Modern methods of treating immune thrombocytopenia. Prospects for the use of rituximab in human autoimmune diseases Interactions with other active substances

MabThera significantly reduces the risk of serious bleeding in people with a life-threatening autoimmune disorder.
New data presented at the 50th Annual Congress of the American Society of Hematology showed that those patients with untreated idiopathic thrombocytopenic purpura who were treated with MabThera in combination with standard therapy were significantly less bleeding-free. long term than those whose prescription list did not include Mabthera. The drug helped maintain the platelet count in their blood at a level that prevented potentially life-threatening bleeding in vital organs such as the brain.
People with chronic idiopathic thrombocytopenic purpura and a very low platelet count live with the constant threat of bleeding. The goal of treatment is to stop the level of platelets in the blood from falling and thus prevent the possibility of bleeding. “The new data proves that Mabthera offers patients suffering from this incurable disease real hope of increasing their life expectancy,” said Francesco Zaya, head of the University of Udine in Italy, who led the team studying the drug.
Idiopathic thrombocytopenic purpura is an autoimmune disease in which the body destroys its own blood and the blood cells do not produce enough blood cells to protect themselves.
This means that the blood does not clot properly. The result is bleeding from the nose, gums, viscera, or even the brain. Chronic idiopathic thrombocytopenic purpura usually affects adults and is most common in women.
Francesco Zaya believes that “news of the emergence similar drug“This is extremely good news for carriers of this potentially life-threatening disease, as existing forms of treatment to date have only resulted in symptomatic relief, not a complete cure.”
The aim of Francesco Zaya's research was to evaluate the effect of the monoclonal antibody drug MabThera in combination with the corticosteroid dexamethasone in adult patients with untreated thrombocytopenic purpura. The study, which was conducted from July 2005 to June 2007, included 101 patients with platelet counts less than 20 x 10E9/L. Of these, 49 patients were treated with MabThera in combination with dexamethasone and 52 patients were treated with dexamethasone alone. After the first six months of treatment, the platelet count in patients of the first group exceeded 50 x 10E9/l. Such results undoubtedly allow us to conclude that Mabthera is a positive indication for the treatment of idiopathic thrombocytopenic purpura.

In case of life-threatening bleeding, platelet transfusions, intravenous corticosteroids, intravenous anti-D immunoglobulin, and IVIG should be given.

ITP usually results from autoantibodies directed against platelet structural antigens. In childhood ITP, the autoantibody may be associated with viral antigens. The trigger in adults is unknown.

Symptoms and signs of immune thrombocytopenia

Symptoms and signs include petechiae, purpura, and mucosal bleeding. Gastrointestinal bleeding and hematuria are uncommon in ITP. The spleen is not enlarged, except in cases of concomitant childhood viral infection. ITP is also associated with an increased risk of thrombosis.

Diagnosis of immune thrombocytopenia

ITP is suspected in patients with isolated thrombocytopenia. Since there are no specific manifestations of ITP, causes of isolated thrombocytopenia (eg, drugs, alcohol, lymphoproliferative diseases, other autoimmune diseases, viral infections) should be excluded when conducting clinical assessment and testing. As a rule, patients are prescribed coagulation studies, liver function tests, and tests for hepatitis C and HIV. The antiplatelet antibody test is pointless for diagnosis and treatment.

To make a diagnosis, research bone marrow not required, but should be performed in cases where abnormalities are found in the blood or blood smear in addition to thrombocytopenia; When clinical signs are not typical. In patients with ITP, bone marrow examination reveals a normal or slightly increased number of megakaryocytes in an otherwise normal bone marrow sample.

Prognosis of immune thrombocytopenia

Children usually recover spontaneously (even from severe thrombocytopenia) within weeks or months.

Spontaneous remission may occur in adults, but this rarely occurs after the first year of illness. However, in many patients the disease progresses in soft form(i.e. platelet count >30,000/µL) with minimal or no bleeding; Such cases are more common than previously thought; many of them, previously detected by automated platelet counting, are now detected using general analysis blood. Other patients have significant symptomatic thrombocytopenia, although life-threatening bleeding and death are rare.

Treatment of immune thrombocytopenia

• Oral corticosteroids.
• Intravenous immunoglobulin (IVIG).
• Intravenous anti-D immunoglobulin.
• Splenectomy.
• Thrombopoietin agonists.
• Rituximab.
• Other immunosuppressants.
• For severe bleeding: IVIG, intravenous administration anti-D immunoglobulin, intravenous corticosteroids and/or platelet transfusion.

Adults with bleeding and platelet counts<30 000/мкл на начальном этапе обычно назначают пероральные кортикостероиды. Альтернативой (но менее эффективной) кортикостероидному режиму является дексаметазон. Если присутствует сильное кровотечение или есть необходимость быстро увеличить количество тромбоцитов, то к кортикостероидам может быть добавлен ВВИГ или внутривенный анти-D иммуноглобулин, У большинства пациентов количество тромбоцитов увеличивается через 2-4 недели; однако при постепенном уменьшении применения кортикостероида у пациентов возникает рецидив. Повторное лечение кортикостероидами может быть эффективным, но увеличивает риск побочных эффектов. Прием кортикостероидов следует прекратить после первых нескольких месяцев; нужно попробовать другие препараты для избежания спленэктомии.

Splenectomy can achieve complete remission in about two-thirds of patients who relapse, but it is typically reserved for patients with severe thrombocytopenia or bleeding and may not be appropriate for patients with mild disease. If thrombocytopenia can be controlled with medical therapy, splenectomy is often delayed for 6 to 12 months to allow spontaneous remission to occur.

Second-line medical therapy is reserved for patients who wish to delay splenectomy in hopes of spontaneous remission; those who are not candidates for splenectomy or who refuse it, and those for whom splenectomy is ineffective. In such patients, the platelet count is usually<10 000 до 20 000/мкл (и, следовательно, подвержены риску кровотечения). Вторая линия медицинской терапии включает агонисты тромбопоэтина, ритуксимаб и другие иммунодепрессанты. Уровень восприимчивости к агонистам тромбоэтина, таким как ромипластин и эльтромбопаг, более 85%. Тем не менее, агонисты тромбоэтина нужно вводить непрерывно, чтобы поддерживать число тромбоцитов >50,000/µl. Susceptibility to rituximab reaches 57%, but only 21% of adult patients remain in remission after 5 years. Patients with severe symptomatic thrombocytopenia unresponsive to other drugs may require intensive immunosuppression with drugs such as cyclophosphamide and azathioprine.

Children are usually prescribed supportive treatment, because... most recover spontaneously. Even after months or years of thrombocytopenia, most children experience spontaneous remissions. If mucosal bleeding occurs, corticosteroids or IVIG may be prescribed. The use of corticosteroids and IVIG is controversial because an increased platelet count may not improve clinical outcome. Splenectomy is rarely done in children. However, if severe symptomatic thrombocytopenia is observed for 6 months or more, splenectomy is considered.

Phagocytic blockade is achieved by using IVIG or anti-D immunoglobulin. High-dose methylprednisolone is cheaper than IVIG or intravenous anti-D immunoglobulin, easier to use, but less effective. Patients with ITP and life-threatening bleeding are also given platelet transfusions. Platelet transfusions are not used for prophylactic purposes.

Oral corticosteroids, IVIG, or intravenous anti-D immunoglobulin may also be used to temporarily increase platelet counts needed during tooth extraction, childbirth, or other invasive procedures.

IAT is a disease characterized by an isolated decrease in the number of peripheral blood platelets (less than 150x10*9/l) due to the reaction of autoantibodies with platelet antigens and subsequent destruction in the RES, especially in the spleen, and a decrease in the lifespan of platelets.

Epidemiology.
The incidence of IAT is on average 60 cases per 1 million population. Women get sick more often than men.

Etiology not installed.
There is a connection between the occurrence of IAT and a viral or, less commonly, bacterial infection.

Pathogenesis.
IAT is an antibody (autoimmune) and immune complex (heteroimmune) disease. It develops as a result of the effect on platelets of antiplatelet ATs, which belong to Fg class G.
The main site of production of antithrombotic ATs is the spleen.
It also serves as the main site of destruction of AT-loaded platelets.
The lifespan of platelets with IAT is reduced to several hours, whereas normally it is 8-10 days.

Clinical manifestations hemorrhagic diathesis of the petechial-spot type develops with thrombocytopenia less than 30x10*9/l.
Characteristic is the appearance on the skin and mucous membranes of painless, without signs of inflammation, pinpoint hemorrhagic rashes - petechiae and (or) spotty (about 1-2 cm in diameter), not tense, not stratifying the tissues of hemorrhages - “bruises”.
There are repeated nosebleeds, bleeding from the gastrointestinal tract, uterine bleeding, hematuria, hemorrhages in the retina with loss of vision and hemorrhages in the brain and its membranes, and other internal bleeding.
The typical localization of hemorrhagic rashes is on the lower extremities and lower half of the torso, mainly along the anterior surface of the abdominal wall. Especially often, hemorrhages first appear in places where the skin is compressed or rubbed by clothing.
IAT can be acute (usually in children) or chronic (adults).

Diagnostics.
Manifestations of hemorrhagic diathesis of the petechial-spot type. Peripheral blood: the presence of IAT will be indicated by an isolated decrease in the number of platelets without changes in other hemogram parameters; often the platelet size is increased.
With massive blood loss, reticulocytosis and hypochromic (microcytic) anemia may develop.
ESR is usually elevated.
Duration of bleeding according to Duke is increased.
Blood clotting time according to the Lee-White method remains within normal limits. Retraction of the blood clot is slowed down.
It is necessary to be aware of the possibility of pseudothrombocytopenia (artifact) when automatically counting the platelet count on an analyzer using EDTA.

The presence of circulating autoantibodies is detected in less than 50% of patients.
The absence of platelet antibodies does not negate the diagnosis of IAT.
For final verification of the diagnosis, it is necessary to perform a morphological examination of the bone marrow and an immunological study.

Pathomorphology bone marrow: hyperplasia of megakaryocytic elements without signs of dysplasia.
There are no changes in erythroid and myeloid lineages.
The number of mature megakaryocytes is increased; among them, cells with a large nucleus and wide cytoplasm predominate, from which platelets are actively “detached.”
In IT with a platelet count of less than (20-10)x10*9/l, megakaryocytes predominate in the bone marrow without signs of active “detachment”, which is not due to a dysfunction of megakaryocytes, but to the effect of increased consumption.

Differential diagnosis.
The diagnosis of IAT is made on the basis of thrombocytopenia if all other possible causes are excluded:
1. Congenital non-immune thrombocytopenia.
2. Secondary autoimmune thrombocytopenia due to HIV infection, other autoimmune diseases (collagenosis, especially SLE, CAH), chronic lymphoproliferation, while taking medications that induce autoimmune thrombocytopenia (heparin-induced thrombocytopenia).
3. Acquired immune thrombocytopenia (post-transfusion thrombocytopenia induced by drugs - kinin, kinidin, gold, sulfonamides, digitoxin, thiazides, etc.).
4. Acquired non-immune thrombocytopenia (severe infections, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, snake bites, hypoxia, heart defects, burns, hypersplenism, medications).
5. Thrombocytopenia due to malignant diseases.

Treatment.
Search and sanitation of foci of infection are required.
Patients with platelet levels above 30x10*9/l do not require treatment unless they undergo interventions with possible bleeding (surgeries, dental extractions, childbirth).

Acceptable platelet levels for various interventions:
1. Dentistry - more than 10x10*9/l
2. Tooth extraction - more than 30x10*9/l
3. Small operations - more than 50x10*9/l
4. Large operations - more than 80x10*9/l.
However, using the above criteria, it is necessary to take into account the individual approach to the patient and the presence of manifestations of hemorrhagic diathesis.

GCS is prescribed as first-line drugs - oral prednisolone at a dose of 2 mg/kg body weight per day for 2-4 weeks. Signs of the effectiveness of therapy are the absence of new hemorrhagic rashes and (or) cessation of bleeding. The platelet count begins to increase on the 5-6th day after the start of treatment.

After normalization of peripheral blood parameters, the dose of prednisolone begins to be slowly reduced until it is completely discontinued.
When administered parenterally, the dosage of GCS should be increased (with intravenous administration, the dose increases three times compared to the dose received orally).
The IM method of administering any medications for thrombocytopenia of any etiology is unacceptable due to the high risk of developing intramuscular hematomas.
If no effect from the therapy is observed within the prescribed time frame, or the result is unsatisfactory, then the dose of prednisolone is increased by one and a half to two times.
When the effect is achieved, it is reduced until it is completely cancelled.
In 2/3 of patients, GCS therapy achieves a complete response.
If, after discontinuation of the drug or when trying to reduce the dose, a relapse of the disease occurs, a return to the original or higher doses of hormones is necessary.
Corticosteroid therapy should be discontinued in patients who fail to respond after 4 weeks of therapy.

If the effect of GCS therapy is incomplete or unsatisfactory for several months (usually 3-4), indications arise for the use of second-line therapy - splenectomy, which gives a lasting positive effect in more than 3/4 of patients with IT.

A prognostically favorable sign of the effectiveness of splenectomy is the good, but unstable effect of GCS therapy.
The place of splenectomy in IAT therapy is currently controversial. Many clinics still use splenectomy as a second-line therapy in patients resistant to GCS therapy or with early relapses after GCS.

Other authors prefer to use splenectomy as a third or even fourth line after the use of MabThera and immunoglobulins.
Splenectomy is performed when the platelet level is 30x10*9/L or higher.
For patients with lower rates, therapy with corticosteroids (prednisolone 1-2 mg/kg/day or dexamethasone 40 mg/day x 4 days) or IV immunoglobulin is required.

In some cases, replacement therapy with platelet suspension or fresh frozen plasma is necessary during surgery.

During splenectomy, an increase in platelet levels is observed almost immediately after applying a ligature to the vessels of the spleen, and in the first days after splenectomy thrombocytosis is often observed, which is a prognostically favorable sign.

Immunoglobulins.
In some countries, immunoglobulins in combination with GCS are used as the first line of therapy.
The use of immunoglobulins as a second line is also indicated.
IV immunoglobulins are effective in 75% of patients; unfortunately, the effect of immunoglobulin monotherapy in most patients does not exceed 3-4 weeks, and therefore the main indication for this therapy is the need to quickly increase platelet levels before planned operations.

Rituximab (mabthera) is a mAb against the B-lymphocyte antigen CD20, now increasingly used as a second or third line before splenectomy: 375 mg/m2 IV drip 1 time per week up to 4 infusions.
Treatment of patients with recurrent IAT after splenectomy or in the presence of contraindications (refusal) to splenectomy includes:
1. High doses of GCS
A. Dexamethasone 40 mg x 4 days orally every 28 days x 6 courses. B. Methylprednisolone 30 mg/kg/day IV x 3 days, followed by a dose reduction to 20 mg/kg/day for 4 days; 5 mg/kg/day x 1 week; 2 mg/kg/day x 1 week; 1 mg/kg/day x 1 week.
The platelet level increases on days 3-5 in all patients, but the duration of the effect does not exceed several weeks and is comparable to immunoglobulins.
Recommended for a rapid transient increase in platelet levels.

2. High doses of IV immunoglobulins: 1 g/kg per day x 2 days, often in combination with GCS.
Intravenous anti-D immunoglobulin is indicated only for Rh+ patients and increases platelet levels in 79-90% of adult patients.

3. Pink vinca alkaloids (vincristine, vinblastine).
Vincristine 1 mg IV once a week x 4-6 weeks.
Vinblastine 5-10 mg IV weekly x 4-6 weeks.

4. Danazol 200 mg x 2-4 times a day for at least 2 months.
Response is observed in 60% of patients.
With continuous use for more than a year, remissions persist even after discontinuation of the drug.
When used for 6 months or less, frequent relapses are observed.
5. Immunosuppressants: azathioprine 2 mg/kg (maximum 150 mg/day) or cyclophosphamide 200-400 mg/day in a course dose of 6-8 g.
Cyclosporine A; dapsone - 75-100 mg/day orally, response observed in 50% of patients.

6. Interferon-a.
7. Rituximab (mabthera) mAb against CD20.
8. Campath (campath-lH) MCA to CD 56.
9. Cell-sept (Mecophenolate mofetil).

It is also possible to carry out immunoadsorption and laserpheresis.
Symptomatic treatment of hemorrhagic diathesis mainly includes local remedies: hemostatic sponge, cryotherapy, electrocoagulation, tampons with e-aminocaproic acid.
In some cases, you can use drugs that improve platelet aggregation - etamsylate or dicinone.

Platelet transfusion should only be performed when strictly indicated, such as the threat of cerebral hemorrhage or severe intractable bleeding.

It is necessary to use high-quality (maximally purified from other cellular elements of peripheral blood) platelet mass obtained by instrumental plateletpheresis from a minimum number of donors.

Forecast.
With adequate therapy, the prognosis of patients with IAT is favorable. Mortality is about 10%.
The main cause of death in patients is cerebral hemorrhage.
Prevention. There is no effective prevention of IAT.
The risk of developing IAT as a consequence of taking medications can be reduced by rational use of drugs that have known side effects such as IAT.

Thrombocytopenia

– a pathological condition characterized by a decrease in the amount

platelets

(red blood platelets) in the bloodstream up to 140,000/µl and below (normally 150,000 - 400,000/µl).

Causes and pathogenesis of thrombocytopenia

Under the influence of a virus or other provoking factor, the immune system makes a mistake and begins to produce autoantibodies ( immunoglobulins IgG or IgM ), attached to the surface of platelets. Cells of the reticuloendothelial system in the spleen take up antibody-studded platelets to remove them. At the same time, immune complexes damage the wall of small vessels, making it permeable to blood.

Classification

Classification of thrombocytopenia according to the mechanism of development is inconvenient for the reason that in many diseases several mechanisms for the development of thrombocytopenia are involved.

• acute - symptoms and changes in the blood are observed for up to 6 months
• chronic - lasts more than 6 months

The symptoms of both acute and chronic idiopathic purpura are absolutely the same!

Causes of thrombocytopenia

The exact cause of idiopathic thrombocytopenic purpura is not known. In children, it most often appears after a viral infection, and in adults against the background of chronic infections, for example, Helicobacter pylori in the stomach or infections in the urinary tract.

Some medications can provoke the first attack.

Disturbances at any of the above levels can lead to a decrease in the number of platelets circulating in the peripheral blood.

Depending on the cause and mechanism of development, there are:

• hereditary thrombocytopenia;
• productive thrombocytopenia;
• thrombocytopenia destruction;
• thrombocytopenia consumption;
• thrombocytopenia redistribution;
• thrombocytopenia dilution.

Hereditary thrombocytopenias

Symptoms in children and adults

• petechiae - small pinpoint hemorrhages on any part of the body, most often on the legs and places where the skin is pressed - by a watch, a belt, an elastic band from underwear
• hematomas or bruises even after the smallest injuries
• hemorrhages and bleeding after minimal trauma and even without it
• petechiae - the standard symptom of idiopathic thrombocytopenic purpura - may not exist; their appearance is extremely individual
• if platelets are less than 25 * 10 9 / l, you should look for petechiae not only on the skin, but also on the mucous membranes of the mouth, nose, and pharynx

• nosebleeds with or without blowing your nose, bleeding gums when brushing your teeth
• bleeding from the gastrointestinal tract - bloody vomiting, black feces with an unpleasant odor(melena)
• bleeding from the urinary tract - blood in the urine (hematuria) visible to the naked eye or only under a microscope
• strong menstrual bleeding in women

Since the function of platelets is hemostasis ( stop bleeding

Mandatory tests!

First of all, if you suspect thrombocytopenia, you need to do a general blood test

to determine the number of cellular elements and verify (confirm) the diagnosis of thrombocytopenia.

Then it is necessary to conduct a general examination to exclude secondary thrombocytopenia.

Many diseases that occur with thrombocytopenia have quite clear symptoms, so the differential diagnostics in such cases it is not difficult.

This applies, first of all, to severe oncological pathologies (leukemia, metastases of malignant tumors in the bone marrow, myeloma, etc.), systemic connective tissue diseases (systemic lupus erythematosus), liver cirrhosis, etc.

In some cases, a thorough history will help (artificial valves hearts , post-transfusion complications).

However, additional research is often necessary ( puncture bone marrow, immunological tests, etc.)

The following criteria are required for the diagnosis of primary idiopathic autoimmune thrombocytopenic purpura:

Below is a list of tests without which it is impossible to diagnose idiopathic thrombocytopenic purpura.

• general urine test - possibly an increased number of red blood cells and a reddish tint to the urine
• biochemical blood test - liver tests (total bilirubin , ALT , AST , GGT , alkaline phosphatase ), kidney tests (creatinine , urea , uric acid), glucose
• ESR , C-reactive protein
• blood clotting (prothrombin time , APTT , fibrinogen , antithrombin , D-dimers ) - within normal limits
• tests for HIV and viral hepatitis C , tests for Helicobacter pylori - exclude secondary causes of thrombocytopenia
• antiplatelet antibodies - in 40-50% of cases of idiopathic thrombocytopenic purpura are negative

• Wiskott-Aldrich syndrome
• HIV-associated thrombocytopenia
• thrombotic thrombocytopenic purpura
• hemolytic-uremic syndrome
• DIC syndrome
• IIb type von Willebrand disease
• hypersplenism
• aplastic anemia
• acute leukemia
• myelodysplasia
• lymphomas
• amegakaryocytic thrombocytopenia
• tumor metastases

If there is any doubt about the diagnosis of idiopathic thrombocytopenic purpura, a bone marrow examination must be performed. If the diagnosis is clear, then treatment is started immediately if necessary.

In most cases, a decrease in platelet count is a symptom of a specific disease or condition. Establishing the cause and mechanism of development of thrombocytopenia allows us to make a more accurate diagnosis and prescribe appropriate treatment.

In the diagnosis of thrombocytopenia and its causes, the following are used:

Treatment of acute form

Treatment of primary autoimmune thrombocytopenia in children

Most children with idiopathic thrombocytopenic purpura have a good prognosis, as most cases recover within 4-6 months without drug therapy. So, in the absence of a threat of intracranial hemorrhage or severe bleeding from the mucous membranes, a wait-and-see approach is carried out.

Treatment of acute idiopathic thrombocytopenic purpura begins only with a critical decrease in the number of platelets!

80% of children do not have symptoms of increased bleeding, so there is no need to administer drugs with a fairly large list of side effects.

• indication for treatment of idiopathic thrombocytopenic purpura - the need to increase platelets to a safe level before surgery, for symptoms of bleeding in the brain or spinal cord, before vaccination
• platelet level 10-20*10 9 /l is potentially life-threatening, but it is not the tests that are treated, but the patient with specific manifestations of the disease (weigh the pros and cons)
• in the treatment of acute idiopathic thrombocytopenic purpura, one of several regimens is used based on corticosteroids - hormones that block the function of macrophages; “chemical removal of the spleen” occurs

• high-dose immunoglobulins (HD-IVIG)
• anti-D immunoglobulin
• platelet transfusion - rare, only in case of life-threatening bleeding
• Removal of the spleen in acute idiopathic thrombocytopenic purpura is not performed

There is no clear answer to the question of the need for treatment of acute idiopathic thrombocytopenic purpura in children! There is also no generally accepted algorithm!

• Only when platelets drop below 25*10 9 /l or visible symptoms (for example, petechiae) begin immediate treatment
• treatment does not affect the duration of the disease, but only increases the platelet count to a safe level
• mandatory - bed rest
• the basis for the treatment of the chronic form of idiopathic thrombocytopenic purpura is blocking the increased activity of the immune system - prednisone 0.5-1 mg/kg, after achieving safe platelet levels, the dose is reduced to the minimum maintenance dose, which is always selected individually

• methylprednisolone 10-30 mg/kg/day intravenously for 30 minutes for 3 days, then switch to prednisone 1-2 mg/kg/day for 10-20 days
• alternative treatment - boluses of methylprednisolone

• HDIVIG - only for very low platelet levels, 7S drugs (Endobulin, Phlebogamma, Venimmune) at a dose of 800 mg/kg/day IV or 400 mg/kg/day IV/ 5 days with repeat if insufficient effectiveness, in 80 % of children platelets will increase to 100*109/l
• thrombopoietin receptor agonists - romiprostim (Enplate), eltrombopag (Revolade)
• platelet concentrate and plasmapheresis - only for life-threatening thrombocytopenia
• danazol
• cyclosporine
• removal of the spleen - only with proven mass death in the spleen
• rituximab - anti-CD20 antibody
• immunoglobulins in high doses
• hemostatic drugs for bleeding

Treatment of thrombocytopenia should be prescribed by a hematologist after a thorough examination of the patient.

What is the severity of the condition of patients with thrombocytopenia?

The decision on the need for specific treatment is made depending on the severity of the disease, which is determined by the level of platelets in the blood and the severity of the manifestations of hemorrhagic syndrome (

bleeding

Thrombocytopenia can be:

• Mild severity. The concentration of platelets is from 50 to 150 thousand in one microliter of blood. This amount is sufficient to maintain the normal condition of the capillary walls and prevent blood from leaving the vascular bed. Bleeding does not develop with mild thrombocytopenia. Drug treatment is usually not required. A wait-and-see approach and identification of the cause of the platelet decrease is recommended.
• Moderate severity. The concentration of platelets is from 20 to 50 thousand in one microliter of blood. There may be hemorrhages in the oral mucosa, increased bleeding of the gums, and increased nosebleeds. With bruises and injuries, extensive hemorrhages may form in the skin that do not correspond to the amount of damage. Drug therapy is recommended only if there are factors that increase the risk of bleeding ( ulcers of the gastrointestinal system , professional activities or sports associated with frequent injuries).
• Severe degree. The concentration of platelets in the blood is below 20 thousand per microliter. Characterized by spontaneous, profuse hemorrhages in the skin, mucous membranes of the mouth, frequent and profuse nosebleeds and other manifestations of hemorrhagic syndrome. The general condition, as a rule, does not correspond to the severity of laboratory data - patients feel comfortable and complain only of a cosmetic defect as a result of skin hemorrhages.

Is hospitalization necessary for the treatment of thrombocytopenia?

Patients with mild thrombocytopenia usually do not require hospitalization or any treatment. However, it is strongly recommended to consult a hematologist and undergo a comprehensive examination to identify the cause of the decrease in platelet count.

For thrombocytopenia of moderate severity without pronounced manifestations of hemorrhagic syndrome, treatment at home is prescribed. Patients are informed about the nature of their disease, the risks of bleeding from injuries and possible consequences. They are advised to limit their active lifestyle for the period of treatment and take all medications prescribed by the hematologist.

Mandatory hospitalization is required for all patients whose platelet level is below 20,000 in one microliter of blood, as this is a life-threatening condition and requires immediate treatment under the constant supervision of medical personnel.

All patients with heavy hemorrhages in the face, oral mucosa, or heavy nosebleeds, regardless of the level of platelets in the blood, must be hospitalized. The severity of these symptoms indicates an unfavorable course of the disease and possible cerebral hemorrhage.

Drug treatment

Drug therapy is most often used to treat immune thrombocytopenia, caused by the formation of antiplatelet antibodies with subsequent destruction of platelets in the spleen.

The goals of drug treatment are:

• elimination of hemorrhagic syndrome;
• eliminating the immediate cause of thrombocytopenia;
• treatment of the disease causing thrombocytopenia.

Medicines used in the treatment of thrombocytopenia

Non-drug treatment

Includes various therapeutic and surgical measures aimed at eliminating thrombocytopenia and the causes that caused it.

Kuzmich A.

9 st Minsk City Clinical Hospital, Belarus

Modern methods of treatment of immune thrombocytopenia

Resume. A brief critical assessment of the evidence base on the effectiveness and safety of first and second line therapy for immune thrombocytopenia (ITP) is provided. It is concluded that it is necessary to introduce new treatment strategies with a better efficacy/safety profile, based on objective information obtained in high-quality clinical studies. Modern data on the results of a clinical study of an innovative orally active drug with a unique mechanism of action (thrombopoietin receptor agonist) - eltrombopag - are presented for ITP. The conclusion is substantiated that eltrombopag, which has high efficacy and a favorable safety profile, opens up new opportunities for short- and long-term management of patients with ITP, which requires priority consideration of the inclusion of eltrombopag in national standards for the monitoring and treatment of ITP.

Key words: chronic immune thrombocytopenia, clinical effectiveness, safety, eltrombopag, rituximab, splenectomy, evidence-based medicine.

Summary. The review is devoted to the main problems and the ways of improvement of treatment program in chronic immune thrombocytopenia (CIT) in adult patients. There is a short assessment of evidence base on the effectiveness and safety of treatment methods used for primary and secondary therapy of CIT. There was made a conclusion on the importance of introduction of the new treatment strategies with a better profile of effectiveness/safety. These strategies should be based on objective information received in clinical research. There are given modern data on the results of clinical study of an innovative orally active drug with a unique action mechanism (antagonist of thrombopoietin receptor) - eltrombopag. There has been proven that eltrombopag is very effective and safe drug. It opens new possibilities in management of patients with CIT, which means possible inclusion of eltrombopag in the national standards of CIT management.

Keywords: chronic immune thrombocytopenia, clinical effectiveness, safety, eltrombopag, rituximab, splenectomy, evidence-based medicine.

Meditsinskie news. - 2014. - N3. - P. 11-14.

Chronic immune (idiopathic) thrombocytopenia (ITP) is an immune-mediated disease characterized by increased destruction and impaired platelet production, accompanied by a transient or persistent decrease in platelet count less than 100´10 9 /l. There are approximately 50 new cases of ITP per million people each year in Europe.

There are newly diagnosed ITP, persistent (from 3 to 12 months) and chronic, defined as its presence more than 12 months from the date of diagnosis. In 50-60% of patients with ITP, platelets are bound by immunoglobulin G (IgG) antibodies, which recognize one of the many glycoproteins on the surface of the platelet membrane. Antibody-bound platelets are recognized by receptors on tissue macrophages, in which they are subsequently phagocytosed. Platelet autoantigen-reactive T and B lymphocytes can be found in the peripheral blood and spleen of patients with ITP, and autoantibody production by spleen, blood, and bone marrow cells has also been demonstrated. Platelet life cycle studies in patients with ITP more often show normal or reduced platelet production. This indicates both inhibition of production and increased destruction of platelets. Recent Research in vitro showed decreased megakaryocyte production and maturation in the presence of ITP patient plasma, likely supporting antibody-induced megakaryocyte suppression.

The diagnosis of primary ITP is made by exclusion. When collecting anamnesis, it is necessary to exclude infection with the human immunodeficiency virus and/or hepatitis C virus, hereditary thrombocytopenia, post-transfusion purpura, as well as taking drugs that could cause secondary thrombocytopenia. ITP can develop in patients with systemic lupus erythematosus, antiphospholipid syndrome, B-cell tumors, and in patients who have undergone autologous hematopoietic stem cell transplantation.

There are different opinions regarding the need to determine antiplatelet antibodies. Antigen-specific methods used to detect antiplatelet antibodies have a sensitivity of approximately 49-66%, a specificity of 78-92%, and a diagnostic yield of 80-83% when comparing patients with ITP and healthy controls. A positive antigen-specific test clearly confirms the diagnosis of immune thrombocytopenia, but a negative test cannot refute it.

Currentproblems improvementprograms treatmentITP

The main therapeutic goal for ITP is to carry out the minimum necessary therapeutic measures to maintain a platelet level sufficient to eliminate the hemorrhagic syndrome (more than 30´10 9 / l) with the least amount of side effects. The American Society of Hematology guidelines consider a platelet count of 30-50´10 9 /L without other risk factors to be sufficient to prevent serious complications of ITP (intracerebral or severe gastrointestinal bleeding), and a platelet count above 50´10 9 /L is defined as “safe”. » for carrying out invasive interventions.

Glucocorticosteroids (GCS) are recommended by various research groups and clinical guidelines as first-line therapy. Prednisolone 0.5-2 mg/kg/day is the generally accepted starting dose for patients with ITP. After the platelet count reaches 50´10 9 /l, it is recommended to reduce the dose to the minimum effective, sufficient to maintain the platelet level at 30-50´10 9 /l. One to four cycles of dexamethasone 40 mg/day for 4 days is the preferred regimen for glucocorticosteroids, with response rates of 50–80% in adult patients with newly diagnosed ITP. According to the international consensus on the research and treatment of ITP, prednisolone, dexamethasone, or methylprednisolone are equally acceptable as first-line therapy. In case of resistance to GCS, the duration of therapy should not exceed 4 weeks.

Intravenous immunoglobulin and anti-Rhesus immunoglobulin (anti-D) are effective in increasing platelet counts, but the effect is usually temporary. These drugs are recommended as first-line therapy in emergency situations.

For patients with chronic ITP who have not responded to corticosteroids or have serious side effects, splenectomy is accepted as second-line treatment. However, approximately 15-20% of patients do not respond to splenectomy, and an additional 15-20% of respondents develop relapses weeks, months, or years later. In addition, many patients with chronic ITP refuse splenectomy due to possible complications such as bleeding, infection, thrombosis, and the risk of death (0.2-1.0%), as well as religion (Jehovah's Witnesses).

There is worldwide experience with the use of vincristine, cyclophosphamide, azathioprine, dapsone, cyclosporine A, mycophenolate mofetil and rituximab in patients refractory to splenectomy, relapsing after splenectomy or who had contraindications to surgery. The response rate for the above types of therapy ranged from 20 to 80%. However, most studies evaluating the effectiveness of immunosuppressive drugs were not randomized, indicating that the rigorous evidence base for the effectiveness and safety of such prescriptions is insufficient. In addition, their long-term use can be accompanied by serious side effects, in particular the development of secondary tumors and infectious complications.

Thus, in a prospective phase II clinical trial in patients with ITP, the use of rituximab at a dose of 375 mg/m2 weekly for 4 weeks allowed one third of patients to achieve a platelet count of 50´109/l or higher. In a study by N. Cooper et al. Achievement of stable complete or partial remission was revealed in one third of patients, but a long relapse-free period was not recorded. Rituximab does not currently have an approved indication for the treatment of chronic ITP. According to Fianchi et al., rituximab can cause fulminant hepatitis in carriers of hepatitis B, so its use is contraindicated in patients with active hepatitis B. Additionally, more than 50 cases of progressive multifocal leukoencephalopathy have been reported associated with rituximab in patients with lymphoma and systemic lupus erythematosus. Before rituximab is recommended as standard therapy for ITP, it is necessary to obtain the results of additional studies assessing its effectiveness and safety in this pathology.

The above-mentioned problems and limitations in the management of patients with ITP have necessitated the search for new drugs with a better profile of proven efficacy and safety, including those based on new pathophysiological and pharmacological approaches.

According to numerous studies, impaired platelet production occurs in many patients with ITP. Therefore, stimulation of megakaryocytopoiesis with thrombopoietin or thrombopoietin-like agents may be pathogenetically justified in the treatment of ITP. The use of recombinant thrombopoietin has demonstrated the ability to increase platelet counts in patients with ITP, but has been associated with the production of autoantibodies that neutralize endogenous thrombopoietin, thereby leading to severe thrombocytopenia.

In the early 2000s, two thrombopoietin receptor (TPO-R) agonists, romiplostim (Nplate; Amgen) and eltrombopag (Revolade, Promacta; GlaxoSmithKline), were licensed for the treatment of chronic ITP. As recommended by the above-mentioned international consensus, thrombopoietin receptor agonists are indicated for recurrent splenectomized patients with chronic ITP refractory to other therapies or nonsplenectomized adult patients in whom splenectomy is contraindicated.

Eltrombopag- the first oral low molecular weight synthetic non-peptide thrombopoietin receptor agonist registered in Belarus. The drug has good oral bioavailability with peak plasma concentrations at 2-6 hours and a half-life of 21-32 hours. The mechanism of action of eltrombopag is to enhance platelet production by inducing proliferation and differentiation of bone marrow progenitors of the megakaryocyte lineage. It has a high affinity for human plasma proteins (>99%). Unlike native thrombopoietin, which binds to the extracellular domain of the thrombopoietin receptor, eltrombopag selectively binds to the transmembrane region of the receptor and does not compete with endogenous thrombopoietin. The drug is indicated for splenectomized patients with ITP who are refractory to other treatments (eg, corticosteroids, immunoglobulins). The recommended starting dose of eltrombopag is 50 mg once daily. If there is no increase in platelet levels after 2-3 weeks of use, the dose may be increased. After achieving a stable platelet level, the dose should be further adjusted to the lowest possible level in order to maintain platelet levels around 50´10 9 /l with minimal hemorrhagic manifestations.

Brief review main clinical research By application eltrombopag at ITP

The clinical efficacy of eltrombopag in chronic ITP was assessed in a 6-week study, a 6-week and 6-month phase III study, an additional ongoing study, and an intermittent therapy feasibility study for ITP.

The aim of the first 6-week study was to determine the optimal effective dose of eltrombopag. A total of 118 patients with chronic ITP were randomized into four groups to receive eltrombopag 30 mg, 50 mg, 75 mg, or placebo daily for 6 weeks. Inclusion criteria for the study were that patients had ITP for at least 6 months and basic level platelets less than 30´10 9 /l. Historically, these patients had not responded to previous therapy, including splenectomy, or the disease had relapsed within 3 months of previous therapy. The main purpose of prescribing eltrombopag was to achieve a platelet level of more than 50´10 9 /l. On average, on the 43rd day, the platelet count in patients with a dose of eltrombopag of 50 and 75 mg/day was 128´10 9 /l and 183´10 9 /l, respectively, in the placebo group - 16´10 9 /l. This increase in platelet counts in the eltrombopag groups was accompanied by a significant reduction in bleeding symptoms. Thrombopoietin levels were within the normal range in all four groups (54-57 ng/L) and remained unchanged during eltrombopag therapy.

The findings formed the basis for the design of a 6-week phase III study in which 114 patients were randomized 2:1 to eltrombopag 50 mg/day or placebo using similar inclusion criteria. Significantly more patients in the eltrombopag group (n=73) demonstrated a response with platelet counts greater than 50´109/L per day compared with the placebo group (n=37) (59% vs 16%; p<0,0001). У 34 пациентов, получавших элтромбопаг, дозировка была увеличена до 75 мг/сут после 22-го дня лечения при отсутствии ответа на дозировку 50 мг/сут. Из них 10 пациентов (29%) на 43-й день достигли количества тромбоцитов более 50´10 9 /л. У пациентов, получавших элтромбопаг, риск кровотечения был ниже по сравнению с пациентами из группы плацебо (p=0,029) .

In both 6-week studies, a similar response to eltrombopag therapy was observed regardless of a history of splenectomy, concomitant ITP therapy, or a baseline platelet level of less than 15´10 9 /L. In patients who responded to therapy, the platelet count began to increase after the 1st week of treatment and reached a maximum after the 2nd week.

The double-blind, randomized, placebo-controlled, 6-month phase III RAISE study assessed the safety and efficacy of long-term eltrombopag in patients with ITP. A total of 197 patients were randomized 2:1 to receive eltrombopag 50 mg/day (n=135) or placebo (n=62). Approximately 80% of patients in the placebo and eltrombopag groups had received at least two prior treatments, and more than 50% in each group had three or more prior treatments. As a result of the study, patients receiving eltrombopag were 8 times more likely to achieve platelet counts between 50 and 400´10 9 /L compared with patients in the placebo group (p<0,001). В группе плацебо количество тромбоцитов не превысило 30´10 9 /л. Среднее число тромбоцитов в группе элтромбопага повысилось до 36´10 9 /л после 1-й недели приема и оставалось на уровне 52-91´10 9 /л до окончания исследования. С 15-го дня приема препарата у пациентов в группе элтромбопага был менее выражен геморрагический синдром по сравнению с пациентами из группы плацебо (79 против 93%). В общей сложности 59% пациентов, получавших элтромбопаг, уменьшили или прекратили прием сопутствующих препаратов (в группе плацебо - 32%) (p=0,02).

The purpose of the multicenter, ongoing, open-label EXTEND study was to evaluate the long-term safety and tolerability of eltrombopag based on clinical laboratory tests and adverse event rates. Analysis of data from 299 patients receiving up to 3 years of eltrombopag therapy is available. The incidence of platelet levels of 50´10 9 /L or more among splenectomized and non-splenectomized patients was 80 and 88%, respectively. This effect remained stable with long-term use of eltrombopag, which allowed some patients (69 out of 100 receiving additional therapy) to attempt to discontinue or reduce the doses of concomitant medications, which was successful in 65% of cases. The rate of bleeding symptoms, which was 56% at study entry, decreased to 20% after 2 years of treatment and to 11% after 3 years of treatment.

The single-arm REPEAT trial evaluating intermittent eltrombopag included patients with pre-treated chronic ITP and a baseline platelet count of 20-50´109/L (n=66). Patients received 3 cycles of eltrombopag at a dose of 50 mg/day for up to 6 weeks with breaks in therapy of up to 4 weeks. Response to therapy was defined as achieving a platelet level greater than 50´10 9 /L. Patients who did not respond to therapy in the 1st cycle were excluded from the study. The end point of the study was to determine the existence of a pattern - the preservation of the ratio of patients who responded in the 1st cycle and also responded in the 2nd or 3rd cycles. A total of 80% of patients responded in cycle 1 and were allowed to continue in the study, and 87% of cycle 1 respondents also responded in cycle 2 or 3. The mean platelet count remained above 70´109/L after day 8 taking eltrombopag in all three cycles.

In a study by G. Cheng et al., 13 of 301 patients (4.5%) had long-term remission (median 50 weeks) without additional ITP therapy after stopping eltrombopag.

Reviewpossible clinicallysignificant sideeffectseltrombopag

Approximately 10% of patients receiving eltrombopag in the studies reviewed above experienced a threefold ULN increase in ALT, compared with 3% in the placebo group (p>0.05). In these patients, elevated ALT levels returned to normal while taking eltrombopag or shortly after its discontinuation. In the EXTEND study, episodes of increased bilirubin were due to the indirect fraction, which is not an indicator of severe liver damage.

Therefore, there is currently no clinical evidence that eltrombopag at the recommended dose can cause serious, irreversible liver damage. However, liver function tests should be performed regularly and, if there is a progressive increase in serum aminotransferases, the drug should be discontinued.

In the RAISE study, three patients (2%) receiving eltrombopag experienced treatment-related thromboembolic events. All three patients had risk factors for the development of venous thrombosis and the platelet count during the period of thrombotic events was less than 50´10 9 /l. In the EXTEND study, 16 patients (5%) experienced 20 confirmed thromboembolic events; Deep vein thrombosis (n=9) and cerebrovascular thrombosis (n=5) were the most common. All 16 patients had at least one risk factor for thrombosis, such as hypertension, smoking or obesity. The incidence of thromboembolic events in patients receiving eltrombopag in the EXTEND study was comparable to that in the ITP population.

Thus, data from global studies do not allow us to conclude that there is a significant increase in the risk of thromboembolic complications when using eltrombopag. However, in patients with known risk factors for thrombosis, eltrombopag should be used with caution, with careful monitoring of platelet counts and the achievement of a minimum platelet level sufficient to relieve the hemorrhagic syndrome.

There are theoretical considerations about the possibility of increasing the risk of deposition of reticulin fibers in the bone marrow when taking thrombopoietin receptor agonists. The EXTEND study analyzed 147 bone marrow samples taken from more than 100 patients on long-term eltrombopag therapy. There was no convincing evidence for the development or progression of fibrosis.

Conclusion

According to global studies evaluating various treatment methods for patients with chronic ITP, only two methods have high proven effectiveness: splenectomy and conservative treatment with thrombopoietin receptor agonists. However, the risk of surgery, postoperative complications, and the lifetime risk of infection limit the use of splenectomy. Thus, eltrombopag, the first thrombopoietin receptor agonist registered in the Republic of Belarus and recommended for the treatment of chronic ITP in patients with an insufficient response to previous therapy, opens up new treatment options for this complex group of patients, based on strict evidence-based medicine.

The main advantages of conservative treatment with eltrombopag are pronounced clinical efficacy (up to 80%) and high safety, including the absence of immunosuppressive or malignant effects, confirmed in high-quality controlled randomized studies. In addition, important positive features of this new strategy for the treatment of ITP are the possibility of once-daily oral dosing, stepwise dose increases or decreases as clinically necessary, and no evidence of decreased effectiveness with long-term use. However, given the high cost of this new pharmacotherapeutic approach, the world's leading pharmacoeconomic experts recommend an individualized approach to the management of patients with ITP, based on a careful assessment of the clinical situation and patient needs, taking into account the latest scientific evidence and considering all current treatment options, including agonists thrombopoietin receptors.

In this regard, I would like to draw the attention of specialists to the fact that in the majority of patients responding to eltrombopag therapy, the platelet count begins to increase after the first week of therapy and reaches a peak in the second week, i.e. This strategy is not a means of providing emergency care or emergency treatment. At the same time, eltrombopag can be used to induce remission when preparing patients with chronic ITP 2 weeks before planned surgery.

The modern scientific information presented allows us to make informed decisions on the inclusion of the innovative drug eltrombopag (Revolade) in national standards for the monitoring and treatment of ITP, with their subsequent updating as new data becomes available.

L I T E R A T U R A

1. Cheng G.// Ther. Adv. Hematol. - 2012. - Vol.3 (3). - P.155-164.

2. Frederiksen H., Schmidt K. // Blood. -1999. - Vol.94. - P.909-913.

3. Rodeghiero F., Stasi R.., Gernsheimer T. et al. // Blood. - 2008. - Vol.113. - P.2386-2393.

4.McMillan R.// Semin. Hematol. - 2000. - Vol.37. - P.239-248.

5. Kuwana K., Kaburaki J., Ikeda Y.// J. Clin. Invest. - 1998. - Vol.102. - P.1393-1402.

6. Kuwana M., Okazaki Y., Kaburaki J. et al. // J. Immunol. - 2003. - Vol.168. - P.3675-3682.

7. McMillan R., Yelenosky R.J., Longmire R.L. Antiplatelet antibody production by the spleen and bone marrow in immune thrombocytopenic purpura / Immunoaspects of the Spleen, ed. J. R. Battisto, J. W. Streinlein. - Amsterdam: North Holland Biomed. - 1976. - P.227-237.

8. Stoll D., Cines D.B., Aster R.H.. et al. // Blood. - 1985. - Vol.65. - P.584-588.

9. McMillan R., Wang L., Tomer A. et al. // Blood. - 2004. - Vol.103. - P.1364-1369.

10. Neylon A.J., Saunders P.W.G., Howard M.R. et al. // Br. J. Haematol. - 2003. - Vol.122. - P.966-974.

11.Drachman J.G.// Blood. - 2004. - Vol.103. - P.390-398.

12. Brighton T.A., Evans S., Castaldi P.A. et al. // Blood. - 1996. - Vol.88. - P.194-201.

13. Warner M.N., Moore J.C., Warkentin T.E. et al. // Br. J. Haematol. - 1999. - Vol.104. - P.442-447.

14. McMillan R., Wang L., Tani P. // J. Thombos. Haemostas. - 2003. - Vol.1. - P.485-491.

15. Provan D., Stasi R., Newland A.C. et al. // Blood. - 2010. - Vol.115 (2). - P.168-186.

16. George J.N.//Clev. Clin. J. Med. - 2004. - Vol.71 (4). - P.277-278.

17.Cines D.B., Blanchette V.S.// N. Engl. J. Med. - 2002. - Vol.346. - P.995-1008.

18. Cheng Y., Wong R.S., Soo Y.O. et al. // N. Engl. J. Med. - 2003. - Vol.349. - P.831-836.

19. Mazzucconi M.G., Fazi P., Bernasconi S. et al. // Blood. - 2007. - Vol.109. - P.1401-1407.

20. George J.N., Raskob G.E., Vesely S.K. et al // Am. J. Hematol. - 2003. - Vol.74. - P.161-169.

21. Spahr J.E., Rodgers G.M.//Am. J. Hematol. - 2008. - Vol.83. - P.122-125.

22.Schwartz J., Leber M.D., Gillis S. et al. //Am. J. Hematol. - 2003. - Vol.72. - P.94-98.

23.Kojouri K., Vesely S.K., Terrell D.R., George J.N.. // Blood. - 2004. - Vol.104. - P.2623-2634.

24. Herná ndez F., Linares M., Colomina P. et al. // Br. J. Haematol. - 1995. - Vol.90. - P.473-475.

25.Reiner A., ​​Gernsheimer T., Slichter S.J.// Blood. - 1995. - Vol.85. - P.351-358.

26. Kappers-Klunne M.C., van’t Veer M.B.. // Br. J. Haematol. - 2001. - Vol.114. - P.121-125.

27. Maloisel F., Andres E., Zimmer J. et al. //Am. J. Med. - 2004. - Vol. 116. - P.590-594.

28. Kotb R., Pinganaud C., Trichet C.. et al. //Eur. J. Haematol. - 2005. - Vol.75. - P.60-64.

29. Boruchov D.M., Gururangan S., Driscoll M.C., Bussel J.B.// Blood. - 2007. - Vol.110. - P.3526-3531.

30. Godeau B., Porcher R., Fain O.// Blood. - 2008. - Vol.112. - P.999-1004.

31. Cooper N., Heddle N.M., Haas M. et al. // Br. J. Haematol. - 2004. - Vol.124. - P.511-518.

32. Fianchi L., Rossi E., Murri R.//Ann. Hematol. - 2007. - Vol.86. - P.225-226.

33. Carson K.R., Evens A.M., Richey E.A.// Blood. - 2009. - Vol.113. - P.4834-4840.

34.Houwerzijl E.J., Blom N.R., van der Want J.J. et al. // Blood. - 2004. - Vol.103. - P.500-506.

35. Nomura S., Dan K., Hotta T. et al. // Blood. - 2002. - Vol.100. - P.728-730.

36. Zhao Y.Q., Wang Q.Y., Zhai M.. et al. // Zhonghua Nei Ke Za Zhi. - 2004. - Vol.43. - P.608-610.

37.Li J., Yang C., Xia Y. et al. // Blood. - 2001. - Vol. 98. - P.3241-3248.

38. Basser R.L., O'Flaherty E., Green M.// Blood. - 2002. - Vol.99. - P.2599-2602.

39. Wang B., Nichol J.L., Sullivan J.T.// Clin. Pharmacol. Ther. - 2004. - Vol.76. - P.628-638.

40. Erickson-Miller C.L., DeLorme E., Tian S.S.// Exp. Hematol. - 2005. - Vol.33. - P.85-93.

41. Promacta (eltrombopag tablets): US prescribing information. Available athttp://us.gsk.com/products/assets/us_promacta.pdf

42. Bussel J.B., Cheng G., Saleh M.N. et al. // N. Engl. J. Med. - 2007. - Vol.357. - P.2237-2247.

43. Bussel J.B., Provan D., Shamsi T. et al. // The Lancet. - 2009. - Vol.373. - P.641-648.

44. Cheng G., Saleh M., Marcher C.// The Lancet. - 2011. - Vol.377. - P.393-402.

45.Saleh M., Bussel J., Cheng G. et al. // Blood. - 2013. - Vol.121. - P.537-545.

46. Bussel J., Psaila B., Saleh M.. et al. // Blood. - 2008. - Vol.112. - P.1176.

47. Cheng G., Federiksen H., Bakshi K. et al. // Haematologica. - 2011. - Vol.96 (Suppl. 2). - P.331.

48.Sarpatwari A., Bennett D., Logie J.W. et al. // Haematologica. - 2010. - Vol.95. - P.1167-1175.

49.Douglas V., Tallman M., Cripe L., Peterson L.C.. //Am. J. Clin. Pathol. -2002. - Vol.117. - P.844-850.

Medical news. - 2014. - No. 3. - pp. 11-14.

Attention!The article is addressed to medical specialists. Reprinting this article or its fragments on the Internet without a hyperlink to the source is considered a violation of copyright