Handbook of health education for aplastic anemia

A disease articleWhat is the 1 AAIs aplastic anemia, aplastic anemia (referred to as English aplastic anemia, AA). By means of chemical, phy

Content

A disease article

What is the 1 AA

Is aplastic anemia, aplastic anemia (referred to as English aplastic anemia, AA). By means of chemical, physical and biological factors or unknown causes of bone marrow failure, with hyperplasia of bone marrow hematopoietic cells reduce whole blood cells and peripheral blood to reduce the characteristics of bone marrow abnormal cell infiltration and reticular fibers increased, clinical anemia, hemorrhage and infection as the main performance.

AA, can be divided into genetic and acquired aplastic anemia, the former to immunosuppressive therapy ineffective, cure for bone marrow transplantation. The latter also distinguishes between the causes of 70-80% in patients with immune mechanisms related to immunosuppressive therapy. At present, many of them will be AA as organ specific autoimmune disease. Since 1960s 70s began to hematopoietic stem cell transplantation and immunosuppressive therapy, the prognosis of patients with aplastic anemia is improved obviously, and the application of blood product support treatment and the progress of new antibiotics, the majority of patients to treatment and long-term survival.

Aplastic anemia is a rare disease in Europe, the incidence was 2 per million population of Asian countries; aplastic anemia incidence was significantly higher than that in Western countries. The prevalence rate of our country is about 8 / million population, which can be seen in all age and sex groups. Because of China's huge population base, more actual incidence of aplastic anemia.

The etiology and pathogenesis of aplastic anemia 2

Pathogeny:

The genetic abnormalities caused by aplastic anemia, congenital aplastic anemia, such as Fanconi anemia, dyskeratosis congenita, congenital pure red cell aplastic anemia. But most of the patients are acquired, in acquired aplastic anemia, some of them can be found a clear reason: such as physical, chemical and biological factors. Radiotherapy and cytotoxic chemotherapy and other chemical drugs, the virus infection and some diseases can cause aplastic anemia performance. But the majority of patients with no obvious cause, for the idiopathic, is considered to be the body's own immune abnormalities, the attack on their own hematopoietic cells. According to the etiological classification of aplastic anemia is shown in table 1.

Table 1 etiological classification of aplastic anemia

Hereditary aplastic anemia

Fanconi anemia

Congenital keratosis

Schwachman-Diamond syndrome

Acquired aplastic anemia

Secondary aplastic anemia

Drugs and chemicals

Radiation

Virus (EB virus, hepatitis virus, parvovirus and HIV)

Bacteria (Mycobacterium tuberculosis)

Immune disease

Paroxysmal nocturnal hemoglobinuria

gestation

Confounding factors

Idiopathic aplastic anemia

About 70% of all cases

Most anticancer drugs can cause irreversible aplastic anemia in more than a certain dose.

Some of the chemicals and toxins may lead to anemia in some specific populations, many of which have been rarely used in clinical medicine. Common may cause aplastic anemia drugs such as: antipyretic analgesics (such as aspirin, phenacetin, salicylamide etc.) and antiarrhythmic drugs (Rue Queenie Martin, amiodarone), anticonvulsants, antihistamines, antihypertensive drugs (such as captopril, Ca Guido Ba), anti-inflammatory drugs (such as Penicillium sp. amine, phenylbutazone, non steroid drugs, Bloven, etc.), naproxen antibiotics (e.g. two methicillin, streptomycin, B- lactam antibiotics, amphotericin and flucytosine, chloroquine and pyrimethamine, sulfonamide drugs), antiplatelet drugs (ticlopidine) and antithyroid drugs (methimazole, methyl propylthiouracil, propylthiouracil, sedatives, etc.) and its derivatives (chlorpromazine and other phenothiazine), diuretic, hypoglycemic drugs and other drugs (such as allopurinol, interferon Etc).

Some drugs are cytotoxic due to aplastic anemia caused by the pharmacological action, related with drug dosage, as long as up to a certain dose in all individuals can lead to bone marrow hematopoietic function is impaired, predictable, and often is reversible; some trait is unpredictable, and the dosage is, only in individual patients with hematopoietic dysfunction, multi drug allergic reaction, which leads to the hematopoietic failure is generally persistent, rarely spontaneous remission.

Pathogenesis:

The pathogenesis of aplastic anemia is a gradual process of cognition, roughly summarized as the following three aspects:

(1) the reduction in the number of hematopoietic stem cells and the inherent defects, can also be understood as hematopoietic cells in addition to the problem of seed, can not take root, the formation of normal blood cells.

(2) hematopoietic microenvironment supports functional defects, such as the poor state of the soil required for the development of hematopoietic seeds, and does not support the growth of hematopoietic stem cells.

(3) abnormal immune response to hematopoietic stem cells: can be understood as a variety of immune attacks, such as pests impede the growth of hematopoietic stem cells. The majority of patients with aplastic anemia after immunosuppressive therapy after their own hematopoietic function may be improved, allogeneic bone marrow transplantation (bone marrow transplantation, BMT) for the treatment of severe aplastic anemia with immunosuppressive pretreatment to engraftment, these are the abnormal immune response to injury of hematopoietic stem cells in the pathogenesis of providing favorable evidence. Study on Mechanism of immune injury, but also provides a theoretical basis for the clinical treatment of aplastic anemia. Most of the pathogenesis of acquired aplastic anemia, such as.

The clinical manifestations of 3 aplastic anemia

The major clinical manifestations of aplastic anemia, hemorrhage and infection. The severity of clinical manifestations depends on the degree of hemoglobin, white blood cells and platelets, but also with the degree of bone marrow failure and peripheral blood cell reduction.

Bleeding is the most common symptom in patients with aplastic anemia, often resulting in medical treatment. Skin purpura, epistaxis and gingival bleeding were the most common, sometimes the patient may also have oral blood blister. Women of childbearing age can show menorrhagia, prolonged menstruation and irregular vaginal bleeding. AA less take the digestive tract, urinary tract and other visceral hemorrhage early, severe hemorrhage often occurs in patients with infection, glucocorticoid therapy, invasive operation and other clinical manifestations of patients has been quite obvious.

Aplastic anemia symptoms and other disease symptoms of anemia are similar, not a characteristic. Patients with fatigue, dizziness, palpitations, shortness of breath and tinnitus. Anemia is often aggravated, the rate of progression of anemia in patients with different patients can be significantly different, when the patient is more than moderate to severe anemia. A long history of non severe aplastic anemia, sometimes has severe or extremely severe, but patients still living, there is no corresponding clinical symptoms.

In order to infection as the first symptom of aplastic anemia is rare. However, the majority of patients in the course of disease infection, mainly depends on the extent and rate of neutrophil reduction. The most common sites of infection were oral cavity, respiratory system, skin soft tissue and perineal anus. Bacteria are the most common pathogens, including gram negative bacteria, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter Bauman, and so on. In recent years, with the wide application of various kinds of indwelling catheters, gram positive bacteria and Candida infections increased. Agranulocytosis occurred in filamentous fungal infections, especially invasive aspergillosis is not uncommon, and is difficult to treat, is one of the important reasons for the death of patients with aplastic anemia.

In addition, many AA patients lack of obvious clinical symptoms, by routine examination, or other medical check routine found.

Physical examination for patients with aplastic anemia anemia and bleeding signs. Patients usually have no liver, spleen and lymph nodes, without sternal tenderness, except hepatitis associated aplastic anemia also should not appear icteric. If the pancytopenia patients showed these signs, often hint for other diseases and non aplastic anemia.

The 4 type of aplastic anemia

The scholars of our country according to aplastic anemia of bone marrow failure severity and clinical course of progress, the AA type of acute aplastic anemia and chronic aplastic anemia, two types of clinical manifestations were aplastic anemia:

1 acute aplastic anemia or severe aplastic anemia (SAA) feature of acute aplastic anemia of acute onset, rapid progression and short duration, early onset of anemia is not obvious, but with the development of the disease, anemia, progressive, were fatigue, dizziness and palpitations and other symptoms, although after massive blood transfusion is also difficult to improve anemia. Bleeding and infection are often the main symptoms at onset, almost all patients had bleeding, bleeding, in addition to skin and mucous membrane (oral, nasal, gum and conjunctiva) were bleeding, often have deep internal bleeding, such as hematochezia, hematuria, vaginal bleeding, retinal hemorrhage and intracranial hemorrhage, the latter often. And the life of patients. More than half of the cases at the onset of disease that infection is more common, with oropharyngeal infection, pneumonia, skin furuncle, intestinal infection and urinary tract infection. Severe sepsis can occur. Infections often aggravate bleeding, often leading to death.

Laboratory examination of peripheral blood and blood routine examination: must have the following 3 items in 2: reticulocyte < 1%, or the absolute value of < 0.015 * 1012 / L; the white blood cells significantly reduced neutrophil < 0.5 * 109 / L; platelet < 20 x 109 / L. Bone marrow: multi site hyperplasia decreased, three hematopoietic cells decreased, non hematopoietic cells increased, such as proliferation activity must have lymphocytosis; hematopoietic cells and fat cells increased non bone marrow smear in. The peripheral blood neutrophil < 0.2 x 109 / L, called extremely severe aplastic anemia (VSAA).

2 or a common type of chronic aplastic anemia (CAA)

The characteristics of chronic aplastic anemia were slow, slower and longer duration of disease progression. Anemia as the first and main performance, blood transfusion can improve fatigue, dizziness and palpitations and other symptoms of anemia. Bleeding is generally lighter, mostly for the skin and mucous membranes and other surface hemorrhage, deep bleeding is rare. During the course of infection and fever, respiratory tract infections are common, relatively light, easy to control.

Laboratory examination, peripheral blood cell counts were not up to the standard of severe aplastic anemia. Bone marrow: three or two reduced, at least one part of reduced proliferation, such as increasing life leap, erythroid often late erythroid nuclear carbon ratio increased, megakaryocyte decreased; bone marrow smear of fat cells and non hematopoietic cells increased.

Note: some patients with chronic aplastic anemia disease duration may change, clinical symptoms, hemogram and bone marrow with acute aplastic anemia, severe aplastic anemia called type II (SAA II).

Laboratory examination of 5 aplastic anemia

(1) blood showed pancytopenia, a few cases in early stage may be only 1 or 2 cells are decreased. Anemia can be positive cell positive anemia; many patients with MCV in the normal upper limit, or a large cell anemia, but MCV mostly < 110 fl. The absolute value of reticulocyte decreased, acute aplastic anemia reticulocyte ratio is less than 1%. The decrease in the number of white blood cells, including neutropenia especially, acute aplastic anemia were lower than 0.5 * 109 / L. The number of lymphocytes increased and the proportion increased. Only a small number of platelets, and form small, can cause bleeding when prolonged, vascular fragility, clot retraction bad. Acute aplastic anemia platelet was often less than 20 x 109 / L. The number of leukocytes and platelets were decreased in peripheral blood smears, the lymphocytes were mainly in white blood cells, and neutrophils were sometimes seen in the cytoplasm.

(2) immune function detection: including T cell subsets, HLA-DR and other cellular immune function testing, in order to clarify the immune function of patients.

(3) acid sugar test, hemolysis test, cobra venom factor hemolysis test; flow cytometry test in peripheral blood erythrocytes and neutrophils in CD59, CD55, Flaer and granulocyte except for paroxysmal nocturnal hemoglobinuria (PNH) or AA/PNH syndrome.

(4) age < 40 year olds can detect HbF%, peripheral blood cell analysis of chromosome, gene mutation detection of telomerase and telomere length, except Fanconi anemia, dyskeratosis congenita (DKC) hereditary disease of bone marrow failure.

(5) serum folate and vitamin B12 concentrations were measured in order to exclude megaloblastic anemia.

(6) detection of viruses, including hepatitis A virus, hepatitis B virus, hepatitis C virus, EB virus, HIV and CMV, parvovirus B19, etc..

(7) screening of immune markers, excluding immune diseases.

(8) the iron metabolism of aplastic anemia patients if there is blood transfusion dependence, serum transferrin saturation increased, ferritin increased, resulting in bone marrow cells and liver and spleen, heart and other organs of iron and iron increased, iron overload.

(9) bone marrow analysis of bone marrow cell morphology is one of the most important examination of aplastic anemia, carefully analyze the morphology of bone marrow cells, can make a clear diagnosis or provide important clues for most of the blood cells resulted in a decrease in patients with hematological diseases. The bone marrow of patients with aplastic anemia is oily or watery, smooth suction. If the bone marrow stem tip may not smoke aplastic anemia, should pay attention to bone marrow fibrosis and other hematologic malignancies and bone marrow metastases.

Observation of aplastic anemia bone marrow smear visible oil drops increased. Microscopic examination of bone marrow smear empty, hematopoietic cells decreased, a non hematopoietic cell scaffold, non hematopoietic cells often exceeding 50%. AA multiple sites of hypocellular bone marrow (should be checked at least 2 or more parts), three hematopoietic cells decreased, non hematopoietic cells including lymphocytes, plasma cells, mast cells and reticular cells, megakaryocytes markedly reduced or absent. Acute aplastic anemia bone marrow nucleated cells decreased much more significantly, even the bone marrow hyperplasia is severely reduced, remaining cells were lymphocytes and other non hematopoietic cells. Chronic aplastic anemia and acute aplastic anemia bone marrow changes similar to that in most cases a hypocellular bone marrow hematopoietic cells decreased, three, of which the immature red blood cells and megakaryocytes decreased significantly, non hematopoietic cells increased, the proportion of more than 50%. Chronic aplastic anemia may have scattered in the bone marrow hyperplasia lesions, such as puncture in the hyperplasia of bone marrow hyperplasia, active in erythroid compensatory hyperplasia, but mature stagnation in the later stage, due to late erythroblasts by nuclear disorder appear more late erythroid nuclear carbon. Even though active proliferation was active, chronic aplastic anemia bone marrow megakaryocyte number is reduced.

Aplastic anemia bone marrow erythroid cells showed morphological abnormalities, mainly mild megaloblastic change, karyoplasms development imbalance and degenerative changes etc.. AA erythroid development abnormal morphology like in myelodysplastic syndrome as obvious, and without the treatment of Aplastic Anemia Bone Marrow rarely granulocyte and megakaryocyte morphological abnormalities.

(10) all patients with aplastic anemia bone marrow biopsy bone marrow biopsy should be performed to assess the bone marrow biopsy specimen area, should be at least LCM long, were not ideal to be taken again. Bone marrow hypoplasia, white aplastic anemia, mainly for fat cells, lymphocytes and other non hematopoietic cells. The proportion of cells above 50%, and bone marrow stromal edema and hemorrhage. Normal bone marrow hematopoiesis decreased with age, and 80% of the normal children and young people were bone marrow biopsy specimens (60%-100%), but only about 30% of the elderly. Therefore, it is necessary to consider the influence of age on the bone marrow hematopoietic area, especially in children and the elderly. General 30% as the lower limit of bone marrow area of normal adult bone marrow.

(11) the number of CFU-Meg (CFU, GM), erythroid progenitor cells (BFU-E and CFU-E) and megakaryocyte progenitor cells were reduced in the hematopoietic progenitor cells. Part of acute aplastic anemia fibroblast progenitor cells (CFU-F) in chronic aplastic anemia is also reduced, half normal, half reduction.

(12) cytogenetic examination to identify patients with aplastic anemia and hypoplastic myelodysplastic syndrome (MDS). AA rare cytogenetic abnormalities, and MDS cytogenetic abnormalities are more common, if there is the characteristic of cytogenetic abnormalities, such as -Y, +8 or 20q-, MDS suspected consideration.

(13) bone marrow and bone marrow mesenchymal stem cells were labeled with radionuclide bone marrow scan, which could be used to estimate the distribution of hematopoietic tissue and the degree of bone marrow damage. Acute aplastic anemia of normal hematopoietic sites significantly reduced, chronic aplastic anemia of normal hematopoietic sites reduced, often visible local compensatory hematopoietic, blood can be used to evaluate the systemic.

The diagnosis of aplastic anemia and 6 types of standards

Note: the clinical diagnosis of pancytopenia, should be considered in patients with aplastic anemia, a typical case of general diagnosis is not difficult; but not typical cases, such as the early cases, clinical manifestations and laboratory characteristics is not obvious, or with aplastic anemia or overlapping other clinical symptoms, the diagnosis can be difficult.

As with other diseases, the diagnosis of aplastic anemia also need detailed history, careful physical examination and auxiliary examination necessary. The history emphasizes the need for a detailed record of the history of occupational history, chemical and radiological exposure, and the 6 months prior to the onset of the drug. The clinical manifestations of progressive anemia, bleeding and susceptible to infection, such as whole blood cells, liver, spleen and lymph nodes, should consider the possibility of aplastic anemia. Children and young patients with developmental delay, deformity, skin pigmentation, leukoplakia and nail dystrophy, etc., should be suspected of congenital aplastic anemia, including Fanconi anemia and congenital keratosis.

The significance of hematological examination for the diagnosis of this disease is beyond doubt. Peripheral blood should be counted for whole cells, including reticulocyte count. Bone marrow smear and bone marrow biopsy should be the most important basis for the diagnosis of this disease. In patients with clinical suspicion of aplastic anemia and atypical bone marrow examination, multiple site puncture and biopsy should be performed.

In addition, liver function, virological examination, serum folic acid and vitamin B, as well as autoantibodies were examined. Flow cytometric detection of paroxysmal nocturnal hemoglobinuria (PNH) and small clone, peripheral blood and bone marrow cytogenetic detection is helpful to diagnose aplastic anemia, the exclusion of other clinical and laboratory manifestations of similar diseases. Children and young people under 35 years of age should be routinely tested for chromosomal fragility in addition to Fanconi anemia.

The AA diagnosis standard of our country, the specific contents are as follows:

1 whole blood cells reduced, reticulocyte absolute value decreased;

2 no splenomegaly;

3 at least one site of bone marrow hyperplasia or severe reduction;

4 except can cause pancytopenia diseases, such as paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome and acute aplastic crisis, bone marrow fibrosis, acute leukemia and malignant histiocytosis;

5 general anti anemia drug treatment ineffective.

The diagnosis of aplastic anemia can be divided into two types, refer to the following standards:

Severe aplastic anemia (SAA), also known as severe aplastic anemia type I (SAA I)

A. bone marrow cell proliferation degree < normal 25%; such as < normal of 50%, then the hematopoietic cells should be < 30%;

B. meets at least 2 of the following 3 items:

(1) neutrophil < * * 109 / L ();

(2) platelet < * * 109 / (L);

(3) reticulocyte < * * 109 / L ().

Severe aplastic anemia (VSAA): SAA; < 0.2 * 109/L.

Non severe aplastic anemia (NSAA): VSAA does not comply with SAA, nor is it associated with aplastic anemia

In the course of non severe aplastic anemia as the condition changes, clinical manifestations, blood and bone marrow with severe aplastic anemia, severe aplastic anemia called type II (SAA II).

7 differential diagnosis of aplastic anemia

Should be identified with the following diseases.

(1) AA of paroxysmal nocturnal hemoglobinuria (PNH) is more difficult to distinguish from paroxysmal nocturnal hemoglobinuria. But the disease is bleeding and infection were less and lighter, reticulocyte absolute value is greater than normal, active bone marrow hyperplasia, young red blood cell proliferation obviously contained hemosiderin positive urine test (Ruos), acidified serum hemolysis test (Ham) and venom (CoF) test positive, flow cytometry GPI anchored proteins detection can rapidly and accurately distinguish the two.

(2) myelodysplastic syndrome (MDS) AA and MDS refractory anemia (RA) is difficult to distinguish. However, the disease is characterized by abnormal hematopoiesis. The peripheral blood often shows the uneven size of red blood cells, and it is easy to see the huge red blood cells and nucleated red blood cells and monocytes. Bone marrow hyperplasia more energetic 2 lines or 3 lines of hematopoiesis, megaloblastic and multinucleated red blood cell is common, the fine grain increased, nuclear growth is not balanced, visible nuclear anomalies or hypersegmentation. A lot of megakaryocytes, lymphoid micromegakaryocyte rare group showed nucleated red blood cell glycogen (PAS) positive ring sideroblast increased, little giant ribozyme labeled positive. Further, it can be identified by bone marrow biopsy, leukemia progenitor cell culture (CFU-L), chromosome and oncogene.

(3) acute hematopoietic dysfunction is often caused by infection and drugs. Onset of high fever, anemia, rapid progression, misdiagnosed as acute aplastic anemia. The following characteristics of acute aplastic crisis is helpful to differentiate the anemia, reticulocyte is 0, with neutropenia, thrombocytopenia but is not obvious, less bleeding; bone marrow hyperplasia active, 2 lines or 3 lines to reduce, but to reduce the red line, the end is visible large primitive red blood cells; the disease is self limiting, without special treatment, 2-6 weeks of recovery; the serum copper increased, erythrocyte Cu decreased.

(4) bone marrow fibrosis (MF) patients often have chronic splenomegaly, peripheral blood immature granulocytes and nucleated red blood cells, bone marrow puncture repeatedly dry pumping, bone marrow biopsy showed that collagen fiber and reticular fiber hyperplasia (or).

(5) acute leukemia (AL) especially hypoplastic acute leukemia is chronic, liver, spleen and lymph nodes, peripheral blood cytopenia, hypocellular bone marrow, easy to confuse with aplastic anemia. We should carefully observe the blood and bone marrow in multiple sites, can be found in the original single grain, or the original lymphocytes increased significantly. Bone marrow biopsy is also helpful in the diagnosis.

(6) malignant lymphoma is often accompanied by non infectious fever, progressive failure, liver, spleen and lymph nodes, Huang Juhe hemorrhage is heavy, can also significantly reduce peripheral whole blood cells, bone marrow cell proliferation decreased, often with hemophagocytic phenomenon. Careful examination, multi site bone marrow examination and lymphocyte immunophenotype detection, as well as immunoglobulin heavy chain gene rearrangement / T cell receptor gene rearrangement detection, often contribute to the diagnosis of lymphoma.

(7) other diseases, such as hairy cell leukemia, childhood acute lymphoblastic leukemia (AML), prolonged starvation and anorexia, tuberculosis, bone marrow metastasis, and hypersplenism.

Harm 8 aplastic anemia

Aplastic anemia is due to human bone marrow hematopoietic function failure occurs after the blood disease. It is a great threat to our health.

Aplastic anemia can cause bleeding in patients. In patients with aplastic anemia and thrombocytopenia caused by bleeding is often the main reason for treatment of patients, but also aplastic anemia disease, manifested as skin petechiae and ecchymosis, bleeding gums and nose bleeding, can appear menorrhagia and irregular vaginal bleeding in young women. Do not underestimate the bleeding of patients with aplastic anemia, severe visceral bleeding, such as urinary tract, digestive tract, respiratory tract and central nervous bleeding rare, and more in the late course of the disease. Patients with severe nasal bleeding, unclear objects, headache, nausea and vomiting, often fatal intracranial hemorrhage precursor manifestations, clinical attention should be fully. Not timely medical treatment, it will often deprive the life of patients with aplastic anemia.

Anemia is one of the hazards of aplastic anemia. Red blood cells to reduce anemia often occur gradually, in patients with fatigue, palpitations, shortness of breath, after dizziness, tinnitus and other symptoms. A small number of patients with anemia due to the ability to adapt to a strong, symptoms can be mild and severe anemia associated with heart disease.

You can also merge aplastic anemia in patients with severe infection, especially in patients with re. The infection can be a variety of common bacteria, fungi, viruses and various rare opportunistic infection, leading to serious illness; moreover, aplastic anemia patients often on the curative effect of various antibiotics is poor, or become chronic infections. Serious infection is often a major cause of death in patients with aplastic anemia.

Thus, aplastic anemia is indeed very dangerous, we have to objectively look at the risk of aplastic anemia. Aplastic anemia due to the risk of large, timely treatment of aplastic anemia is particularly important, the clinical treatment of aplastic anemia in many ways, the effect of the treatment of the disease are good.

Treatment articles

The treatment of aplastic anemia can be divided into supportive treatment and targeted treatment of two diseases. Support the purpose of treatment is to prevent and cure hematocytopenia related complications; target therapy improve the damaged hematopoietic stem cells from the root, the disease itself, such as allogeneic hematopoietic stem cell transplantation (allo-SCT) or immunosuppressive therapy (IST), the remnants of the normal or impaired recovery of hematopoietic stem cells.

AA rare self-healing, once diagnosed, should be clear about the severity of the disease, make the appropriate measures in the professional center for disease treatment carried out as soon as possible. A new diagnosis of aplastic anemia patients, if there is a standard therapy for severe aplastic anemia, HLA matched sibling donor allogeneic bone marrow transplantation, or a combination of antithymocyte globulin (ATG) and cyclosporin (cyclosporin A, CsA (immunosuppressive) treatment inhibited the immune therapy, IST). In recent years, severe aplastic anemia HLA matched unrelated donor transplantation has made considerable progress, can be used for invalid ATG and CsA treatment of young patients with severe aplastic anemia.

Bone marrow transplantation or IST must be controlled for bleeding and infection, and the risk of bone marrow transplantation or IST is high in cases of infection or uncontrolled bleeding. Infection is a common cause of death due to aplastic anemia, aplastic anemia and neutropenia in the short term is difficult to recover, with active infections, such as pulmonary infection, bone marrow transplantation or IST can provide patients with hematopoietic stem / progenitor cells, or correct the abnormal immunity, so as to win the chance to recover the aplastic anemia patients hematopoietic. Delayed transplantation aggravates lung infection.

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Infection prevention should pay attention to diet and environmental health, severe aplastic anemia protective isolation; avoid bleeding, prevent injury and violent activities; prevent exposure to risk factors, including damage effect and inhibition of platelet function of drugs on bone marrow; the necessary psychological care.

Patients with aplastic anemia can occur in bacteria, viruses and fungi infection. Patients with severe aplastic anemia due to severe and prolonged neutropenia, Aspergillus infection can be fatal. For neutrophils < 0.2 * 109/L need to prevent the use of antibiotics and antifungal drugs and pay attention to diet to avoid bacterial and fungal contamination. It is difficult to determine the advantages and disadvantages of prophylactic use of 109/L in neutrophils (0.2-0.5) patients.

Patients with severe aplastic anemia should be admitted to the hospital were being singled out, conditions can use laminar flow ward. Regular oral nursing; prophylactic application of antibiotics and antifungal drugs; transplantation of aplastic anemia patients should be preventive antiviral and prophylactic anti Pneumocystis treatment such as SMZco.

Actively communicate with the patients with aplastic anemia, and their family and friends to provide psychological support. Because after chronic aplastic anemia, and slow response to treatment is easy to cause the pressure to the patients in the early stage of the disease. The recovery of the disease for more than 6 months, should explain to patients and their families can sometimes recover is one year or longer, delayed recovery is not uncommon, encourage patients to adhere to treatment, can not give up or free to switch to other drugs are not suitable for the method.

2 symptomatic treatment

Transfusion of blood products:

Aplastic anemia patients with infusion of red blood cells and platelets are essential for maintaining the blood cell count. Blood transfusion can improve the symptoms of anemia in patients, alleviate the lack of oxygen is appropriate, no need to correct the hemoglobin level. General at Hb< 60g/L infusion, or accompanied by intolerance of anemia symptoms. The elderly (> 65), compensatory response capacity is limited (such as with heart and lung diseases), oxygen demand (such as infection, fever, pain, etc.), lack of oxygen supply increased (such as bleeding, pneumonia), these conditions can be relaxed without transfusion threshold, Hb< 60g/L. As far as possible infusion of red blood cells, white blood cells even in patients with aplastic anemia or / and reduced platelet count, the anemia should lose red cell concentration, rather than whole blood transfusion. There is a risk of heart failure, control infusion speed, 2 to 4 hours to be given to the 1 units of red blood cells (preferably concentrated red blood cells), may be appropriate to diuretics. Patients undergoing allogeneic hematopoietic stem cell transplantation should be irradiated with red blood cells and platelets.

Suggested the presence of platelet consumption risk factors such as infection, hemorrhage, or the use of antithymocyte globulin / anti lymphocyte immunoglobulin (ATG/ALG) can be in platelet < 20 * 109/L platelet transfusion, active bleeding may develop bleeding should be concentrated platelet infusion. Severe bleeding has occurred, such as gastrointestinal bleeding, hematuria, or accompanied by headache, vomiting, elevated intracranial pressure symptoms, suspected intracranial hemorrhage, immediate infusion of apheresis or platelet concentrate.

Where possible, should try to reduce blood transfusion, blood transfusion and blood transfusion to avoid prolonged interval, hemochromatosis. In order to reduce the risk of allogeneic and transfusion transmitted diseases, it is recommended to remove the red blood cells and platelets. The production of anti platelet antibodies, resulting in ineffective infusion should be transfused HLA matched platelet. The direct supply of blood and platelets between members of the family can be sensitized to the recipient, and the risk of graft rejection is significantly higher in the family members of the hematopoietic stem cell donor. However, patients with a variety of HLA antibodies and the urgent need for platelets, and a family member can provide the most consistent platelet, can be used as an exception to emergency infusion.

Prevention of bleeding in addition to the infusion of platelets, the use of oral hygiene, oral hemostatic drugs, hormonal control of menstruation and other measures, but also help. There is still no evidence of evidence-based medicine in the treatment of irradiated blood products during and after ATG treatment.

For patients with agranulocytosis can be injected into the lives of patients with white blood cells, but the side effects, there is little clinical use. Granulocyte transfusion indications: neutrophil duration < 0.5 * 10^9/L, can not control bacterial and fungal infection or with the broad-spectrum antibiotics and antifungal therapy are still no signs of clinical infection in patients with bone marrow myeloid cells, low proliferation. Granulocyte half-life (6 ~ 8 hours), continuous infusion, usually for 5 to 7 days. Granulocyte transfusion in the infectious foci distribution is more, better effect, it should ensure sufficient quantity. White blood cell transfusion related complications such as fever, HLA immune response and transfusion related lung injury should be paid attention to and prevented.

Long term blood transfusion leads to serum ferritin level more than 1000 g/L should be given iron therapy.

Treat infection

AA fever patients need hospital treatment immediately, should be in accordance with the principles of treatment of neutropenic fever treated patients. Patients with fever should be examined in the lungs and sinuses, including X-rays and CT scans. Fungal infections are common in lung and sinus infections.

General antibiotics recommend the use of broad-spectrum antibiotics, such as beta lactam antibiotics + aminoglycosides, after the results of culture, according to the drug sensitivity and then select the appropriate antibiotics. The choice of drug should also refer to the history of infection and antibiotic use.

Patients with persistent fever were treated with systemic antifungal therapy. Aplastic anemia patients with neutropenia for a long time, once the Aspergillus infection is difficult to cure. A diagnosis of fungal infection should be systemic use of first-line antifungal drugs, suspected fungal infections, or previous history of systemic fungal infection should be used first-line antifungal drugs. Immunosuppressive treatment in a timely manner to improve the patient's white blood cell count, is effective in reducing infection in patients with aplastic anemia means.

3 hematopoietic factor therapy

In the use of immunosuppressive therapy or bone marrow transplantation, combined with G-CSF 5 g/kg/d subcutaneous injection, may stimulate the bone marrow in residual granulocyte or granulocyte function, especially when combined with infection, can accelerate neutrophil recovery, but not too much impact on the long-term prognosis of patients.

Other stimulating factors such as erythropoietin (EPO) and platelet growth factor IL-11 or TPO promote megakaryocyte and platelet function of growth remains to be confirmed in patients with aplastic anemia. Patients with conditions may be used as appropriate.

4 immunosuppressive therapy (immunosuppressive therapy, IST)

Severe aplastic anemia should provide the necessary security in being able to have experience in the use of the ATG medical staff, including the ability to recognize and deal with the adverse reaction of ATG hospital.

ATG CsA combined with severe aplastic anemia IST efficiency in 60%-80%, the 5 year survival rate is about 75%-85%, in patients with severe aplastic anemia with ATG alone, CsA's disease free survival and the effective rate was significantly lower than that of ATG combined with CsA, CsA can be used to separate light aplastic anemia patients. ATG combined with CsA more than 3-4 months after the onset. We should continue to use CsA as effective after 2-3 years, slow reduction, reduction of excessive lead to disease recurrence. There are reports of aplastic anemia patients after IST may be delayed clonal disease, including PNH, MDS, AML, solid tumor.

IST treatment of ATG combined with CsA for: (1) blood transfusion dependent light AA patients; (2) non transfusion dependent light AA patients, agranulocytosis is at risk of infection; (3) severe aplastic anemia.

Non transfusion dependent and blood cell count in the safe range of the light of aplastic anemia aplastic anemia patients, can choose CsA treatment.

IST use method

ATG is a potent immunosuppressant, antiplatelet activity, aplastic anemia patients with ATG require close monitoring, active prevention and treatment of fever and infection, to ensure adequate platelet count, generally in more than 20 * 109/L.

At present, the domestic market for the treatment of aplastic anemia ATG are: pig ALG, at a dose of 20-30mg/kg/d; rabbit ATG (Thymoglobuline, Genzyme), at a dose of 2.5-3.5mg/kg/d.

ATG/ALG need to be applied for 5 days, every day by intravenous infusion 12-18 hours. First, ATG or ALG 25mg was added to 100ml saline for intravenous infusion of > in rabbits, 1 hours after intravenous administration of 2.5mg, to observe whether there was a severe systemic reaction or allergic reaction, and the patients could not be transfused. Pig ATG standing with skin test medication, but more positive, rabbit ATG without skin test.

Each time 30 minutes before ATG/ALG, intravenous corticosteroids and oral antihistamines. The daily application of glucocorticoid to total prednisone 1mg/kg/d conversion for methylprednisolone, dexamethasone or hydrocortisone, through another vein passage and ATG/ALG synchronous infusion. Acute side effects include hypersensitivity, fever, stiff, rash, hypertension or hypotension and fluid retention. Patients should be prepared by the side of the trachea incision kits, epinephrine.

During the treatment, the platelet count should be maintained at > 20 * 109/L, the platelet number should be guaranteed before ATG/ALG, and platelet transfusion should not be taken at the same time as ATG/ALG.

Serum disease usually occurs seventh to 30 days after ATG treatment. Therefore, glucocorticoids sufficient to 21 days, followed by reduction in the end of the week after 2. The serum of patients, symptoms include joint pain, rash, myalgia, mild proteinuria and thrombocytopenia, while intravenous corticosteroid therapy, the total daily dose of prednisone was given to the 1mg/kg/d conversion of hydrocortisone or methylprednisolone, adjust the hormone dosage and course of treatment according to the patient's condition.

CsA oral 3-5mg/kg/d, can be combined with ATG/ALG treatment, start with, or after the use of corticosteroids, ATG 4 weeks after the use of. CsA general target plasma concentration (Valley concentration) is 150-250 mu g/L. The blood concentration of CsA in the treatment of aplastic anemia is not clear, the treatment concentration window is relatively large, the need for individual adjustment of concentration, both efficacy and adverse drug reaction. CsA reduction too fast will increase the risk of recurrence, the general recommendation of the efficacy of up to 12 months after the end of the continuous medication for a period of time, and then slowly reduce the drug, the monthly reduction of not more than 10%. Blood pressure, liver and kidney function should be regularly detected during CsA.

The first time ATG treatment is invalid or relapse patients recommend second times with ATG treatment. The two interval should not be less than 3 months, preferably for 6 months, because most patients 3-6 months or so to show efficacy. Good effect of previous treatment, treatment again the majority still sensitive, but the effect of poor treatment may not work again. Second courses of ATG/ALG, the general choice of another animal source of ATG/ALG, to reduce the incidence of allergic reactions and serum disease.

Application of IST in elderly patients

ATG/ALG treatment for aplastic anemia is no age limit, but to assess the complications of treatment in elderly patients with aplastic anemia, excluding low proliferative MDS. Elderly patients with aplastic anemia treated with ATG increased bleeding, infection and the risk of cardiovascular events, need evaluation of circulatory failure, liver toxicity, high blood lipids, irreversible impairment of glucose tolerance and prostate damage and other problems. CsA treatment in view of the risk of nephrotoxicity and hypertension, it is recommended that the plasma concentration of 100-150 g/L. Plus androgen for elderly patients will have some help. The best supportive treatment should be given to elderly patients who are not suitable for IST therapy.

Curative effect judgment

Because it is difficult to compare the efficiency, so there is no recognized criteria for the efficacy of immunosuppressive therapy. The new evaluation standard recently approved by the Committee of experts should evaluate the curative effect of aplastic anemia, there is no use of hematopoietic growth factors in patients with two or more times the blood cell count 4 weeks at least.

The ATG follow-up after treatment

Accept ATG/ALG and CsA treated patients should be closely followed up regularly to check blood routine found recurrence or evolution of clonal diseases such as PNH, MDS and AML. PNH should be screened for 3-4 months after ATG treatment. Further examination should be done if the blood cell count and blood smears indicate recurrence or other abnormalities. A careful examination of the blood film helps to find MDS. PNH screening is recommended for all patients. Aplastic anemia patients should be followed up regularly, understand whether recurrence or evolution of clonal diseases such as MDS, PNH, leukemia and solid tumors.

5 allogeneic hematopoietic stem cell transplantation

Newly diagnosed patients with aplastic anemia preferred sibling allogeneic bone marrow transplantation should meet the following conditions: (1) severe or very severe aplastic anemia patients; or non transfusion dependent patients with severe aplastic anemia (2) age < 40; (3) HLA identical sibling donors.

About 75%-90% long term survival in severe aplastic anemia sibling matched bone marrow transplantation after treatment. With cyclophosphamide and ATG pretreatment, implantation failure rate was about 4%-14%. Although acute graft versus host disease (aGVHD) is rare, chronic GVHD is up to 30%-40%, which is the main problem affecting the quality of life of patients.

HLA matched sibling bone marrow transplantation for severe aplastic anemia is the age limit is still controversial, over the age of 40 in severe aplastic anemia, the failure of ATG combined with CsA after treatment with HLA matched sibling bone marrow transplantation, transplantation due to increased risk, proposed in the experience of the center.

Recommend the use of bone marrow stem cells and peripheral blood stem cells G-CSF mobilization, peripheral blood stem cell transplantation in young patients are more susceptible to chronic GVHD, the survival rate was significantly lower than bone marrow stem cell transplantation. Children get sibling donor bone marrow stem cells compared with peripheral blood stem cells more easily, and can avoid the application of G-CSF. The reinfusion of cells suggests at least 3 * 108 mononuclear cells /kg, CD34+ cells of at least 3 x 106/kg.

The impact of gender has recently been a large retrospective study evaluated, donor and recipient gender consistent survival rate of donor sex mismatch increased, male recipients of female donor serious risk of GVHD increased, while the female recipient male donor is an increased risk of graft rejection. Pretreatment with ATG helps to eliminate the negative effects of gender inconsistency between donor and recipient.

Umbilical cord blood transplantation is associated with lower risk of acute and chronic GVHD compared with bone marrow transplantation. Umbilical cord blood transplantation can also be considered for children without HLA matched sibling donors or unrelated donors. Adult patients with aplastic anemia is currently on trial double cord blood transplant, the main problem facing the implant failure.

Unrelated donor bone marrow transplantation

Patients who meet the following criteria may consider unrelated donor bone marrow transplantation:

A has a complete match (class I and class II antigens) at the DNA level

B age < 50 years of age (50-60 years old, must be in good condition)

C severe or very severe aplastic anemia patients

D does not have a HLA matched sibling donor

E failed at least once in combination with ATG/ALG and CsA

There was no active infection or bleeding during f bone marrow transplantation

Regardless of whether the donor bone marrow transplant or the second ATG/ALG treatment was given to the patient, the need for careful consideration, especially in patients with mild clinical signs. The bone marrow is nearly 5-10 years matched unrelated donor transplantation treatment of acquired aplastic anemia have significantly improved, unrelated donor bone marrow transplantation can no longer serve as the final remedy invalid two course of treatment of ATG/ALG. Application of continuous ATG/ALG therapy, infection and sepsis, Tie Chao caused by overload of the patient's general condition continued to deteriorate, resulting in the decrease in the rate of successful transplantation. In view of the special risk of AA unrelated donor bone marrow transplantation, the need for transplantation in experience center.

6 reasonable treatment options

(1) general aplastic anemia (non-SAA)

The detection of peripheral blood regularly, when blood phase changes affect the quality of life, treatment of aplastic anemia can be started. The treatment of chronic aplastic anemia including general supportive treatment, androgen + CsA, when the illness in treatment of severe aplastic anemia. Usage as follows:

A. stanozolol (winstrol):2mg TID or 40mg TID eleven acid testosterone, effective maintenance treatment reduced gradually for about 2 years. Monitoring of liver and kidney function.

B. cyclosporin A:3-5mg/kg/d, divided into two times (q12h is appropriate) oral, monitoring the valley of blood concentration, with a concentration of 150 G-250 g/L is appropriate. Course of 2 years, the gradual reduction of effective maintenance. Monitoring of liver and kidney function during drug use, as appropriate to stop the drug.

If the disease progresses to blood transfusion infusion or SAA infection or SAA, depending on the treatment.

(2) severe aplastic anemia (SAA)

Allogeneic bone marrow transplantation should be SAA and early HLA matched sibling donor (Allo-BMT) or ATG/ALG+CsA.

Age < 40 years old, with HLA matched sibling donor, can choose HLA Allo-BMT, otherwise you can choose CSA+ATG/ALG.

Age > 40, timely strengthening of IST (CSA+ATG/ALG); such as 6 months without treatment response, can be considered the second ATG/ALG (may be considered for a different species of ATG) treatment, or at the same time finding HLA matched sibling donors, unrelated or haploidentical donors have the condition can be considered as allo-BMT; the second ATG/ALG treatment is still no reaction, can be considered unrelated or haploidentical Allo-BMT or other clinical trials, treatment of maintenance or support.

7 common adverse drug reactions and treatment

(1) androgen:

Effects: male hormones are often slow onset, long course of treatment, remission rate is related to the length of treatment, medication 3 months remission rate at 35%-53%, 6 months up to 45% -60%. Medication alone can appear incomplete recovery after treatment, there are 25%-50% of patients with curative effect to relapse after withdrawal, but relapse after medication is still effective. Part of the patients with male hormone dependence, drug resistance. The main male hormone for chronic aplastic anemia, when the hematopoietic micro environment is perfect, there are residual hematopoietic cells has significant effect.

Adverse reactions: the male reproductive system and its effect on the patients with aplastic anemia, such as female hair increased, amenorrhea, clitoral hypertrophy, thick and scratchy, voice of breast reduction in childhood; long-term use can lead to female male. Liver damage, jaundice, transaminase and alkaline phosphatase. So in the process of treatment and regularly check liver function, the liver damage. Other, such as sodium retention, edema, etc., can be symptomatic treatment. The adverse effects of androgen were generally mild.

(2) cyclosporin A:

There are two dosage forms of oral administration of intravenous drugs. Including cyclosporine nephrotoxicity: common adverse reactions: about 1/3 patients have renal toxicity can occur, serum creatinine and urea nitrogen increased, reduced glomerular filtration rate and renal function impairment; hepatic toxicity: hypoproteinemia and hyperbilirubinemia, serum transaminase increased; the nervous system: exercise-induced spinal cord syndrome. Tremor, abnormal sensation, is rare; the gastrointestinal tract: anorexia, nausea, vomiting, and hypertension; hirsutism; the gingival bleeding and pain associated with health promotion, increase students generally disappear in the gum 6 months after drug withdrawal. The intravenous administration showed occasional acute allergic reaction. In the event of an immediate withdrawal of the drug, the patient should be given epinephrine and oxygen.

The blood concentration of the drug should be monitored regularly to maintain the appropriate concentration of the drug, such as adverse reactions should be immediately given the appropriate treatment, and reduce the amount of drugs or disable.

(3) ATG/ALG:

For the intravenous formulation, including common side effects: the allergic reaction: the performance of chills, fever, tachycardia, vomiting and breathing difficulties. Rare delayed allergic reaction, such as the first time after 7-21 days, serum sickness may occur (fever, itching, rash accompanied by joint pain). Immediate severe allergic reactions are extremely rare. The most common and serious adverse events occurred after the first infusion. The use of cortisol and antihistamines in the prevention and treatment of slow down or increase the amount of diluent (isotonic 0.9% saline or 5% glucose solution) can reduce or reduce the occurrence of side effects. The blood phase: a short-term decline in patients during the use of Rabbit anti thymocyte globulin and after the occurrence and adverse reaction reports generated by the antibody, including neutrophil cross reaction resulted in a decrease and the decrease of platelet. Such reactions may occur at the first 2 days of treatment or after treatment. White blood cell and platelet counts were monitored, and symptomatic treatment could reduce the incidence and severity of these side effects. The infection: during the use of Rabbit anti thymocyte globulin and after the occurrence and immune excessive inhibition toxicities, including infectious complications (bacteria, fungi, viruses and protozoa), can carry out the corresponding anti infection treatment. The long-term side effects: a rare malignant disease (especially lymphocyte hyperplasia) reports, often appear in allogeneic transplant patients, should be particularly cautious early collaborative use of immunosuppressive therapy will be excessive immune suppression caused. The damage of liver function: low incidence of symptomatic treatment. The local side reaction at the local pain and peripheral infusion thrombophlebitis report.

8 prevention of aplastic anemia

Most of aplastic anemia etiology is not clear, it is very difficult to prevent. For those who are sensitive to physical fitness, try to avoid the use of suspicious drugs, to avoid exposure to adverse factors in the environment, such as air pollution, over fitting, a variety of toxic chemicals, radiation, etc..

If you have a diagnosis of aplastic anemia, should carry out the following precautions: prevention of bleeding: to prevent bleeding, to prohibit the use of toothbrush bristles, a toothpick, eating slowly, avoid oral mucosa and gingival damage. The prevention of nasal mucosa dry, protect the oil when necessary, prohibit digging nostril, so as not to damage the nasal mucosa, causing bleeding. Pay attention to the color of urine, female patients pay attention to menstrual volume and time. If you have a headache, dizziness, nausea, etc., should be timely to the hospital for treatment. Prevention of infection: the winter cold is easy to cause infection, so in life to keep warm, timely change clothes, avoid cold. Personal hygiene must do a good job, we must keep the skin clean, develop the habit of taking a bath, changing clothes, cut nails, and then try to use a sterile or less bacterial diet. Drug abuse is prohibited: in the life of long-term abuse of some drugs may have a serious impact on their own hematopoietic system, leading to the occurrence of the disease. Therefore, in daily life, we must make reasonable use of drugs that may affect the hematopoietic system, and try to avoid. If the situation must be taken, must be under the guidance of a doctor medication, do not blindly medication. Life prevention: diet to avoid spicy, stimulating, cold, excellent food. Easy to eat light digestible food rich in vitamins. Daily care: regular daily life, emotional stability, appropriate activities, to avoid fatigue. Avoid exposure to harmful substances, radiation and the use of drugs affecting the bone marrow. Anemia, bleeding heavier, to bed rest, reduce activity, if necessary, hospitalization.

Rehabilitation articles

1 home care & Life Guide

First of all to maintain health and clean living environment, especially to carry out strict disinfection linens, timing window ventilation, maintain indoor ventilation. Pay attention to personal hygiene, mouthwash after meals to prevent pharyngeal ulcer. Usually according to the change of weather pay attention to add and subtract clothing; avoid contact with cold, hepatitis and other infectious diseases of patients, as far as possible do not go to the large flow of public places. Avoid traumatic bleeding, bleeding gums, skin, mucous membrane bleeding, etc., should be carried out according to the appropriate treatment of bleeding, gastrointestinal bleeding occurs or the risk of intracranial hemorrhage, should be timely treatment. Eat more nutritious, easy to digest and clean food. Patients and relatives should actively cooperate with the doctor, the patient should maintain peace of mind, spirit of optimism, in ensuring the rest and does not affect the recovery of the disease under the premise of reasonable arrangement of life, relatives to give enough care and care. Regularly to the hospital for examination and treatment, according to the doctor's medication.

2 maintain a reasonable diet

AA diet has no special requirements, adjusted according to personal taste. But the general requirements for clean food, nutritious, easy to digest food. Food to avoid excessive stimulation, too hard, resulting in oral or esophageal injury, resulting in ulcers or infection. If you are allergic to certain foods, try to avoid them.

3 adhere to treatment and regular review

IST is effective in the treatment of aplastic anemia, mostly in the 1 months later showed hematologic response, some slower reaction, up to six months or longer, should help patients establish confidence, treatment is not smooth, also should be timely communication with the patient, the doctor. When the treatment is effective, it is necessary to carry out the maintenance treatment of cyclosporine, which can lead to the recurrence of the disease.

Aplastic anemia can occur in patients with various changes in the course of the disease; at the same time, has certain side effects of various drugs in treating aplastic anemia, cyclosporine concentration also need regular inspection, to ensure the exact efficacy and acceptable side-effects; some patients may appear late complications, such as paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome acute leukemia, therefore, should be regularly reviewed.

4 moderate exercise

Patients with acute aplastic anemia is severe, platelets and white blood cells is very low, excessive activity will lead to increased risk of bleeding and infection, therefore, should pay attention to rest, avoid excessive activity. Chronic aplastic anemia or acute aplastic anemia patients, if the blood is acceptable, appropriate activities to the body can be accepted as appropriate, not reluctantly. After the complete recovery of blood, and then increase the intensity of exercise.

 

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