Pure red cell aplasia (PRCA) is anemia caused by a significant reduction or absence of red blood cells in the bone marrow, characterized by an orthocytic anemia with reticulocytopenia and an extreme reduction or absence of red precursor cells in the bone marrow. In the past, PRCA has been associated with erythroblast hypoplasia, erythroblastopenia, red cell agenesis, hypoplastic anemia, and aregenerative anemia. In 1922, Kaznelson, a foreign scholar, first described PRCA and separated it from aplastic anemia. Despite its low incidence, PRCA has attracted much attention because its pathogenesis is related to immune mechanisms. PRCA can be divided into two types: hereditary and acquired. Hereditary PRCA (Diamond-Blackfan anemia) develops mostly within the first year of life and is autosomal dominant in one-third of cases. 75% of patients are effectively treated with glucocorticoids, and allogeneic hematopoietic stem cell transplantation is feasible for those who fail. The latter can be secondary to microvirus B19 infection, large granular lymphocytic leukemia (LGLL), other lymphoproliferative disorders, thymoma, autoimmune diseases, post-hematopoietic stem cell transplantation, anti-erythropoietin antibodies, use of certain damaging drugs, etc. PRCA is classified as primary or secondary. PRCA can also be divided into acute and chronic according to the course of the disease, with acute cases being more common in children and showing a self-limiting course, and chronic cases being more common in adults. Due to different etiologies, the clinical manifestations of PRCA are highly heterogeneous, so the choice of treatment plan should be determined according to its pathogenesis. I. Etiology and pathogenesis: (a) Microvirus B19-associated PRCA: Parvovirus is the smallest DNA virus, containing a single-stranded DNA genome with tissue tropism. The blood group P antigen (erythrocyte glycosylate) is the main receptor for viral entry into cells and viral replication is restricted to erythroid progenitor cells [1]. In vivo and in vitro studies have found that this virus lyses target cells and terminates erythropoiesis. It is possible that erythropoietic failure is the only manifestation of microvirus B19 infection. The response is normally terminated by humoral immunity 1-2 weeks after infection with the virus. In immunodeficient hosts such as organ transplant recipients, HIV-infected or post-chemotherapy patients, the viral infection persists due to the lack of specific antibodies and results in the development of pure red reperfusion [2]. Infection with PV-B19 in non-immunodeficient populations can cause infectious erythema in children, hemolytic anemia remittent crisis, and stillbirth during pregnancy. (ii) T-cell and NK cell-mediated PRCA: It was found that abnormal proliferation of large granular lymphocytes (LGLs) is closely associated with PRCA. LGLs can be divided into two types: T-cell type and NK-cell type. t-LGLs express CD3 and αβTCR (a few are γδTCR); NK-LGLs Most are chronic lymphoproliferative disorders, CD3-negative and do not express TCRs. LGLs can trigger lysis of young erythrocytes by (1) recognition of an unknown ligand expressed on erythroid progenitors via the T cell receptor (TCR) [3]. (2) Binding to FcR (i.e., CD16 molecule) on the membrane surface of LGLs via antibodies against erythroid progenitor cells [4]. (3) “Loss of inhibition” mechanism due to reduced expression of HLA-I-like molecules in target cells. Due to the reduced or absent expression of MHC class I molecules in erythroid progenitor cells (CFU-E), they are recognized and lysed by their own NK cells [5]. This type of PRCA often occurs in patients with γδT-LGL proliferative disease. (iii) Antibody-dependent PRCA: Krantz et al. first reported that plasma from PRCA patients could inhibit hemoglobin synthesis in their own bone marrow cells in vitro. Anti-EPO antibody-associated sera from PRCA patients also inhibit the growth of red lineage progenitor cells in vitro [6]. Although PRCA can be caused by anti-endogenous EPO autoantibodies, it rarely occurs in patients who have never been treated with recombinant human EPO. The occurrence of recombinant human EPO-associated PRCA has been reported to be mainly related to dosage form changes, followed by rare conditions such as uncoated rubber plugs of the product and subcutaneous administration [7]. Antibody-dependent PRCA can also occur in patients undergoing allogeneic HSCT. Delayed hemolysis and PRCA have been reported to occur in HSCT patients receiving ABO blood group incompatible donors, possibly due to the reaction of allogeneic hemagglutinin antibodies, especially IgA antibodies, with incompatible red lineage progenitor blood group antigens in patients, and it has also been observed that the time to recovery of reticulocytes in patients is directly correlated with the time to disappearance of hemagglutinin antibodies [8]. (iv) Thymoma-associated PRCA: Thymomas are epithelial tumors of the thymus gland associated with paraneoplastic autoimmune disease, most commonly in myasthenia gravis. The specific pathogenesis of thymoma leading to PRCA is unknown and may be due to a lower inhibitory capacity of thymoma cells than normal thymic epithelial cells for the formation and activation of autoreactive T-cell clones. Many patients develop PRCA after thymectomy. effective immunosuppressive therapy and expansion of oligoclonal T cells support the idea that thymoma-associated PRCA is mediated by autoimmune mechanisms [9]. (v) MDS-associated dysplasia of the red lineage: acquired PRCA can be an early manifestation of MDS. An analysis of erythropoiesis in 360 patients with MDS showed that six of them (1.7%) were associated with erythropoietic hypoplasia [10]. There may be multiple unrelated genetic defects that can lead to erythropoietic failure in MDS patients, such as in vitro experiments in which mutations in the N-RAS gene were observed to induce defects in the proliferation of erythroid precursor cells [11]. (vi) Other causes of PRCA: various malignant hematological diseases, solid tumors, infections, autoimmune diseases and collagen vascular disease, pregnancy, and severe renal failure can lead to PRCA. more than 50 other drugs have been reported to be associated with PRCA, such as phenytoin sodium, sulfonamides, azathioprine, antituberculosis drugs, procaine, ribavirin, etc. II. Diagnosis and initial evaluation Careful history including medication and infection history; liver and kidney function tests; autoantibody series (including antinuclear antibodies, anti-EPO antibodies, etc.); bone marrow aspiration and biopsy are essential for the diagnosis of PRCA (e.g., the presence of scattered giant primitive red blood cells on bone marrow smear is a characteristic change of persistent PV-B19 infection); bone marrow cytogenetic examination; TCR analysis and flow cytometry Immunophenotyping (CD2, CD3, CD4, CD5, CD8, CD16, CD56, CD57, etc.), with particular attention to exclude LGLL and NK cell chronic lymphoproliferative disorders; virology-related tests; CT or MRI imaging to exclude thymoma or other lymphoma. There is no international standard for the diagnosis of pure red cataract. The criteria formulated by the Fourth National Conference of the Chinese Society of Hematology in 1987 are as follows: 1, clinical symptoms and signs of anemia, no bleeding, no fever, no hepatosplenomegaly. 2, laboratory tests: hemoglobin lower than normal; reticulocyte <1%, absolute value reduced; white blood cell and platelet counts are in the normal range, classification and morphology are normal. MCV, MCH, MCHC were within normal range. The bone marrow picture: the red lineage was significantly lower than normal, with less than 5% nucleated red blood cells; the granulocyte and megakaryocyte lineages were normal; there was no pathological hematopoiesis and few genetic abnormalities in the three lineages; the Ham test and Coombs test were negative; the urine Rous test was negative. Serum iron, total iron binding capacity and ferritin may be increased. The main point of diagnosis of pure red anemia is a significant decrease in the red lineage of the blood and bone marrow images. The other tests are to differentiate from other anemias. Immunosuppressive therapy: Immunosuppressive therapy should be considered for patients with thymoma, EPO antibodies or no sign of recovery of the red lineage even after one month of relevant treatment. Immunosuppressive agents include glucocorticoids, cyclosporine, CTX, ATG, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, etc [12]. The efficacy of hormones, CTX, and cyclosporine in the treatment of PRCA has been reported in the literature to be 30-62%, 7-20%, and 65-87%, respectively; the efficiency of hormones combined with CTX is about 50% in refractory patients [13]. Since PRCA is a rare disease and there are no large series of prospective studies to base the best treatment choice on, the long-term efficacy of drugs should be carefully weighed against adverse effects. (1) Corticosteroids: glucocorticoids were the first immunosuppressive agents used in the treatment of PRCA and are currently the treatment of choice especially in adolescent patients. Prednisone 1mg/Kg/d orally until remission, about 40% of patients are in remission within four weeks, and the dose can be gradually reduced when the erythrocyte pressure reaches 35%, and the recommended dose is usually not more than 12 weeks. The main shortcoming of hormonal therapy is relapse, which occurs mostly within one year after remission, and about 77% of relapsed patients can achieve remission again after treatment [14]. The side effects of glucocorticoids such as myopathy, infection, hyperglycemia, and fracture often lead to forced discontinuation of the drug, and care should be taken during its use. (2) Cyclosporin A (CsA): the total efficiency of CsA reported so far is 65% ~87%, and it is recommended for the first-line treatment of acquired PRCA. csA is also the most effective drug for thymoma-associated PRCA [15]. A retrospective analysis of 185 patients by the Japanese PRCA Research Collaborative Group [16] showed that the remission rates of CsA and glucocorticoid therapy were 74% and 60%, respectively; the mean relapse-free survival was 103 months in the CsA group, which was better than that in the hormone therapy group (33 months). the starting effective dose of CsA was 4.8 ± 1.2 mg/Kg, and maintenance therapy reduced relapse and transfusion-related adverse The maintenance treatment reduced the occurrence of relapse and transfusion-related adverse events. Nephrotoxicity is the main limiting side effect of CsA, which should be closely monitored and gradually reduced to the minimum maintenance dose during the drug administration. (3) Cytotoxic drugs: These include azathioprine and cyclophosphamide, which are more suitable for LGLL-associated PRCA and other diseases that themselves require cytoreduction. CTX alone or in combination with glucocorticoids and cyclosporine have been reported for the treatment of PRCA. the overall response rate in CTX ± glucocorticoids was approximately 66% to 100%, with a median duration of remission of 32-53 months, and the combination of CTX had a longer duration of remission than prednisone alone [17]. Two of 14 patients with LGLL-associated PRCA were still reported to have relapsed 21 and 39 months, respectively, after discontinuation of CTX maintenance therapy. Clinicians should be aware of treatment-related second tumors, gonadotoxicity, and other adverse effects of long-term CTX application. It is recommended that oral CTX induction therapy should ideally last no longer than 6 months and then be replaced with other relatively less toxic agents such as CsA maintenance therapy. Some treatment-naïve patients may respond to fludarabine or cladribine [18]. 2, Biological treatment of PRCA and other measures: It has been reported in the literature that the application of ATG, alemtuzumab (alemtuzumab), and dalizumab (daclizumab) for acquired PRCA is effective, but the long-term efficacy needs further observation. Intravenous gammaglobulin contains neutralizing antibodies to microvirus B19 and is effective in PRCA associated with B19 virus infection in immunodeficient patients, significantly increasing reticulocyte count and hemoglobin levels. Remission by splenectomy and plasma replacement therapy has also been reported. Some patients with PRCA have experienced long-term improvement after plasma exchange, presumably due to the removal of the causative antibody. Thymoma should be removed promptly to prevent local spread of the malignancy, but surgery does not improve bone marrow hematopoiesis. Androgens, erythropoietin, splenectomy, and hematopoietic stem cell transplantation are not recommended as routine first-line treatment options for pure red reoccurrence.