How is thrombocytopenic purpura treated?

Since the pathogenesis of idiopathic thrombocytopenic purpura is the destruction of platelets loaded with autoantibodies by cells of the reticulogistiocytic system, the main principles of treatment of thrombocytopenic purpura are:

• a decrease in the production of autoantibodies;
• disruption of binding of autoantibodies to platelets;
• elimination of the destruction of platelet-sensitized antibodies by the cells of the reticulogistiocytic system.

In the absence of bleeding from the mucous membranes, poorly expressed ecchymosis after bruises, the number of platelets more than 35,000 / mm ^3, treatment is usually not required. Patients should avoid contact sports. Menstruating girls are useful for long-acting progesterone preparations (Depo-Provera and others) to delay menstruation for several months in order to prevent intensive uterine bleeding.

Glucocorticoids

Mechanism of action

• Inhibition of phagocytosis of platelets with antibodies fixed in their surface in the spleen.
• Violation of the production of antibodies.
• Violation of binding of autoantibodies with antigen.

Indications

Bleeding from mucous membranes; pronounced purpura and abundant bruises on the bruises, especially on the head and neck; progressive purple; thrombocytopenia for more than 3 weeks; recurrent thrombocytopenia; the number of platelets is less than 20,000 / mm ³ in primary patients with minimal purpura.

Modes of introduction

• Standard doses of oral corticosteroids are prednisolone 1-2 mg / kg per day or 60 mg / m ² per day for 21 days with gradual cancellation. The dose is reduced regardless of the number of platelets, remission is evaluated at the end of the course. In the absence of remission or a decrease in the number of platelets after achieving normal glucocorticoid effects continue. In the absence of a complete hematologic response during the standard course of corticosteroids, the discontinuation of prednisolone is produced by a "discontinuous course" (the day after the 5 mg break). It is possible to repeat the course of corticosteroids after 4 weeks. Long-term use of corticosteroids with idiopathic thrombocytopenic purpura is undesirable, since it can lead to depression of thrombocytopoiesis.
• High doses of oral corticosteroids are 4-8 mg / kg per day for 7 days or 10-30 mg / kg per day of methylprednisolone for 3-7 days with rapid drug withdrawal. A week later, the courses are repeated (2-3 courses).
• High doses of parenteral corticosteroids 10-30 mg / kg per day of methylprednisolone or soludomedil 500 mg / m ² per day intravenously for 3-7 days in severe cases for more rapid relief of hemorrhagic syndrome. If necessary, further treatment of the patient is transferred to the reception of standard doses inside.
• For steroid-resistant patients with idiopathic thrombocytopenic purpura, a "pulse-therapy" of dexamethasone is possible - 6 cycles of 0.5 mg / kg per day (max. 40 mg / day) for 4 days every 28 days, ingestion.

The effectiveness of reception of cotricosteroids, according to different authors, is 50-80%. Side effects in their use: a symptom of hypercorticosis, peptic ulcer, hyperglycemia, hypertension, increased risk of infection, myopathy, hypokalemia, steroid psychosis, impaired ovarian function in girls, stunted growth.

Intravenous immunoglobulin

Mechanism of action:

• reversible blockade of macrophage Fc receptors;
• suppression of autoantibody synthesis by B lymphocytes;
• protection of platelets and / or megakaryocytes from antibodies;
• modulation of helper and suppressor activity of T-lymphocytes;
• suppression of complement-dependent tissue damage;
• recovery from persistent viral infections through the introduction of specific antibodies.

Indications for acute idiopathic thrombocytopenic purpura:

• if possible, the impact of the first line;
• neonatal symptomatic immune thrombocytopenia;
• Children under the age of 2 years, resistant to the effects of corticosteroids.

Modern intravenous immunoglobulin (IVIG) preparations must meet WHO requirements as defined in 1982: at least 1000 blood samples, at least 90% of immunoglobulin G, native immunoglobulin G (high Fc activity), normal division of immunoglobulin G into subclasses, physiological half-life . In addition, IVIG should have low anticomplementary activity and double virus inactivation (pure immunoglobulin G).

Intravenous immunoglobulin preparations permitted for use

Ready-to-eat	In the form of concentrates
The human immunoglobulin is normal (intraglobin) (Biotest, Germany), the human immunoglobulin is normal for intravenous administration (imbio-gam) (IMBIO, Russia), Octagam (Octapharma, Switzerland), IG VIENNA NI. AT. ("Kedrion", Italy)	Immunoglobulin ("Biochemie", Austria) Sandoglobulin ("Sandoz", Switzerland), a normal human immunoglobulin (Endobulin S / D) (Austria), (Biaven BH ("Pharma Biajini", Italy), (Penga Merieux, France), normal human immunoglobulin (Gabriglobin) ("Ivanovskaya 0SPK", Russia)

Comparative characteristics of intravenous immunoglobulin preparations

	IG Vienna	The human immunoglobulin is normal (octagam)	The human immunoglobulin is normal (intraglobin)	Sando-globulin
IgG, mg / ml	49-51	51-53	41-42	45-47
Fc integrated molecules,%	98-101	99-102	68-87	81-88
IgA, mg / ml	0-0.015	0.05-0.1	1.5-2.0	0.5-0.75
IgM, mg / ml	0	0.01-0.02	0.06-0.08	0.01-0.02
Stabilizer	Maltose	Maltose	Glucose	Sucrose
Titer of CMV antibodies, U / ml	50.0	22.0-23.0	12.0	More than 10.0

Modes of intravenous immunoglobulin

• In acute idiopathic thrombocytopenic purpura - a total dose of 1-2 g / kg per course according to the scheme: 400 mg / kg per day for 5 days or 1 g / kg per day for 1-2 days. Children under the age of 2 years are more likely to tolerate a 5-day protocol for taking medications of I and II generations.
• In chronic idiopathic thrombocytopenic purpura, the initial dose is 1 g / kg per day for 1-2 days, then single infusions in a dose of 0.4-1 g / kg, depending on the response, to maintain a safe level of platelets (more than 30,000 / mm ³ ). The use of IVIG is useful to combine with alternating courses of corticosteroids.

Response to the effect in patients with acute idiopathic thrombocytopenic purpura occurs in 80-96,5% of cases. Compared with the use of corticosteroids, the number of platelets increases more rapidly with episodes of bleeding of comparable duration. About 65% of children with idiopathic thrombocytopenic purpura resistant to corticosteroids achieve long-term remission after the course of IVIG.

Side effects of IVIG preparations:

• anaphylactic reactions (in patients with a reduced level of IgA);
• headache (20% of cases);
• fever with chills (1-3% of cases);
• Hemolytic anemia with a positive breakdown of Coombs.

In the scientific literature, the case of the development of aseptic meningitis after infusion of IVIG, as well as the infection of the recipients of IVIG (Gammagard \ "Baxter") with the hepatitis C virus, has been described, but since 1994, after improving the technology of production of drugs, such situations have not occurred.

Preventive administration of paracetamol (10-15 mg / kg every 4 hours) and diphenhydramine (dimedrol) (1 mg / kg every 6-8 hours) reduces the frequency and severity of fever with chills, and intravenous dexamethasone at a dose of 0.15-0, 3 mg / kg allows to stop a headache at infusions of IVIG.

Combined use of glucocorticoids and intravenous immunoglobulin

Indications:

• bleeding from the mucous membranes;
• extensive petechiae, purpura and ecchymosis;
• symptoms and / or signs of internal bleeding, especially intracranial.

Combined use causes a faster increase in the number of platelets than each drug individually. It is used in life-threatening bleeding and in preparation for surgery. In urgent cases, methylprednisolone 30 mg / kg per day for 3 days or 500 mg / m ^{2 of} salumedrol can be used as a glucocorticoid .

Anti-RhD-immunoglobulins

Mechanism of action:

• blockade of macrophage Fc receptors by erythrocyte-loaded antibodies;
• suppress the formation of antiplatelet antibodies;
• immunomodulating effect.

Conditions for use in idiopathic thrombocytopenic purpura are RhD-positive non-splenectomized patients.

Anti-RhD immunoglobulin preparations: WinRho (Winnipeg, Manitoba, Canada), NABI (Boca Ration, FL, USA), Partogamma (Biagini, Pisa, Italy), Resogam (Genteon Pharma, Germany) .

Mode of administration:

• the optimal course dose of 50 mcg / kg per course in the form of a single intravenous infusion or a fractional intramuscular injection within 2-5 days;
• when the concentration of hemoglobin in the patient's blood is less than 100 g / l, the dose of the drug is 25-40 μg / kg per course, with hemoglobin 100 g / l - 40-80-100 mcg / course;
• repeated courses of anti-D-immunoglobulin at intervals of 3-8 weeks to maintain a platelet count of more than 30,000 / mm ³.

The number of platelets and the level of hemoglobin is monitored for 3-4 days after the onset of exposure. The absence of a hematologic response to the first course of anti-D-immunoglobulin is not a contraindication for the second course, as 25% of patients who do not respond to treatment achieve a hematologic response with repeated administration of the drug. Among patients resistant to corticosteroids, 64% achieve remission after a course of anti-D-immunoglobulin. A significant increase in the number of platelets noted after 48 hours after the administration of the drug, so it is not recommended to use in life-threatening situations.

Adverse Reactions:

• influenza-like syndrome (temperature, chills, headache);
• drop in hemoglobin and hematocrit due to hemolysis, confirmed by a positive breakdown of Coombs.

Cases of infection with viruses when using anti-D-immunoglobulin preparations have not been reported. Acute allergic reactions are unlikely. IgE-mediated and immune complex-induced allergic reactions are described. In patients with IgA deficiency, allergic reactions are not described. Hemolysis is usually extravascular. In the few cases of intravascular hemolysis described, chronic renal failure did not develop. The average decrease in hemoglobin is 5-20 g / l and is transient (1-2 weeks).

The use of anti-RhD immunoglobulin is safe, convenient, cheap and effective in 79-90% of patients with chronic idiopathic thrombocytopenic purpura, and in children more than in adults.

The mechanism of action of glcocorticoids, intravenous immunoglobulin and anti-D-immunoglobulin

Effect	Corticosteroids	Intravenous immunoglobulin	Anti-D-immunoglobulin
Increased resistance of capillaries	+	-	-
Blockade of reticuloendothelium	+/-	+	+
Binding of antibodies to platelets	+	+/-	-
Violation of Fc R binding	+	+	+/-
Inhibition of T-lymphocytes	+	+	-
Synthesis of immunoglobulins	Increases	Increases	Norm / increase
Cytokine production	Increases	Increases	Norm

Interferon-alpha

Interferon-alpha-2b can be used in the treatment of patients with chronic idiopathic thrombocytopenic purpura, resistant to corticosteroids. Hematologic response is achieved in 72% of patients, including 33% who did not respond to corticosteroids.

Mechanism of action in idiopathic thrombocytopenic purpura: suppression of autoantibody production due to the inhibitory effect of interferon-alpha-2b on the production of immunoglobulins by B lymphocytes.

Mode of administration: 0,5-2x10 ⁶ units, depending on age, subcutaneously or intramuscularly 3 times a week (usually Monday-Wednesday-Friday) for 1-1.5 months. Hematologic response is noted on the 7-39th day from the beginning of treatment. In the absence of a hematologic response, treatment is discontinued, if available - continue until 3 months. After the end of the course, the drug is either canceled or prescribed in a maintenance dose with a reduction in the frequency of administration to 1-2 times per week (selected individually). If the disease recurs (usually 2-8 weeks after the end of the application), a second course is shown, which has the same efficacy. The duration of maintenance treatment of interferon-alpha-2b in the presence of a hematologic response is not determined.

Side effects: flu-like syndrome (fever, chills, headache, myalgia), pain and redness at the injection site, hepatic toxicity, myelopoiesis depression (at doses exceeding 2x10 ⁶ U), depression in adolescents.

To reduce the severity of side effects (influenza-like syndrome), the preventive administration of paracetamol is recommended before the first administration of the drug.

Danazol

Danazol is a synthetic androgen with weak virilizing activity and immunomodulating action (recovery of T-suppressor function).

The mechanism of action of danazol in idiopathic thrombocytopenic purpura:

• modulates the expression of Fc-gamma receptors on mononuclear phagocytes and prevents the destruction of antibody-loaded platelets;
• suppresses the production of autoantibodies;
• has a synergism with corticosteroids, promotes the release of steroids from binding to globulins and increases their access to tissues.

Mode of administration:

10-20 mg / kg per day orally (300-400 mg / m ² ) in 2-3 doses for 3 months or more to stabilize the effect.

Side effects:

Acne, hirsutism, weight gain, hepatic toxicity.

The hematologic response occurs in about half of children with chronic idiopathic thrombocytopenic purpura, including patients resistant to corticosteroids. The effectiveness of treatment increases after splenectomy. In most cases, the answer is incomplete.

Vincristine

Apply vincristine in a dose of 0.02 mg / kg (maximum 2 mg) intravenously, weekly, only 4 injections.

Vinblastine

Vinblastine is used at a dose of 0.1 mg / kg (max. 10 mg) intravenously, weekly, with only 4 injections.

In the case of the efficacy of vincristine and vinblastine, a rapid increase in the number of platelets occurs, often to a normal level. Most children need repeated injections of the drug at a 2-3-week interval to maintain a safe amount of platelets. If there is no response to treatment within 4 weeks, further use of the drugs is not indicated.

Complete hematologic remission for 0.5-4 years is described in approximately 10% of patients, transient response in half.

Side effects: peripheral neuropathy, leukopenia, alopecia, constipation, necrosis upon ingestion into the subcutaneous tissue.

Cyclophosphamide

Cyclophosphamide (cyclophosphamide) is used as an immunosuppressant. Hematological response in patients with chronic idiopathic thrombocytopenic purpura during treatment reaches 60-80% and persists longer than in other drugs. A complete hematologic response after the end of treatment occurs in 20-40% of cases. Better results are shown in splenectomized patients with a short duration of the disease.

The mechanism of action is suppression of the proliferation of lymphocyte clones involved in the immune response.

Mode of administration: 1-2 μ / kg per day, taken internally. Hematologic response is achieved in 2-10 weeks from the beginning of the course.

Side effects: myelopoiesis suppression, alopecia, hepatic toxicity, hemorrhagic cystitis, leukemia (distant complication).

Azathioprine

In patients with autoimmune diseases, azathioprine is used as an immunosuppressant. An increase in the number of platelets is noted in 50% of patients with idiopathic thrombocytopenic purpura, and a complete hematologic response in 10-20%.

Mode of administration: 1-5 mg / kg per day (200-400 mg). Until the maximum response is reached, the duration of treatment can be 3-6 months. Since after the end of the use of the drug the disease recurs, supportive treatment is necessary.

Side effects: anorexia, nausea, vomiting, moderate neutropenia, lymphomas (distant complication).

The advantage of this drug in children is a lower incidence of tumors compared to cyclophosphamide (cyclophosphamide).

Cyclosporin

Cyclosporine (cyclosporin A) is a non-steroid immunosuppressant that causes inhibition of cellular immunity. The drug acts on activated T-lymphocytes-effectors, suppressing the production of cytokines (interleukin-2, interferon-gamma, tumor necrosis factor).

Mode of administration: taken internally at a dose of 5 mg / kg per day for several months. The hematologic response is observed after 2-4 weeks from the beginning of admission in the form of some stabilization of clinical and hematological indicators, a decrease in the level of antiplatelet antibodies. Relapses of the disease occur immediately after the drug is discontinued.

Side effects: hypomagnesemia, hypertension, hepatic and renal toxicity, secondary tumors (distant complications). The severity of side effects and the unconvincing effect caused by the use of cyclosporine, makes its use in idiopathic thrombocytopenic purpura undesirable.

Transfusion of platelets

The transfusion of platelets is indicated in the case of development of neurological symptoms, indicating the possibility of intracranial hemorrhages, as well as in conducting surgical interventions in patients with deep thrombocytopenia, resistant to conservative treatment. Although the life span of the blood platelets is small, platelet transfusions can have a temporary hemostatic effect. However, the fear of increasing the duration of idiopathic thrombocytopenic purpura due to the risk of sensitization is only theoretical. Platelet transfusions are used in patients with idiopathic high-risk thrombocytopenic purpura with a positive clinical effect. Transfusion of thromboconcentrate is carried out fractionally at 1-2 doses per hour or 6-8 doses every 4-6 h until the clinico-hematologic response is achieved. The effect of transfusion is enhanced by the preliminary introduction of IVIG.

Splenectomy

In the absence of the effect of conservative treatment of thrombocytopenic purpura, the presence of deep thrombocytopenia, hemorrhagic syndrome and the threat of life-threatening bleeding, patients are shown to perform splenectomy. The question of the operation is decided individually for each case.

Indications for splenectomy:

• severe acute idiopathic thrombocytopenic purpura with life-threatening bleeding in the absence of response to medication;
• duration of the disease is more than 12 months, thrombocytopenia less than 10 000 / mm ³ and bleeding in the anamnesis;
• chronic idiopathic thrombocytopenic purpura with signs of hemorrhage and a constant platelet count of less than 30,000 / mm ³ in the absence of response to treatment for several years.

In the leading active lifestyle, often traumatized patients, splenectomy can be performed earlier.

Due to the risk of developing generalized infections after surgery, splenectomy is performed only if there are clear indications. The operation is rarely necessary for 2 years from the date of diagnosis, since thrombocytopenia is well tolerated and is easily controlled by the use of corticosteroids and IVIG. Spontaneous platelet count recovery may occur after 4-5 years, hence a very cautious approach is required to perform the operation. In children with chronic idiopathic thrombocytopenic purpura, cases of spontaneous remission are noted in 10-30% of cases several months or years after diagnosis, in adults very rarely.

Preparations for splenectomy include the administration of corticosteroids, IVIG or anti-D-immunoglobulin. Corticosteroids are prescribed in a full dose a day before, on the day of the operation and for several days after the procedure, as most patients have adrenal insufficiency due to their previous use. When an active bleeding occurs immediately before surgery, transfusions of platelets and erythromass may be required, as well as the administration of methylprednisolone (salumedrol) at a dose of 500 mg / m ² per day. Before the planned operation, ultrasound examination of the abdominal cavity organs is necessary to identify additional spleen (15% of cases), and in disputable cases - radioisotope scintillation.

Complete and prolonged recovery of platelet count after splenectomy occurs in approximately 50% of patients. A good prognostic sign is the response to the intake of corticosteroids and IVIG prior to surgery (splenectomy efficiency in 80-90%), and the absence of antiplatelet antibodies after it. 25% of children who have had splenectomy do not reach a clinico-hematologic response and need further treatment.

Preferably, the laparoscopic procedure (possible in 90% of patients) allows to reduce the volume of surgical intervention, the level of operational blood loss, to provide the patient with a faster return to active life and shorten the period of hospitalization. The postoperative scar has a length of about 1 cm and does not cause discomfort.

Cases of death from bacterial infections in the late postoperative period, especially in children who underwent splenectomy to 5 years, is 1: 300 patients per year. Most of them occur within 2 years after the operation. The main causes include pneumococcal and meningococcal infections that develop as a type of fulminant sepsis with DIC of the blood and hemorrhages in the adrenal glands. Therefore, no later than two weeks before the operation, the administration of pneumococcal, meningococcal and vaccines against Haemophilus influenzae and a prolonged, at least 2 years, preventive administration of benzylpenicillin after splenectomy are recommended. Some authors propose to restrict the introduction of bicillin-5 (benzathine benzylpenicillin + benzylpenicillin procaine) monthly for 6 months after the operation.

A possible alternative to splenectomy is the endovascular occlusion of the spleen, which can also be performed in patients with deep thrombocytopenia. To achieve a stable clinical and hematological effect, a phased disabling of 90-95% of the parenchyma of the organ is necessary. Immunological reactivity of the organism after endovascular occlusion of the spleen is maintained due to the functioning of 2-5% of the spleen tissue, which preserve blood supply through collaterals, which is important in pediatric practice. It is possible to use proximal endovascular occlusion of the spleen several days before splenectomy in order to reduce the risk of surgery.

Plasmapheresis

In patients with persistent thrombocytopenia and life-threatening bleeding, despite the drug intervention and splenectomy, it is possible to use reinfusion of plasma passed through the protein A columns to rapidly remove antiplatelet antibodies. In patients with severe idiopathic thrombocytopenic purpura, elimination of the circulating antiplatelet factor is accelerated.

Treatment of children with life-threatening bleeding:

• transfusion of platelets;
• salumedrol 500 mg / m ² per day intravenously in 3 injections;
• intravenous immunoglobulin 2 g / kg per course;
• immediate splenectomy.

These measures can be performed individually or in combination, depending on the severity and response to treatment.

Prognosis in children with idiopathic thrombocytopenic purpura

• In 70-80% of patients, remission occurs within 6 months, in 50% - within 1 month from the onset of the disease.
• The onset of spontaneous remission after a year of illness is uncharacteristic, but can be noted even after several years.
• The prognosis of the disease does not depend on sex, the severity of the initial condition and the detection of eosinophilia in the bone marrow.
• When the cause of idiopathic thrombocytopenic purpura is identified, the prognosis depends on its elimination.
• The condition of approximately 50-60% of patients with chronic idiopathic thrombocytopenic purpura stabilizes without any treatment and splenectomy.

[1], [2], [3], [4], [5], [6], [7]