Thrombocytopenia. Causes, symptoms, diagnosis and treatment.

Thrombocytopenia in children and adults can be an independent disease (primary form) or a symptom of pathologies of other systems and organs (secondary thrombocytopenia). The problem most often occurs in preschoolers and people over 40 years of age.

According to the criterion of duration of occurrence in the body, the disease is classified into:

• Spicy. There are no immediate symptoms; thrombocytopenia affects the organs for no more than six months.
• Chronic. The decrease in platelets in the blood continues for more than six months. Treatment is long-term, taking up to two years.

Causes

Platelets are formed elements of blood, nuclear-free flat plates ranging in size from 1 to 2 microns. They are formed from megakaryocytes (precursor cells) in the red bone marrow.

Megakaryocytes are relatively large cells. They have long processes and are almost completely filled with cytoplasm. During maturation, tiny fragments of their processes break off and enter the bloodstream. These are platelets. According to scientific data, from 2000 to 8000 platelets can be formed from one donor cell.

Thrombopoietin, a protein hormone produced in the kidneys, liver and muscles, is responsible for the development and growth of megakaryocytes. It is transported through the bloodstream to the red bone marrow, where it ensures the formation of megakaryocytes and platelets. The more platelets there are, the more the process of thrombopoietin formation is inhibited. This allows you to maintain the number of blood cells at the same level.

If any of these steps fail, the number of platelets in the peripheral blood decreases. Thrombocytopenia develops.

Taking into account the causes and mechanism of development, the disease comes in different forms:

• hereditary;
• productive;
• destruction;
• consumption;
• redistribution;
• breeding.

Hereditary thrombocytopenias

Hereditary thrombocytopenia is observed with various congenital anomalies. Its causes are genetic mutations:

• Wiskott-Aldrich syndrome. Caused by mutations that cause the red bone marrow to produce very small platelets (less than 1 µm in diameter). Due to their abnormal structure, they are quickly (within a few hours) destroyed in the spleen.
• May-Hegglin anomaly. A very rare genetic pathology, due to which the process of separating platelets from megakaryocytes is disrupted. As a result, the number of blood cells decreases, but their sizes become gigantic (6-7 microns). In parallel, there is a disturbance in the formation of leukocytes (leukopenia).
• Congenital amegakaryocytic thrombocytopenia. Typically, this form of thrombocytopenia is diagnosed in infants. It is associated with impaired platelet production by the bone marrow.
• Bernard-Soulier syndrome. Thrombocytopenia in a child appears only if he has inherited a defective gene from both his mother and father. The disease manifests itself in early childhood. It is characterized by the formation of functionally incompetent giant platelets (6-8 µm), unable to attach to damaged vascular walls and communicate with each other.
• TAR syndrome. A very rare cause of congenital thrombocytopenia, combined with the absence of both radius bones.

Productive thrombocytopenia

The group of productive thrombocytopenias includes pathologies of the hematopoietic system associated with disruption of the process of platelet formation in the red bone marrow. Causes of diseases:

• Acute leukemia. Stem cells mutate, and a large number of clones appear that are unable to perform specific functions. Gradually, clones displace hematopoietic ones from the red bone marrow. Not only the number of platelets decreases, but also the number of leukocytes, lymphocytes and erythrocytes.
• Myelodysplastic syndrome. The bone marrow cannot produce enough healthy cells. Hematopoietic cells multiply rapidly, but their maturation processes are disrupted. As a result, many functionally immature cells are formed (among them platelets) that undergo apoptosis (self-destruction).
• Aplastic anemia (the body produces very few new blood cells).
• Cancer metastases. Tumor cells in the final stages of cancer begin to leave the primary focus and spread throughout the body. Settling on tissues and organs, they begin to actively reproduce. This leads to the displacement of hematopoietic cells from the red bone marrow.
• Myelofibrosis. The stem cells mutate and the bone marrow is replaced by scar tissue. Foci of hematopoiesis develop in the liver and spleen (the size of the organs increases greatly due to this).
• Radiation. Ionizing radiation has a destructive effect on the hematopoietic cells of the red bone marrow. They begin to mutate.
• Alcoholism. Alcohol inhibits the processes of hematopoiesis in the red bone marrow, which reduces the content of platelets, leukocytes and red blood cells in the blood.
• Cytostatic drugs. Used to treat tumors. They can inhibit hematopoiesis in the bone marrow, which reduces the number of platelets.
• Allergic reactions to certain medications (diuretics, antibiotics, antipsychotics, anticonvulsants and anti-inflammatory drugs, antidiabetic drugs).
• Megaloblastic anemia. They develop with a deficiency of folic acid and vitamin B12.

Thrombocytopenia destruction

The cause of thrombocytopenia in this case is the increased destruction of platelets in the spleen (can also be in the lymph nodes, vascular bed or liver). Pathology is observed when:

• thrombocytopenia of newborns;
• Evans-Fisher syndrome;
• some viral diseases (viral thrombocytopenia);
• post-transfusion thrombocytopenia;
• taking medications (drug-induced thrombocytopenia);
• idiopathic thrombocytopenic purpura.

Thrombocytopenia of newborns

Occurs if there are antigens on the surface of children's platelets that are not on maternal platelets. Antibodies produced by the mother's body enter the newborn's bloodstream and destroy his platelets. The described process can last up to 20 weeks of intrauterine development. As a result, the child may be born with thrombocytopenia.

Fisher syndrome

It is a consequence of systemic diseases - autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus. Also, Evans-Fisher syndrome can develop against a background of relative well-being. Then they talk about idiopathic thrombocypenia.

Viral thrombocypenia

Once entering the body, viruses actively multiply. Antibodies are formed on the surface of the affected cells, and the cell's own antigens also change. The affected cells are destroyed in the spleen. Among the viruses that can cause thrombocypenia are measles, rubella, influenza, and chickenpox.

Post-transfusion thrombocytopenia

Post-transfusion thrombocytopenia is a consequence of platelet or blood transfusion. They are characterized by pronounced destruction of platelets in the spleen. The cause of the disease is that foreign platelets enter the body during a transfusion, to which antibodies begin to be produced.

Drug-induced thrombocytopenia

Some medications can bind to antigens on the surface of blood cells. Antibodies are produced to the formed complexes, which causes platelets to begin to be destroyed in the spleen. Among the “provoking” drugs are Quinidine, Meprobamate, Chloroquine, Ranitidine, Heparin, Cimetidine, Gentamicin, Ampicillin, etc.

Idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (also known as autoimmune thrombocytopenia or essential thrombocytopenia) is characterized by a sharp decrease in the level of platelets in the peripheral blood. At the same time, the composition of other blood elements is not disturbed.

Causes of thrombocytopenia

There are 3 main mechanisms for the development of thrombocytopenia: impaired platelet formation, their redistribution in the spleen, or accelerated consumption. Therefore, there can be many reasons for this disease. Most often, the development of thrombocytopenia is influenced by the following factors:

• Hereditary diseases
  that provoke pathological bleeding: Bernard-Sourya syndrome, May-Hegglin, TAR;
• Pathologies that prevent the creation of new platelets
  : bone marrow disorders, oncology, leukemia, reaction to chemical and radioactive elements, alcohol consumption;
• Diseases in which the body rapidly consumes platelets
  : DIC syndrome, immune disorders;
• Enlarged spleen
  . The spleen is a depot for platelets. This is where they are stored. If the organ enlarges, it takes a significant amount of red blood cells from the bloodstream. Bone marrow will not be able to compensate for such a deficiency;
• Autoimmune factors
  . When the immune system is impaired, the body begins to independently destroy its own platelets. This can occur due to systemic lupus erythematosus, encephalomyelitis;
• Taking certain medications
  . The active ingredients in medications can destroy platelets and interfere with their production by the bone marrow. Long-term use of cytostatics always leads to a similar consequence.

Causes

Why this disease occurs is unknown. Doctors talk about hereditary predisposition and the negative effects of the following factors:

• bacterial and viral infections;
• vaccinations;
• excessive exposure to solar radiation (insolation);
• general hypothermia of the body;
• some medications (Indomethacin, Furosemide).

On the surface of platelets there are molecular complexes called antigens. If a foreign antigen enters the body, the immune system immediately begins to produce specific antibodies. By interacting with antigens, they destroy the cells on whose surface they are located.

In essential thrombocytopenia, the spleen produces antibodies to its platelet antigens. They are fixed on platelet membranes and, as it were, mark them. As they pass through the spleen, blood cells are captured and destroyed.

Due to a decrease in the number of platelets, the liver begins to produce them more. The rate of maturation of megakaryocytes and the formation of platelets from them in the red bone marrow increases significantly. But gradually the compensatory capabilities of the bone marrow become thinner, and the disease makes itself felt.

If autoimmune thrombocytopenia is diagnosed during pregnancy, this means that antibodies to one’s own platelets cross the placental barrier and destroy normal fetal platelets. As a result, the child may be born sick.

Thrombocytopenia consumption

Platelets are activated in the vascular bed, and the blood clotting mechanism is activated. Due to the increased consumption of platelets, the red bone marrow begins to actively produce them, and if the cause of the pathology is not eliminated in time, their level in the blood will decrease to a critical level.

The activation of formed elements is caused by:

• Thrombotic thrombocytopenic purpura. Caused by an insufficient amount of prostacyclin in the blood. This anticoagulant factor is produced by the endothelium and prevents platelets from sticking to each other. When its release is disrupted, local platelet activation occurs and microthrombi form. Vessels are damaged and intravascular hemolysis develops.
• Disseminated intravascular coagulation syndrome. Appears as a result of severe damage to internal organs or tissues (infections, burns, injuries, surgeries, etc.), due to which the blood coagulation system is depleted. Numerous blood clots form in the vascular bed. They clog small vessels, preventing normal blood supply to the kidneys, brain and other organs. In response, the anticoagulant system is activated, aimed at restoring blood flow by breaking up blood clots. Over time, the blood completely loses its ability to clot. Severe internal bleeding may occur, which can be fatal.
• Hemolytic-uremic syndrome. Associated with intestinal infections, hereditary predisposition, systemic diseases and the use of certain medications. Bacterial toxins are released into the blood. They damage the vascular endothelium and activate platelets by attaching them to damaged areas. As a result, microthrombi are formed and microcirculation of internal organs is disrupted.

Thrombocytopenia redistribution

Normally, about 30% of all platelets are deposited in the spleen. In some diseases, the organ greatly increases in size, which is why up to 90% of the formed elements of blood are deposited in it. The disease can be caused by cirrhosis of the liver, systemic lupus erythematosus, infections, tumors, and alcoholism.

Thrombocytopenia dilution

Develops in patients who are transfused with large volumes of plasma, fluids, red blood cells, plasma substitutes, without replacing platelets. As a result, the concentration of the latter decreases to such a level that even their release from the depot is not able to maintain the normal functioning of the coagulation system.

Introduction

It is generally accepted that the diagnosis and treatment of thrombocytopenia (TP) are within the professional competence of a hematologist. At the same time, a lot of data has now been accumulated indicating a decrease in the number of platelets in various pathological conditions. This explains the need for wider discussion of this issue among doctors of various clinical specialties.

General provisions

The term “thrombocytopenia” is usually used when platelet levels are below 100.0 × 109/L, although normal platelet levels are generally considered to be between 150.0 × 109/L and 450.0 × 109/L [1]. Therefore, a number of experts identify latent AFL at platelet levels from 100.0×109/L to 150.0×109/L [2]. The identification of latent TP, in our opinion, is justified from a practical point of view. On the one hand, such a clinical situation requires dynamic monitoring of platelet levels regardless of the cause, on the other hand, when the platelet count is 100.0 × 109/l or more, hemostasis is fully ensured, which, as indicated in most available guidelines, is safe in the context of the risk of developing bleeding [3] and which allows for various surgical interventions, incl. and delivery, at the specified platelet level.

Moreover, platelet concentrations from 100×109/L to 50×109/L, occurring without spontaneous hemorrhagic syndrome, can also be considered safe. In cases where signs of bleeding appear at the specified number of platelets, one should look for an additional factor provoking hemorrhagic syndrome, or take into account the presence of vascular pathology, for example, in elderly patients. Existing approaches indicate that correction of TP should be carried out when the platelet count is from 50×109/L to 30×109/L only in the presence of hemorrhagic manifestations. A platelet count below 10.0×109/L is critical for the development of life-threatening hemorrhagic manifestations. Patients with this level of TP require immediate treatment, regardless of the degree of clinical manifestations of hemorrhagic syndrome [3, 4].

Etiopathogenesis of TP

Speaking about TP, it is necessary to emphasize the diversity of pathogenetic mechanisms leading to it and the even greater number of pathological conditions in which these pathogenetic mechanisms are realized [5]. There are two main mechanisms of the pathogenesis of TP (Table 1): impaired platelet formation and increased platelet destruction.

Diagnostic algorithms for TP

When identifying TP in a patient, a detailed analysis of the disease history is very important, in particular, establishing the factors that preceded the development of TP: bacterial or viral infection, incl. and viral hepatitis; vaccination or use of medications; stay in countries with a risk of contracting infectious diseases (malaria, rickettsiosis, dengue fever, etc.); consumption of alcoholic and quinine-containing drinks; varicose veins, thrombosis, cardiovascular pathology and its therapy with anticoagulants and antiplatelet agents; the presence of concomitant diseases, especially autoimmune, infectious or tumor ones, occurring with TP, DIC syndrome; transfusion; history of organ transplantation; pregnancy; the presence and duration of bleeding after surgery.

In the family history, it is necessary to clarify the presence of diseases of the hematopoietic system in relatives.

When conducting an objective study, one should actively identify symptoms such as hypo- or hyperthermia, weight loss, symptoms of intoxication, hepato- and splenomegaly, lymphadenopathy, pathology of the mammary glands, heart, veins of the lower extremities, as well as congenital anomalies. All this data is not specific.

Laboratory and instrumental diagnostics includes several areas. In a clinical blood test, an optical count of the number of platelets and an assessment of the morphology of platelets (microforms and giant platelets) are required, but it should be remembered that in the presence of platelet aggregates, a repeat analysis is necessary to exclude “false” LT when using the preservative EDTA (ethylenediaminetetraacetate calcium-sodium). a test tube containing sodium citrate is used). All patients undergo an ultrasound or computed tomography (CT) scan of the abdominal cavity and retroperitoneal space, radiography or CT of the chest, as well as an examination to exclude oncological diseases. Taking into account that idiopathic thrombocytopenic purpura (ITP) is a diagnosis of exclusion, the range of laboratory tests used is quite wide (Table 2), according to their diagnostic significance they are divided into mandatory, potentially useful and tests with unproven informativeness.

Principles of ITP treatment

There are several lines of therapy in the treatment of ITP. At the first stage, hormones (prednisolone, dexamethasone) and specific immunoglobulin are used. Second-line therapy includes splenectomy and thrombopoiesis stimulators (thrombopoietin mimetics). Rituximab and other drugs with immunosuppressive effects (azathioprine, cyclophosphamide, cyclosporine A, vincristine, vinblastine) are considered as a reserve agent (third line of therapy) [4].

TP in gastroenterology

Taking into account the multiplicity of causes of TP, it is necessary to exclude diseases that may have a decrease in platelet levels in the clinical picture; in the practice of a gastroenterologist, these are primarily H. pylori-associated diseases and liver lesions of various origins.

In 1998, A. Gasbarrini et al. published in the Lancet journal the article “Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori”, which marked the beginning of a new direction in the study of helicobacter pylori, associated conditions, as well as closer interaction between doctors of two clinical specialties, namely gastroenterologists and hematologists [6] . It has previously been shown that autoimmune reactions through cross-mimicry between Lewis system antigens of gastric epithelial cells and H. pylori may play a role in Helicobacter-induced mucosal damage; monoclonal anti-H. pylori antibodies interact with tissues outside the gastrointestinal tract, namely with epithelial cells of the ducts of the salivary glands and renal tubules [7]; polyclonal anti-H. pylori antibodies interact with the capillaries of the renal glomeruli, which can lead to membranous nephropathy [8]. Based on data from previous studies, in particular on the results of observations [9] on the relief of manifestations of Henoch-Schönlein disease after successful eradication therapy, A. Gasbarrini et al. suggested a pathophysiological link between ITP and chronic H. pylori infection. They described an increase in platelet levels in all 8 ITP patients who received eradication therapy, while the platelet level in 3 people who did not receive such therapy remained unchanged.

To date, a lot of works, systematic reviews have been published that have studied the relationship between ITP and H. pylori, the mechanisms of development of this relationship, identifying predictors of a positive response to eradication therapy.

Several hypotheses have been proposed for the mechanisms by which H. pylori causes the development of ITP. It is believed that cross-reactive antibodies are produced that interact with both components of H. pylori and platelet surface antigens through molecular mimicry. Italian scientists led by R. Scandellari have shown that infection with H. pylori strains expressing CagA (cytotoxin-associated gene A) can cause chronic cases of ITP. According to their study, an increase in platelet count after eradication therapy was observed in 43% of patients after 6 months of follow-up. Patients were comparable for all major clinical features with one exception: serum anti-CagA antibodies were present in 83% of responders and only 12.5% ​​of non-responders (p=0.026). The authors concluded that antibiotic therapy for H. pylori infection can lead to the disappearance of immune cross-reacting antibodies and, therefore, can be considered as a treatment option for patients with ITP, especially for those individuals who have antibodies to CagA [10]. Subsequently, based on data obtained by R. Scandellari et al., and also taking into account the fact that almost all CagA-positive strains of H. pylori also express a vacuolating toxin, a group of researchers led by N. Figura suggested the existence of molecular mimicry of some platelet peptides with vacuolating cytotoxin A of H. pylori. In particular, the platelet component binding domain of the 289 amino acid receptor for von Willebrand factor (GP1b-platelet) showed some structural similarity to H. pylori VacA-[11]. M. Michel et al. [12] also explored the molecular mimicry hypothesis and found that platelets from H. pylori-infected ITP patients, which have the ability to react with GPIIb/IIIa or GPIb, cannot recognize H. pylori antigens. On the other hand, T. Takahashi et al. [13] reported that platelets from patients with ITP infected with H. pylori “recognized” CagA in an immunoblotting reaction, but platelets from patients infected with H. pylori but without ITP did not. Y. Bai et al. studied the cross-reaction of a monoclonal antibody against Helicobacter urease B with the platelet surface glycoprotein GPIIb/IIIa and suggested that the immune response to UreB may be involved in the pathogenesis of ITP [14]. Taken together, these data suggest that cross-reacting antibodies against H. pylori may be present in patients with ITP, but their pathogenetic role is not completely clear.

Another mechanism considered is that chronic H. pylori infection may nonspecifically affect the host immune system, stimulating acquired immune responses through the production of T and B autoantibodies. Japanese researchers S. Yamanishi et al. [15] showed that H. pylori urease is capable of initiating autoimmune reactions by activating B1 cells, but this does not explain the development of a platelet glycoprotein-specific autoimmune response in ITP. Moreover, in the work of R. Pellicano et al. showed no differences in the production of nonspecific autoantibodies (antinuclear, antimicrosomal, antismooth muscle) in ITP in individuals with and without H. pylori [16].

M. Kuwana et al. [17] proposed a “pathogenic loop” model: the appearance of antiplatelet autoantibodies in patients with ITP. The point is that macrophages of the reticuloendothelial system “capture” platelets through Fcγ receptors and “transfer” platelet antigens (glycoproteins) to T cells (CD4+), which in turn, being activated, stimulate B cells to produce antiplatelet antibodies , resulting in binding to circulating platelets, thereby closing the “pathogenic loop”. After successful eradication of H. pylori, antiplatelet antibodies are removed [18], therefore, the “pathogenic loop” is stopped. M. Kuwana et al., having conducted a prospective study, showed increased phagocytic ability and low levels of expression of the inhibitory FcγRIIB in circulating monocytes in ITP patients infected with H. pylori; similar changes were not detected in H. pylori-negative patients. In the case of successful eradication, suppression of the activated monocyte phenotype was observed, followed by a decrease in the level of antiplatelet autoantibodies and an increase in the number of platelets. Thus, H. pylori may modulate the monocyte/macrophage Fcγ receptor balance in favor of Fcγ receptor activation [17, 19].

A number of studies have attempted to define the characteristics of H. pylori-associated ITP by comparing the clinical findings of adult patients with ITP with or without H. pylori infection. ITP patients infected with H. pylori were significantly older than those uninfected [20], but this may be because the prevalence of H. pylori infection increases with age in the general population. Many other studies found no significant differences in any other demographic or clinical characteristics, including gender, platelet count, or response to therapy. Several studies have found differences in the genetic factors of patients with ITP with or without H. pylori. Italian researchers D. Veneri et al. [21] studied the HLA-DRB1 and DQB1 alleles of patients with ITP and found that H. pylori-positive patients had lower frequencies of DRB1*03 and higher frequencies of DRB1*11, DRB1*14 and DQB1*03 compared with H pylori-negative patients. However, in Japanese patients with ITP, no association was found between H. pylori infection and the HLA-DRB1 or DQB1 alleles, but gene polymorphisms at loci for interleukin-1β (IL-1β) were found to be associated with H. pylori infection in patients with ITP in under 50 years of age [17, 22]. There were no differences in IL-2, -4, or -6 levels between ITP patients with and without H. pylori infection [23]. Serum levels of chemokines, typically regulated by T cells, were significantly higher in ITP patients with H. pylori infection than in patients without it, but similar increases also occurred in individuals who had H. pylori-associated gastrointestinal pathology. -intestinal tract, but there was no ITP [24]. Thus, to date, no demographic, clinical, genetic, or immunologic characteristics unique to H. pylori-infected ITP patients have been identified. This is likely due to the fact that there are at least two distinct subgroups of ITP patients infected with H. pylori: patients with secondary ITP caused by H. pylori, in which case these patients respond to eradication therapy, and those with primary ITP. ITP and “occasional” co-infection with H. pylori.

Factors predicting the positive effect of eradication therapy on the course of ITP, namely an increase in the number of platelets, have been widely studied. The most frequently identified favorable predictor is a shorter history of ITP [20, 25, 26], but other studies do not find this association [27–29]. Some investigators have reported a significant beneficial effect of H. pylori eradication in patients with mild AFL, but patients with severe AFL showed a poor response to eradication [30]. Clinical characteristics such as age less than 65 years at diagnosis of ITP [25], higher baseline platelet count [25], no prior corticosteroid therapy [27], no concomitant corticosteroid therapy [31, 32], and no prior therapy for ITP [25 ], are also considered as factors predicting a positive platelet “response” to treatment, but information about their reliability is even more controversial. Several studies have examined genetic predisposition to platelet response to H. pylori therapy; in particular, an association has been shown between HLA-DQB1*03 haplotypes and a higher likelihood of a positive platelet response [21]. Single nucleotide polymorphisms in the tumor necrosis factor β and Fcγ receptor IIB inhibitor (FcγRIIB) genes have been found to be useful for predicting the response of LT to eradication therapy [32, 33]. The presence of antiplatelet-specific anti-GPIb autoantibodies has been found to predict resistance to H. pylori eradication therapy [17]. There is conflicting evidence regarding the effect of anti-CagA antibodies on the prognosis of elevated platelet counts: a study in Italy found that patients with ITP and anti-CagA antibodies were more likely than patients without them to respond favorably to eradication therapy [10], but a study in Japan, this observation was not confirmed [26]. R. Sato et al. [34] assessed the potential relationship of platelet response to H. pylori eradication with fibroesophagogastroduodenoscopy data and the results of histological examination of gastric biopsies: severe inflammation and signs of atrophy in the body of the stomach were regarded as predictors of a favorable outcome. Thus, both genetic background and bacterial factors that regulate the level of inflammatory response to H. pylori infection can be used to predict the success of eradication therapy for the treatment of LT.

Despite encouraging research data, a number of scientists doubt the existence of a causal relationship between ITP and H. pylori infection, and, accordingly, the effect of eradication therapy on platelet counts. Thus, the results of work carried out by AD Samson et al. [35] report no significant differences between H. pylori-positive and H. pylori-negative patients in terms of platelet counts. Researchers from Malaysia [36] reported a low prevalence of H. pylori infection in patients with ITP and no significant effect of H. pylori eradication on platelet counts.

LT is a common hematological disorder in patients with chronic liver disease [2, 37]. The prevalence of LT varies depending on a number of factors, such as the patient population and the severity of the underlying liver disease, and the degree of LT serves as an early prognostic marker (APRI - Aspartate-aminotransferase-to-Platelet Ratio Index), allowing a preliminary assessment of the presence of significant liver disease. liver fibrosis without resorting to biopsy [38]. The incidence of AFL among patients with liver cirrhosis reaches 80% [39].

The genesis of TP in liver diseases is multifactorial. The pathophysiology of TP in chronic liver disease has long [40] been associated with the hypothesis of hypersplenism, when portal hypertension causes the pooling and sequestration of all corpuscular elements of the blood, mainly platelets, in an enlarged and congested spleen. Liver transplantation normalizes liver failure and reduces hypersplenism [41].

Impaired platelet formation in liver diseases is also associated with a decrease in the activity and level of thrombopoietin, the main cytokine produced by the liver and affecting all stages of megakaryocyte differentiation and platelet synthesis.

In addition to the effect on hematopoietic cells, there is an assumption that thrombopoietin binds directly to platelets circulating in the vascular bed, which leads to an increase in their functional activity [42]. A decrease in thrombopoietin synthetic function of the liver leads to a decrease in thrombopoiesis in the bone marrow and, consequently, to TP in the peripheral blood. Restoration of adequate thrombopoietic production after liver transplantation leads to a rapid restoration of platelet production [43].

Suppression of platelet formation in the bone marrow can be caused by alcohol, one of the common etiological factors of liver disease. Alcohol-induced AFL is due to the direct toxic effect of alcohol on megakaryocytes, resulting in decreased platelet production, survival time, and function [44, 45]. A number of drugs used in the treatment of liver diseases (azathioprine, β-lactam antibiotics and fluoroquinolones, interferon) can potentially cause drug-induced AFL, having both a direct myelosuppressive effect and immune-mediated platelet destruction. Until recently, treatment regimens for patients with HCV (Hepatitis C Virus) included interferon, a common side effect of which is dose-dependent LT, interferon-induced myelotoxicity and cytopenia became a common reason for discontinuation of therapy [2, 46].

Another proven pathogenetic mechanism for the development of TP is autoimmune disorders. Among patients with chronic liver diseases of various etiologies, up to 64% have antiplatelet antibodies, which are mainly directed against the glycoprotein IIb-IX complex [47]. Most often, immune-mediated LT occurs with HCV, bacterial and drug-induced liver damage. Autoimmune liver diseases (autoimmune hepatitis and primary biliary cholangitis - PBC) are often associated with other autoimmune conditions. About 50% of patients with PBC have at least one additional autoimmune disease, which may include ITP [48].

Some etiological factors of liver damage have their own mechanisms that affect platelet levels. Thus, it has been shown that HCV infection can lead to the appearance of TP in a patient before the stage of cirrhosis and hypersplenism appears. More than 20 years ago, studies appeared indicating the association of HCV and TP [49–51]. Up to 30% of patients with ITP without evidence of progressive liver disease are HCV seropositive [52]. Chronic HCV infection can lead to LT through various mechanisms [53], one of which is direct suppression of bone marrow hematopoiesis [54]. Patients with HCV demonstrate platelet depression even in the absence of splenomegaly [55] and normalization of platelet levels after successful treatment of infection [56]. Chronic HCV infection is known to be associated with a variety of autoimmune disorders, with approximately 40% of patients with HCV infection having at least one immune-mediated extrahepatic manifestation during the course of their disease [57, 58]. A decrease in platelet levels in HCV correlates with the severity of the disease and is accompanied by an increase in antiplatelet Ig titers [49, 55]. In addition, HCV can directly interact with platelets to bind platelet membranes through multiple cell surface receptors, ultimately leading to phagocytosis of platelets with antibody and accelerated platelet destruction by the reticuloendothelial system [59].

Binding of HCV to platelets can also induce the formation of antigens on the platelet surface or alter the properties of the platelet glycoprodeid membrane, which contributes to the formation of autoantibodies, such as GPIIb/IIIa, and the subsequent development of LT [60]. Finally, HCV is closely associated with cryoglobulinemia, and cryoglobulins may play a role in the formation of immune complexes and the development of TP [61].

Conclusion

TP is a complex and multifactorial phenomenon, often encountered in the practice of a gastroenterologist. A thorough understanding of the pathophysiology of TP in relation to its cause is critical when choosing treatment strategies. Awareness of specialists about the mechanisms of development of TP in diseases of the digestive system will help to increase the success of therapy.

Symptoms of thrombocytopenia

The mechanism for the development of thrombocytopenia symptoms is always the same. Due to a decrease in platelet concentration, the nutrition of the walls of blood vessels is disrupted, and capillary fragility increases. At a certain moment, due to a minor physical factor or spontaneously, the integrity of the capillaries is disrupted, and severe bleeding occurs (this is usually depicted in the photo as thrombocypenia). The lack of platelets prevents the formation of a platelet plug in the burst vessels, so blood flows from the circulation into the surrounding tissues.

The main symptoms of thrombocytopenia:

• Purpura (bleeding into mucous membranes, skin). Small red spots form on the body. They do not disappear when pressed, do not hurt and do not rise above the surface of the skin. Their size can range from a few millimeters to several centimeters in diameter. At the same time, bruises may appear.
• Bleeding gums. It forms on a large surface and does not stop for a long time.
• Frequent nosebleeds. Can be caused by sneezing, microtrauma, colds. The blood that comes out is bright red. Sometimes the bleeding cannot be stopped for an hour.
• Hematuria (blood in the urine). Occurs due to hemorrhage in the mucous membranes of the bladder or urinary tract.
• Gastric and intestinal bleeding. They are a consequence of increased fragility of the vessels of the gastrointestinal mucosa, traumatizing it with rough food. The stool becomes red and bloody vomiting may occur.
• Heavy and prolonged menstrual bleeding.

If you experience similar symptoms,
consult your doctor . It is easier to prevent a disease than to deal with the consequences.

Classification of thrombocytopenia

Let's talk about the causes of thrombocytopenia that underlie the different types of this disease.

Hereditary thrombocytopenias

These conditions are based on diseases of genetic origin. These may be May-Hegglin anomaly, Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, TAR syndrome, as well as congenital amegakaryocytic thrombocytopenia.

Each of these diseases has many characteristics. For example, Wiskott-Aldrich syndrome occurs exclusively in boys and occurs in four to ten cases per million. Bernard-Soulier syndrome can only develop in a baby who has received the altered gene from both parents, and May-Hegglin anomaly can develop in 50% of cases, provided that only one parent has the prerequisites for this. As a rule, all of these diseases have among their symptoms not only a low level of platelets, but also a number of other pathological conditions, and therefore require special treatment.

Diagnostics

The presence of thrombocytopenia in children and adults is indicated by a decrease in the number of platelets in the blood. To make an accurate diagnosis and prescribe quality treatment, additional studies are carried out, which can be completed in any modern hematology clinic

:

• general blood analysis;
• Duke bleeding time assessment;
• puncture of red bone marrow (allows you to study the state of the hematopoietic system);
• determination of blood clotting time;
• genetic research (carried out if hereditary thrombocytopenia is suspected);
• determination of antibodies in the blood (clarification of the ratio of antibodies and platelets);
• Ultrasound (makes it possible to study the density and structure of internal organs, determine the size of the liver and spleen);
• MRI (to obtain layer-by-layer images of blood vessels and internal organs).

Thrombocytopenia in cancer patients

Thrombocytopenia is a problem that is familiar to many cancer patients. It develops due to chemotherapy: due to the use of platinum drugs (carboplatin, cisplatin, oxaliplatin) and gemcitabine. Each drug has its own mechanism for the development of thrombocytopenia:

• Platinum preparations
  . These are alkylating agents that affect stem cells. Because of this, the production of platelets, as well as leukocytes and red blood cells, is suppressed;
• Cyclophosphamide
  . Affects the formation of megakaryocytes, from which platelets are subsequently formed;
• Bortezomib
  . Disturbs the process of separation of platelets from megakaryocytes;
• Some medications cause platelet death
  .

Radiation therapy also causes thrombocytopenia: it impairs bone marrow function, leading to low red blood cell levels. Thrombocytopenia develops especially often after radiation therapy in the pelvic area.

The likelihood of developing thrombocytopenia is even higher when radiation and chemotherapy are administered simultaneously. Certain tumors can also contribute to the development of this disease: lymphoma and leukemia. In this case, cancer cells quickly attack the red bone marrow, replacing its tissue with pathological ones. Less commonly, thrombocytopenia develops with damage to the bones, mammary glands, prostate and spleen.

When the level of platelets in the blood of cancer patients decreases, doctors need to determine the exact causes of this phenomenon. It may be necessary to change the treatment regimen or replace medications. Due to thrombocytopenia, the patient’s well-being significantly worsens, and difficulties arise in the treatment of oncology. Among them:

• When platelets decrease to less than 100*109 per liter
  , the risk of bleeding increases;
• Less than 50*109 per liter
  – surgical interventions are not possible due to the risk of bleeding;
• Less than 10*109 per liter
  – multiple spontaneous bleeding occurs.

Treatment of thrombocytopenia

Thrombocytopenia is treated by a hematologist. First, the patient’s condition is assessed and the severity of the hemorrhagic syndrome is studied.

• With mild severity (50,000-150,000 platelets per μl of blood), the capillary walls are in normal condition, so blood does not leave the vascular bed. Severe bleeding does not develop. Therefore, the problem can be solved without medications. The cause of the disease is being determined. The doctor adheres to a wait-and-see approach. The patient is not hospitalized.
• With moderate severity (25,000-50,000 platelets per μl of blood), hemorrhages in the oral mucosa and nosebleeds are observed. With minor bruises, large bruises form. If there is a risk of bleeding (presence of a stomach ulcer, playing professional sports, etc.), drug therapy is carried out. The patient can undergo treatment at home.
• With severe thrombocypenia (less than 20,000 platelets per μl of blood), spontaneous bleeding occurs in the mucous membranes of the mouth and skin. Hemorrhagic syndrome appears. Prescription of complex drug therapy is mandatory. The patient is hospitalized.

Treatment of thrombocytopenia with drugs

Drug treatment for any form of thrombocytopenia is aimed at:

• stopping bleeding;
• eliminating the cause;
• treatment of the disease that caused the problem.

Patients are usually prescribed medications:

• "Prednisolone";
• "Intraglobulin", "Imbiogam";
• "Revolade";
• "Vincristine";
• "Etamzilat";
• "Depo-Provera";
• vitamin B12.

Non-drug treatments for thrombocytopenia

Treatment of thrombocypenia can be carried out using therapeutic and surgical measures. Most often, hematologists resort to:

• Transfusion therapy. The patient is transfused with donor blood (plasma or platelets).
• Removal of the spleen. The spleen is the main source of antibodies in immune thrombocytopenia and the main site of platelet destruction, so sometimes it is completely or partially removed. In most patients, after removal of the spleen for thrombocytopenia, the condition returns to normal and the clinical symptoms of the disease disappear.
• Bone marrow transplant. First, the patient is prescribed large doses of anticancer drugs that suppress the immune system. This is done in order to prevent the immune system from reacting to the introduction of donor bone marrow, as well as to destroy tumor cells if we are talking about a tumor of the hematopoietic system.

Treatment of thrombocytopenia during pregnancy

Thrombocytopenia in pregnant women requires proper treatment. Typically, expectant mothers are prescribed short courses of glucocorticosteroids (Dexamethasone, Prednisolone). In the third trimester, they accelerate the maturation of the fetal lungs, which makes early delivery possible.

If glucocorticosteroids are ineffective, immunoglobulin is administered intravenously. During the entire pregnancy it is used three to four times, and then again immediately after childbirth. In emergency situations, platelet transfusions are used.

If all the measures taken do not eliminate the symptoms of the disease, the spleen is removed in the second trimester (surgery is especially often resorted to if severe gestational thrombocytopenia is diagnosed in the first trimester). Ideally, surgery should be performed laparoscopically.

The issue of delivery is always decided on an individual basis. Thrombocytopenia during childbirth can lead to severe bleeding, so doctors carefully weigh the pros and cons. A cesarean section is considered less traumatic for the female body.

Treatment of thrombocytopenia with folk remedies

Thrombocytopenia is treated with the leaves of nettle, yarrow, and strawberry. Herbs are brewed with boiling water and drunk chilled, 1/4 cup 3-4 times a day.

Sesame oil has proven itself well for thrombocytopenia. It should be taken one tablespoon 3 times a day.

Forms and types of thrombocytopenia

In medicine, there are several types of thrombocytopenia:

1. Autoimmune. A “failure” occurs in the body and the immune system begins to perceive its own platelets as foreign bodies. The result is the destruction of these blood cells. How to treat autoimmune thrombocytopenia? Doctors provide symptomatic therapy and administer special medications that support the immune system. The complex of treatment measures consists of a course of glucocorticosteroids, after which, in the absence of positive dynamics, surgical removal of the spleen is performed, followed by the prescription of immunosuppressants.

.

2. Essential thrombocytopenia. It is most often diagnosed in people aged 50-70 years. Its development is often associated with previous surgical interventions, chronic pathologies of internal organs, and iron deficiency. Treatment of essential thrombocytopenia is reduced to taking Aspirin. Since no serious problems in the functioning of the body are identified, the prescription of aggressive toxic drugs is considered unjustified.
3. Thrombocytopenic purpura syndrome - this type of disease was first described by doctors. It is diagnosed mainly in childhood. It occurs much more often in girls than in boys. The syndrome is associated with a blood clotting disorder, so the patient will need to not only undergo a course of treatment, but also be constantly monitored by a hematologist.
4. Thrombocytopenia in newborns. It can develop both as an accompanying condition with congenital pathologies, and as a secondary disease with infection of the baby, premature birth or asphyxia during childbirth. Treatment begins in the maternity hospital, using prednisolone, immunoglobulin, and ascorbic acid. Thrombocytopenia in newborns often requires platelet transfusion. For the entire period of treatment, the baby is removed from breastfeeding.

Treatment and severity

Treatment of thrombocytopenia most often comes down to identifying the primary disease and its treatment, as well as eliminating various unpleasant symptoms. In the process, it is also important to take into account that the severity of thrombocytopenia varies:

Mild degree. It assumes that the platelet concentration is from 50 to 150 thousand units per microliter. The condition of the capillaries is usually normal, bleeding does not develop. Usually, treatment is not necessary at this stage - doctors recommend waiting and monitoring the development of the patient’s condition.

Average degree. In this case, the concentration is 20-50 thousand platelet units per microliter. Under this condition, bleeding gums and nosebleeds are observed. If injuries and bruises occur, serious hemorrhages form in the skin. At this stage, drug therapy may be prescribed.

Severe degree. The platelet concentration is below 20 thousand, hemorrhages are spontaneous and severe. At the same time, the patient himself may feel quite comfortable, does not complain of feeling unwell, but tests show that he needs help.

Since the treatment of thrombocytopenia requires the most thorough and detailed diagnosis, it is important to choose a modern clinic that will help you. JSC "Medicine" in Moscow is just the place where you can get qualified help from the best specialists. The clinic has everything necessary for both examination and treatment of each patient.