Pediatric idiopathic thrombocytopenic purpura
Introduction
Introduction to idiopathic thrombocytopenic purpura in children Idiopathic thrombocytopenic purpura (ITP) is also known as autoimmune thrombocytopenic purpura. Clinically divided into acute and chronic subtypes, the basic characteristics of the skin, spontaneous bleeding of the mucosa, thrombocytopenia, prolonged bleeding time, poor blood clot systolic and increased vascular fragility, bone marrow smear shows normal or increased megakaryocyte count, There is also a disorder of differentiation. ITP is an autoimmune disease in which the reticuloendothelial system phagocytose and destroys platelets and causes thrombocytopenia. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: intracranial hemorrhage
Cause
The cause of idiopathic thrombocytopenic purpura in children
(1) Causes of the disease
So far, it is believed that acute ITP is associated with viral infections. Chronic ITP has multiple insidious onsets and unclear causes. In recent years, with the development of immunology, people's understanding of their pathogenesis has been greatly improved, not limited to Traditional antigen-antibody reactions, but more deeply involved in cellular immunity, immune inheritance and so on.
Acute ITP and viral molecular simulation (20%):
Relative to chronic ITP, there are relatively few studies on the pathogenesis of acute ITP. The reason may be that acute ITP is a self-limiting process, as long as the clinical complications are controlled, but because acute ITP is more secondary to viral infection. It indicates that infection may be a triggering factor for acute ITP. Wright et al. first confirmed that the "antigen molecule simulation" may have broken the original immune tolerance, causing the body to produce antibodies against autologous platelets, which are related to varicella virus. Studies in children with ITP have found that IgG and IgM in serum of children can be purified by varicella glycoprotein chromatography column, and eluted IgG molecules can cross-react with platelets of normal blood type O, Chia Etc. also found that the glycoprotein on the surface of HIV can cross-react with platelets in HIV-related ITP patients. Semple et al further confirmed that the reactive T cell activity of patients with acute ITP was no different from that of normal people.
It is indicated that T cells are not a key factor in mediating anti-platelet immunity in the pathogenesis of acute ITP. These studies indicate that at least in some patients with acute ITP, anti-platelet antibodies are due to interaction between antiviral antibodies and autologous platelets. The results of the response, which also help us understand why many children with ITP can heal without treatment - as the source of infection clears, antibodies gradually disappear and antiplatelet responses gradually end, however, there are still some The unresolved question is why 20% to 30% of children will develop chronic ITP? Can these patients develop early into chronic ITP? There is still a lot of work to be learned and explored. Coompath et al. speculate that in these children, it may be due to the immune disorder caused by the infection period. The cross-reactive anti-platelet autoantibodies (IgG) produced by B cells persist in the body. Being is related to proliferation, but in general, there is no way to predict which patients may develop into chronic ITP.
Platelet immunity (20%):
It is well known that abnormal expression of autoantigens in immune targeting tissues can be recognized by autoreactive T helper cells (T helper, Th), which is an important cause of autoimmune diseases. Recent studies have also confirmed that platelets are an active "immunization". "Event participants", from the perspective of immunology, ITP is an organ-specific autoimmune disease, and platelets as an immunological target of this disease undoubtedly play a vital role. A series of studies have shown that as a characteristic glycoprotein on the surface of platelets - Platelet glycoprotein (GP), the main target of autoantibodies.
According to the order of immunogenicity from strong to weak: GPIIb/IIIa, Ia/IIa, IV and V, and some other determinants of platelet surface, Kuwana et al. further confirmed that CD4 T cells of ITP patients mainly belong to GPIIb/IIIa. The amino terminus is highly reactive. In addition, Sinha et al. confirmed that HLA class II antigens that are not present on the surface of normal cells can be induced under specific conditions. This event is closely related to the occurrence of autoimmune diseases because they can be activated. Autoreactive Th cells, which are usually at rest, are analyzed by flow cytometry. The percentage of platelets in HLA-DR is inversely related to platelet count, and contact with macrophages under physiological conditions can induce high expression of HLA in platelets. -DR; macrophages pre-stimulated with inflammatory mediator IFN can further increase the expression of HLA-DR on the surface of platelets, thereby enhancing the immunogenicity of platelets and facilitating the phagocytosis and destruction of platelets by the reticuloendothelial system.
Affinity of Fc receptors to macrophages (20%):
The reticular endothelial system plays a crucial role in the pathogenesis of ITP, and its phagocytic cells carrying Fc receptor (FcR) have a destructive effect on autologous platelets. We know that the Fc segment is exposed after the antibody binds to the antigen. The FcR from the reticuloendothelial system (phagocytic cells) of the liver and spleen binds to it, thereby inducing phagocytosis, splenectomy and the effectiveness of IVIG in the treatment of ITP. The role of the reticuloendothelial system in the pathogenesis of ITP, phagocytic expression FcRs can generally be classified into three classes according to their affinity: high-affinity FcRI, which can bind to IgG monomers and bind to IgG immune complexes; while low-affinity FcRIIA and FcRIIIA can only bind to IgG immune complexes. Among them, the latter two are particularly important in the pathogenesis of ITP. Ericson confirmed that blocking FcRI with a monoclonal antibody does not affect the condition of ITP patients, and the two receptors can increase the number of platelets after blocking, suggesting that the latter two receptors May be associated with platelet clearance, studies in animal models have also shown that blocking FcRIIA and/or FcRIIIA with a monoclonal antibody can prevent the reticuloendothelial system Phagocytosis of IgG-sensitive antigens, these results indicate that low-affinity FcRIIA and FcRIIIA are closely related to platelet destruction in patients with ITP. Further studies have shown that human FcRIIA and FcRIIIA are polymorphic, showing a different affinity for binding to IgG, resulting in Differences in platelet destruction between different individuals, Pol et al believe that these changes are related to the susceptibility of immune disorders, Parren study found that FcRIIA and FcRIIIA allelic variation can significantly affect the ability of the two to bind antigen, Donomme recently analyzed 98 The single amino acid substitutions of FcRIIA H131R and FcRIIIA V158F in children with ITP were found to be significantly higher in children with ITP than in healthy people. Therefore, the relationship between FcR polymorphism and susceptibility to ITP is very high. There may be a close relationship.
Cytokine and T helper cell polarization (16%):
T helper cells (Th) play an important role in maintaining the body's homeostasis. According to the secretory pattern of cytokines, Th cells can be divided into two categories: Th1 and Th2. Th1 cytokines mainly include IL-2, IL-12, IL. -15, TNF and IFN, and Th2 cytokines are IL-4, IL-10, IL-13, etc. Under normal circumstances, Th1/Th2 cytokines are dynamically balanced to maintain the body in a relatively stable state. The balance is destroyed, one side can not effectively control the other side, leading to Th polarization, it will produce immune disorders, and even disease, it is found that a variety of autoimmune diseases involve Th polarization, Th1 polarization and organ specific itself It is related to immune diseases, and the Th2 model is related to systemic autoimmune diseases. Current research shows that chronic ITP in children and adults mainly reflects the Th1 polarization pattern during disease activity, and Garcia-Suarez et al found T in patients with chronic ITP. Cells stimulated by PHA to secrete high levels of TNF and IFN, so it is speculated that lymphocytes in ITP patients have a trend of Th1 polarization. Our recent study found that serum leptin levels were significantly higher in patients with chronic ITP. Ordinary, and leptin can regulate Th0 cells to differentiate into Th1 in the upstream direction, which leads to the Th1 polarization pattern of ITP. After treatment, the Th1 polarization pattern of ITP patients can be transformed into Th2 mode, and we treat different treatments. The study of the T-polarization pattern of the ITP patients in the phase shows that patients who are treated with IVIG and/or DXM (dexamethasone) can exhibit the Th2 pattern in a short period of time (the second to fourth days of treatment), therefore, Reversing the Th polarization pattern may become a new direction for ITP treatment.
Autoreactive T cells (10%):
In 1991, Semple and Fredman first reported that CD4 T helper cells were defective in patients with chronic ITP. They used autologous platelets to stimulate peripheral blood T cells to secrete IL-2, suggesting that chronic ITP may be due to abnormal T helper cell function defects. B cells differentiate and produce autoantibodies. In 1996, Filion et al. demonstrated that the disabled T helper cells of normal individuals can be activated by gpIIb/IIIa and exogenous substances, and T helper cells can secrete IL-2 by themselves. Lead to tolerance changes, these results suggest that T cell tolerance to autologous platelet tolerance may be related to post-transcriptional regulation of IL-2, and Shimomura et al found that a cluster of cumulative oligoclones in peripheral blood of patients with chronic ITP, these clones The TCR has high frequency of V3,6,10 gene characteristics, and it is speculated that chronic ITP patients have a clear accumulation of T cell clonality, which is closely related to the pathogenesis of ITP. Subsequently, Kuwana et al. performed a series of work. It is confirmed that some fragments of GPIIb/IIIa are "hot spots" for the recognition of autoreactive T cells in patients with ITP. Recent experimental results also indicate that the spleen may show Their primary site reactive T cells.
HLA and genetic susceptibility (5%):
Studies have shown that HLA molecules are closely related to autoimmune diseases. At least to some extent, HLA molecular polymorphisms can represent the susceptibility between antigens and autoreactive T cells. For specific autoimmune diseases, HLA molecular polymorphism Small amino acid fragments in the sexual region have an important impact on disease susceptibility/resistance. Previous studies have shown that chronic ITP and HLA-DR2 (HLA-II molecules) and HLA-A28, B8, B12 and other HLA-I Molecularly related, but Gramtama and Gaiger et al. did not find a correlation between HLA and chronic ITP. For example, there is no correlation between HLA-DPB1*1501 allele and anti-platelet antibody, and HLA-DPB1 *0402 allele patients respond poorly to spleen treatment. These lack of consistency may be related to the heterogeneity of ITP. Although they are also diagnosed as ITP, their genetic background is different due to their different causes. The same, so it is necessary to expand the sample size and ethnicity to clearly define the link between HLA molecules and chronic ITP.
Recently, two Japanese research groups have reached different conclusions by detecting HLA serotypes and alleles. Nomura et al. found the frequency of HLA-DR4.1 associated with HLA-DRB1*0410 alleles in chronic ITP patients. Gao, speculate that this phenomenon may be caused by ethnic differences between Japanese and Europeans and Americans. However, Kuwana et al.'s research confirmed that among Japanese people with ITP, HLA-II genes are directly related to autoantibodies, such as HLA- DRB1*0405 and HLA-DQB1*0401 are involved in the formation of anti-GPIIb/IIIa antibodies. They believe that HLA-II genes are involved in the production of autoantibodies, and the relationship with the progression of the disease itself is not very large. In general, different races There may be clear genotypes and phenotypic differences. In addition to the FcR polymorphism discussed above, there are other genetic studies that are mainly related to the correlation between cytokine polymorphism and ITP. For example, lymphotoxin A has a certain association with FcR polymorphism. Recently, Atabay et al. confirmed the presence of TGF-1 gene polymorphism in children with ITP, and Pavkovic et al analyzed the relationship between CTLA-4 gene polymorphism and ITP. However, no positive results were found, which may be related to the small amount of samples they tested. The status and role of these cytokines and signaling molecules in the pathogenesis and immune response of autoimmune diseases are not fully understood. 7. Others such as Helicobacter pylori infection. The initiation of the immune mechanism, the apoptosis of megakaryocytes, etc. are still in the discussion stage, and there are still many problems to be solved.
(two) pathogenesis
ITP thrombocytopenia is caused by increased peripheral damage. The platelet life of 51 chromium (51Cr)-labeled patients has been shown to shorten its lifespan to 1 to 4 hours, or even as short as several minutes. Shortening is associated with the presence of specific antibodies in the blood circulation, and the source of antibodies is available.
1. From acute viral infection
Cross-antibody formed after acute viral infection.
2. An antibody derived from an anti-platelet antigen component
Recent studies suggest that platelet glycoprotein (GP) IIb/IIIaGPIb/IX, GPV is the primary target antigen for these antibodies.
3. Related antibodies derived from platelets
Mainly IgG (platelet-associated IgG, PAIgG), PAIgG is significantly increased in ITP, and its level is proportional to the rate of platelet destruction. The source of PAIgG is not very clear at present, and molecular weight analysis indicates that it is a component. The anti-platelet antibody; the other component is equivalent to the immune complex of IgG, which may be a plasma protein that is non-specifically adsorbed on the platelet membrane. The ITP associated with non-specific adsorption may not increase the PAIgG due to the above-mentioned antibody to platelets. Injury or binding eventually leads to clearance by mononuclear macrophages, destroying all spleen, liver and bone marrow in the field, mainly the spleen. Studies have shown that white blood cell antigen (HLA) B8 and B12 phenotypes are higher in ITP patients, ie People with this phenotype are at greater risk of developing the disease.
Prevention
Prevention of idiopathic thrombocytopenic purpura in children
Spotted itch, can be rubbed with calamine lotion or Jiuhua powder lotion, pay attention to skin hygiene, avoid scratching the skin and causing infection.
Actively prevent and cure all kinds of infectious diseases, especially acute viral infectious diseases, and do a good job in vaccination. In the epidemic period of infectious diseases, avoid crowds. Enhance the physique of children, pay attention to indoor air fresh, increase and decrease clothes in time, strengthen nutrition and so on.
Complication
Pediatric idiopathic thrombocytopenic purpura complications Complications intracranial hemorrhage
Accompanied by gastrointestinal tract, urinary bleeding, etc., intracranial, spinal cord and meningeal hemorrhage are less common, but if you have oral, large tongue purple spots or blood blister, accompanied by headache or vomiting, often a precursor to intracranial hemorrhage, special alert. The general degree of bleeding is directly proportional to the degree of thrombocytopenia. The course of the disease is usually 4 to 6 weeks, and the longest period of time can be self-healing. The liver and lymph nodes of the disease are generally not enlarged, and 10% to 20% of patients may have mild splenomegaly. Corresponding neurological symptoms can occur during intracranial hemorrhage.
Can be complicated by retinal hemorrhage, intracranial hemorrhage, gastrointestinal bleeding and hematuria; may be complicated by deep muscle hematoma or joint cavity bleeding; long-term bleeding can cause anemia.
Symptom
Symptoms of idiopathic thrombocytopenic purpura in children Common symptoms After the collision, the skin is prone to cyanosis, thrombocytopenia, skin mucosal bleeding, skin, spot, spot, nose, hemorrhage, lymph node enlargement, gum bleeding, gastrointestinal bleeding, hematuria
Acute type
This type accounts for about 80% of ITP. It is more common in children aged 2-8 years. There is no difference between men and women. 50%-80% of sick children have a history of pre-infection 1 to 3 weeks before onset, usually acute viral infection, such as respiratory infection. , rubella, measles, chickenpox, mumps, infectious mononucleosis, etc., bacterial infections such as whooping cough can also be induced, occasionally vaccinated with measles live vaccine or intradermal injection of tuberculin, the incidence of patients, Spontaneous skin, mucosal bleeding is prominent, the skin can be seen in varying sizes of sputum, ecchymosis, scattered throughout the body, common in the front of the lower extremities and skeletal bulging skin, severe cases of subcutaneous hematoma, mucosal bleeding can be seen in the conjunctiva , buccal mucosa, soft palate mucosa, severe cases of nose bleeding, bleeding gums, gastrointestinal bleeding, and even hematuria, adolescent girls may have menorrhagia, intra-organ hemorrhage such as retinal hemorrhage, middle ear bleeding are rare, rare Intracranial hemorrhage is regarded as a serious complication, often with poor prognosis; deep muscle hematoma or joint cavity hemorrhage or seeing it, clinically, unless there is severe anemia, there is generally no anemia Less than 10% of patients may have mild splenomegaly, sometimes viral infections can cause swollen lymph nodes, this time to pay attention to rule out secondary ITP.
2. Chronic type
Patients with a course of more than 6 months are chronic ITP. This type accounts for about 20% of the total number of ITP in children. It is more common in older children. The ratio of male to female is about 1:3. There is no pre-infection before chronic ITP, and the onset is slow or insidious. , skin, mucosal bleeding symptoms are mild, platelet counts are mostly (30 ~ 80) × 10 9 / L, skin defects, ecchymosis is more common in the distal extremities, light is only seen in the skin scratches, mucosal bleeding can be light Can be heavy, with nosebleeds, bleeding gums and menorrhagia, oral mucosa followed by gastrointestinal bleeding and hematuria is very rare, this type can be persistent or recurrent, the latter attack and relief alternate, the length of remission A few years from the end of the week, about 30% of the sick children will naturally relieve after a few years of onset. The clinical recurrent authors may have mild splenomegaly. According to hemorrhage, thrombocytopenia, and bone marrow-derived platelet megakaryocytes, diagnosis can be made. PAIgG The measurement is helpful for diagnosis. Secondary thrombocytopenia should be excluded before clinical diagnosis, such as aplastic anemia, leukemia, hypersplenism, microangiopathic hemolytic anemia, systemic lupus erythematosus, drug-induced immune platelet reduction. Purpura, acute viral infection.
Examine
Examination of pediatric idiopathic thrombocytopenic purpura
1. Blood picture: The platelet count is often <20×10 9 /L, the weight can be <10×10 9 /L, the platelet volume (MPV) is increased, the hemoglobin is decreased when there is hemorrhagic anemia, the reticulocyte is increased, and the white blood cell count is More normal, acute type of about 25% of the sick children can see elevated eosinophils, prolonged bleeding time, poor blood clot dysfunction, poor consumption of serum prothrombin.
2. Bone marrow: The number of megakaryocytes is normal or increased, the proportion of classified immature type is increased, the plate-forming megakaryocytes are decreased, the vacuolar degeneration phenomenon is observed in the cytoplasm of some megakaryocytes, the erythroid cell line and the granulocyte cell line are normal, and some cases have eosinophilicity. Increased granulocytes, if there is hemorrhagic anemia, the red blood cell system proliferates.
3. Other
(1) Determination of PAIgG: The content was significantly increased, and the acute type was more remarkable.
(2) Beam arm test: The beam arm test result is positive, chest X-ray examination, B-ultrasound examination, CT examination if necessary.
Diagnosis
Diagnosis and diagnosis of idiopathic thrombocytopenic purpura in children
diagnosis
The ITP diagnostic criteria developed by the Chinese Medical Association's National Conference on Thrombosis and Hemostasis in December 1986 are as follows:
1. Multiple tests to check for a decrease in platelet count.
2. The spleen does not increase or slightly increase.
3. Bone marrow examination The number of megakaryocytes is increased or normal, and there are mature obstacles.
4. There should be any points in the following 5 points: (1) prednisone treatment is effective; (2) effective spleen treatment; (3) increased PAIgG; (4) increased platelet-associated complement 3 (PAC3); (5) platelets Life measurement is shortened.
5. Exclude secondary thrombocytopenia.
Differential diagnosis
First of all, it is necessary to make clear that the diagnosis of ITP is a negative diagnosis. The diagnosis of ITP can be established based on the combination of medical history and laboratory tests to exclude the following diseases.
Neonatal alloimmune thrombocytopenic purpura
Although the disease can be seen at any age, attention should be paid to the exclusion of maternal ITP or alloimmune thrombocytopenic purpura for thrombocytopenia in the neonatal period.
2. Thrombocytopenic purpura associated with viral infection
The disease can occur after an acute viral infection or vaccination. The varicella-related ITP is particularly noticeable because individual children develop complicated coagulation disorders, mainly related to anti-protein S or anti-protein C antibodies, measles, mumps and Rubella vaccine (MMR) can induce ITP, usually within 6 weeks after receiving the vaccine, so the UK Health Care Board recommends that children who develop MTP within 6 weeks of MMR for the first time should be serologically examined before revaccination, if serum The results showed that the child had not yet fully immunized against the three viruses and should be given another vaccination.
3. Chronic ITP
Chronic processes are common in children older than 10 years of age. The history of acute ITP is relatively short. Generally, purpura and ecchymoses can occur 24 to 48 hours. At this time, the platelet count is generally (10-20)×10 9 /L or even Fewer, if the child's platelet count is relatively high, and skin bleeding, ecchymosis and other bleeding history lasting longer should consider chronic ITP.
4. Periodic thrombocytopenia
It is a disease characterized by low to high fluctuations in the number of regular platelets. This disease is more common in young women and can occur in men. It is considered to be a variant of chronic ITP with a mean platelet fluctuation period of 30 days. In some cases, platelet fluctuations in some patients are parallel to menstruation, and the cause of this cyclical fluctuation is unknown. Some scholars believe that it is related to menstruation. Recently, it has been found that clonal T cells mediate this cycle in patients with periodic thrombocytopenia. Sexual thrombosis.
5. Other
Children with bleeding points or purpura that last for weeks or months, although the clinical signs are similar to ITP, should also pay attention to whether some congenital diseases are combined. These congenital diseases are related to age, in young children (after birth) Several weeks or months) similar diseases include: Wiskott-Aldrich syndrome, Bernard Soulier syndrome and other congenital or hereditary thrombocytopenia diseases. In older children, Fanconi anemia is common, type 2B vascularity Hemophilia, severe bone marrow disease (Down syndrome, aplastic anemia, etc.), the probability of developing a chronic ITP in children over 10 years old is relatively high, and should be noted with other autoimmune diseases such as systemic lupus erythematosus, antiphospholipid synthesis In recent years, AIDS has been expanding globally, so ITP should be considered after HIV infection in children.
