I. Overview
Idiopathic (or primary) thrombocytopenic purpura (ITP) is a common bleeding disorder caused by excessive destruction of peripheral platelets (usually more than 20 times normal). Since the 1950s, there has been much evidence that platelet destruction in ITP involves an immune mechanism, hence the name Immune thrombocytopenia, or autoimmune thrombocytopenia. Autoimmune thrombocytopenia (ATP). The disease was first reported by the American scientist Werlholf in 1735 and was known as Werlholf’s disease in ancient times.
The incidence of ITP is about 1.67/100,000 population, and there are about 1700~4000 new cases per year (Japan). It is generally believed that ITP accounts for roughly 70% of bleeding disorders in Japan.
ITP is divided into two types: acute type (AITP) and chronic type (CITP). The former is mostly seen in children, 85% of patients are younger than 8 years old, and the incidence of men and women is comparable. The course of the disease is mostly self-limiting, and more than 80% of patients can heal spontaneously, and most patients’ platelets return to normal within 6 weeks, and relapses are rare. The latter accounts for about 80% of ITP patients, mostly in adults aged 20 to 50 years, especially in young and middle-aged women, with a male to female incidence ratio of 1:1.86 to 1:3. 90% or more cannot resolve on their own.
Second, modern medical research on the pathogenesis and treatment of ITP
(A) Pathogenesis
Childhood ITP (equivalent to AITP) is a natural immune response to acute viral infection, and is cured once the virus is cleared. Adult ITP (equivalent to CITP) is an autoimmune disease.
Studies of the pathogenesis have focused on immune mechanisms such as platelet-associated antibodies (PAIgG), erythrocyte immune function, circulating immune complexes (CIC), lymphocyte subsets, and platelet membrane alterations. The results showed that ITP is an immune response of the body to platelet-associated antigens, producing anti-platelet antibodies, which in turn sensitize platelets and lead to their premature destruction in the reticuloendothelial system.
The possibility that immune thrombocytopenic purpura may be mediated by autoantibodies has long been suspected, on the grounds that transient thrombocytopenia can occur in newborns born to mothers with the disease, and this suspicion has been confirmed by the fact that transient thrombocytopenia can also occur in normal subjects when plasma, including IgG-rich plasma, is passively administered to the patient. The clearance of platelets encapsulated by IgG-type autoantibodies is accelerated mainly in the liver and spleen by macrophage-expressed Fcγ. Most patients have a compensatory increase in platelet production, while in others, platelet production appears to be impaired due to destruction of antibody-coated platelets by macrophages in the myeloid, or suppression of macrophage production. Thrombopoietin levels were not elevated, suggesting an overall normal megakaryocyte population.
A detailed analysis of the autoantigen profile has been reported in the literature. The first antigen identified was based on the inability of platelets with inherited defects in the glycoprotein IIb/IIIa complex to bind to antibodies against immune thrombocytopenic purpura. Since then, various antibodies that react with glycoprotein Ib/IX, Ia/Iia, IV, V and other platelet antigen determinants have been identified, and antibodies against multiple antigens are commonly present. Platelets are destroyed within antigen-presenting cells – presumably (although not necessarily inevitably) initiated by antibodies that can generate a series of new antigens that produce enough antibodies to cause thrombocytopenic purpura.
Naturally occurring anti-glycoprotein IIb/IIIa antibodies have clonal limitations with respect to light chain use, and antibodies generated from phage antibody libraries have high limitations with respect to VH gene expression. Sequencing of the antigen-binding sites of these antibodies confirms that they are generated by antigen-driven affinity selection and somatic mutations in a limited number of several B-cell lines. adult patients with ITP frequently have increased numbers of HLA-DR+ T cells, increased numbers of soluble interleukin 2 receptors, and a cytokine profile indicative of T-helper cell precursor cell and type 1 T-helper cell activation. In these patients, T cells stimulated antibody synthesis after exposure to glycoprotein IIb/IIIa fragments, whereas no similar response was observed after exposure to natural proteins. The reason for the derivation of these in vivo cryptic antigenic determinants clusters and the persistent activation of T cells is not known.
The approaches now used to treat ITP focus on the various aspects of antibody production and platelet sensitization, clearance and metabolites.
Genetics
ITP has been diagnosed in monozygotic twins and in some family lines, and a propensity for autoantibody production in family members has been noted. The increased incidence of HLA-DRw2 and DRB1＊0410 alleles in certain ethnic populations has been noted, with HLA-DR4 and DRB1＊0410 alleles being associated with poor and good corticosteroid outcomes, respectively, and HLA-DRB1＊1501 being associated with poor splenectomy outcomes. However numerous studies (albeit on a tiny scale) have failed to confirm a consistent association of ITP with class I or II specific major histocompatibility complex polymorphisms.
The mechanism of platelet ring-breaking can be summarized in two ways: 1. Anti-platelet antibody IgG first binds specifically to the relevant antigen on the platelet membrane through its Fab fragment, exposing the Fc fragment and binding to the Fc receptor on macrophages, causing platelets to be destroyed by phagocytosis. 2. CIC binds to the Fc receptor on platelets through the Fc fragment on its IgG molecule and activates complement, causing complement to be anchored to platelets, which are eventually recognized and destroyed by macrophages.
The main sites of platelet destruction are the spleen, liver and bone marrow, with the spleen in particular being the most damaged. The spleen is also the main site of anti-platelet antibody production, followed by the bone marrow.
The disease is also associated with abnormal platelet aggregation and adhesion functions.
Free radicals also play a role in its pathogenesis. A large number of CICs are formed during the onset of the disease, which activates the complement system. The respiratory burst and increased oxygen consumption during phagocytosis and clearance of CIC increase the metabolic activity of the pentose phosphate pathway and produce large amounts of superoxide anions, leading to changes in the vascular endothelium, vascular basement membrane, and tissue matrix, which aggravate or induce bleeding.
Vascular endothelial cells can synthesize and release a variety of active mediators to regulate the diastole of vascular smooth muscle, and changes in their own skeletal structure can in turn affect vascular permeability, which is also an important link in ITP. Platelets have a supportive and protective effect on endothelial cells to maintain the vascular barrier, so that red blood cells cannot cross the endothelium and escape from the blood vessels. When blood vessels are damaged, platelets adhere to exposed subendothelial tissue and release their inclusions, such as ADP, platelet factor 4 (PF4), β-platelet globulin (β-TG) and platelet-derived growth factor (PDGF). It also forms thromboxane A2 (TXA2) ADP through the membrane phospholipid metabolic pathway. TXA2 and locally formed thrombin contribute to the activation of circulating platelets, which undergo viscous deformation and aggregate into clusters with the participation of fibrin. thrombin and platelet secretions in turn feedback to endothelial cells to synthesize and release prostacyclin (PGI2), which inhibits excessive platelet aggregation, thus making the hemostatic thrombus formation is confined to the damaged vessel.
Diagnosis
The diagnosis of ITP is still based on the exclusion method.
Diagnostic criteria (December 1986)
1. Decreased platelet count on multiple laboratory tests.
2. No or only mild enlargement of the spleen.
3. Increased or normal megakaryocyte count on bone marrow examination with maturation disorder.
4. Any one of the following five points should be present.
(1) Prednisone treatment is effective.
(2) Treatment with splenectomy is effective.
(3) PAIgG is increased.
(4) PAC3 is increased.
(5) Shortened platelet lifespan measurement.
5. Exclude secondary thrombocytopenia.
The occurrence of secondary forms of this disease is often associated with the following diseases or states: systemic lupus erythematosus, antiphospholipid syndrome, immunodeficiency states (IgA deficiency and common variant hypogammaglobulinemia), lymphoproliferative diseases (chronic lymphocytic leukemia, large granular lymphocytic leukemia and lymphoma), human immunodeficiency virus (HIV) infection, hepatitis C virus infection and drug therapy such as heparin , quinidine, etc. In infants less than three months old, passively acquired autoimmune or alloimmune thrombocytopenia should be excluded. Hereditary non-immune thrombocytopenia may resemble immune thrombocytopenic purpura. Anticardiolipin antibodies, antinuclear antibodies, and positive direct antiglobulin tests are not uncommon in this disease, but in the absence of clinical manifestations of the disease, these indicators have little to no diagnostic or therapeutic value. The prognosis is poor in the presence of combined autoimmune hemolytic anemia, neutropenia, or both.
The duration of bleeding helps to differentiate between acute and chronic. The absence of systemic symptoms helps to exclude secondary thrombocytopenic purpura and other diagnoses. Physical examination usually reveals only evidence of platelet-based bleeding (petechiae, purpura, conjunctival bleeding, and other types of cutaneous mucosal bleeding). Smears of peripheral blood must be performed to rule out pseudo-thrombocytopenia, hereditary macrothrombocytic syndrome, and other blood disorders. Large immature platelets (macroplatelets) can often be observed. These naïve reticulocytic platelets can be detected by flow cytometry based on their messenger RNA content, and it is assumed that these platelets are more metabolically active, which may explain why bleeding due to ITP is generally not as severe as that seen in bone marrow failure states, given the same number of platelets. Laboratory tests should be performed sparingly if there is no atypical presentation at the time of consultation.
One of the most controversial issues is the need for a bone marrow aspiration. The American Society of Hematology guidelines state that bone marrow aspiration is not necessary in adults under 60 years of age with typical presentations, but that it is appropriate to perform the test prior to splenectomy. Bone marrow testing may be waived in pediatric patients if management involves only observation or intravenous immunoglobulin. In atypical cases, including patients with lethargy, prolonged fever, bone or joint pain, unexplained macrocytosis or neutropenia, a bone marrow examination should be routinely performed.
Determination of platelet-related antibodies
The estimated sensitivity of the direct assay for platelet-binding antibodies is 49% to 66%, the estimated specificity is 78% to 92%, and the estimated positive predictive value is 80% to 83%. Ginkgo results do not exclude the diagnosis. When combined with other diseases such as systemic lupus erythematosus, chronic hepatitis, myelodysplasia or B-cell lymphoma, the predictive values are less convincing. These experiments have yet to confirm whether they help to distinguish both whether ITP is primary or secondary and whether the course of the disease is self-limited or whether it progresses to chronic disease in the child.
(ii) Treatment
Initial treatment
Adult area
ITP most often develops between 18 and 40 years of age, and is about 2 to 3 times more common in women than in men. For those with platelet counts above 5,000/mm3, they are usually detected only incidentally; those between 30,000 and 50,000/mm3 may be noted to cause severe petechiae with smaller trauma; those between 10,000 and 30,000/mm3 can develop petechiae or petechiae spontaneously; and those below 10,000/mm3 are at risk of internal bleeding. In a recent series of studies, half of the patients presented with a platelet count of 10,000/mm3 or less. Therefore, adult patients usually require treatment at the time of presentation. Treatment is usually oral prednisolone (at a dose of 1.0 to 1.5 mg/kg per day). The efficiency of treatment depends on the intensity and duration of treatment and ranges from 50% to more than 75%. The majority of efficacy responses occur within the first 3 weeks of treatment, but there is no uniformity regarding the appropriate duration of treatment. Sustained remission rates range from less than 5% to more than 30%, depending on the duration of disease, criteria for judging efficacy, and length of follow-up. Anti-D immunoglobulin treatment (75ug/kg) given at the time of presentation to Rh-positive patients can be equally effective, but is much more expensive and generally less toxic.
Intravenous immunoglobulin infusion (1 g/kg/day for 2-3 days) is used to treat internal bleeding in the following cases: when the platelet count remains below 5000/mm3 after several days of corticosteroid treatment; when there is widespread or progressive purpura. Treatment is effective in about 80% of patients, but lasting remission is uncommon and the use of intravenous immunoglobulin is quite costly. It can cause renal failure and pulmonary insufficiency, and can cause allergic reactions in patients with congenital IgA deficiency.
The decision to perform splenectomy depends on the severity of the disease, tolerance to corticosteroids, and the patient’s willingness to undergo surgery. Most hematologists recommend that the spleen should be removed within 3 to 6 months if prednisolone dosage must be above 10 to 20 mg/day to maintain platelet counts above 30,000/mm3, although a growing body of data supports that a strategy of continued observation should be followed.
Children
There is controversy about whether to proceed with initial treatment of typical acute ITP in children, in part because the regression is also very good without treatment. The decision to treat such children is primarily based on concerns about intracranial hemorrhage and limitations in physical activity. The actual incidence of intracranial hemorrhage is 0.2% to 1%. Almost all patients with intracranial hemorrhage have platelet levels below 20,000/mm3 and generally below 10,000/mm3. Risk factors that predispose to intracranial hemorrhage include head trauma and antiplatelet drug exposure. Most intracranial hemorrhages occur within 4 weeks of the onset of symptoms, often within the first 1 week. Because intracranial hemorrhage is extremely rare, it is not possible to directly evaluate the effectiveness of treatment. Therefore, treatment decisions for children with ITP rely on the unproven hypothesis that shortening the duration of severe thrombocytopenia has a protective effect on patients.
Randomized clinical trials have confirmed that intravenous immunoglobulin infusion shortens the duration of severe thrombocytopenia (defined as a platelet count below 20,000/mm3). Adverse effects were mostly transient. and are related to the rate of infusion. Adverse reactions include headache, fever, nausea and, rarely, aseptic meningitis (which can raise concerns about intracranial hemorrhage). Intravenous immunoglobulin has a faster onset of action than intravenous anti-D immunoglobulin (25ug/kg per day for 2 days); while high-dose anti-D immunoglobulin (75ug/kg) has comparable efficacy to intravenous immunoglobulin. The average decrease in hemoglobin level was about 1.3 g/dl, and intravascular hemolysis was rare. The short-term benefit of oral conventional doses of corticosteroids (prednisolone 1 to 2 mg/kg per day) is uncertain, but the use of higher doses can cause a rapid rise in platelet counts. Behavioral changes, weight gain, osteoporosis, and positive urine glucose can occur even during short courses of high-dose corticosteroid therapy. The most basic treatment should be to maintain platelets at a level sufficient to stop bleeding. A single dose of intravenous immunoglobulin infusion (0.8 g/kg) is usually effective. An uncontrolled prospective study has also reported that oral prednisolone (4 mg/kg/day for 4 days) produced an excellent early therapeutic response.
Emergency treatment
In the presence of neurological symptoms, internal bleeding, or emergency surgery, immediate intervention should be given. Intravenous methylprednisolone (30 mg/kg per day; maximum amount 1.0 g/day for 2-3 days) over a period of 20-30 minutes and concomitant application of intravenous immunoglobulin (1 g/kg per day for 2-3 days) and platelets (2-3 times the usual infusion amount); vincristine may be used as one of the combination therapy agents. Splenectomy is to be considered in patients who have not undergone splenectomy. Plasma replacement therapy has limited benefit. Antifibrinolytic therapy (e.g., aminocaproic acid) may reduce mucosal bleeding; recombinant factor VIIa may also be considered. for severe persistent bleeding, the course of high-dose intravenous immunoglobulin may be extended to 5 days with continuous intravenous platelet infusion (1 unit/hour).
Treatment of first recurrence
Adults
Most adult patients present with one or more relapses during corticosteroid tapering or when corticosteroid therapy fails and intravenous immunoglobulin or anti-D immunoglobulin infusion is required. Asymptomatic patients with platelet counts >30,000/mm3 do not require treatment unless treatment is indicated due to comorbidities or at the patient’s own request. Some patients may resolve without additional treatment. However, for most adult patients who have had a previous relapse or who have failed to respond to corticosteroids, intravenous immunoglobulin or anti-D immunoglobulin, the next appropriate treatment is splenectomy.
Children
Relapses occur in approximately 25% of children after initial treatment. Since there is no evidence that drugs improve the long-term prognosis, the goal of treatment is only to maintain platelets at safe levels. Splenectomy should be postponed as long as possible because 1/3 of children resolve spontaneously and only 5% of children with severe thrombocytopenia still require treatment one year after diagnosis. The risk of death from the aggressive bacterial sepsis is highest in young children and is lifelong. The Hematology Society guidelines in the United States and the United Kingdom recommend that splenectomy should be considered in children with symptomatic and severe thrombocytopenia lasting at least one year. In Rh-positive children, if clinically effective, anti-D immunoglobulin is preferred over intravenous immunoglobulin, as the former is easy to administer and has similar efficacy to the latter but is less expensive. The efficacy rate is about 70% and most of the treatment lasts more than three weeks. Long-term corticosteroid therapy can cause unacceptable adverse effects, and intermittent shock therapy with oral dexamethasone has produced disappointingly long-lasting efficacy.
Splenectomy
Adults
There is no means to predict the response of individual patients to treatment with splenectomy. Results of numerous studies have shown that surgical treatment is effective in approximately 2/3 of patients, usually within a few days after surgery. Patients with platelet counts below 50,000/mm3 may require preoperative treatment with corticosteroids, intravenous immunoglobulin or anti-D immunoglobulin. Laparoscopic splenectomy appears to have both immediate and long-term benefits, while complication rates are similar to those of open splenectomy. Laparoscopic surgery also accelerates recovery and shortens the length of hospital stay. Splenic radiation therapy has been used as a short-term treatment for patients who are too weak to tolerate surgery.
Children
In children, the rate of complete remission after splenectomy is about 70% to 80%. When performed by an experienced surgeon, laparoscopic splenectomy appears to be superior to open splenectomy.
Post-splenectomy sepsis
Patients undergoing splenectomy are at substantially increased risk of developing severe bacterial sepsis. Immunizations against Haemophilus influenzae type B and pneumococcus should be administered at least 2 weeks prior to splenectomy, depending on the patient’s age and immunization history. or with Streptococcus meningitidis vaccine. Because the protection provided by the vaccine is incomplete, daily prophylactic penicillin is recommended for children before 5 years of age (switch to an equivalent drug if allergic to penicillin) for at least one year after splenectomy. In the UK, physicians recommend prophylactic antibiotics until adulthood.
Chronic refractory ITP
Adults
Approximately 30-40% of adults with splenectomy fail or relapse at some time after splenectomy. These patients are unlikely to be cured and are at greatest risk of death, although spontaneous remission does occur. The starting point for treatment is to maintain platelet counts at safe levels with minimal therapy while taking into account the following: coexisting risk factors for bleeding (including the need for treatment with drugs that impair platelet function), patient acceptance of lifestyle modifications, tolerance to treatment, and potential toxic effects of various interventions. Geriatric patients are not only more likely to experience severe bleeding, but may also suffer the adverse effects of treatment-induced debilitation. The American Society of Hematology guidelines state that a platelet level of 30,000 to 50,000/mm3 is a more appropriate surrogate endpoint in patients without other risk factors, and that this level minimizes the risk of spontaneous bleeding to the greatest extent possible.
There is no single treatment process that can be applied to all patients. Case reports usually involve only a small number of severely affected patients; efficacy is judged by an arbitrary increase in platelet count without confirmation of its clinical significance; in addition, evaluation of the impact of treatment on survival and mortality is not possible because of the small number of patients and the short follow-up period. Therefore, treatment must be individualized and the success rates reported in the literature should be considered optimistic.
Relapsed patients are generally treated again with prednisolone, but rarely can be treated long-term with an acceptable low dose or alternate-day regimen. When long-term corticosteroids are planned, measures should be taken to slow the onset of osteoporosis. If typical changes in blood smears after splenectomy are not evident, the presence of a parasplenium should be suspected. Residual splenic tissue can be detected by magnetic resonance imaging or sensitive scanning techniques (e.g., labeling of heat-damaged red blood cells), but very rarely surgical excision of the paratenic spleen has a long term efficacy. Repeated intravenous immunoglobulin infusions are frequently life-saving, but it is not uncommon for drug resistance to occur.
In patients requiring adjuvant therapy, the second step is usually, the application of drugs that block platelet clearance to reduce corticosteroid dosage. Danazol (10-15 mg/kg per day) is beneficial in 20-40% of patients. If the drug is used for 3 to 6 months, it may occasionally cause remission. In some patients, platelets can be maintained at normal levels with a low dose of 50 mg/day. Treatment with this drug is rarely effective in patients who are already resistant to corticosteroids. Side effects include hepatotoxicity, skin rash, and masculinization. Aminophenazone (75 mg/day) has a success rate of 40% to 50% in the treatment of patients with only one relapse, but is rarely effective in the treatment of patients with refractory ITP. Vinca alkaloids are now used sparingly because of their low efficiency (3%-30%), short duration of effectiveness, and often associated with neuropathy. Post-splenectomy patients should not be treated with anti-D immunoglobulin. Isolated plasma perfusion via staphylococcal A protein columns has occasionally been effective, but serious side effects have been reported. Immunosuppressive therapy is generally used only in patients with platelet counts below 20,000/mm3 and where the above therapies are ineffective or intolerable. Treatment with azathioprine (1-4 mg/kg per day, orally), or cyclophosphamide (1-2 mg/kg per day, orally) for 2-6 months is effective in 20%-40% of patients, and the dose of the drug is adjusted to cause mild neutropenia during treatment. Cyclophosphamide has been administered in the following ways: as a single intravenous shock (1.0 to 1.5 g/m2 body surface area, 1 to 5 doses every 4 weeks) or in combination with a combination regimen consisting of prednisolone, vincristine alkaloids, and other drugs. Patients usually tolerate azathioprine well, but care should be taken to monitor liver function; the potential carcinogenic risk of azathioprine should be argued with, but it is not clear whether it causes carcinomas in patients with ITP. Cyclophosphamide can cause not only myelosuppression, hemorrhagic cystitis, cystic fibrosis, alopecia, sterility, and myeloid leukemia, but also malformations. There has been striking evidence of effective treatment with cyclosporine alone or in combination with cyclophosphamide. The effect may be more pronounced when drugs such as azathioprine, danazol or prednisolone are combined.
For patients with severe ITP who are refractory to conventional therapy, treatments under investigation include human-derived anti-CD2087 and CD154 monoclonal antibodies. Clinical trials have also been conducted on thrombopoietin. It has also been reported in the literature that ITP appears to subside after the elimination of H. pylori infection. The National Institutes of Health recently found that high-dose immunosuppression followed by autologous bone marrow transplantation resulted in complete remission in 4 of 14 patients and partial remission in 4 of 14 patients who could be evaluated.
Children
Difficult to manage are children who are occasionally symptomatic and who have failed splenectomy or have contraindications; and whose platelet counts are not maintained after treatment with acceptable doses of corticosteroids, anti-D immunoglobulin, or intravenous immunoglobulin. The American Society of Hematology guidelines recommend treatment for such children with symptomatic thrombocytopenia and a platelet count below 30,000/mm3. No treatment option is broadly effective. We recommend treatment with the lowest dose of azathioprine that will maintain hemostasis (2 to 3 mg/kg per day orally, with dose adjustment to the extent that it causes mild neutropenia); azathioprine may be used alone or in combination with prednisolone. Transient benefit may be obtained with 0.02 mg/kg (maximum dose 2 mg) per dose of vincristine or 0.1 mg/kg (maximum dose 10 mg) of vincristine administered intravenously once at 5-7 day intervals for a maximum of 3 courses. In refractory cases, pulsed intravenous administration of cyclophosphamide (at a dose of 1.5 g/m2 body surface area per dose, given 2-4 doses at 4-week intervals), cyclosporine, or combination chemotherapy may be useful for patients.
Some experts have proposed a platelet count of 20,000/mm3 rather than 30,000/mm3 as the threshold for ITP treatment. There is no consensus on how long the duration of corticosteroid therapy is appropriate. Whether intravenous immunoglobulin or anti-D immunoglobulin has been administered as initial therapy depends on the severity of thrombocytopenia and the extent of skin mucosal bleeding. Treatment of patients with platelet counts between 30,000 and 50,000/mm3 depends on the combination of other risk factors for bleeding and the presence of risk factors for trauma. Patients with chronic ITP with platelet counts below 30,000/mm3 may benefit from intravenous immunoglobulin or methylprednisolone infusions to elevate platelet counts immediately prior to splenectomy. Intravenous immunoglobulin or anti-D immunoglobulin is usually used only for severe thrombocytopenia where oral medications have failed. Whether to perform splenectomy, continue medication, or reduce and eventually discontinue medication in patients with chronic ITP with platelet counts above 30,000/mm3 depends on the intensity of therapy needed, tolerance of side effects, risks associated with surgery, and patient preference. The need for treatment in patients with chronic refractory ITP involves a trade-off between the risk of bleeding and the side effects of each form of treatment. Drugs are often used in combination. Patients receiving long courses of corticosteroid therapy should be monitored for the development of osteoporosis and cataracts.
Prednisone is usually the first choice for initiation of treatment, with amineptine or high-dose vitamin C for mild bleeding symptoms. small doses of danazol may be added during prednisone taper if prednisone is not effective. Anti-Rh globulin may also be used. Human leukocyte factor injection is often used for patients with positive rheumatoid factor. Dermatomectomy is often chosen for patients who have been treated for more than one year, who have failed to respond to the above treatment or who are prednisone dependent (requiring prednisone maintenance of 20 mg or more per day) or who have counter indications for corticosteroids. Remission can be expected in more than 70% of cases with the above treatment.
The mechanisms of action of prednisone are: 1. inhibition of Fc receptors and C3b receptors in monocytes-macrophages, which reduces phagocytic clearance of platelets coated with antibodies and prolongs platelet life; 2. reduction of capillary fragility; 3. inhibition of antibody production; 4. inhibition of antigen-antibody reactions and freeing of bound antibodies.
The mechanism of action of danazol may be to reduce platelet antibody production by modulating the immunomodulatory effects of T cells.
The mechanism of action of splenectomy is: 1. the spleen is the main organ that produces platelet antibodies, and removal of the spleen reduces antibody production. 2. the spleen is an important site for destruction of cleared platelets, and platelet destruction is reduced after splenectomy. In cases where splenectomy is not effective, the reasons may be: 1. the presence of a paratenic spleen that is not removed. 2. the main site of destruction is not in the spleen. 3. the compensatory effect of other immune tissues.
In addition, high-dose IVIgG treatment for ITP has received great attention since the 1980s. IVIgG is considered to be a more satisfactory therapy at present, and its mechanism is still under investigation. The following observations have been made: 1. exogenous antibodies compete with the Fc receptors of the monocyte macrophage system and inhibit their ability to phagocytose platelets that have bound autoantibodies. 2. high doses of antibodies enter the body and feedback inhibit the body’s ability to produce antibodies, including autoantibodies. 3. imported immunoglobulins may contain anti-unique antibodies that enter the body and affect the unique – anti-unique network system, causing This may affect the unique – anti-unique network system and bring it into normal balance.
When the above general methods are not effective, immunosuppressants can also be tried, commonly azathioprine reinforced pine, or cyclophosphamide reinforced pine, and vincristine can also be used, but the efficacy is not satisfactory. Colchicine can affect the function of macrophages, and there are cases of remission in tolerant patients. In recent years, cyclosporine has been used with good results. Infusion of platelets “loaded” with vincristine has been reported to be more than 50% effective, with a sustained remission rate of 33-75%. Plasma exchange and injection of anti-neutrophil and macrophage Fc receptor monoclonal antibodies have been shown to be effective, but long-term remission is difficult to achieve.
Mortality
The leading cause of fatal bleeding in patients with ITP is intracranial hemorrhage, with the highest risk in the elderly, those with a history of bleeding, and those who are treatment-naive. In a small subgroup of patients with severe thrombocytopenia, the expected five-year mortality rate due to bleeding ranges from 2.2% in those under 40 years of age to 47.8% in those over 60 years of age, suggesting the need for ongoing treatment in those with severe disease.
The physician’s perspective
ITP is a common disease that affects children and adults. Basic questions regarding its pathogenesis and treatment have not been resolved. Some physicians have overemphasized normalization of platelet counts as a guideline for treatment. To improve treatment outcomes, further research is needed on well-designed clinical trials that include a combination of clinically relevant endpoints (e.g., severity of bleeding), quality-of-life measures, and economic analyses.
Overview of research on the etiology and treatment of ITP in Chinese medicine
This disease belongs to the “blood evidence”, “hair spots”, “purple spots”, “epistaxis”, “epistaxis” and “epistaxis” in Chinese medicine. Epistaxis”, “Epistaxis” and “Grape disease” in Chinese medicine.
The Medical Journal (Ming. (Ming. Yu Tuan) was the first to name all kinds of bleeding as “blood evidence”. The Blood Gate” (Ming. (Ming. Dai Yuanli) was the first to name skin bleeding as “myxedema”.
Before the Ming and Qing dynasties, the discussion on bleeding from the skin was not separated from bleeding from other parts of the body, and only generalized the etiology and pathogenesis of bleeding.
The Nei Jing summarizes the causes of bleeding as the six sexes, the seven emotions and diet, labor and fatigue. In the Jin Kui Yao, it is believed that fire-heat, deficiency fire, damp-heat, deficiency cold, alcohol poisoning and stasis can all cause bleeding.
During the Jin-Yuan period, various schools of thought emerged and competed. The leader of the cold and cool school, Liu Heshan, advocated real fire as the cause of bleeding, while Zhu Danxi, the master of the zhiyin school, advocated the theory of deficiency fire. Since the Ming and Qing dynasties, bleeding from the skin has been gradually distinguished from bleeding from other parts of the body. Zhang Jinyue: “Therefore, to inspect the fire, but to inspect its fire without fire; to inspect the qi, but to inspect its qi deficiency qi real. Know these four and get the reason.” Tang Rongchuan’s Treatise on Blood Evidence and Wang Qingren’s Medical Lin Correction suggest that stasis can lead to bleeding.
Modern TCM theories on the pathogenesis of ITP are broadly summarized as (1) fire-heat and poisonous evil; (2) Qi deficiency and non-intake; (3) Yin deficiency and fire; and (4) internal blockage of stagnant blood.
Among the above four points, Qi deficiency, Yin deficiency and internal blockage of blood are the most common, being both the cause and the result of bleeding, and often co-exist. Among them, qi deficiency and yin deficiency are the root cause, while fire and blood stasis are the symptoms. Therefore, in the final analysis, the pathogenesis of ITP is deficiency of Qi and Yin, which is the initiating link, while fire-heat and stasis are the secondary causes. It can be summarized as deficiency, fire and stasis.
The most common classification is blood-heat delusion, qi deficiency and yin deficiency.
Since 1989, studies on the relationship between TCM evidence and modern immunological indicators have yielded some results, focusing on PAIgG and T-lymphocyte subsets, and finding that the immunological changes in the actual evidence group are less severe than those in the deficiency evidence group.
In summary, there are two main categories of TCM treatment: evidence-based treatment and disease-based treatment. The former is subdivided into two types of treatment, namely, treatment based strictly on the identification of evidence and treatment based on the addition and subtraction of basic formulae. The latter refers to the treatment that is not guided by the identification and typing of evidence, but fixed on one side. It can also be divided into two forms: single-sided single medicine and compound prescription. In terms of herbs used, the most commonly used is raw earth, followed by roasted astragalus and angelica. The herbs involved include strengthening the spleen, tonifying the blood, nourishing the liver and kidney, tonifying the kidney and strengthening the yang, clearing heat and detoxifying the toxin, clearing heat and cooling the blood, activating blood circulation and removing blood stasis, cooling the blood and stopping bleeding, collecting astringent blood and softening the liver. In addition, there are about seventy kinds of medicines like Guan Gong Shu, Cuttings, etc., which are used sparingly. From the legislative point of view, the most commonly used to tonify the kidneys, strengthen the spleen and support the righteousness and treatment of blood.
1, the identification of evidence to treat
(1) not fixed prescriptions, identify the evidence and type of treatment. Some people also add special drugs such as Shangluo, Xuejiancao (Lychee grass), cuttings (elderberry), tomb head back (tomb head ash, arrowhead wind, iso-leaf septoria), weasel flesh, etc. on the basis of diagnosis and treatment.
(2) Fix the basic formula and add or subtract according to the evidence. Among them, there is Gardenia Di Huang Tang which is based on benefitting Qi, nourishing Yin, clearing heat and invigorating Blood; there is Yi Qi, tonifying kidney and diarrhea of fire which is based on benefitting Qi, tonifying kidney and diarrhea of fire; there is also the main formula of clearing heat and invigorating Blood which is based on treating the symptoms, with reference to the identification of the internal organs, adding and subtracting according to the evidence.
2. Treatment by disease identification
It is not guided by the identification and typing of the disease, and fixed one side of targeted treatment. There are two forms as follows.
(1) Single-sided single drug: there is Jiangnan rolled cypress tablets (formerly known as purpura Qing), its total efficiency is similar to the prednisone control group. If combined with prednisone can improve the total efficiency single line efficiency is still not ideal. There are also Kunming Shanhaigang Tablets, Blood Ning Capsules, Gynostemma Punch with Oral Liquid and Blood Kang Oral Liquid (Dried Infusion of Swelling Wind), etc.
(2) Compound formula: It is composed of two or more Chinese herbs, with a fixed kitchen and no addition or subtraction according to the evidence. According to the basic functions of compound prescriptions, there are roughly the following categories.
(1) Grouping formula mainly to double nourish the spleen and kidney: such as a school of strong yang and warm kidney medicine Ba Ji Tian, Lock Yang, Cistanches, Pieces of Radix et Rhizoma, Radix Codonopsis, Huai Shan, etc. Lock Yang Punch is suitable for patients with deficiency of spleen and kidney yang, weakness of spleen qi and deficiency of both yin and yang. Another example is 90 Blood Enhancement Punch, mainly composed of Angelica sinensis, Astragalus membranaceus, Lychee couch, and Epimedium, which is effective in correcting T lymphocyte subpopulation disorders. (②Treatment purely from the spleen: such as Blood Ning II, Gui Shen Tang combined with Si Sheng Wan are all treated from the spleen. (iii) Promoting blood circulation and eliminating blood stasis is the main formula. For example, one side uses Angelica sinensis, Chuanxiong rhizome, red flowers, red peony and motherwort to promote blood circulation and eliminate blood stasis, and adds chicken blood vine to benefit qi and activate blood circulation, and Huangqi and dang ginseng to strengthen the spleen and benefit qi. ④ Clearing heat and detoxifying the blood to cool the blood and stop bleeding legislation, such as honey pills composed of tortoise shell, lady’s mantle, earth rhubarb, yellow herb seeds, shamrock root, raw earth, dandan bark, angelica, cyperus root, comfrey, cynthia, and dry lotus grass. (5) Treatment from the liver, such as Xiao Chai Hu Tang with the addition of mucuna pruriens, stone reed, verbena raw earth, etc. (6) Treatment from the lung, such as black dragon soup with lung-clearing and fire-removing effects, consisting of black bean coat, ripe earth, black sesame, longan, longan flesh, niu xixi, raw shouwu and jujube, together with zeng hong san (pomegranate peel, chicken blood vine, lutong and peppercorn, etc. sub-pulverized). (7) Injections made of Chinese medicine, such as Niu Xixi injection (made of sheep’s trotter root, Xi Cao, deer antler grass and licorice), cancer spirit injection (made of arsenic and light powder), etc.
3. Other Chinese medical methods
It refers to acupuncture, physiotherapy and other methods other than traditional Chinese medicine, and the legislative principles are roughly similar to those of drug treatment.