Idiopathic Thrombocytopenic Purpura (ITP) in Adults: Clinical Guidelines

List of Abbreviations

Terms and Definitions

Secondary immune thrombocytopenia – immune thrombocytopenia presenting as a symptom of other autoimmune diseases: systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, etc.

Primary immune thrombocytopenia – idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease caused by the production of antibodies against membrane structures of platelets and their precursors (megakaryocytes), leading to both increased platelet destruction and inadequate thrombopoiesis, characterized by isolated thrombocytopenia below 100.0×10⁹/L with or without hemorrhagic syndrome of varying severity.

Thrombocytopenia – a pathological condition characterized by a decrease in platelet count below 150.0×10⁹/L.

First-, second-, and third-line therapy – sequence of ITP treatment regimens.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Primary immune thrombocytopenia – idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease caused by the production of antibodies against membrane structures of platelets and their precursors (megakaryocytes), leading to both increased platelet destruction and inadequate thrombopoiesis, characterized by isolated thrombocytopenia below 100.0×10⁹/L with or without hemorrhagic syndrome of varying severity [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of ITP is unknown. ITP is an autoimmune disease characterized by the production of immunoglobulin G₁ subclass antibodies (IgG₁) against platelet and megakaryocyte (MKC) membrane glycoproteins (GPs), primarily GPIIb/IIIa, less commonly GPIb-IX-V, GPIa/IIa, GPIV, or GPVI, and the formation of an antigen-antibody complex that binds via its immunoglobulin Fc fragment to Fcγ receptors on macrophages and dendritic cells of the reticuloendothelial system. Destruction of the pathological antigen-antibody complex occurs through its degradation primarily in the spleen, less commonly in the liver and lymph nodes, as well as via cytotoxic T-cell lysis. In addition to antibody production, T-lymphocyte subpopulations play a major role in the pathogenesis of ITP [2].

1.3 Epidemiology of the Disease or Condition

The global incidence of ITP ranges from 1.6 to 12.5 cases per 100,000 population per year, and the prevalence ranges from 4.5 to 20 cases per 100,000 population. In the Russian Federation, the incidence of ITP in adults averages 2.09 per 100,000 individuals. ITP has no geographic predilection. Men are affected 2–3 times less frequently than women [3–5].

1.4 Features of Coding the Disease or Condition

D69.3 – Idiopathic thrombocytopenic purpura.

1.5 Classification of the disease or condition

1. By disease duration [1, 6–7]:

• newly diagnosed – up to 3 months from diagnosis;

• persistent – 3 to 12 months from diagnosis;

• chronic – more than 12 months from diagnosis.

2. By the nature and severity of hemorrhagic syndrome (World Health Organization [WHO] classification) [1, 6–7]:

• Grade 0 – no hemorrhagic syndrome;

• Grade 1 – petechiae and ecchymoses (few);

• Grade 2 – mild blood loss (hematuria, hemoptysis);

• Grade 3 – severe blood loss (bleeding requiring blood transfusion or blood substitutes);

• Grade 4 – massive blood loss (cerebral and retinal hemorrhages, fatal hemorrhages).

Severe ITP refers to cases presenting with bleeding symptoms at disease onset that required therapy initiation, or cases of bleeding recurrence requiring additional therapeutic interventions to increase the platelet count or an increase in the dosage of medications used.

Refractory ITP is defined by the absence of an immediate response to splenectomy, loss of response after splenectomy, and the need for further treatment to control clinically significant bleeding.

Resistant ITP should refer to cases with no response or loss of response after 2 or more courses of drug therapy, requiring the resumption of treatment [1, 6–7].

Chronic ITP is included in the list of rare (orphan) diseases with a prevalence of no more than 10 cases per 100,000 population and in the List of Life-Threatening and Chronic Progressive Rare Diseases [Appendix A3].

1.6 Clinical presentation of the disease or condition

ITP is characterized by isolated thrombocytopenia below 100.0×10⁹/L with or without a hemorrhagic syndrome of varying severity [7].

Clinically, ITP manifests as a hemorrhagic syndrome: spontaneous or post-traumatic, cutaneous (single or generalized petechial rash and ecchymoses), petechiae and ecchymoses on mucous membranes, epistaxis and gingival bleeding, menorrhagia and metrorrhagia, and less commonly gastrointestinal bleeding and hematuria. The frequency of life-threatening hemorrhages does not exceed 0.5% [7].

2. Diagnostics, medical indications and contraindications for diagnostic methods

There are currently no specific diagnostic markers for ITP; the diagnosis of ITP is a diagnosis of exclusion, which requires a comprehensive evaluation to rule out immune and non-immune diseases and conditions presenting with thrombocytopenia [1,8].

The diagnosis of ITP is established based on the following criteria:

• isolated thrombocytopenia less than 100.0×10⁹/L registered in at least two consecutive blood tests;

• absence of morphological and functional platelet abnormalities;

• absence of lymphocyte, granulocyte, and erythrocyte pathology;

• normal hemoglobin, erythrocyte, and reticulocyte counts, unless significant blood loss has occurred;

• increased or normal megakaryocyte count in the myelogram;

• normal spleen size;

• absence of other pathological conditions causing thrombocytopenia;

• presence of platelet-associated antibodies [1,4].

Diagnosing ITP requires meeting all criteria except the test for platelet-associated antibodies. A normal titer of platelet-associated antibodies does not rule out ITP, but significantly aids in diagnosis.

2.1 Complaints and Anamnesis

• When taking the disease and family history for all patients to determine the scope of evaluation, the hematologist is recommended to identify factors preceding the development of thrombocytopenia (bacterial or viral infection, vaccination or use of medications, alcohol and quinine-containing beverages, stress, varicose veins, thrombosis, cardiovascular pathology, concomitant diseases, history of transfusions or organ transplantation, pregnancy, presence and duration of bleeding after surgical procedures); and to clarify the family history regarding bleeding disorders, thrombocytopenia, thrombosis, and hematopoietic disorders in blood relatives [1,4,5].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

2.2 Physical Examination

• During the physical examination of all patients, the hematologist is recommended to pay attention to the following findings: hypo- and hyperthermia, weight loss and intoxication symptoms, hepato- and splenomegaly, lymphadenopathy, pathology of the mammary glands, heart, lower limb veins, congenital anomalies, as well as the nature, degree, and severity of the hemorrhagic syndrome. This will help differentiate thrombocytopenia in ITP from secondary thrombocytopenias and assess the severity of ITP [1,4,5,7,9].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

2.3 Laboratory Diagnostics

To obtain the maximum amount of data for diagnosing ITP, which is a diagnosis of exclusion, mandatory laboratory tests are performed.

Comments: the scope of the study includes differential blood cell counting using an automated analyzer; determination of the reticulocyte count, evaluation of erythrocyte, platelet, and neutrophil morphology on a blood smear, and erythrocyte sedimentation rate (ESR); attention should be paid to the presence of platelet aggregates to rule out consumption thrombocytopenia and "pseudothrombocytopenia" caused by the use of ethylenediaminetetraacetic acid (EDTA) anticoagulant. ITP presents only with isolated thrombocytopenia, diagnostic signs of posthemorrhagic iron deficiency anemia (IDA) and reticulocytosis after massive blood loss are permissible.

Comments: An expanded coagulogram (screening hemostasis test) includes: activated partial thromboplastin time (APTT), international normalized ratio (INR) and/or prothrombin time by Quick, thrombin time (TT), fibrinogen concentration, antithrombin III, protein C, protein S, and von Willebrand factor.

• To rule out secondary thrombocytopenia, all patients are recommended to undergo blood tests for syphilis, human immunodeficiency virus (HIV), and antibodies to hepatitis B and C viruses [4, 9, 10, 11]:

1) determination of antibodies to Treponema pallidum in blood serum using an enzyme immunoassay (EIA) or determination of antibodies to Treponema pallidum using nontreponemal tests (rapid plasma reagin (RPR) test and rapid plasma reagin qualitative and semi-quantitative study) in blood serum;

2) determination of IgM and IgG antibodies to Human immunodeficiency virus 1 (HIV-1) in blood serum; determination of IgM and IgG antibodies to Human immunodeficiency virus 2 (HIV-2) in blood serum;

3) determination of hepatitis B surface antigen (HBsAg) in blood and determination of antibodies to hepatitis C virus (HCV) in blood [11].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Serological tests are repeated in case of ITP relapse, treatment failure, or for diagnostic clarification. If serological tests for hepatitis B and C viruses are positive (determination of hepatitis B surface antigen (HBsAg) in blood and antibodies to hepatitis C virus (HCV) in blood), refer to the diagnostic algorithm in the relevant clinical guidelines.

• To rule out virus-induced thrombocytopenia, all patients are recommended to undergo testing for antibodies to Herpes simplex virus in blood, antibodies to Epstein-Barr virus viral capsid antigen (VCA) in blood, IgG antibodies to Epstein-Barr virus viral capsid antigen (VCA) in blood, IgG antibodies to Epstein-Barr virus nuclear antigen (NA) in blood, and antibodies to Varicella-Zoster virus and Cytomegalovirus in blood [4, 9].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Polymerase chain reaction (PCR) testing for these viruses should be performed in case of positive serological tests, suspected relapse, latent infection, or viral persistence.

• To rule out immunodeficiency states, all patients are recommended to have a blood immunoglobulin assay (IgG, IgM, IgA) [9, 11, 12].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: thrombocytopenia may accompany immunodeficiency states.

Comments: Cytological examination of a bone marrow smear (myelogram) allows for the exclusion of acute leukemias, myelodysplastic syndrome, aplastic anemia, bone marrow metastasis of tumors, etc. ITP is characterized by an increased or normal megakaryocyte count, with normal or giant forms lacking morphological abnormalities. Pathological examination of bone marrow biopsy (surgical) material is indicated for recurrent and refractory forms of ITP (lasting $\ge$ 6 months), prior to splenectomy, in patients over 60 years of age, when the megakaryocyte count in the myelogram is low, or when secondary thrombocytopenia is suspected.

• To clarify the diagnosis and perform differential diagnosis of secondary immune thrombocytopenia , all patients are recommended to undergo blood testing for: total anti-platelet antibody levels, lupus anticoagulant values, anti-cardiolipin antibodies (IgM and IgG), anti-beta-2-glycoprotein 1 antibodies (IgM and IgG), antinuclear factor levels, anti-native (double-stranded) deoxyribonucleic acid (DNA) antibodies, and anti-thyroperoxidase (TPO) antibodies [14].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: These diagnostic methods are essential in determining patient management tactics. If secondary immune thrombocytopenia is suspected and based on a history of positive test results these tests should be repeated every 12 weeks. During glucocorticoid (GC) therapy, the diagnostic reliability of the results is reduced.

2.4 Instrumental Diagnostics

• To rule out lymphoid hyperplasia and other mass lesions, all patients are recommended to undergo ultrasound examination (ultrasound) or computed tomography (CT) of the abdominal cavity to assess the presence of intra-abdominal lymph nodes, spleen size, and liver size [9,11,15].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• To rule out intrathoracic lymph node hyperplasia and thoracic pathology, all patients are recommended to undergo chest X-ray or chest CT [9,11,15].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

2.5 Other Procedures

Not required.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Modern therapeutic methods do not achieve a complete cure for ITP. Achieving remission of varying duration or a state of clinical compensation is possible. Clear prognostic criteria for the disease course, treatment response, and outcomes have not been established [4-6,9,11,15].

The sequence of pathogenetic (specific) therapy administration in ITP, developed based on years of clinical experience, is referred to as treatment lines [1]. The effectiveness of the therapy administered is assessed by the following criteria:

Complete response – platelet count greater than 100.0×10⁹/L.

Response – platelet count greater than 30.0×10⁹/L or a 2-fold increase from the baseline count + absence of bleeding.

Time to response – the time from the initiation of therapy to achieving a response or complete response.

No response – platelet count less than 30.0×10⁹/L, or less than a 2-fold increase from the baseline count, or ongoing bleeding.

Loss of complete response – decrease in platelet count below 100.0×10⁹/L or recurrence of hemorrhagic syndrome.

Loss of response – decrease in platelet count below 30.0×10⁹/L, or less than a 2-fold increase from the baseline count, or presence of bleeding.

Duration of response – the time from the achievement of a response to its loss. [1].

3.1 Therapy in emergency situations

In cases of uterine, gastrointestinal, renal, intra-abdominal, nasal bleeding, hemorrhages into the brain, orbit, etc., emergency therapy is administered for the rapid relief of severe hemorrhagic syndrome [4-5, 9, 11, 16–18].

• To rapidly stop bleeding, it is recommended that all patients undergo pulse therapy with #methylprednisolone** – 1000 mg/day IV infusion for 1–2 hours over 3–5 days, 2–6 cycles at an interval of 10–21 days [19].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For the rapid cessation of bleeding, it is recommended that all patients undergo pulse therapy with #dexamethasone** at 40 mg IV daily for 4 days, every 2–4 weeks, 1–4 cycles [4-5,9,11,16-18].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For the most rapid relief of hemorrhagic syndrome, IVIG** (normal human immunoglobulin (solution for intravenous administration)) is recommended for all patients – a course dose of 2 g per 1 kg of body weight, divided over 2–5 consecutive days; daily dose from 0.4 g/kg to 1 g/kg of body weight] [4-5,9,17-23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: it should be used with caution in elderly individuals, patients with hypertension, allergic reactions, and thrombosis. The efficacy of 5% and 10% IVIG solutions is equivalent and ranges from 72.2% to 80.7%. Adverse events are comparable.

• If conservative treatment methods are ineffective, patients are recommended to undergo splenectomy to achieve remission [4-5,9,11,18,20,24-25].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3.2 Therapy for patients with newly diagnosed ITP (disease duration up to 3 months)

• It is recommended to initiate treatment in patients with hemorrhagic syndrome and a platelet count of less than 30–50.0×10⁹/L (Appendix G2) to achieve a therapeutic effect [9,16,24,25].

Standard GCS therapy in therapeutic doses: prednisolone^** (1 mg/kg body weight orally), methylprednisolone^** and dexamethasone^** (calculated in terms of prednisolone** dose) should not exceed 2–3 weeks due to the potential development of complications. High-dose GCS pulse therapy utilizes #methylprednisolone^** (1000 mg/day IV infusion for 1–2 hours for 3–5 days, 2–6 cycles with an interval of 10–21 days) and #dexamethasone^** (40 mg IV daily for 4 days, every 2–4 weeks, 1–4 cycles).

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: To prevent the development of complications, the GCS dose should not exceed 80 mg of prednisolone** or equivalent doses of other GCSs.

3.2.1 First-line therapy for newly diagnosed ITP (GCS and IVIG)

• It is recommended to initiate treatment in patients with newly diagnosed ITP in the presence of hemorrhagic syndrome and platelets < 30–50.0×10⁹/L, or in the absence of hemorrhagic syndrome with thrombocytopenia < 20.0×10²/L to achieve a therapeutic effect [4-6,9,11,15,18,25].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: The efficacy of the first course of GCS therapy is 70–80%, although remission is rarely stable (in 20–30% of patients), and relapse occurs. High doses of dexamethasone** are effective in 86% of patients with response maintenance for up to 8 months. A sustained response is achieved in 50% of patients with newly diagnosed ITP.

Adverse events: decreased glucose tolerance, adrenal suppression, Cushing's syndrome, gastric and duodenal ulcers, erosive gastritis and esophagitis, gastrointestinal bleeding and perforation, flatulence, arterial hypertension, hypercoagulation, insomnia, hiccups, agitation, anxiety, euphoria, depression, development of secondary bacterial, fungal, and viral infections, weight gain, osteoporosis, skin hyper/hypopigmentation, generalized and local allergic reactions.

Contraindications for GCS: diabetes mellitus; severe forms of arterial hypertension and arrhythmias; active infections; mental disorders.

Dosages of glucocorticoids: prednisolone** at a dose of 1 mg/kg body weight orally for 2–4 weeks followed by a gradual taper. The therapeutic dose of methylprednisolone^** orally is calculated relative to the prednisolone** dose, i.e., 5 mg of prednisolone** per tablet corresponds to 4 mg of methylprednisolone**. High-dose methylprednisolone^** (1000 mg/day IV infusion for 1–2 hours for 3–5 days, 2–6 cycles with an interval of 10–21 days). High-dose dexamethasone** – 40 mg/day orally or IV for 4 days – 4 treatment cycles every 14–28 days.

IVIG** is effective in 72.2–80.7% of cases; the efficacy of 5% and 10% IVIG solutions is equivalent, and adverse events are comparable. The hemostatic effect occurs on day -2, with a response duration of 1–4 weeks. Indications for IVIG** therapy: urgent situations (massive bleeding, emergency surgical interventions, type 1 diabetes mellitus, hypertension, treatment and delivery in pregnant women with ITP. IVIG** provide a rapid increase in platelet count compared to GCS. IVIG** dosage: a course dose of 2 g per 1 kg of body weight, divided into 2–5 consecutive IV infusions; daily dose ranging from 0.4 g/kg to 1 g/kg of body weight. Use with caution in elderly patients, patients with hypertension, allergic reactions, and thrombosis.

• Initiating therapy in newly diagnosed ITP patients is not recommended when the platelet count is >30–50.0×10⁹/L and there is no hemorrhagic syndrome [4-5,7,9,11,15,18,25].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: when the platelet count is >30-50.0×10⁹/L and there is no hemorrhagic syndrome, watchful waiting and angioprotective therapy alone are indicated: etamsylate^** 0.25–0.5 g 3–4 times daily orally or 2–4 mL (250–500 mg) IV 1–2 times daily, #ascorbic acid^** 50–100 mg twice daily orally [26-27], herbal medicine (#nettle leaf infusion, 2 tablespoons per 400 mL of boiling water, 1/2 cup 3 times daily) [28].

3.2.2 Therapy for patients with newly diagnosed ITP (second line)

• Splenectomy in newly diagnosed ITP is recommended for patients with an absent/lost response to 1st-line therapy to achieve a therapeutic effect [18-20,29-32].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: indications for splenectomy in newly diagnosed ITP: resistance to GCS therapy, loss of response or complete response after 1st-line therapy (GCS and IVIG**), and severe exacerbations of ITP refractory to 1st-line drugs (GCS and IVIG**) in pregnant women during the 2nd trimester of pregnancy (12–20 weeks) [31-34]. Splenectomy in newly diagnosed ITP is rarely performed due to the short disease duration.

3.3 Therapy for patients with persistent ITP (disease duration from 3 to 12 months)

• Initiating therapy in patients with persistent ITP is recommended in cases of thrombocytopenia less than 30-50.0×10⁹/L with hemorrhagic syndrome (as the primary determining factor) and thrombocytopenia less than 20.0×10⁹/L without hemorrhagic syndrome to achieve a therapeutic effect [4,5,9,11,15,24-25].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: with platelets >30–50.0×10⁹/L and no hemorrhagic syndrome, watchful waiting alone is indicated. The main approaches to the treatment of persistent ITP are presented in Appendix G3.

3.3.1 First-line therapy for persistent ITP

• Initiating 1st-line therapy in patients with persistent ITP is recommended in cases of thrombocytopenia <30–50.0×10⁹/L with hemorrhagic syndrome (as the primary determining factor) and thrombocytopenia <20.0×10⁹/L without hemorrhagic syndrome to achieve remission [4,5,9,11,15,24-25].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: if no therapy is administered during the first 3 months after the ITP diagnosis is established, treatment is carried out according to the regimens recommended for newly diagnosed ITP – GCS and IVIG**. With platelets >30–50.0×10⁹/L and no hemorrhagic syndrome, watchful waiting alone is indicated.

3.3.2 Second-line therapy for persistent ITP

• Initiating 2nd-line therapy for persistent ITP (hematopoiesis stimulants and a hemostatic agent – romiplostim** and eltrombopag**) (ATX: other systemic hemostatics), splenectomy is recommended for patients with loss of or no response to 1st-line therapy (GCS or IVIG**) to achieve a therapeutic effect [4,5,9,11,15,24-25].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• A hemostatic agent (romiplostim**) (ATX: other systemic hemostatics) is recommended for patients with failure of 1st-line therapy, complications from GCS and IVIG**, contraindications to splenectomy, refusal of splenectomy, and to reduce the risk of bleeding prior to elective surgery [35-38].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: romiplostim** belongs to the group of drugs that stimulate platelet production by activating the thrombopoietin receptor; it is effective and safe in both short-term and long-term ITP therapy. Use with caution in the presence of genetic risk factors for thrombosis (Factor V Leiden mutation, prothrombin mutation, etc.). Romiplostim** is effective in an average of 95% of patients, in 88–97% of patients before splenectomy and in 79–90% after. The dose of the drug is individual and titrated from 1–3 up to 10 µg/kg of body weight. In initial combination therapy (GCS and romiplostim**), GCS is discontinued first when the platelet count reaches 100.0–200.0×109/L and the romiplostim** dose is stable, followed by determining the individual dose of romiplostim**. It is also used in case of failure or intolerance of eltrombopag**.

The scheme for selecting an individual drug dose is given in Appendix G4

• The hematopoiesis stimulant eltrombopag** (ATX: other systemic hemostatics) is recommended for patients with failure of 1st-line therapy, complications from GCS and IVIG**, contraindications to splenectomy, refusal of splenectomy, and to reduce the risk of bleeding prior to elective surgery [9,39-49].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: the efficacy of eltrombopag** in persistent ITP is 90–93.3%, with a complete response achieved in 75.9–86.7% of cases. In the chronic form, efficacy is lower – 50–88.8%. Treatment outcomes in patients with and without splenectomy are similar. The drug has undergone international phase I–IV clinical trials with placebo-controlled groups. When consuming dairy products or mineral supplements containing aluminum, calcium, iron, magnesium, selenium, and zinc, as well as enveloping medications, this interval is increased to 4 hours. Simultaneous therapy with a hematopoiesis stimulant (eltrombopag**) and lipid-lowering agents is not possible. The dose of the drug is individual (Appendix G5). In initial combination therapy (GCS and eltrombopag**), GCS is discontinued first when the platelet count reaches 100.0×109/L and the eltrombopag** dose is stable, followed by determining the individual dose of eltrombopag** [9,39-49]. Criteria for predicting the efficacy and timing of discontinuing therapy with eltrombopag** and romiplostim** are currently lacking.

Twelve months after achieving a sustained response to therapy, a gradual reduction in drug doses should be initiated. Discontinuation is recommended to be carried out slowly with gradual dose titration. The goal is complete drug discontinuation while maintaining a therapeutic response, or, if impossible, maximum minimization of the dose to maintain a minimum platelet count with minimal hemorrhagic manifestations and minimal side effects.

In cases of intolerance (e.g., allergic reactions), primary or developed resistance to the maximum permitted dose of one of the drugs—eltrombopag** or romiplostim**—switching from one to the other is possible. When switching to another drug, side effects caused by the predecessor are resolved in all patients. In 50–80% of patients, switching the drug leads to the cessation of platelet fluctuations and achieves a therapeutic response [9,25,49]. The drugs have undergone international phase I–IV clinical trials with placebo-controlled groups [35-49]. Contraindications: history of severe thrombosis, hepatic impairment, pregnancy, and lactation. Use with caution in the presence of genetic risk factors for thrombosis (Factor V Leiden mutation, prothrombin mutation, etc.).

• Splenectomy is recommended for patients with a loss of/no response to 1st-line therapy when treatment and achievement of remission are necessary [9,20,29-31,33,34,50,51].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The rate of complete and partial immediate responses to splenectomy is 80–88%, and long-term responses (lasting 5 years or more) are 60–78%. The relapse rate is 20–33%. Splenectomy is ineffective in 12–19% of patients. The complication rate is 9.6%, with an increased risk of thromboembolism and infections, especially in patients over 65 years of age [52–53]. The mortality rate is 0.2–1%. If the platelet count is below 20.0×10⁹/L accompanied by hemorrhagic syndrome, preoperative preparation is recommended (methylprednisolone** pulse therapy 500–1000 mg/day IV for 3 days over 1–2 hours; immunoglobulin preparations** (normal human immunoglobulin**) IV 1 g/kg of body weight (daily dose) for 2 days; combined use of methylprednisolone** and IVIG**). Currently, there are no clear clinical and laboratory predictors of splenectomy efficacy. The choice between the two second-line therapy options for persistent ITP—splenectomy, a hematopoiesis stimulator (eltrombopag**) or a hemostatic agent (romiplostim**)—is determined not only by medical indications, but also by patient preferences [9, 20, 25]. In case of relapse after splenectomy, an ultrasound or CT scan of the abdominal cavity should be performed to search for an accessory spleen that may have triggered the relapse [54].

Splenectomy is advisable no earlier than 12–24 months from the time of diagnosis due to the likelihood of remission or stabilization [9].

3.3.3 Third-line therapy for persistent ITP

• Upon loss of response to second-line therapy, patients with persistent ITP are recommended to use #Rituximab** to achieve a therapeutic effect [9, 55–65].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: the drug #rituximab** is not approved for the treatment of ITP, but it may be used for life-saving indications by decision of the medical board and with the patient's informed consent. It is effective in 60-80% of patients, with complete response achieved in 38-40% and partial response – in 19%. Response time is 1-8 weeks. In 21-38% of patients a stable response persists for 3-5 years. The relapse rate one year or more after complete remission is – 31%, and after partial remission – 53%. Prior splenectomy does not affect the efficacy of #rituximab^** therapy. Indications for use: failure of previous treatment methods, contraindications/complications of first- and second-line therapy, patient refusal of splenectomy. Contraindications: chronic viral hepatitis B. The decision on the need for #rituximab** therapy is made individually by the medical board with the patient's consent. There is a risk of hepatitis B virus reactivation during treatment with #rituximab**, which requires monitoring before, during, and after therapy.

The single dose of #rituximab** is 375 mg/m² (average 500 mg IV). Administration frequency – once a week; course duration – 4 infusions. There are reports of alternative dosing regimens: 1000 mg once every 2 weeks or 100 mg once a week for 4 weeks [9, 11, 15, 25, 64–65].

3.4 Therapy for patients with chronic ITP (disease duration over 12 months)

• It is recommended to initiate therapy in patients with chronic ITP when thrombocytopenia is <30–50.0×10⁹/L with hemorrhagic syndrome (as the primary determining factor) and thrombocytopenia is <20.0×10⁹/L without hemorrhagic syndrome to achieve a therapeutic effect [9, 11, 15, 25].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: the main criterion for prescribing treatment is the presence and severity of hemorrhagic syndrome, and not just thrombocytopenia. Approaches to the treatment of chronic ITP are presented in Appendix G6.

3.4.1 First-line therapy for chronic ITP

• It is recommended to initiate first-line therapy for patients with chronic ITP to achieve a therapeutic effect in the absence of any therapy for 1 year or more after diagnosis when treatment indications appear: hemorrhagic syndrome with thrombocytopenia <30.0×10⁹/L, thrombocytopenia <20.0×10⁹/L without hemorrhagic syndrome. GCS and IVIG** are prescribed in doses identical to those for newly diagnosed and persistent ITP [9, 11, 15, 25].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

3.4.2 Therapy for patients with chronic ITP (second line)

• It is recommended to initiate second-line therapy for chronic ITP in patients upon loss or absence of response to first-line therapy (GCS or IVIG**) to achieve a therapeutic effect [4, 5, 9, 11, 15, 24–25].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The main methods of conservative treatment for chronic second-line ITP are a hematopoiesis stimulator (eltrombopag**), hemostatic agents (romiplostim** and avatrombopag) (ATC other systemic hemostatics).

• A hematopoiesis stimulator (ATC other systemic hemostatics) (eltrombopag**) or a hemostatic agent (ATC other systemic hemostatics) (romiplostim**) are recommended for patients with ineffectiveness of first-line therapy, complications and contraindications to GCS and IVIG**, inability to undergo splenectomy, and to reduce the risk of bleeding before elective surgery [35–49].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: drug doses (romiplostim**, eltrombopag**) are individual and selected by gradual titration. The treatment algorithm is similar to second-line therapy for persistent ITP.

• The hemostatic agent avatrombopag (ATC other systemic hemostatics) is recommended for patients with ineffectiveness of first-line therapy, complications and contraindications to GCS and IVIG**, inability to undergo splenectomy, and to reduce the risk of bleeding before elective surgery [9, 25].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: avatrombopag acts rapidly: on day 8 of therapy, a platelet response is achieved in 65.6% of patients, on day 28 in 84.4% of patients, and a complete response in 71.9%, compared to 0% in the placebo group (P <0.0001). A long-term response with a median platelet count from 50.0×10⁹/L to 150.0×10⁹/L over 6 months of therapy is observed in 34% of individuals. A sustained clinically significant response (platelets ≥30.0×10⁹/L for 6 of the last 8 weeks of the main study phase) occurred in 64.0% of patients receiving avatrombopag and 0% of patients receiving placebo [66].

In a study switching patients with chronic ITP to avatrombopag upon loss of efficacy of eltrombopag** or romiplostim** therapy, a platelet response was achieved in 86% of patients, and a complete response in 71% [67].

Avatrombopag is available in tablet form (20 mg), taken orally once with food, and does not require dietary restrictions. The drug may be taken crushed. The recommended starting dose of the drug is 20 mg (1 tablet) once daily. The dosing regimen is adjusted based on the platelet count. The daily dose of 40 mg should not be exceeded [9, 24].

The most frequent adverse events (AEs) with avatrombopag are: headache, upper respiratory tract infections, arthralgia, fatigue, gum bleeding and petechial rash, epistaxis, ecchymosis. The frequency of all listed AEs, adjusted for the duration of therapy, is comparable to or lower than that in the placebo group. Pronounced hepatotoxicity of avatrombopag has not been reported [66, 68], continuous liver function monitoring is not required [9, 24], and the drug is approved for correcting thrombocytopenia in patients with chronic liver disease when preparing for an elective invasive procedure [69].

The individual dose titration schedule for the drug is given in Appendix G7.

3.4.3. Third-line therapy for patients with chronic ITP

• #Rituximab^** is recommended for patients with chronic ITP: upon loss of response or ineffectiveness of second-line therapy to achieve remission [9, 55–65].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comments: #Rituximab** is not approved for the treatment of ITP; however, it can be used by decision of the medical commission and with the patient's informed consent. The dose, regimen, course duration, and contraindications are similar to those described above.

• Treatment of chronic and refractory third-line ITP with other antineoplastic agents and immunosuppressants is recommended for patients with ineffectiveness or loss of response to second- and third-line therapy to achieve remission [4–5, 9, 11, 15, 25, 70].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Treatment is carried out according to individual programs. An algorithm has not been developed. Therapy options are presented in Appendix G8.

3.4.4 Treatment of patients with refractory ITP. Combination therapy.

• Treatment for patients with refractory ITP is recommended if there are indications for therapy after loss of response or ineffectiveness of splenectomy and other previous first- and second-line conservative treatments to achieve remission [9, 11, 15, 25, 70].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: refractory ITP is characterized by a severe course and a constant need for specific therapy, occurring in 25% of patients with the chronic form. In refractory ITP, combination therapy—a combination of 2 or more drugs—is more frequently used.

The most commonly used regimens include: #rituximab** at a standard dose of 375 mg/m2 (average 500 mg IV) once weekly for 4 weekly infusions. Other dosing regimens are used: 1000 mg once every 2 weeks or 100 mg once weekly for 4 weeks [9] in combination with glucocorticoids: dexamethasone** 28 mg/m2 (maximum dose 40 mg/day)—three 4-day courses on days 1–4, 15–18, and 29–32 [71–74], eltrombopag**, avatrombopag, or romiplostim** with GCs at a daily dose of 2.5–5 mg [9]. With initial combined therapy of a hematopoiesis stimulator or hemostatic agent with GCs, upon reaching a platelet count of 100.0–200.0×109/L, GCs are discontinued first, followed by titration of the individual dose of eltrombopag**, avatrombopag, or romiplostim** [9, 24].

Dietary therapy

Not used

3.5 Anesthesia

• If acute or chronic pain syndrome occurs, after determining its etiology, it is recommended to perform analgesic therapy according to existing pain management protocols (see relevant clinical guidelines on chronic pain, clinical guidelines on anesthesiology), including, by indication, the use of opioid analgesics [75].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation methods have not been developed.

5. Prevention and Dispensary Observation

Methods of prevention and dispensary follow-up have not been developed.

• Patients with ITP as part of dispensary follow-up are recommended dynamic monitoring by a hematologist to prevent relapses [11].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: The follow-up schedule is established individually by each hematologist for every patient, depending on the severity of the disease. Once remission is achieved, check-ups are recommended 1–2 times a year, followed by a subsequent decrease in visit frequency. It is necessary to follow the hematologist's treatment prescriptions, avoid self-medication, avoid disease-triggering factors, limit sun exposure and physiotherapeutic treatments, and complete a training course on independent methods for managing hemorrhagic syndrome. It is advisable to change the type and conditions of work to safe and lighter employment. Harmful work includes tasks involving heavy physical labor and significant psycho-emotional stress, exposure to toxic agents, vibration, working at heights, operating moving mechanisms, driving vehicles, dispatching professions, etc.

6. Organization of Medical Care

The majority of patients with ITP (except for severe forms of the disease) can receive outpatient treatment and do not need hospitalization for examination, diagnosis clarification, and conservative therapy in therapeutic doses.

Indications for planned hospitalization:

• Conservative therapy with high-dose GCs;

• Surgical treatment of ITP (splenectomy);

• Complications from ongoing therapy;

• Presence of comorbid conditions aggravating the patient's condition;

• Non-compliance by the patient with the treatment regimen in an outpatient setting.

Indications for emergency hospitalization:

• Grade III–IV hemorrhagic syndrome;

• Severe thrombocytopenia no more than 20.0×10⁹/L in the presence of a pronounced history of hemorrhagic syndrome.

Indications for patient discharge from the hospital:

• Improvement of the patient's condition—relief of hemorrhagic syndrome;

• Completion of the therapy course provided the patient's condition improves.

7. Additional Information

Pregnancy

Idiopathic thrombocytopenic purpura may debut during pregnancy, relapse, or worsen in patients with a history of ITP [9, 11, 15, 24, 77, 78, 79].

Pregnancy is not contraindicated for patients with ITP, but is desirable in a state of remission and clinical-hematological compensation of ITP, as well as in mild forms of the disease not requiring treatment [7, 9, 35–37]. Pregnancy is not recommended in resistant and refractory forms of ITP with severe hemorrhagic syndrome [9, 11, 15, 24, 77, 78, 79].

In ITP, pregnancy should not be interrupted without obstetric indications solely due to thrombocytopenia and hemorrhagic syndrome. Pregnancy planning is one of the most important conditions for its favorable course [7, 9].

Differential diagnosis of ITP with life-threatening conditions in obstetrics

Thrombocytopenia in pregnant women is observed in a wide range of hematological and non-hematological diseases and conditions: gestational thrombocytopenia (a variant of normal), ITP, von Willebrand disease type II, thrombotic microangiopathies (TMAs), severe forms of preeclampsia (PE) and HELLP syndrome due to microvascular thromboses as manifestations of TMA [80–82].

To prevent maternal mortality and ensure timeliness and adequacy of therapy for life-threatening conditions, differential diagnosis of thrombocytopenias should be performed in all pregnant women with a platelet decrease of more than 25% from baseline [80–82].

Management of pregnancy in women with ITP

All pregnant women with ITP must be under joint dynamic monitoring by an obstetrician-gynecologist and a hematologist. During monitoring, obstetric status comes to the fore, followed by the pregnant woman's condition (hemorrhagic syndrome, platelet count, comorbidity). The frequency of dynamic monitoring should be 1 time in 1–2 weeks [7, 9].

Pregnant women with severe, resistant forms of ITP require treatment as preparation for pregnancy, as well as planning its onset for a period of remission or clinical-hematological compensation [7, 9, 24, 77, 78].

Treatment of pregnant women with ITP

The goal of therapy in pregnant women with ITP is to increase the platelet count to the minimum level ensuring the safety of gestation and delivery. Indications for prescribing therapy are hemorrhagic syndrome of varying severity with a platelet count of less than 30.0×10⁹/L or thrombocytopenia of less than 30.0×10⁹/L without hemorrhagic syndrome [9, 11, 15, 77].

Pregnant women with ITP in remission or clinical compensation (absence of hemorrhagic syndrome and platelets above 30–50.0×10⁹/L) are indicated only for dynamic monitoring with angioprotective and herbal therapy [7, 9, 11, 15, 24].

Drugs used for the treatment of pregnant women with ITP are similar to those in non-pregnant women: GCs, IVIG**, their combination, splenectomy (rarely in the 1st and 2nd trimesters for vital indications). The administration of GCs before 16 weeks of gestation is undesirable, and IVIG** is the primary therapeutic agent. A hematopoiesis stimulator (ATC other systemic hemostatics) (eltrombopag**) or a hemostatic agent (ATC other systemic hemostatics) (romiplostim**, avatrombopag), #rituximab^**, and other antineoplastic and immunosuppressive agents are not recommended due to the risk of teratogenicity [7, 9, 11, 15, 24, 25].

According to current international guidelines, thrombopoietin receptor agonists can be considered as a treatment option in late pregnancy when other treatment options are ineffective [9, 83, 84].

Rituximab** is used before and during pregnancy, but treatment with this drug is associated with the risk of perinatal and neonatal immunosuppression and infections [85].

Comment: #rituximab** at a standard dose of 375 mg/m² once weekly IV for 4 weekly infusions or 1000 mg once every 2 weeks IV (2 infusions) [85].

The algorithm for the management of pregnancy and labor in ITP is presented in Appendix G9.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Melikyan Anait Levonovna, Doctor of Medical Sciences, Head of the Department of Standardization of Treatment Methods for Hematological Diseases at the National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematological Society Association for the Promotion of Hematology and Bone Marrow Transplantation.

2. Ptushkin Vadim Vadimovich, Doctor of Medical Sciences, Professor, Deputy Chief Medical Officer for Medical Affairs (Hematology) at Botkin City Clinical Hospital of the Moscow Healthcare Department

3. Pustovaya Elena Igorevna, Candidate of Medical Sciences, hematologist at the Department of Standardization of Treatment Methods for Hematological Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematological Society Association for the Promotion of Hematology and Bone Marrow Transplantation.

4. Tsvetayeva Nina Valentinovna, Candidate of Medical Sciences, Senior Researcher at the Department of Chemotherapy for Orphan Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematological Society Association for the Promotion of Hematology and Bone Marrow Transplantation.

5. Egorova Elena Konstantinovna, Candidate of Medical Sciences, hematologist at the Department of Standardization of Treatment Methods for Hematological Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematological Society Association for the Promotion of Hematology and Bone Marrow Transplantation.

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologist;

2. Oncologist;

3. General practitioner (internist);

4. Obstetrician-gynecologist.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Chronic ITP is included in the list of rare (orphan) diseases with a prevalence of no more than 10 cases per 100,000 population and in the list of life-threatening and chronic progressive rare diseases based on the following documents:

1. Decree of the Government of the Russian Federation No. 403 dated April 26, 2012;

2. Decree of the Government of the Russian Federation No. 1390 dated November 20, 2018.

Differential diagnosis of ITP with other disorders presenting with thrombocytopenia

Diseases are grouped by the mechanism of thrombocytopenia development.

Management of newly diagnosed ITP depending on platelet count and hemorrhagic syndrome

Treatment of persistent ITP depending on platelet count and hemorrhagic syndrome

Dose titration of romiplostim** in patients with ITP

Dose titration of eltrombopag** in patients with ITP

Treatment of chronic ITP depending on platelet count and hemorrhagic syndrome

Dose titration of avatrombopag in patients with ITP

Table 3: Avatrombopag dose levels for dose titration in patients with primary chronic immune thrombocytopenia

*Starting dose for all patients except those receiving moderate or strong dual inducers or moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5 isoenzymes, or CYP2C9 isoenzyme alone

Other 3rd-line therapy with immunosuppressive drugs in patients with chronic ITP

Management of pregnancy and delivery in female patients with ITP

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Primary immune thrombocytopenia – idiopathic thrombocytopenic purpura (ITP) – is an autoimmune disease characterized by the production of antibodies against one's own platelets and their destruction in the spleen. This causes a decrease in platelet count and clinically leads to increased bleeding or hemorrhagic syndrome. It manifests on the skin as ecchymoses (bruises), solitary or generalized petechial rash, and large hematomas; on the oral mucosa as well, with petechiae and ecchymoses, gingival bleeding both after tooth brushing and spontaneously without trauma (a taste of blood in the mornings after sleep). Patients may be disturbed by frequent, heavy, and prolonged (more than 10-15 minutes) nosebleeds that do not stop with simple pressure and require nasal packing, as well as subconjunctival hemorrhages. A problem for girls and young women is heavy menstrual bleeding (both in terms of daily volume and lasting more than 5 days). Health-threatening conditions include gastrointestinal (black tarry stools) and renal bleeding (hematuria – blood in the urine). Hemorrhages can also be observed in other organs and tissues. The frequency of life-threatening intracranial hemorrhages is very rare.

The normal platelet count ranges from 150.0x10⁹/L to 450.0x10⁹/L. A platelet count of 100.0x10⁹/L or more fully ensures normal blood clotting and allows surgical interventions and delivery to be performed without any risk of bleeding complications, requiring no therapy. A platelet count of 50x10⁹/L and above is considered "safe," as no bruising or other bleeding is observed at rest without trauma.

Currently, there are many treatment methods for ITP. Patient compliance with the doctor's prescriptions and timely adherence to all established guidelines guarantee a rapid improvement in condition and a return to a normal, full life.

Pregnancy is not contraindicated for patients with ITP, but it must be planned. Conception should occur during remission. Throughout pregnancy, patients should be monitored not only by gynecologists but also by hematologists.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.