Idiopathic thrombocytopenic purpura: from Werlhof to the present day

Idiopathic thrombocytopenic purpura: from Werlhof to the present day

Spontaneous skin bleeding, known for more than 2500 years, was already called “purpura” in the Greek and Roman healing period. In 1735, Paul Werlhof (ITP is also called "Werlhof's disease") described a 16-year-old girl with epistaxis and mucosal bleeding that was controlled by the use of citric acid. He named this disease "Morbus Maculosus Haemorhhagicus". But noticeable progress in the treatment of patients with ITP was achieved later: in 1916 in Prague, Professor Schloffer removed the spleen from a woman with this disease. A significant increase in platelet counts followed surgery. And until now, splenectomy is one of the treatment options for patients with ITP. However, the most complete picture of this pathology, our understanding of the mechanisms of its occurrence and approaches to diagnosis and therapy have begun to emerge only recently.

Idiopathic thrombocytopenic purpura (ITP), or primary immune thrombocytopenia (ITP), is an acquired autoimmune disease characterized by isolated thrombocytopenia with a platelet count below 100x109/L. It can manifest itself as a hemorrhagic symptom of varying severity - from petechial skin hemorrhages to life-threatening bleeding. Both children and adults get sick. The etiology of ITP is unknown. That's why it's called "idiopathic". Among the triggering factors, the largest group includes infections, pregnancy, as well as vaccinations and stress.

It is known that the dominant mechanism for the development of thrombocytopenia in ITP is due to the production of autoantibodies to the membrane structures of platelets and their precursors - megakaryocytes, which lead to increased destruction of platelets by phagocytes, mainly in the spleen, less often in the liver, and insufficient production of platelets in the bone marrow. Patients with ITP develop primarily IgG autoantibodies against platelet surface glycoproteins GPIIb/IIIa or GPIb/IX. The process of forming an immune response to one’s own platelets is complex, multi-stage, and cyclical. B lymphocytes, T lymphocytes, NK cells, and macrophages take part in it. In addition to antibody formation, subpopulations of T-lymphocytes and the development of an imbalance in the T-cell component of the immune response play a major role in the pathogenesis of ITP. An association has been identified between ITP and some candidate genes, which also indicates the presence of a genetic predisposition to ITP.

Taking into account the concomitant pathology, the patient develops a certain phenotype of the disease. Thus, the pathogenesis of ITP is associated with profound disorders of the immune system. In this regard, idiopathic thrombocytopenic purpura has been renamed to primary immune thrombocytopenia of unknown etiology. Accordingly, in all other forms, immune thrombocytopenia with a known etiology will be a symptom of other autoimmune diseases - systemic lupus erythematosus (SLE), antiphospholipid syndrome (AFLS), rheumatoid arthritis (RA), etc.

Currently, the search continues for etiopathogenetic mechanisms of the development of this rare pathology, which could stratify patients into risk groups to individualize treatment tactics.

In the literature, ITP is described as a rare orphan disease. It must be said that in the medical world there is no single definition of this group of diseases. In some countries, orphan pathologies are identified depending on the number of sufferers, in others - on the availability of treatment methods, in others - only chronic, life-threatening ones are classified as rare diseases.

Russia has its own history of orphan diseases. Since the time in our country the definition of “orphan diseases” was legislatively adopted (Law No. 323 “On the fundamentals of protecting the health of citizens in the Russian Federation” dated November 21, 2011)1, namely: rare (orphan) diseases are diseases that are widespread no more than 10 cases of the disease per 100 thousand population, all oncohematological and many hematological diseases began to be considered orphan. As for ITP, according to Decree of the Government of the Russian Federation No. 403 of April 26, 2012, idiopathic thrombocytopenic purpura (D69.3) was included in the short list of life-threatening and chronic progressive rare (orphan) diseases leading to a reduction in the life expectancy of citizens or their disability. This short list also included such hematological conditions as paroxysmal nocturnal hemoglobinuria (Marchiafava-Miceli disease), aplastic anemia, hereditary metabolic diseases, hemolytic-uremic syndrome, etc.

All these legislative decisions led to the creation of a department - a hospital for orphan diseases (headed by Professor E.A. Lukina) at the Federal State Budgetary Institution "National Medical Research Center of Hematology" in 2012. The nosological range of pathologies dealt with by the department is very wide.

Medicines developed to treat rare diseases are also called orphan drugs and include a list of expensive drugs. Assigning orphan status to diseases and any drugs is a social and political issue in many countries, as well as in Russia. Government support for rare disease research has led to medical breakthroughs that could not have been achieved under the previously existing funding system.

The orphan disease status for ITP also opened up new opportunities for improving its diagnosis and treatment with modern methods that could not be achieved without it. We are talking primarily about two orphan expensive thrombopoietin receptor agonist (aTPO) drugs (romiplostim from Novartis and eltrombopag from Amgen). Medicines are provided at the expense of the budgets of the constituent entities of the Russian Federation.

Epidemiology

It should be recalled that in our country, the incidence of ITP at the population level was not studied until 2014. And there was not enough information to assess the course, effectiveness and safety of various treatment options for patients with ITP. To solve these problems, under the auspices of the National Hematological Society (chairman of the Supervisory Board of the NGO - chief freelance hematologist of the Russian Federation, director of the Federal State Budgetary Institution "National Medical Research Center for Hematology" of the Ministry of Health of Russia, academician of the Russian Academy of Sciences, Professor V.G. Savchenko) in early December 2012, " Registry of diseases of the blood system.”3 Since 2014, work has started in its subsection “ITP” - a multicenter prospective observational cohort study “Epidemiological and clinical characteristics of ITP in adults in Russia” (head: A.L. Melikyan) began.

According to the register of the National Hematological Society (NGO), the incidence of ITP in the adult population in the Russian Federation averages 2.0 (1.6‒3.6) per 100 thousand population per year. ITP has no geographical features. Men get sick 2–3 times less often than women. The largest proportion of patients (45.4%) were in the age group from 18 to 40 years, in the group from 41 to 60 years - 26.0% and over 60 years - 28.6%. Thus, among patients with ITP, 71.4% are of working age. The highest incidence of ITP was registered in women of fertile age 4. Our results are quite comparable with data from registers in other European countries.

Diagnostics

The main clinical manifestation of ITP is hemorrhagic syndrome, and the prognosis of the disease depends entirely on its severity. The risk of bleeding in patients with ITP is assessed by the platelet count in a peripheral blood test. According to the register, in 70.0% of cases, the number of platelets at the onset of the disease ranges from 3 to 30x109/l, among them, 35% have a critical level of platelets (from 3 to 10x109/l) with the risk of developing spontaneous alarming, life-threatening bleeding, which requires immediate treatment.

Hemorrhagic syndrome manifests itself in the form of: skin hemorrhages - 77% of cases; bleeding of oral mucosa – 39%; nosebleeds – 31%; menometrorrhagia – 15% (among women); gastrointestinal bleeding – 7%; hematuria – 4%; intracerebral bleeding - 0.9%, others - 1% (retinal hemorrhage, hemorrhoidal bleeding).4

Thus, about 1/3 of patients at the time of diagnosis have hemorrhagic manifestations corresponding to a severe form of ITP (grade 3–4 bleeding according to the WHO classification). ITP is not a genetic disease, but usually accompanies the patient throughout his life and is incurable. The course of the disease is further complicated by the fact that in 60–70% of patients after 12 months (chronic phase), the disease becomes chronic and relapsing again.

ITP is not a genetic disease, but usually accompanies the patient throughout his life and is incurable. The course of the disease is further complicated by the fact that in 60–70% of patients after 12 months (chronic phase), the disease becomes chronic, relapsing, and hemorrhagic syndrome reappears, requiring an anti-relapse course of therapy.

The diagnosis of ITP is a diagnosis of exclusion, i.e. To date, there is no specific test for the disease. Thrombocytopenia of various origins is recorded in a wide range of diseases of hematological, non-hematological and congenital nature, in which isolated thrombocytopenia may be the dominant clinical symptom for a long time. Therefore, to establish the true causes of thrombocytopenia, it is necessary to conduct an expanded diagnostic search at the onset of the disease.4

The initial approach to diagnosing the causes of thrombocytopenia is based on the patient's medical history (his underlying diseases and previous drug therapy), his objective physical examination and examination according to the protocol. The protocol for the differential diagnosis of thrombocytopenia that we developed is included in the National Clinical Guidelines for ITP.5 The most important thing is that all the proposed laboratory and instrumental studies exist in routine practice and are mandatory for all patients with suspected ITP.

After excluding other causes of thrombocytopenia, the diagnosis of ITP is made based on the following criteria:

• isolated thrombocytopenia less than 100.0x109/l, recorded in at least two consecutive blood tests;
• absence of morphological and functional platelet abnormalities;
• absence of pathology of lymphocytes, granulocytes and erythrocytes;
• normal hemoglobin, red blood cells and reticulocytes, if there was no significant blood loss;
• increased or normal number of megakaryocytes in the myelogram;
• normal size of the spleen.

It is important to keep in mind: to quickly relieve hemorrhagic syndrome, patients are often prescribed corticosteroids without examination according to the protocol, which blurs the true clinical picture of secondary immune thrombocytopenia and affects the true results of immunological tests. According to our department, in up to 15–20% of cases, during repeated examination according to the protocol, the diagnosis of ITP is replaced by another. The picture of the disease may change over time; therefore, it is necessary to constantly update data on the patient’s condition and carry out differential diagnosis at each stage of observation/therapy for ITP. Thus, it is very important to carry out a differential diagnosis between primary and secondary thrombocytopenia not only at the onset of the disease, but also during relapse of thrombocytopenia.

Establishing the true causes of thrombocytopenia is extremely important for choosing adequate therapy for such patients

In many cases, patients with primary and secondary ITP receive similar treatment. However, if ITP develops in the context of an underlying disease (eg, SLE, APS, HCV infection, HIV infection, or lymphoproliferative disorder), then treatment should be directed primarily at it.

It should be noted that our doctors’ awareness of this disease is at a fairly high level. Firstly, as stated above, ITP was described 275 years ago. Secondly, ITP is a fairly common rare disease. Every year, more than 300 patients diagnosed with or suspected of ITP are consulted in our department alone. And finally, for the first time in Russia (in 2014), National Clinical Recommendations (NCR) for the diagnosis and treatment of idiopathic thrombocytopenic purpura in adults, along with other nosologies, were developed on the initiative of the Russian Ministry of Health.4 These recommendations are constantly updated and are publicly available.4 The latest edition was published in 2022.

In 2022, updated clinical guidelines from the American Association of Hematology (ASH) and updated International Consensus on the Diagnosis and Treatment of Primary Immune Thrombocytopenia were released. We analyzed these recommendations and compared them with Russian clinical guidelines for ITP.

I want to say that we have not noticed any global changes: special attention is paid to correct diagnosis, and approaches to treatment are described in more detail.

In addition, the study of ITP is included in the educational and scientific plans of our Hematology Center for hematologists, residents, students in advanced training cycles of the Federal State Budgetary Institution “National Medical Research Center for Hematology” of the Ministry of Health of Russia and for specialists in other specialties, since there are hematological masks for various diseases. Our Center organizes on-the-job training for medical specialists on current issues in hematology for both hematologists and other specialists. All these programs are included in the system of continuing medical education. In the era of digitalization and distance learning technologies, holding webinars, master classes, and discussing specific clinical examples, the audience of students is significantly expanding, which contributes to the continuous professional growth of doctors.

Treatment

Splenectomy (SE), introduced into treatment practice at the beginning of the last century by Schloffer, is still one of the treatment options for patients with ITP. It is performed relatively frequently, but over the past three years the number of such interventions has decreased from 26 to 17%, while the proportion of patients receiving modern drugs (thrombopoietin receptor agonists, aTPO) has increased from 5.9 to 45.7%. The same trend is observed abroad, where the frequency of splenectomy is lower than in the Russian Federation.

Since 1951, corticosteroids have been used in the treatment of the disease; they still remain the first line of treatment for patients with newly diagnosed ITP in foreign and Russian protocols - with hemorrhagic syndrome and platelets less than 30‒50.0x109/l or in the absence of hemorrhagic syndrome with thrombocytopenia 9/ l.

According to our registry data, in 92.2% of cases, as a first line, patients receive treatment with corticosteroids, both in the form of standard treatment and pulse therapy, with an effectiveness of up to 70–80% with rapid relief of hemorrhagic syndrome and an increase in platelet counts above a safe level. However, after discontinuation of the drug, a relapse of the disease quickly occurs. Corticosteroids are effective, but they are associated with a large number of potential complications: diabetes mellitus; severe forms of arterial hypertension and arrhythmias; gastrointestinal ulcer, active infections; mental disorders. Therefore, repeated and frequent courses are undesirable. All clinical guidelines strictly limit the duration of treatment with corticosteroids to 3–4 weeks. Unfortunately, due to availability, corticosteroids are also prescribed in subsequent lines of therapy.

In 1980, at the University Children's Hospital in Bern, a 12-year-old boy with acute ITP and immunodeficiency was treated with intravenous immunoglobulin (IVIG), which resulted in a marked increase in platelet count within 24 hours. Since then, IVIG has been widely and successfully used in both first and subsequent lines of therapy as an “ambulance” in emergency and life-threatening situations and is an absolutely invaluable tool for the treatment of pregnant women with ITP. IVIG as a first-line therapy is effective in 80% of cases, the hemostatic effect occurs on days 1–2, and the duration of response is 1–4 weeks. Thus, in fact, after first line therapy, almost all patients are candidates for second line therapy.

To systematize the procedure for prescribing treatment options, the international working group for the study of ITP identified 3 stages of the disease:

• newly diagnosed with a duration of up to 3 months from the moment of diagnosis;
• persistent with a duration of 3–12 months;
• chronic with a duration of more than 12 months.

And the sequence of prescribing therapy for ITP, developed on the basis of many years of clinical experience, is called lines of therapy, which generally correspond to the stages of the disease.

At the end of 2000, without a doubt, a new era of treatment for ITP begins: with modern-generation drugs - thrombocytopoiesis stimulants, thrombopoietin receptor agonists, and TPOs - romiplostim (Novartis) and eltrombopag (Amgen). In 2009, they were approved in Russia as orphan drugs for adults with refractory chronic ITP with or without splenectomy. In 2015, both drugs were included in the List of vital and essential drugs for medical use, approved by order of the Government of the Russian Federation. The use of aTPO (these data are based on evidence-based medicine and are supported by several solid and very high-quality prospective control studies) is effective both before and after splenectomy. With the advent of these drugs, the prognosis of the disease has improved, since they prevent the development of severe side effects of treatment and allow achieving an 80% level of immediate effect.1,6

I believe (like many of my colleagues) that their important features are organ-preserving and corticosteroid-restraining effects.

Another drug for the treatment of ITP, rituximab, has recently appeared in clinical practice, which was developed for the treatment of hematological malignancies. Rituximab is currently used to treat patients with ITP who are refractory to other treatments. Its use in chronic ITP is based on the removal of autoreactive B lymphocytes. Rituximab is included as 3rd line therapy. There is approximately a 60% chance of obtaining a primary response. But in Russia it is not registered for the treatment of ITP, so the decision is made individually by a medical commission.

In 2022, the US Food and Drug Administration (FDA) approved a new oral drug, the selective small molecule splenic tyrosine kinase inhibitor, fostamatinib, for medical use in patients with refractory ITP. And in 2022, a bioavailable small molecule thrombopoietin receptor agonist, avatrombopag, for the treatment of adult patients with chronic ITP who have had an insufficient response to previous therapy. Both drugs are not registered in Russia for the treatment of ITP. This is perspective.

If various treatment options are unsuccessful in subsequent lines of therapy, it is recommended to use a non-implementing method or carry out complex therapy using immunosuppressants.

As a rule, modern methods of therapy still make it possible to achieve remission of varying durations or states of clinical compensation. But clear prognostic criteria for the course of the disease, response to therapy and disease outcomes have not yet been developed - due to the nature and unpredictable course of the disease.

When starting treatment for chronic, recurrent ITP, it is necessary to remember that the choice of therapy should be aimed at stopping bleeding of any location, improving the patient’s quality of life, and not at normalizing the platelet count at any cost.

In clinical practice, it is important to remember that therapy should always be selected individually for a particular patient, taking into account his age, comorbidity, concomitant pathology, and also taking into account the patient’s preferences. But our practice often collides with the objective realities of life.

According to E.Yu. Krasilnikova (head of the project office “Rare (orphan) diseases” of the National Research Institute of Public Health named after N.A. Semashko), when preparing the Annual Bulletin on rare (orphan) diseases9, information was received from 76 regions of the Russian Federation in which, as of January 1, 2022, There were 3,860 patients with ITP (873 of them were children), 2,069 people needed drug therapy (468 of them were children), 1,606 patients (of which 446 were children) received drug therapy. That is, pathogenetic treatment was provided to 42% of patients included in the Federal Register of Persons Suffering from Rare Life-Threatening Diseases.8

In fact, more than half of patients do not receive the intended orphan treatment. The quality of medical care, which includes diagnosis, determination of treatment tactics, correction and control over these indicators, became possible thanks to the development of a patient routing scheme, which represents the patient’s path from diagnosis to provision of necessary medications, that is, from the attending physician to the inclusion of patients in federal register list.

Our experience with regional hematologists is that they are all knowledgeable and respectful of patient routing pathways for orphan drugs. In difficult situations, they turn to federal centers to obtain a decision from a medical commission on expensive drugs. Providing only 42% of patients with ITP in the regions with modern, expensive orphan drugs is mainly due to insufficient funding in a number of regions. And this also has its explanation. The number of patients requiring expensive orphan drugs is increasing due to improved diagnostics. The only way out is to include ITP in the federal program for financing high-cost nosologies.

Thus, idiopathic thrombocytopenic purpura (ITP) is a rare (orphan) chronic, relapsing disease that significantly worsens the health and quality of life of patients as assessed by physical, social functioning, and mental state. Bleeding causes fear, anxiety and depression in them due to the short-term effect of the therapy and side effects of drugs during long-term treatment with corticosteroids and immunosuppressants.

ITP cannot be completely cured, but it can be effectively controlled. Modern drugs (thrombopoietin receptor agonists) that have appeared in recent years, with adequate choice of dose and control of the course of the disease, can quickly stop hemorrhagic syndrome, achieve remission of varying durations or a state of clinical compensation, prevent the development of severe side effects of treatment, improve the prognosis of the disease, which, naturally, not only increases the life expectancy of patients with orphan diseases, but also its quality. Therefore, it is very important to include them in the therapy of all patients who need it. Today, this equal accessibility is possible only with the inclusion of ITP in the federal program for financing high-cost nosologies.

Literature

1. “On the fundamentals of protecting the health of citizens in the Russian Federation” No. 323-FZ dated November 21, 2011. RG, federal issue No. 263 (5639) (dated November 23, 2011). https://rg.ru/2011/11/23/zdorovie-dok.html
2. Decree of the Government of the Russian Federation No. 403 of April 26, 2012 “On the procedure for maintaining the Federal Register of persons suffering from life-threatening and chronic progressive rare (orphan) diseases leading to a reduction in the life expectancy of citizens or their disability, and its regional segment.” May 2, 2012. https://www.garant.ru/products/ipo/prime/doc/70068888/
3. Chernikov M.V., Kulikov S.M., M.A. Rusinov M.A. et al. Multinosological register of diseases of the blood system. Composition, structure, results of trial operation // Hematology and transfusiology. T. 59, No. 1, 2014, p. 30. Melikyan A.L., Egorova E.K., Pustovaya E.I., Kolosheinova T.I., Volodicheva E.M., Kaporskaya T.S., Ilyasov R.K., Shelekhova T.V., Fedorova N.A., Zotova I.I., Sycheva T.M., Kontievsky I.N., Shestopalova I.A., Kurkina N.V., Syrtseva E.B., Tarasenko E.V. Interim results of an epidemiological study of idiopathic thrombocytopenic purpura in adults in the Russian Federation // Hematology and Transfusiology. 2022. T 64. No. 4. P. 436‒446.
4. Melikyan A.L., Pustovaya E.I., Egorova E.K., Kalinina M.V., Kolosheinova T.I., Subortseva I.N., Gilyazitdinova E.A., Dvirnyk V.N. Differential diagnosis of thrombocytopenia // Oncohematology. 2017;12(1):78‒87. https://doi.org/10.17650/1818-8346-2017-12-1-78-87
5. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2022 guidelines for immune thrombocytopenia. 2019;3(23):3829‒3866. doi:10.1182/bloodadvances.201900096
6. Melikyan A.L., Pustovaya E.I., Egorova E.K., Kalinina M.V., Kolosheinova T.I., Subortseva I.N., Gilyazitdinova E.A., Dvirnyk V.N. Differential diagnosis of thrombocytopenia // Oncohematology. 2017;12(1):78‒87. https://doi.org/10.17650/1818-8346-2017-12-1-78-87
7. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780‒3817. doi:10.1182/bloodadvances.2019000812
8. Annual bulletin of the expert council on rare (orphan) diseases. https://komitet2-.km.duma.gov.ru/upload/site21/Byulleten_po_redkim_zabolevaniyam_2020.pdf
9. Clinical guidelines “Idiopathic thrombocytopenic purpura (ITP) in adults” (approved by the Ministry of Health of Russia), 2022. https://npngo.ru/uploads/media_document/283/5eb37419-9276-4e9a-b075-0e26a788f623.pdf

3. Symptoms of the disease

The symptoms of ITP are divided into two types of the disease: dry and wet.

In the first case, only subcutaneous capillary hemorrhages are observed. With wet thrombocytopenic purpura, external bleeding from the nose and mucous membranes also occurs. In both cases, bleeding begins for no apparent reason. More often, spots appear at night, when a person is practically motionless and the likelihood of mechanical damage is excluded. In patients with idiopathic thrombocytopenic purpura, the disease does not affect the internal organs. The body temperature is normal, the lymph nodes are not enlarged, there are no symptoms of intoxication or inflammation.

Hemorrhages on the skin occur mainly on the front surface of the body, on the forehead and extremities. There is never any subcutaneous bleeding on the palms or soles. External bleeding - from the nose, gums, tonsils, eyes, as well as uterine and stomach.

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Treatment of pathology

Treatment of thrombocytopenic purpura is aimed at:

• restoration of normal platelet levels and adequate bone marrow activity;
• prevention of bleeding;
• removal of autoimmune complexes from the bloodstream.

The treatment regimen is developed for each patient individually and depends on the severity of the patient’s condition and the degree of progression of TP.

Pharmacotherapy

Treatment with corticosteroids, thrombopoietin receptor agonists (stimulation of hematopoiesis), immunosuppressive drugs, and intravenous immunoglobulins is used.

Etiology and pathogenesis

In thrombocytopenic purpura, thrombocytopenia develops due to the destruction of platelets through immune mechanisms. Antibodies to one’s own platelets may appear 1-3 weeks after viral or bacterial infections, preventive vaccinations, taking medications if they are individually intolerant, hypothermia or insolation, after surgery, or injuries. In some cases, no specific cause can be identified. Antigens that enter the body (for example, viruses, drugs, including vaccines) settle on the patient’s platelets and induce an immune response. Antiplatelet antibodies are classified predominantly as IgG. The Ag-AT reaction occurs on the surface of platelets. The lifespan of platelets loaded with antibodies in thrombocytopenic purpura is reduced to several hours instead of 7-10 days normally. Premature platelet death occurs in the spleen. Bleeding in thrombocytopenic purpura is caused by a decrease in the number of platelets, secondary damage to the vascular wall due to loss of angiotrophic function of platelets, impaired vascular contractility due to a decrease in the concentration of serotonin in the blood, and the inability to retract a blood clot.