein synthesis, leading to cell death. Receptors for verotoxin are determined on the membranes of the endothelium of microvessels, including glomerular capillaries, mainly in childhood. With age, their number decreases, which explains the predominant incidence of hemolytic-uremic syndrome in children. When entering the body with contaminated food or water, verotoxin-producing strains of E. coli bind to specific receptors on the mucous membrane of the colon, produce exo- and endotoxins, multiply and cause damage and death of cells, which leads to the development of colitis, often hemorrhagic. When entering the systemic bloodstream, verotoxin causes damage to target organs, which in the vast majority of cases manifests itself in clinical symptoms of hemolytic uremic syndrome, less often - thrombotic thrombocytopenic purpura.

Bacterial lipopolysaccharide (endotoxin) can act synergistically with verotoxin, aggravating endothelial cell damage by inducing local synthesis of proinflammatory cytokines - tumor necrosis factor α (TNF-α), interleukin 1β (IL-1p). In turn, an increase in TNF-α production contributes to increased endothelial damage by stimulating the activation of neutrophils in the damaged area of the vessel with subsequent release of mediators toxic to the vascular wall. The synergistic effect of verotoxin and bacterial endotoxin on local renal enhancement of TNF-α synthesis, demonstrated in the experiment, partially explains the severity of kidney damage in typical hemolytic uremic syndrome.

The key link in the pathogenesis of thrombotic thrombocytopenic purpura is currently considered to be the presence of super-large multimers of von Willebrand factor (v. W.) in the blood, the massive release of which from endothelial cells during thrombotic microangiopathy is considered an important mechanism of increased platelet aggregation, since these super-large multimers bind receptors on the platelet membrane more effectively than normal ones, which leads to rapid thrombus formation in the microcirculatory bed. Super-large v. W. multimers are detected in the bloodstream of patients with thrombotic thrombocytopenic purpura and disappear after recovery, probably as a result of the fact that their excess amount during the acute period of the disease exceeds the capabilities of proteolysis. The persistence of super-large v. W. multimers in thrombotic thrombocytopenic purpura is associated with a deficiency of the protease that breaks them down. In familial cases of the disease, this defect is hereditary and permanent; in acquired forms of thrombotic thrombocytopenic purpura, it is transient, caused by the presence of inhibitory antibodies.

The consequence of endothelial damage, regardless of the cause, is the loss of its natural thromboresistance, 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 platelet aggregation and the formation of fibrin clots. Activated endothelium, on the contrary, produces mediators that have a pronounced procoagulant and proaggregant effect: von Willebrand factor, plasminogen activator inhibitor, tissue factor. In response to damage to the vascular endothelium in thrombotic microangiopathy, in addition to excessive release of f. V., there is a decrease in the production of prostacyclin and nitric oxide, which are powerful antiaggregants, which also contributes to thrombus formation. In addition to the enhancement of platelet function, the pathogenesis of thrombotic microangiopathy is greatly affected by the disruption of the plasma link of coagulation and fibrinolysis. This is caused by increased expression of tissue factor on the surface of endothelial cells, followed by local activation of coagulation in areas of endothelial damage with increased formation and deposition of fibrin. Fibrin formation processes are also facilitated by reduced production of tissue factor inhibitor, an endogenous anticoagulant protein belonging to the serine protease family. In addition, thrombotic microangiopathy is characterized by local suppression of fibrinolysis in areas of microvascular damage due to increased production of plasminogen activator inhibitor. Thus, damage to the vascular endothelium in thrombotic microangiopathy leads to a pronounced imbalance between anti- and procoagulant mechanisms with a predominance of the latter, which results in increased thrombus formation in the microcirculatory bed of various organs, but mainly the kidneys and central nervous system.

The pathogenesis of D-HUS is less well understood. Most cases are associated with the effects of drugs or other factors that damage the endothelium or enhance microvascular thrombosis. In familial forms of the disease, low levels of the complement component C3 are found in the blood plasma, which is a consequence of a deficiency of factor H, a protein that regulates the alternative pathway of complement activation. This defect is caused by multiple mutations in the factor H gene. As a result of the loss of the regulatory influence of factor H, there is constant activation of complement, leading to endothelial damage and microthrombosis.

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

Pathomorphology of thrombotic microangiopathy

Regardless of the cause and the main pathogenetic mechanisms, the morphological picture is the same for all forms of thrombotic microangiopathy. Vascular renal pathology, characteristic of thrombotic microangiopathy, is characterized by damage to the endothelium and thrombosis of small-caliber vessels, predominant damage to arterioles and glomerular ischemia. The main morphological signs of thrombotic microangiopathy are edema of endothelial cells with their detachment from the basement membrane, expansion of the subendothelial space with accumulation of newly formed membrane-like material in it. Thrombotic microangiopathy is a special type of vascular damage, 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 hemolytic uremic syndrome depends on its form and the age of the patients. There are 2 main types of pathology that may overlap. D + HUS in children under 2 years of age is characterized mainly by glomerular damage. In the early phase of the disease, thrombi in the glomerular capillaries predominate without or with minimal damage to arterioles. After several months, the changes practically disappear in most glomeruli, but some glomeruli become sclerotic. In the most clinically severe cases, focal cortical necrosis is observed. Diffuse cortical necrosis, described in 1955 by S. Gasser, is currently extremely rare.

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

Thrombotic thrombocytopenic purpura is characterized by damage to the microcirculatory bed of not only the kidneys, but also the brain, heart, pancreas, and adrenal glands. Morphological changes in the kidneys in thrombotic thrombocytopenic purpura are similar to those in the arteriolar type of damage within the hemolytic uremic syndrome.

In all forms of thrombotic microangiopathy, glomerular lesions are focal, and, as a rule, only individual glomerular segments are affected. Important signs of thrombotic microangiopathy are thickening and double-contour of the glomerular basement membranes, which can imitate the picture of mesangiocapillary glomerulonephritis. Mesangiolysis and aneurysmal dilation of glomerular capillaries and arterioles are noted in renal biopsies in a small number of patients with thrombotic microangiopathy. Immunohistochemical examination in all types of thrombotic microangiopathy reveals fibrin deposits in glomerular capillaries and arterioles; in thrombotic thrombocytopenic purpura, IgG deposits can be detected, and in hemolytic uremic syndrome, IgM and C3 along the capillary wall. After acute thrombotic microangiopathy, focal segmental glomerulosclerosis may develop, which is usually detected in patients with long-term arterial hypertension.

Classification of thrombotic microangiopathies

I. Primary forms:

• Hemolytic uremic syndrome
  • Typical
  • Atypical
  • Hereditary
• Thrombotic thrombocytopenic purpura
  • Acute
  • Chronic relapsing
  • Hereditary

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

• malignant arterial hypertension
• systemic diseases (systemic lupus erythematosus, systemic scleroderma)
• antiphospholipid syndrome
• malignant tumors
• transplantation of organs and tissues
• HIV infection
• drug therapy
• other diseases and conditions (pancreatitis, glomerulonephritis,
• coronary artery bypass grafting, artificial heart valves)

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