Multi-target therapy for autoimmune hemolytic anemia under the guidance of traditional Chinese medicine pharmacology

Jiu-Wei Li

Shandong University of Traditional Chinese Medicine, Second Clinical Medical College, Jinan China.

Abstract Autoimmune hemolytic anemia (AIHA) is a rare and refractory acquired autoimmune disease.At present, western medicine treatment has obvious side effects, low drug sensitivity, easy to relapse and other problems.Multi-target treatment of autoimmune hemolytic anemia through the study of pharmacology of traditional Chinese medicine can effectively improve the clinical efficacy of autoimmune hemolytic anemia, and the price is low, worthy of promotion.This paper discusses the effects of traditional Chinese medicine on maintaining acid-base balance,alleviating liver and kidney function damage and immune collapse.

Keywords: gastric cancer; experiences of famous doctors; qi activity; phlegm and stasis.

Introduction

Autoimmune hemolytic anemia is a kind of acquired hemolytic anemia caused by B lymphocyte immune regulation disorder, which produces autoantibodies and destroys erythrocyte membrane by combining with erythrocyte surface antigen, or activates complement to accelerate destruction of erythrocyte [1].It has been reported abroad that AIHA accounts for about 1/3 of the total number of patients with hemolytic diseases.In China, the incidence of AIHA is second only to PNH,accounting for the second place of acquired hemolytic anemia [2].The typical clinical features are specific erythrocytic decline and anemia co-existing with acute indirect bilirubin elevation.Due to its difficult to determine the pathogenic cause, it often occurs repeatedly and is difficult to recover.In recent years,it has become a research hotspot to closely combine traditional Chinese medicine pharmacology, traditional Chinese medicine theory and Western medicine theory to realize the multi-target and accurate treatment of diseases with traditional Chinese medicine in order to realize the objectification of traditional Chinese and Western medicine.

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Autoimmune hemolytic anemia has no corresponding disease name in Traditional Chinese medicine,according to its clinical manifestations can be classified as "consumptive disease" "jaundice" "blood deficiency" "infantile hemopyretic jaundice" category.The disease is caused by the stagnation of blood stasis,the imbalance of spleen and stomach and the abnormal function of liver in storing blood ,which result in the abnormal function of dispersion that makes bile does not follow a regular path and overflow on the surface of the skin.In recent years, many doctors have carried out in-depth discussions on the etiology and pathogenesis of AIHA, with different views.Professor Yongsheng believes that the occurrence of AIHA is based on the loss of Yin and Yang deficiency of qi and blood, and the standard of depression within fire.The treatment should be supplementing qi, nourishing blood, strengthening spleen and stomach, and supplementing Yin and clearing heat [3].Hu believes that the pathogenesis of this disease is blood stasis and toxin accumulation, and the syndrome of deficiency of Qi, blood and Yin and Yang can be seen for a long time.The treatment should be based on promoting blood circulation and removing stasis, that is, detoxification and removing stasis should be the priority in the early stage, while tonifying spleen and warming kidney should be the priority in the late stage [4].Western medicine mainly uses glucocorticoids, immunosuppressants, splenectomy and so on, but the side effects are greater [5].In recent years, many doctors have conducted pharmacological studies on the treatment of autoimmune hemolytic anemia with traditional Chinese medicine, and further discussed the characteristics and advantages of the twoway regulation of traditional Chinese medicine on the immune system.The results are as follows.

1 Immune regulation

The etiology of autoimmune hemolytic anemia is the disorder of autoimmune regulation and immune hyperactivity, followed by a series of physiological changes caused by erythrocyte destruction and anemia [6].First of all , hemolysis causes acid-base imbalance and renal damage; Secondly, anemia causes bone marrow and systemic compensatory symptoms;Thirdly, hemolysis causes ductile pressure on the erythrocyte membrane; Fourthly , excessive destruction of red blood cells results in accumulation of bilirubin metabolism and liver damage; Fifthly, persistent anemia causes physical and immune decline.

Therefore, AIHA is the preferred modern treatment for immunosuppressants and glucocorticoids that reduce the destruction of red blood cells to correct anemia,such as large doses of glucocorticoid, immunoglobulin,cyclosporin, tacrolimus were used.However, such drugs widely interfere with the normal immune process of various systems in the body, and the side effects are almost inevitable, which often lead to osteoporosis,decreased immune function and other symptoms.Obviously, the overall suppression of immune response is not what we hope for.Therefore, the selective suppression of immune cells or molecules that play a pathological role in the occurrence and development of the disease by TCM targets without affecting or less affecting other normal immune cells has become a breakthrough point in the treatment of AIHA by TCM.The first principle of TCM treatment of AIHA is still suppress the immune hyperfunction and immune expression, autoimmune hemolytic anemia belong to abnormal immune function of red blood cells, is the body B lymphocyte immune adjustment disorder,produce autoantibodies and (or) complement, and combining with the red cell membrane, the destruction caused by acceleration caused by group a hemolytic anemia.In addition to humoral immunity, cellular immunity also plays a very important role in the pathogenesis of AIHA.AIHA patients not only have abnormal immune tolerance in B cells, but also in T cells.CD4 is the surface marker of T helper/inducer cells.CD4+ T cells have the function of assisting T cells to transform into effector cells, promoting proliferation and differentiation of B cells into plasma cells, and enhancing humoral immune response.

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The acute stage of AIHA can be complicated with acute renal insufficiency, which is life-threatening.Therefore, traditional Chinese medicine treatment of AIHA in the acute stage should take into account the principle of "promoting blood circulation, dredging intestines and discharging turbidity".Drugs such as Tufuliing (Smilacis Glabrae Rhizoma), Mianbixie(Dioscoreae Spongiosae Rhizoma), Chixiaodou (Vignae Semen), Zisuye (Perillae Folium), Shiwei (Pyrrosiae Folium), Chuanniuxi (Cyathulae Radix), Zangchangpu(Acori Calami Rhizoma) and Dahuang (Rhei Radix Et Rhizoma) should be selected as appropriate.Such turbidity discharging drugs such as rhubarb can effectively inhibit the synthesis of urea and increase the excretion of urea nitrogen and creatinine.In addition,the protective effect of blood activating drugs such as Danshen (Salviae Miltiorrhizae Radix Et Rhizoma) on kidney is to improve microcirculation, anticoagulant and increase renal cortical blood flow, which is conducive to the recovery of renal function.

In addition, other "detoxification, heat clearing,blood cooling" class of Traditional Chinese medicine,such as Qinjiao (Gentianae Macrophyllae Radix),Rendongteng (Lonicerae Japonicae Caulis), Gancao(Glycyrrhizae Radix Et Rhizoma) and other drugs modern pharmacological studies show that they can inhibit immune hyperactivity of the body to varying degrees, clean up immune disorders, so that the excessive expression of red blood cell antibodies are inhibited, reduce the destruction of red blood cells.

Meanwhile, Kushen (Sophorae Flavescentis Radix) can directly inhibit JAK/STAT signaling and T cell receptor(TCR) pathway, thus inhibiting pathological CD4+T cell differentiation and overall inflammatory response.Tianhuafen (Trichosanthis Radix) (trichosanthin) [8]inhibits T lymphocyte activation and proliferation through the TCR-CD3 signaling pathway.Chuipencao(Sedi Herba) (clonoside) [9] can significantly reduce the number of thymocytes in the thymus of mice and inhibit the T-cell mediated response.Qinghao(Artemisiae Annuae Herba) (dihydroartemisinin)[10] can inhibit delayed allergic reaction, inhibit the proliferation of non-activated T lymphocytes and reduce the phagocytic function of macrophages.Other studies have shown that artemisinin can significantly inhibit the proliferation of T lymphocytes induced by Daodou protein A, and has a higher safety compared with dexamethasone.The extract of Dengzhanhua(Erigerontis Herba) [11] can inhibit the activity of T lymphocytes in peripheral blood.In addition,Shanzhuyu (Corni Fructus) (total glycosides of Cornus officinalis) [12] can significantly inhibit the proliferation of T lymphocytes, and its mechanism is caused by activating apoptosis.

In the acute stage of AIHA, metabolic acidosis and changes in osmotic pressure are not only pathophysiological changes caused by hemolysis, but also one of the main internal environmental factors that further aggravate the destruction of erythrocyte membrane.The main method of traditional Chinese medicine to correct acidosis and maintain acid-base balance is "diuresis and dampness".In clinic, Fuling(Poria), Zexie (Alismatis Rhizoma), Cheqianzi (Plantaginis Semen), Yiyiren (Coicis Semen) and Qumai(Dianthi Herba) are used in clinical practice, and such drugs can also relieve the side effects of water and sodium retention caused by glucocorticoid drugs.

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2 Maintain acid-base equilibrium

In particular, it is recommended to use high-dose Gancao (Glycyrrhizae Radix Et Rhizoma)[13].The chemical structure of glycyrrhetinic acid, the main component of Gancao (Glycyrrhizae Radix Et Rhizoma), is quite similar to steroid hormones, has glucocorticoid like effects, shows mild hormone like effects when applied alone, and the long-term side effects are significantly less than hormones.It is mainly suitable for the treatment of acute AIHA.

Studies have shown that some traditional Chinese medicine can selectively inhibit cellular immunity and humoral immunity in varying degrees through different ways.Among them, the most representative are heat-clearing and detoxifying drugs such as Kushen (Sophorae Flavescentis Radix), Tianhuafen(Trichosanthis Radix) and Qinghao (Artemisiae Annuae Herba) and so on.Heat clearing and detoxifying traditional Chinese medicine, such as Chuanxinlian(Andrographis Herba), Daqingye (Isatidis Folium),Pugongying (Taraxaci Herba), Longdan (Gentianae Radix Et Rhizoma), Huangbo (Phellodendri Chinensis Cortex) and Dahuang (Rhei Radix Et Rhizoma).Other anti-wind and dehumidification drugs such as Chantui (Cicadae Periostracum), Cangerzi (Xanthii Fructus), Chaihu (Bupleuri Radix), Mahuang(Ephedrae Herba), Guizhi (Cinnamomi Ramulus)and Xixin (Asari Radix Et Rhizoma).Toxic attack drugs such as Jinqianbaihuashe (Bungarus Parvus),Chansu (Bufonis Venenum).Activating blood stasis drugs such as Danshen (Salviae Miltiorrhizae Radix Et Rhizoma), Chishao (Paeoniae Radix Rubra),Chuanxiong (Chuanxiong Rhizoma), Taoren (Persicae Semen), Honghua (Carthami Flos).Other such as Gancao (Glycyrrhizae Radix Et Rhizoma), Wumei(Mume Fructus), Aiye (Artemisiae Argyi Folium).The mechanism of immunosuppression is mainly through inhibition of T cell production, B cell production and DNA synthesis of tumor cells.

3 Impaired liver and kidney function

It is mainly traditional Chinese medicine of clearing away heat and detoxification that inhibits the proliferation of T cells.Studies have shown that Kushen (Sophorae Flavescentis Radix) is a two-way immune regulator.Kushen (Sophorae Flavescentis Radix) [7] inhibits the proliferation of T cells in a dose-dependent manner, and a small dose can promote the proliferation of T cells in mouse lymph nodes.

Protecting the liver and reducing jaundice are the key contents of traditional Chinese medicine treatment of hemolytic anemia, including autoimmune hemolytic anemia.Drugs for protecting the liver and reducing jaundice that can not only clearing damp and promoting diuresis, but also regulate immunity, such as Chuipencao (Sedi Herba), Yinchen (Artemisiae Scopariae Herba), Shuifeiji (Silybi Fructus), Jigucao(Abri Herba), Qinjiao (Gentianae Macrophyllae Radix), Wuweizi (Schisandrae Chinensis Fructus),Muli (Ostreae Concha), etc.Muli (Ostreae Concha)is not only an important drug for protecting liver, but also a metabolic adhesive for kidney; Shuifeiji (Silybi Fructus) can not only increase the toughness of red blood cells, but also protect hepatocyte membrane and anti liver fibrosis; Chuipencao (Sedi Herba) and Yinchen (Artemisiae Scopariae Herba) can not only protect the liver, but also reduce jaundice.

4 Immune collapse

Another characteristic of AIHA is that it is easy to relapse and repeatedly occur.If autoimmune hemolytic anemia persists and repeatedly hemolyses,the patient will be in anemia for a long time, which will affect another important physiological function of red blood cells - immune function [14].Patients may be accompanied by the decline of leukocytes,immune complement and globulin.Clinically, it is often accompanied by physical decline, bacterial or viral infection, or even fungal infection.After longterm immunosuppressive treatment, it may reduce the immune collapse, thymus atrophy and erythrocyte regeneration compensation ability of patients.At this time, the treatment should start with the spleen and kidney, and select the drugs of "supplementing qi,strengthening the spleen and tonifying the kidney"to restore and regulate immunity, such as Huangqi(Astragali Radix), Fangfeng (Saposhnikoviae Radix),Baizhu (Atractylodis Macrocephalae Rhizoma),Danggui (Angelicae Sinensis Radix), Shengma(Cimicifugae Rhizoma), Zhongjiefeng (Sarcandrae Herba), Banlangen (Isatidis Radix), Jixueteng(Spatholobi Caulis), ect.These drugs can not only promote the ability of bone marrow to regenerate red blood cells, but also effectively improve the toughness and permeability of red blood cell membrane and reconstruct the immune function of red blood cells.

The extension period of AIHA should take into account the adjustment and recovery of various physiological states of anemia and decline of erythrocyte function after erythrocyte damage.It mainly includes: Immune function of red blood cells (function of spleen); Genetic expression function of erythrocytes(renal function); Hypoxia and compensation of anemia(Qi deficiency); Liver and kidney damage and acidbase imbalance (dampness and turbidity).It is easy to relapse and recurrent hemolysis in the later stage of the disease.In the recovery period, the method of "supplementing qi, strengthening the spleen and tonifying the kidney" should be used to slow down and consolidate its foundation and prevent recurrence.

To sum up, AIHA should start with yang jaundice in the treatment of acute phase, the treatment theme should be specific, and the therapeutic drug dose should be large.Treatment should focus on "promoting diuresis, removing jaundice, detoxifying and cooling blood".