How is thrombotic thrombocytopenic purpura treated?

Since the pathogenesis of idiopathic thrombocytopenic purpura is based on the destruction of autoantibody-laden platelets by cells of the reticulohistiocytic system, the main principles of treating thrombocytopenic purpura are:

• decrease in production of autoantibodies;
• impaired binding of autoantibodies to platelets;
• elimination of destruction of antibody-sensitized platelets by cells of the reticulohistiocytic system.

In the absence of bleeding from the mucous membranes, mild ecchymosis after bruises, and a platelet count of more than 35,000/mm ^3, treatment is usually not required. Patients should avoid contact sports. Menstruating girls benefit from long-acting progesterone preparations (Depo-Provera and others) to delay menstruation for several months to prevent intense uterine bleeding.

Glucocorticoids

Mechanism of action

• Inhibition of phagocytosis of platelets with antibodies fixed on their surface in the spleen.
• Disruption of antibody production.
• Impaired binding of autoantibodies to antigen.

Indications

Bleeding from mucous membranes; marked purpura and copious hematomas at sites of contusions, especially on the head and neck; progressive purpura; thrombocytopenia for more than 3 weeks; recurrent thrombocytopenia; platelet count less than 20,000/mm3 ⁱⁿ primary patients with minimal purpura.

Modes of administration

• Standard doses of oral corticosteroids are prednisolone 1-2 mg/kg per day or 60 mg/ ^m2 per day for 21 days with gradual withdrawal. The dose is reduced regardless of the platelet count, remission is assessed at the end of the course. In the absence of remission or a decrease in the platelet count after achieving normal values, glucocorticoid action is not continued. In the absence of a complete hematological response during a standard course of corticosteroids, prednisolone is discontinued in an "intermittent course" (every other day after a break, 5 mg). It is possible to repeat the course of corticosteroids after 4 weeks. Long-term use of corticosteroids in idiopathic thrombocytopenic purpura is undesirable, as it can lead to depression of thrombopoiesis.
• High doses of oral corticosteroids 4-8 mg/kg per day for 7 days or 10-30 mg/kg per day of methylprednisolone for 3-7 days with rapid withdrawal of the drug. After a week, the courses are repeated (2-3 courses).
• High doses of parenteral corticosteroids 10-30 mg/kg per day methylprednisolone or solumedrol 500 mg/ ^m2 per day intravenously for 3-7 days in severe cases for faster relief of hemorrhagic syndrome. If further treatment is necessary, the patient is transferred to standard oral doses.
• For steroid-resistant patients with idiopathic thrombocytopenic purpura, “pulse therapy” with dexamethasone is possible - 6 cycles of 0.5 mg/kg per day (maximum 40 mg/day) for 4 days every 28 days, taken orally.

The effectiveness of taking corticosteroids, according to different authors, is 50-80%. Side effects when using them: symptoms of hypercorticism, peptic ulcer, hyperglycemia, hypertension, increased risk of infection, myopathy, hypokalemia, steroid psychosis, ovarian dysfunction in girls, growth retardation.

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 - first line intervention;
• neonatal symptomatic immune thrombocytopenia;
• children under 2 years of age who are resistant to the effects of corticosteroids.

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

Intravenous immunoglobulin preparations approved for use

Ready to eat	In the form of concentrates
Human immunoglobulin normal (intraglobin) (Biotest, Germany), human immunoglobulin normal for intravenous administration (imbio-gam) (IMBIO, Russia), (octagam) (Octapharma, Switzerland), IG VIENNA N.I.V. (Kedrion, Italy)	Immunoglobulin (Biochemie, Austria), sandoglobulin (Sandoz, Switzerland), normal human immunoglobulin (Endobulin S/D) (Austria), (Biaven BH (Pharma Biajini, Italy), (Venoglobulin) (Paster Merieux, France), normal human immunoglobulin (Gabriglobin) (Ivanovskaya SPK, Russia)

Comparative characteristics of intravenous immunoglobulin preparations

	IG Vienna	Human immunoglobulin normal (octagam)	Human normal immunoglobulin (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
CMV antibody titer, U/ml	50.0	22.0-23.0	12.0	More than 10.0

Intravenous immunoglobulin administration regimens

• 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 2 years of age tolerate a 5-day protocol of taking drugs of the first and second generations better.
• In chronic idiopathic thrombocytopenic purpura - initial dose 1 g/kg per day for 1-2 days, then single infusions at a dose of 0.4-1 g/kg, depending on the response, to maintain a safe platelet level (more than 30,000/mm ³ ). The use of IVIG is useful in combination with alternating courses of corticosteroids.

The response rate in patients with acute idiopathic thrombocytopenic purpura occurs in 80-96.5% of cases. Compared with the use of corticosteroids, the platelet count increases more rapidly during bleeding episodes of comparable duration. About 65% of children with idiopathic thrombocytopenic purpura resistant to corticosteroids achieve long-term remission after a course of IVIG.

Side effects of IVIG drugs:

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

A case of aseptic meningitis after IVIG infusion, as well as infection of IVIG recipients (Gammaguard "Baxter") with the hepatitis C virus, has been described in the scientific literature, but since 1994, after the improvement of drug production technology, such situations have no longer been encountered.

Prophylactic administration of paracetamol (10-15 mg/kg every 4 hours) and diphenhydramine (diphenhydramine) (1 mg/kg every 6-8 hours) reduces the frequency and severity of fever with chills, and intravenous administration of dexamethasone at a dose of 0.15-0.3 mg/kg helps relieve headaches during IVIG infusions.

Combined use of glucocorticoids and intravenous immunoglobulin

Indications:

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

The combined use causes a more rapid increase in platelet count than either drug alone. It is used in life-threatening bleeding and in preparation for surgery. In emergency cases, methylprednisolone 30 mg/kg per day for 3 days or solumedrol 500 mg/m ² can be used as a glucocorticoid.

Anti-RhD immunoglobulins

Mechanism of action:

• blockade of macrophage Fc receptors by antibody-loaded erythrocytes;
• suppression of the formation of antiplatelet antibodies;
• immunomodulatory effect.

Conditions of use in idiopathic thrombocytopenic purpura - 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 is 50 mcg/kg per course in the form of a single intravenous infusion or fractional intramuscular administration over 2-5 days;
• if the concentration of hemoglobin in the patient's blood is less than 100 g/l, the dose of the drug is 25-40 mcg/kg per course, if hemoglobin is 100 g/l - 40-80-100 mcg/course;
• Repeated courses of anti-D immunoglobulin at intervals of 3-8 weeks to maintain the platelet count above 30,000/mm ³.

The platelet count and hemoglobin level are monitored on the 3rd-4th day after the start of the treatment. The absence of a hematological response to the first course of anti-D immunoglobulin is not a contraindication for a second course, since 25% of patients who did not respond to treatment achieve a hematological 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 platelet count is noted 48 hours after the drug is administered, so it is not recommended for use in life-threatening situations.

Side effects:

• flu-like syndrome (fever, chills, headache);
• a drop in hemoglobin and hematocrit levels due to hemolysis, confirmed by a positive Coombs test.

No cases of viral infection have been reported with the use of anti-D immunoglobulin preparations. Acute allergic reactions are unlikely. IgE-mediated and immune complex-induced allergic reactions have been described. Allergic reactions have not been described in patients with IgA deficiency. Hemolysis is usually extravascular. In the few cases of intravascular hemolysis described, chronic renal failure did not develop. The average decrease in hemoglobin level is 5-20 g/l and is short-lived (1-2 weeks).

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

Mechanism of action of glucocorticoids, intravenous immunoglobulin and anti-D immunoglobulin

Effect	Corticosteroids	Intravenous immunoglobulin	Anti-D immunoglobulin
Increasing capillary resistance	+	-	-
Reticuloendothelial block	+/-	+	+
Binding of antibodies to platelets	+	+/-	-
Fc R binding disorder	+	+	+/-
T-lymphocyte suppression	+	+	-
Synthesis of immunoglobulins	It's increasing	It's increasing	Normal/increases
Cytokine production	It's increasing	It's increasing	Norm

Interferon alpha

Interferon-alpha-2b can be used in the treatment of patients with chronic idiopathic thrombocytopenic purpura resistant to corticosteroids. Hematological 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.

Administration regimen: 0.5-2x10 ⁶ U, depending on age, subcutaneously or intramuscularly 3 times a week (usually Monday-Wednesday-Friday) for 1-1.5 months. Hematological response is noted on the 7th-39th day from the start of treatment. In the absence of a hematological response, treatment is stopped, if present, it is continued for up to 3 months. After completion of the course, the drug is either discontinued or prescribed in a maintenance dose with a decrease in the frequency of administration to 1-2 times a week (selected individually). In case of relapse of the disease (usually 2-8 weeks after the end of use), a repeat course is indicated, which has the same effectiveness. The duration of maintenance treatment with interferon-alpha-2b in the presence of a hematological response has not been determined.

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

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

Danazol

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

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 synergy with corticosteroids, promotes the release of steroids from their bonds with globulins and increases their access to tissues.

Mode of administration:

10-20 mg/kg per day orally (300-400 mg/m2 ⁾ in 2-3 doses for 3 months or more to stabilize the effect.

Side effects:

Acne, hirsutism, weight gain, liver toxicity.

Hematologic response occurs in about half of children with chronic idiopathic thrombocytopenic purpura, including those resistant to corticosteroids. Treatment efficacy is increased after splenectomy. Response is incomplete in most cases.

Vincristine

Vincristine is used at a dose of 0.02 mg/kg (maximum 2 mg) intravenously, weekly, for a total of 4 administrations.

Vinblastine

Vinblastine is administered at a dose of 0.1 mg/kg (maximum 10 mg) intravenously, weekly, for a total of 4 administrations.

When vincristine and vinblastine are effective, platelet counts increase rapidly, often to normal levels. Most children require repeat doses at 2- to 3-week intervals to maintain safe platelet counts. If there is no response within 4 weeks, no further use is indicated.

Complete hematological remission within 0.5-4 years has been described in approximately 10% of patients, and a transient response in half.

Side effects: peripheral neuropathy, leukopenia, alopecia, constipation, necrosis when entering the subcutaneous tissue.

Cyclophosphamide

Cyclophosphamide (cyclophosphamide) is used as an immunosuppressant. The hematological response in patients with chronic idiopathic thrombocytopenic purpura during treatment reaches 60-80% and lasts longer compared to other drugs. Complete hematological response after completion of treatment occurs in 20-40% of cases. The best 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.

Administration regimen: 1-2 mcg/kg per day, taken orally. Hematological response is achieved 2-10 weeks after the start of the course.

Side effects: suppression of myelopoiesis, alopecia, liver toxicity, hemorrhagic cystitis, leukemia (remote complication).

Azathioprine

In patients with autoimmune diseases, azathioprine is used as an immunosuppressant. An increase in platelet count is noted in 50% of patients with idiopathic thrombocytopenic purpura, and a complete hematological response is observed in 10-20%.

Administration regimen: 1-5 mg/kg per day (200-400 mg). Until the maximum response is achieved, the duration of treatment may be 3-6 months. Since the disease recurs after the end of drug use, maintenance treatment is necessary.

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

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

Cyclosporine

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

Administration regimen: taken orally at a dose of 5 mg/kg per day for several months. Hematological response is observed 2-4 weeks after the start of administration in the form of some stabilization of clinical and hematological parameters, a decrease in the level of antiplatelet antibodies. Relapses of the disease occur immediately after discontinuation of the drug.

Side effects: hypomagnesemia, hypertension, liver and kidney toxicity, secondary tumors (remote complications). The severity of side effects and the inconclusive effect caused by the use of cyclosporine make its use in idiopathic thrombocytopenic purpura undesirable.

Platelet transfusions

Platelet transfusion is indicated in case of development of neurological symptoms indicating the possibility of intracranial hemorrhage, as well as during surgical interventions in patients with deep thrombocytopenia resistant to conservative treatment. Although the lifespan of blood platelets is short, platelet transfusions can have a temporary hemostatic effect. At the same time, 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 high-risk idiopathic thrombocytopenic purpura with a positive clinical effect. Transfusion of platelet concentrate is carried out fractionally by 1-2 doses per hour or 6-8 doses every 4-6 hours until a clinical and hematological response is achieved. The effect of transfusion is enhanced by preliminary administration of IVIG.

Splenectomy

In case of lack of effect from conservative treatment of thrombocytopenic purpura, presence of deep thrombocytopenia, hemorrhagic syndrome and risk of development of life-threatening bleeding, patients are recommended to undergo splenectomy. The question of surgery is decided individually in each case.

Indications for splenectomy:

• severe acute idiopathic thrombocytopenic purpura with life-threatening bleeding in the absence of response to drug therapy;
• disease duration greater than 12 months, thrombocytopenia less than 10,000/mm3 ^and a history of bleeding;
• chronic idiopathic thrombocytopenic purpura with signs of bleeding and a persistent platelet count of less than 30,000/mm3 ⁱⁿ the absence of a response to treatment for several years.

In patients with an active lifestyle and frequent injuries, splenectomy may be performed earlier.

Because of the risk of developing generalized infections after surgery, splenectomy is performed only when there are clear indications. Surgery is rarely necessary within 2 years of diagnosis, as thrombocytopenia is well tolerated and easily controlled with corticosteroids and IVIG. Spontaneous recovery of platelet count may occur after 4-5 years, so a very cautious approach to performing surgery is necessary. In children with chronic idiopathic thrombocytopenic purpura, spontaneous remission is noted in 10-30% of cases several months or years after diagnosis, but very rarely in adults.

Preparation for splenectomy includes administration of corticosteroids, IVIG, or anti-D immunoglobulin. Corticosteroids are given in full doses the day before, on the day of, and for several days after surgery, as most patients have adrenal insufficiency due to previous corticosteroid use. If active bleeding occurs immediately before surgery, platelet and red blood cell transfusions and methylprednisolone (solumedrol) 500 mg/m2 ^daily may be required. Before elective surgery, an abdominal ultrasound is mandatory to detect additional spleens (15% of cases), and in controversial cases, radioisotope scanning is required.

Complete and long-term recovery of platelet count after splenectomy occurs in approximately 50% of patients. A good prognostic sign is the response to corticosteroids and IVIG before surgery (splenectomy is 80-90% effective), as well as the absence of antiplatelet antibodies after it. 25% of children who have undergone splenectomy do not achieve a clinical and hematological response and require further treatment.

Preferably, the operation is performed laparoscopically (possibly in 90% of patients) allowing to reduce the volume of surgical intervention, the level of surgical blood loss, provide the patient with a faster return to active life and reduce the hospitalization period. The postoperative scar is about 1 cm long and does not cause discomfort.

The incidence of fatal bacterial infections in the late postoperative period, especially in children who underwent splenectomy before the age of 5, is 1:300 patients per year. Most of them occur within 2 years after the operation. The main causes include pneumococcal and meningococcal infections, developing as fulminant sepsis with DIC and hemorrhages in the adrenal glands. Therefore, no later than two weeks before the operation, it is recommended to administer pneumococcal, meningococcal and Haemophilus influenzae vaccines and long-term, at least 2 years, prophylactic administration of benzylpenicillin after splenectomy. Some authors suggest limiting the administration to bicillin-5 (benzathine benzylpenicillin + benzylpenicillin procaine) monthly for 6 months after the operation.

A possible alternative to splenectomy is endovascular occlusion of the spleen, which can also be performed in patients with profound thrombocytopenia. To achieve a stable clinical and hematological effect, a step-by-step exclusion of 90-95% of the organ parenchyma is necessary. The body's immunological reactivity after endovascular occlusion of the spleen is preserved due to the functioning of 2-5% of the splenic tissue, which maintains blood supply due to 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 medical intervention and splenectomy, reinfusion of plasma passed through protein A columns may be used to rapidly remove antiplatelet antibodies. In patients with severe idiopathic thrombocytopenic purpura, this accelerates the elimination of circulating antiplatelet factor.

Treatment of children with life-threatening bleeding:

• platelet transfusions;
• solumedrol 500 mg/m2 ^per day intravenously in 3 doses;
• intravenous immunoglobulin 2 g/kg per course;
• immediate splenectomy.

These measures may 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 gender, severity of the initial condition and detection of eosinophilia in the bone marrow.
• Once the cause of idiopathic thrombocytopenic purpura is identified, the prognosis depends on its elimination.
• Approximately 50-60% of patients with chronic idiopathic thrombocytopenic purpura will stabilize without any treatment or splenectomy.

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