Acquired pure red cell aplasia in adults

INTRODUCTION — Acquired pure red cell aplasia (PRCA) is a rare cause of profound anemia characterized by a very low reticulocyte count and the virtual absence of erythroid precursors in the bone marrow. All other cell lineages are present in normal numbers and appear morphologically normal.

This topic discusses the causes, evaluation, and management of acquired PRCA in adults. Separate topic reviews discuss related conditions:

●Transient erythroblastopenia of childhood (TEC) – (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.)

●Diamond-Blackfan anemia (DBA) – (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

●Acquired PRCA due to anti-erythropoietin antibodies – (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)

PATHOGENESIS — Acquired PRCA is characterized by the complete or nearly complete cessation of red cell production in the bone marrow without effects on other hematopoietic cells.

Erythroid target cell — The target of attack in PRCA is an antigen expressed on an early erythroid precursor or progenitor cell rather than one on a multipotent hematopoietic stem cell (figure 1). (See "Regulation of erythropoiesis" and "Overview of hematopoietic stem cells".)

Mature red blood cells (RBCs) are derived from hematopoietic stem cells (HSCs), which differentiate into highly proliferative erythroid progenitor cells, which in turn differentiate into less mitotically active and more specialized erythroid precursor cells.

●HSCs can give rise to RBCs, white blood cells, and platelets. The HSC is not the target cell in PRCA because lymphopoiesis, granulopoiesis, and megakaryocytopoiesis are all normal, with the exception of cases in which an associated disease affecting them is present. (See 'Secondary PRCA' below.)

●Erythroid progenitor cells are committed to the erythroid lineage and are actively proliferating in the bone marrow. They represent a small portion of bone marrow cells and cannot be recognized morphologically. The progenitor cells are not thought to be the target in most cases of acquired PRCA. Bone marrow from patients with PRCA that is grown in semisolid media contains the committed erythroid progenitor cells known as Burst Forming Units erythroid (BFUe) and Colony Forming Units erythroid (CFUe), even though the marrow is devoid of erythroid precursors [1,2]. This suggests that the target cell is distal to (more differentiated than) these BFUe and CFUe progenitor cells. (See "Regulation of erythropoiesis", section on 'Erythroid progenitor cells'.)

●Erythroid precursor cells refers to the first morphologically identifiable cells of the erythroid lineage; the earliest precursor cell that can be reliably assigned to this category is the proerythroblast (also called pronormoblast) (figure 2). Proerythroblasts are absent or nearly absent from the bone marrow in the majority of cases of PRCA. Thus, the site of suppression is usually at the stage between CFUe and the proerythroblast, although arrest between BFUe and CFUe has been demonstrated in a few cases [1]. Differentiation between these stages is a continuous process, so a distinct target is difficult to define in most cases. BFUe are also decreased, the clinical significance of which is unclear [1]. (See "Regulation of erythropoiesis", section on 'Precursors and mature cells'.)

In parvovirus infection, the bone marrow characteristically shows large numbers of giant proerythroblasts (picture 1), suggesting a slightly later block in erythropoiesis (after the proerythroblast stage rather than before it).

In some cases associated with erythropoietin therapy and very rare cases of primary (non-drug-related) PRCA [3], the target of immune attack is not a cell but the growth factor erythropoietin, which acts at several stages in erythropoiesis including CFUe. (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)

Mediators of suppression — The suppression of erythropoiesis in PRCA is primarily immune mediated, especially in primary (idiopathic) PRCA and also in many forms of secondary PRCA. In primary (idiopathic) and some drugs and other disorders, the suppression is antibody-mediated; in others, such as that associated with lymphoproliferative disorders, it is mediated by other immune effectors such as T lymphocytes [4].

●Autoantibodies (immunoglobulins) – In approximately 60 percent of patients with idiopathic PRCA, patient serum (and the IgG fraction) inhibits the growth of patient and control erythroid progenitor cells in vitro [1,5]. The target antigen is usually not known. In a few cases, the IgG fraction contains an inhibitor of erythropoietin rather than an antibody directed against a RBC antigen. (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies", section on 'Anti-EPO antibodies'.)

●T lymphocytes and other immune effectors – In cases of autoimmune PRCA that are not associated with an autoantibody, suppression of erythropoiesis seems to be mediated by T lymphocytes (T cells) [1,6]. A subset of T cells has been implicated, and clonal changes may be seen [1].

•One study evaluated 14 of 47 patients with PRCA for T cell receptor gene rearrangements and noted clonal rearrangement in nine (64 percent) [6]. Clonal abnormalities were also identified by karyotypic studies in 4 of 28 patients (14 percent).

•Another study evaluated mutations in STAT3, a gene commonly mutated in T cell large granular lymphocyte (LGL) leukemia, and found somatic mutation of STAT3 in 18 of 42 (43 percent) of the patients with acquired PRCA, compared with 0 of 82 controls (individuals with aplastic anemia [AA], paroxysmal nocturnal hemoglobinuria [PNH], or myelodysplastic syndrome [MDS]) [7]. Many of the individuals with STAT3 mutation had LGL leukemia, but others had idiopathic PRCA, thymoma, or an autoimmune disorder. In the individuals with STAT3 mutation, the mutation was isolated to CD8-positive T cells. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytotoxic T lymphocyte function'.)

EPIDEMIOLOGY — Acquired PRCA is extremely rare; the prevalence is unknown. In a series from the National Health Service in South Korea (population approximately 40 million), only three individuals with PRCA were identified in a 10-year period, giving an approximate prevalence of 5 per million [8]. A 2022 registry series from Japan identified a lower incidence (1.06 per million, 95% CI 0.83-1.28 per million) [9].

Some reports suggest that the condition is more common in individuals from some countries in Asia, but cross-population epidemiologic data are lacking. It appears that males and females are affected in roughly equal proportions.

CLASSIFICATION — Acquired PRCA in adults can be divided into primary (also called idiopathic or autoimmune) PRCA and secondary PRCA (PRCA associated with another condition).

In one large series, which identified 185 individuals with acquired PRCA using a nationwide survey in Japan, 72 cases (40 percent) were primary [10]. Common secondary causes were thymoma in 41 (22 percent) and large granular lymphocyte (LGL) leukemia in 14 (8 percent). A more recent epidemiologic study from Japan involving 1055 new cases between 2012 and 2019 reported 69 percent of cases to be primary. In another series of 100 patients from China, 60 percent were primary and 40 percent were secondary [11]. The most common underlying cause of secondary PRCA was large granular lymphocyte (LGL) leukemia, with 28 cases (70 percent).

Primary (idiopathic, autoimmune) PRCA — The most common form of primary PRCA is an idiopathic autoimmune disorder. Immune attack of erythroid precursor cells may be caused by an autoantibody or other autoimmune process [4]. (See 'Pathogenesis' above.)

In 4 to 20 percent of cases of primary PRCA, this disorder is the initial presentation of a myelodysplastic syndrome (MDS) [1,12,13] (see "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'). In some cases, there will be signs of dysplasia on the bone marrow aspirate and in others, obvious dysplasia may not be present. This is why individuals undergoing bone marrow aspiration and biopsy for the diagnosis of PRCA should have standard cytogenetics as a routine part of the examination. (See 'Bone marrow' below.)

Secondary PRCA — Common associated disorders are summarized in the table (table 1) and discussed below in approximate order of frequency.

Lymphocyte and plasma cell disorders — Secondary PRCA is most commonly a manifestation of a hematopoietic neoplasm or preneoplastic disorder involving lymphocytes or plasma cells. Common examples include the following:

●Large granular lymphocyte (LGL) leukemia — In two of the larger series of secondary PRCA (one from the Mayo Clinic and one from China) LGL leukemia was the most common underlying cause [6,11]. LGL leukemia can have mild to moderate neutropenia and/or thrombocytopenia. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Clinical features'.)

●Chronic lymphocytic leukemia (CLL) and other lymphoproliferative disorders — PRCA has been described in a number of T cell and B cell lymphoproliferative disorders. As an example, in CLL, as many as 6 percent of patients have PRCA. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Laboratory abnormalities'.)

PRCA has also been described with monoclonal gammopathies that were not clinically apparent. In a series of 51 individuals with PRCA who were evaluated with serum and urine protein electrophoresis (SPEP and UPEP) and review of their bone marrow samples using immunohistochemical staining for plasma cells, 12 (24 percent) were identified as having monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma [14]. Three of these individuals had a response to anti-myeloma therapy and no longer required transfusions for anemia. (See "Clinical course and management of monoclonal gammopathy of undetermined significance" and "Smoldering multiple myeloma".)

Autoimmune disorders — A number of immunologic disorders are associated with PRCA. PRCA has been described in patients with autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

In some of these individuals, patient serum and its IgG fraction inhibit the growth of patient and control erythroid progenitor cells. Serum from other individuals lack inhibitory activity, and in those cases, the suppression appears to be mediated by T lymphocytes [1,6]. (See 'Mediators of suppression' above.)

ABO-incompatible hematopoietic stem cell transplantation — PRCA may complicate 7 to 8 percent of ABO-incompatible hematopoietic stem cell transplantations [15]. This occurs most commonly when hematopoietic stem and progenitor cells from blood group A donors are transplanted to blood group O recipients. PRCA in these cases is mediated by anti-donor isohemagglutinins (antibodies that cross react with donor ABO or other blood group antigens). (See "Donor selection for hematopoietic cell transplantation", section on 'ABO and Rh status'.)

Medications — At least 50 drugs have been associated with secondary PRCA. The most commonly implicated drugs include antimicrobials, anticonvulsants, and myelosuppressive agents (table 1) [1,4,16-18]. Recovery from anemia after drug discontinuation varies depending on the pharmacokinetics of drug metabolism, duration of treatment, and mechanisms by which erythropoiesis is suppressed. PRCA associated with anti-erythropoietin antibodies in patients treated with erythropoietin may persist indefinitely after drug discontinuation. If there has been no recovery by four to six weeks, treatment should be initiated as outlined below. (See 'Management' below.)

A number of cases of acquired PRCA were reported in the 1990s in individuals undergoing hemodialysis who were treated with recombinant human erythropoietin (rhEPO). These were due to neutralizing antibodies that developed after rhEPO exposure. These cases were ultimately linked to adjuvant characteristics of the rubber stoppers of the syringes used with a specific rhEPO product, and since the specific syringe was discontinued, new cases are uncommon [19,20]. This complication has also been seen in patients with hepatitis C virus (HCV) infection who are receiving antiviral therapy (eg, ribavirin, interferon) along with an erythropoiesis-stimulating agent [21]. (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)

Infections — PRCA may be a manifestation of a number of infectious agents, particularly viruses.

●Parvovirus B19 — PRCA is a well-described manifestation of B19 parvovirus infection, with specific management implications [22-24]. The parvovirus is thought to directly attack and destroy proerythroblasts by attaching to the blood group P antigen (globoside) receptor [25,26]. Cytotoxic antibodies are not found, and there is no evidence of T cell-mediated immunosuppression [22].

•Transient anemia from parvovirus infection is most likely to occur in immunocompetent individuals with underlying hemolytic anemia such as sickle cell disease or hereditary spherocytosis (table 2). (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient aplastic crisis'.)

•Chronic B19 parvovirus infection typically occurs in severely immunocompromised individuals and causes sustained anemia with a course resembling idiopathic PRCA (most commonly those with HIV infection). (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Chronic infection in immunosuppressed hosts'.)

The erythroid aplasia associated with B19 parvovirus often produces a characteristic morphologic finding in the bone marrow: giant proerythroblasts (also called giant pronormoblasts) (picture 2) [23,24]. This finding should be considered strongly suggestive of parvovirus infection but not diagnostic [4]. Since most patients with persistent PRCA from parvovirus infection are significantly immunocompromised, parvovirus serology is not sufficient to confirm or exclude this diagnosis. The standard for diagnosis of parvovirus-associated PRCA is detection of B19 parvovirus DNA by polymerase chain reaction. This test can be performed on peripheral blood [4]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Nucleic acid detection'.)

●Other viral infections — Transient episodes of PRCA have been described following a number of other viral infections such as hepatitis A, HCV, HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), but often these cases are not recognized clinically [27-30]. PRCA has also been reported after infection with SARS-CoV-2 (the virus that causes COVID-19) [31].

Thymoma and other cancers — Secondary PRCA has been associated with a number of non-lymphoid/non-plasmacytic neoplasms.

●Thymoma – A thymoma is present in approximately 5 percent of patients with PRCA overall, although some series have reported a frequency as high as 22 percent [1,4,10,32]. A number of cases of coexisting myasthenia gravis and PRCA have been described in the literature; all were thymoma associated except for one with thymic hyperplasia [33].

●Others – PRCA has also been reported in association with chronic myelogenous leukemia (CML), primary myelofibrosis (PMF), and more rarely, with non-thymic solid tumors. Reports of associations with non-thymic tumors are very uncommon and may represent coincidence rather than a causal association [4].

Pregnancy — PRCA has been reported in pregnancy; it usually resolves with delivery [34,35].

CLINICAL FEATURES

Typical presentation — PRCA generally presents insidiously, with most individuals lacking signs and symptoms of anemia until the reduction in hemoglobin and hematocrit becomes quite severe, often to a hematocrit of <10 percent. Extreme pallor or decreased exercise tolerance may be the first signs of this disorder in a previously healthy individual. A major exception is parvovirus infection in an individual with sickle cell disease, where severe anemia can develop abruptly (table 2). (See "Overview of the clinical manifestations of sickle cell disease", section on 'Aplastic crisis'.)

Other aspects of the presentation depend on the underlying disorder, if present.

●In one series, the median age of individuals with idiopathic, drug-associated, or autoimmune disease-associated PRCA was in the 60s and 70s, while the median age of thymoma and parvovirus-associated PRCA was in the late 40s [7].

●Generally, there are no specific physical findings unless there is an associated or underlying disorder, such as lymphadenopathy or splenomegaly with chronic lymphocytic leukemia (CLL); joint changes with rheumatoid arthritis (RA); or rash and arthralgias with systemic lupus erythematosus (SLE).

The major laboratory finding in PRCA, whether primary or secondary, is normochromic, normocytic anemia with absence of reticulocytes in the peripheral blood and a marked reduction or absence of all recognizable red blood cell (RBC) precursors in the bone marrow.

The anemia in PRCA occurs gradually because circulating RBCs die and are not replaced. The loss of RBCs occurs at an approximate rate of 0.8 percent per day. This daily percentage reflects the typical RBC lifespan of 120 days (0.8 percent is 1/120 of the circulating RBCs). This pace is slow enough to allow the body to compensate for a reduced oxygen-carrying capacity, which explains why patients with PRCA may not present until a significant degree of anemia is present, at which point these compensatory changes are no longer sufficient. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Role of blood in oxygen delivery'.)

Laboratory findings

●Anemia – Anemia may be severe in PRCA with presenting hemoglobin <4 g/dL and hematocrit <10 percent reported. However, PRCA can be associated with anemia of any degree. The hallmark is anemia accompanied by severe reticulocytopenia.

The RBC indices are generally normal (ie, the anemia is normocytic and normochromic). The blood smear is generally unremarkable. Spherocytes, RBC fragments, macrocytic RBCs, and polychromatophilic RBCs are not routinely seen. An exception is parvovirus-associated transient suppression of erythropoiesis seen in chronic hemolytic anemia, in which cells typical of the underlying anemia (eg, spherocytes in the case of hereditary spherocytosis) are evident on the blood smear.

●Reticulocytopenia – Severe reticulocytopenia despite anemia is the characteristic feature of PRCA. Reticulocytes are often absent or markedly decreased (absolute reticulocyte count often <10,000/microL).

●WBC and platelets – There are no changes in white blood cell (WBC) or platelet counts, and circulating WBCs appear normal. Exceptions include individuals with an underlying hematologic disorder (eg, lymphocytosis in CLL, lymphoblasts in large granular lymphocyte leukemia).

●Absence of hemolysis (with some exceptions) – Markers of hemolysis and ineffective erythropoiesis (eg, increased bilirubin and lactate dehydrogenase [LDH], decreased haptoglobin) are absent unless the individual has a chronic hemolytic anemia and parvovirus-associated transient PRCA. The direct antiglobulin (Coombs) test is negative unless there is chronic immune-mediated hemolysis and/or the individual has received a blood transfusion and has developed an alloantibody.

●Iron studies – Iron metabolism does not contribute to the pathogenesis of PRCA. Reported values for hepcidin (a key regulator of iron homeostasis) and iron markers reflect erythroid suppression [36]. Increased serum iron and very high transferrin saturation (TSAT), in the range of 100 percent, may be seen. This is because the transfer of iron from its transport form in the circulation to the erythroid precursors in the bone marrow ceases once the bone marrow stops making RBCs. Iron overload from transfusions may also contribute to high TSAT and high ferritin levels.

EVALUATION

When to suspect the diagnosis — The diagnosis of PRCA is suspected in an individual with isolated anemia with severe reticulocytopenia (absolute reticulocyte count <10,000/microL). The anemia is typically normochromic and normocytic.

A high index of suspicion for transient PRCA due to parvovirus B19 infection is appropriate in individuals with chronic hemolytic anemias, especially if their reticulocyte count drops precipitously.

PRCA should also be considered in any individual with anemia severe enough to require transfusions for whom the cause of the anemia has not been determined.

Laboratory testing — Laboratory testing includes the following in all patients:

●CBC and blood film – Review of complete blood count including red blood cell (RBC) indices, peripheral blood film, and white blood cell (WBC) differential.

●Reticulocyte count – Many laboratories use automated cell counters that can provide an absolute reticulocyte count that is measured directly (by flow cytometry). In other laboratories, the absolute reticulocyte count can be approximated by multiplying the RBC count and the reticulocyte percentage. Either an absolute count or a reticulocyte percentage can guide the diagnosis, although the absolute count (measured or estimated) is preferred for following the response to treatment and/or recovery from anemia.

●Iron studies and vitamin B12 – Iron, total iron binding capacity (TIBC), ferritin, and vitamin B12 level. Iron deficiency and vitamin B12 deficiency are common causes of anemia and should be excluded before more extensive testing such as bone marrow is done.

●Complete metabolic panel – Liver and kidney disease are common causes of anemia and should be excluded.

●Other anemia testing – Other testing may be appropriate, as indicated by the history and physical examination. A more general approach to evaluating normocytic anemia and causes of anemia with a low reticulocyte count is presented separately. (See "Diagnostic approach to anemia in adults".)

Bone marrow — Bone marrow examination is required in all individuals in whom PRCA is suspected, with the exception of those with a chronic hemolytic anemia (eg, sickle cell disease, hereditary spherocytosis) who develop an acute decline in hemoglobin concentration with severe reticulocytopenia and no evidence of bleeding or hyperhemolysis. In this limited setting, it is reasonable to attribute the reticulocytopenic anemia to a transient acute parvovirus infection and to defer further evaluation while monitoring recovery over the next two weeks.

Further testing for genetic changes associated with MDS is appropriate when there are morphologic changes in other hematopoietic lineages, abnormalities in white blood cell or platelet counts, macrocytosis, or minimal response to immunosuppression.

The testing on the bone marrow should include the following:

●Histologic stains – Routine histologic/cytochemical studies, including iron staining to identify ring sideroblasts if present. Ring sideroblasts are characteristic of sideroblastic anemias, including certain myelodysplastic syndromes (MDS). These may be challenging to find in individuals with PRCA because erythroid precursors are extremely sparse.

●Clonality studies – Cellular immunology studies to identify immature myeloid cell and clonal lymphocyte populations such as in chronic lymphocytic leukemia (CLL).

●Genetic/cytogenetic studies – Cytogenetics and/or other genetic testing as appropriate (eg, testing related to MDS if dysplasia is suspected based on the peripheral blood smear; testing for genetic changes associated with CLL in an individual with peripheral blood lymphocytosis if not done already).

Typical findings associated with MDS and sideroblastic anemias are discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Cytogenetic and molecular features' and "Sideroblastic anemias: Diagnosis and management", section on 'Molecular (genetic) testing'.)

Diagnosis — The diagnosis of PRCA is established when all of the following are present [1,4]:

●Normocytic, normochromic anemia.

●Absolute reticulocyte count <10,000/microL (or reticulocyte percentage <0.5 percent; typically <0.2 percent).

●Normal WBC and platelet counts, in the absence of a concurrent disorder such as CLL.

●Normocellular bone marrow, with erythroblasts totaling <1 percent or proerythroblasts plus basophilic erythroblasts totaling <5 percent of nucleated cells.

●No significant abnormalities in the myeloid, lymphocytic, or megakaryocyte lineages, unless the patient has a concurrent diagnosis of CLL or chronic myeloid leukemia (CML). There may be a slight increase in polyclonal lymphocytes or plasma cells.

Determining the cause — Once the diagnosis of PRCA is made, additional testing is used to distinguish idiopathic PRCA from myelodysplastic PRCA or secondary PRCA [4]. Review of the peripheral blood film by an experienced individual is essential to direct subsequent testing.

Since T-cell LGL is one of the most common causes of PRCA in adults, appropriate clonality studies with flow cytometry and molecular testing are especially important.

●Peripheral blood – White blood cell (WBC) abnormalities may be especially useful in determining appropriate initial testing. Dysplastic features such as pseudo-Pelger-Huet cells may indicate a myelodysplastic syndrome (MDS). Abnormal-appearing lymphocytes may indicate a lymphoid malignancy. Some patients with T-LGL may have mild to moderate neutropenia.

●Flow cytometry – Individuals who appear to have T-LGL, CLL, or another lymphoproliferative disorder based on increased lymphocytes in the peripheral blood or bone marrow should have testing for clonality (typically with flow cytometry) if not done already. (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Assessment of clonality'.)

●Molecular testing – Patients in whom flow cytometry suggests LGL and those who do not show evidence of a clonal B-lymphocyte population should have T cell receptor clonality studies performed on peripheral blood. Next generation sequencing (NGS) studies including STAT3 mutations should be performed in most cases, both to confirm an LGL/STAT3 association, and to identify myeloid clonal hematopoiesis potentially indicating MDS [37]. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)

Individuals who appear to have a myeloproliferative neoplasm (eg, CML) based on a peripheral blood or bone marrow finding should have appropriate genetic or cytogenetic testing if not done already. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

●Bone marrow – Dysplastic features in the bone marrow suggest MDS. Ring sideroblasts (which may be rare due to erythroid hypoplasia) indicate sideroblastic anemia. Appropriate testing is discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Sideroblastic anemias: Diagnosis and management", section on 'Laboratory and bone marrow findings'.)

In parvovirus infection, numerous giant pronormoblasts (picture 2) may be present in the bone marrow aspirate smear; this is considered strongly suggestive but not diagnostic of parvovirus-related PRCA.

●Parvovirus testing – All individuals who do not have a lymphoid or myeloid neoplasm should have nucleic acid testing of peripheral blood for B19 parvovirus DNA (typically assayed by polymerase chain reaction [PCR]). Therapy should not be initiated until the parvovirus result is back. The turnaround time is usually <7 to 10 days. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Nucleic acid detection'.)

●Response to drug discontinuation – Individuals who are taking a causative drug such as one of those listed in the table (table 1) should have the drug discontinued and should be monitored (with transfusion support if necessary) for up to six weeks to see if reticulocytosis occurs.

●Testing for rheumatologic disorders – Individuals with findings suggestive of other diseases associated with PRCA (systemic lupus erythematosus [SLE], rheumatoid arthritis [RA] abnormal liver function tests) should have testing for those disorders, especially when other secondary causes are not found. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Evaluation' and "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated serum aminotransferases'.)

●ADA – In an adult with a lifelong history of anemia and a clinical picture suggesting PRCA, testing for Diamond-Blackfan anemia (DBA) with adenosine deaminase (ADA) and molecular testing may be appropriate. (See 'Differential diagnosis' below.)

●T cell receptor (TCR) analysis and CT scans – All individuals who do not have the above findings and do not undergo the testing described above, as well as those for whom parvovirus DNA is not detected, should have (unless pregnant) computed tomography (CT) of the chest to evaluate for thymoma or other thymic lesions. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PRCA includes a number of other causes of isolated reduction in erythropoiesis:

●Myelodysplastic syndrome – Myelodysplastic syndromes (MDS) are acquired disorders of bone marrow that generally produce one or more cytopenias and can sometimes progress to acute myeloid leukemia. Isolated anemia is a common presenting finding, in some cases macrocytic and in others normocytic.

Like acquired PRCA, the reticulocyte count is typically low, but often the reduction is less severe in MDS than in PRCA. Unlike PRCA, in MDS there may be other cytopenias; the bone marrow generally shows evidence of dysplasia, but marked erythroid hypoplasia is absent; and cytogenetic abnormalities are often present. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)".)

●Sideroblastic anemia – Sideroblastic anemia refers to a number of congenital and acquired conditions associated with abnormal heme synthesis and mitochondrial function that produce ring sideroblasts in the bone marrow. Some sideroblastic anemias are subtypes of MDS, and others are due to certain drugs, copper deficiency, and excess alcohol use.

Like acquired PRCA, sideroblastic anemia may produce isolated normocytic anemia with a low reticulocyte count, and the bone marrow may show reduced erythroid precursors. Unlike PRCA, sideroblastic anemias generally do not have a complete loss of erythroid precursors, and additional testing may reveal a genetic or acquired cause known to be associated with formation of ring sideroblasts. (See "Sideroblastic anemias: Diagnosis and management".)

●Diamond-Blackfan anemia – Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome due to abnormalities of ribosome synthesis that is characterized predominantly by anemia. DBA almost always presents in the first decade of life and is associated with congenital anomalies (short stature, thumb abnormalities, congenital heart disease), but increasing use of genetic testing has identified nonclassical presentations in adulthood in which these congenital anomalies are lacking [38].

Like acquired PRCA, there may be normocytic anemia (although more typically the anemia is macrocytic) with a low reticulocyte count and severe erythroid hypoplasia in the bone marrow. Unlike acquired PRCA, in DBA there is often macrocytosis, and the family history often reveals a similar condition in other family members. Testing for elevated serum adenosine deaminase (ADA) levels is often positive in DBA, and genetic testing often reveals a pathogenic variant affecting one of the genes involved in ribosome biogenesis. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

MANAGEMENT

Overview of management — The management in individuals who do not have a spontaneous remission includes supportive care, treatment of any underlying disorders that may be contributing, and immunosuppressive or immunomodulatory therapy for individuals who have severe anemia that does not resolve spontaneously or after treatment of associated conditions [39].

●Observation for spontaneous remission – As with most autoimmune disorders, a small proportion of individuals with primary immune-mediated PRCA will likely have spontaneous resolution, with return of the hemoglobin level to baseline, typically over the course of weeks to months. In general, there are no predictors of which individuals with idiopathic PRCA are most likely to have resolution of anemia without treatment.

A series of 37 patients from 1984 reported spontaneous resolution in five (14 percent) [40]. However, some of these individuals may have had parvovirus-associated, pregnancy-associated, or drug-related PRCA, which are most likely to remit spontaneously [34]. PRCA that occurs following ABO-incompatible hematopoietic stem cell transplantation (HSCT) is self-limited in 60 to 70 percent of cases.

During the period while the patient is being observed (typically over the course of three to four weeks) for spontaneous recovery or a response to drug discontinuation, a thorough evaluation for possible underlying causes should be conducted (eg, careful medication history, review of other medical illnesses) (see 'Determining the cause' above); specific interventions for specific underlying causes are outlined below. (See 'Interventions for specific conditions' below.)

●Therapy – In the absence of spontaneous remission or an underlying condition amenable to treatment, persistent PRCA is treated by immunosuppression or immunomodulatory therapy. Examples include glucocorticoids, cyclosporin A, and other agents [11].

We generally consider immunosuppressive therapy appropriate for individuals with the following:

•No concurrent self-limited illness

•Anemia with reticulocytopenia that persists for more than a month

•Needing transfusion for symptomatic anemia on two or more separate occasions

The optimal treatment for PRCA is unknown; PRCA is rare and includes a number of underlying causes, some of which have distinct behaviors. As a result, there are no randomized clinical trials in this disorder, and different treatment regimens have not been directly compared. In a series of 100 patients (60 percent primary PRCA, 40 percent secondary), response rates were greatest with cyclosporin A (71 percent), followed by glucocorticoids (67 percent) and other therapies (50 percent) [11]. In this study, LGL leukemia-associated PRCA had a lower response rate to cyclosporin A than primary PRCA (42 versus 86 percent).

Patients with STAT3 mutations (a frequent feature of LGL leukemia-associated PRCA) may have a lower rate of response to cyclosporine [7].

Transfusions — Transfusions are used for symptomatic or severe anemia. Generally, thresholds used for other patient populations are appropriate, with clinical judgment regarding the appropriate threshold that takes into account the patient's overall medical status and concurrent conditions. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

●Routine good transfusion practice should be followed.

●No special modifications of the red blood cell product are required.

●The frequency of transfusions depends on the rate of decline in the hemoglobin concentration.

●Transfusion generally does not suppress reticulocytosis to an extent that it interferes with determination of a recovery.

Interventions for specific conditions — Treatment of associated causes may include the following:

●Suspected medication-associated PRCA – Drug discontinuation. If recovery does not occur within four to six weeks, immunosuppression is considered. (See 'Immunosuppression' below.)

●Hematologic malignancy – Appropriate systemic therapy is used for large granular lymphocyte (LGL) leukemia, myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), lymphoma, or other lymphoproliferative disorders.

●ABO-incompatible HSCT — If anti-donor isohemagglutinins persist longer than two months, spontaneous remission is unlikely. Reported treatment modalities include adjustment of immunosuppression or addition of bortezomib, daratumumab, plasma exchange, donor lymphocyte infusion, rituximab, or intravenous immune globulin (IVIG). A number of small studies have reported success with bortezomib or daratumumab [15,41-44].

●Thymoma — Resection. This rarely produces a complete or sustained response, and immunosuppression (see 'Immunosuppression' below) is typically required [32,45]. Responses of thymoma-associated PRCA to a combination of immunosuppression and the somatostatin analogue octreotide have been reported [46].

●Parvovirus B19 infection — Persistent parvovirus infection causing sustained PRCA typically occurs in immunocompromised patients. IVIG contains antibodies against parvovirus and can reverse PRCA. Responses have been reported with doses as low as 400 mg/kg, although some have used the 2 g/kg dose divided over two to five days, similar to dosing used in immune thrombocytopenia. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'IVIG dosing and administration'.)

The initial response rate to IVIG has been reported as greater than 90 percent, but relapses requiring retreatment are seen in up to one-third of patients within a median of four months [4,47,48]. Most individuals treated with IVIG do not require immunosuppressive therapy.

●Pregnancy – In most cases, pregnancy-associated PRCA resolves with delivery, and the outcome of pregnancy is successful if anemia is controlled. The primary therapy is transfusion support, although glucocorticoids are sometimes used. There is little experience with other agents due to concerns about their use in pregnancy [34,35].

●Anti-erythropoietin antibodies – This subject is discussed separately. (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)

Immunosuppression — Immunosuppression is considered first-line therapy for individuals with no concurrent self-limited illness who have severe or prolonged anemia for more than three to four weeks.

Cyclosporine A and/or glucocorticoids — As noted above, there is no high-quality evidence regarding the relative efficacy of different immunosuppressive/immunomodulatory agents and no data from randomized trials to guide the dosing or duration of therapy.

Cyclosporine A, with or without glucocorticoids, is the most effective immunosuppressive agent in PRCA. Some hematologists chose to start with glucocorticoids alone before moving to cyclosporine, and this is also a reasonable choice.

●Cyclosporine A – Cyclosporine A is frequently used as a second-line agent and may reasonably be used as a first-line therapy [49]. The response rate appears to be approximately 75 to 80 percent based on pooled data from case series [4]. Responses typically occur within four to eight weeks.

A typical approach is to give 3 mg/kg orally twice daily, for a total daily dose of 6 mg/kg [49]. Trough concentrations are measured three to five days after starting, and the dose is titrated to a target trough concentration of approximately 150 to 250 ng/mL. Frequently, this is given in combination with prednisone at a dose of 20 to 30 mg daily [50]. Following a response, the dose is tapered at weekly or biweekly intervals guided by the hemoglobin and reticulocyte results. In some cases, prolonged maintenance treatment may be required [10].

●Glucocorticoids – Glucocorticoids have traditionally been used as a first-line agent. The response rate appears to be approximately 40 percent based on pooled data from case series [4]. Responses typically occur within four to six weeks.

A typical approach is to give prednisone, 1 mg/kg daily. The dose is continued until a response occurs. Following a response, the dose of prednisone is tapered slowly at a rate guided by the hemoglobin and reticulocyte count. If a response does not occur within six to eight weeks, the prednisone is discontinued or continued at a lower dose in combination with another drug.

Retreatment for relapse — If an individual has an initial response to glucocorticoids or cyclosporine A and experiences a relapse during or after tapering, the first step should be to reinstitute the original agent used at the dose to which the individual previously had a response. In many cases, this will restore the response [10,49].

Refractory disease — It is this author's impression that refractoriness to initial therapy is more common than an initial response followed by refractoriness to therapy after recurrence.

In either case, treatment with a cytotoxic agent (cyclophosphamide or azathioprine) or sirolimus is reasonable, based on clinician experience with the specific agent. The response rate appears to be approximately 40 percent in individuals with disease refractory to prednisone, based on pooled data from case series [4].

●Cyclophosphamide – A typical dose is 100 mg orally per day, usually given in combination with prednisone.

●Azathioprine – A typical dose is 100 mg orally per day, usually given in combination with prednisone.

The dose is adjusted to maintain an absolute neutrophil count greater than 1500/microL.

Limited experience is available with other approaches such as the following:

●Sirolimus – Response rates similar to cyclosporine (approximately 75 percent) have been reported in preliminary studies, including patients whose disease is refractory to cyclosporine [51,52].

●Rituximab – Responses have been reported, mostly with PRCA secondary to chronic lymphocytic leukemia (CLL) [53,54]. On occasion, responses also occur in idiopathic PRCA.

●Intravenous immune globulin (IVIG) – Responses have been reported, especially in individuals with parvovirus B19 infection [55].

●Daratumumab – Responses have been reported, even in individuals with refractory disease for over a decade that did not respond to multiple prior therapies [56].

●Other agents – Responses have been reported with antithymocyte globulin, the monoclonal anti-CD52 antibody alemtuzumab, and the monoclonal anti-interleukin 2 receptor antibody daclizumab, which is no longer available [57-67].

●Hematopoietic stem cell transplantation (HSCT) – Allogeneic HSCT can be considered a treatment of last resort in eligible patients. Case reports have described successful outcomes [68].

PROGNOSIS

Expected recovery and complications — Some cases of acquired PRCA are self-limited, such as secondary PRCA associated with pregnancy, parvovirus infection, or drug-induced PRCA. (See 'Overview of management' above and 'Interventions for specific conditions' above.)

Complications may be related to severe anemia or adverse effects of treatment. Examples include the following:

●Effects of anemia or its treatment on general quality of life.

●Iron overload in those who have received a significant number of RBC transfusions (eg, more than 10 or 20). If a patient has had a response to treatment or spontaneous recovery, iron overload can be managed by cautious phlebotomy.

Survival — PRCA generally does not shorten survival as long as appropriate therapy is given and the individual does not succumb to their underlying disorder. Most series that have followed long-term prognosis have not reached a median survival even after more than 10 to 20 years of observation [10,40].

In one series, median survival for PRCA associated with thymoma or large granular lymphocyte (LGL) leukemia was approximately 12 years [10]. Estimated overall survival was 213 months (18 years). Principal causes of death were infection and organ failure. Predictors of death included refractoriness to therapy and relapse after a response.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Acquired pure red cell aplasia (PRCA) is characterized by the complete or nearly complete cessation of red cell production in the bone marrow without effects on other hematopoietic cells. The target cell is usually an early erythroid precursor or progenitor cell and the effector is typically an autoantibody or a T lymphocyte. (See 'Pathogenesis' above.)

●Prevalence – PRCA is very rare. It may be more frequent in individuals with ancestry from Asia, but data are insufficient to make firm conclusions. (See 'Epidemiology' above.)

●Classification – Acquired PRCA can be classified as primary (idiopathic) or secondary to another condition (lymphoproliferative disorder such as large granular lymphocyte [LGL] leukemia, autoimmune disorder or ABO-incompatible hematopoietic stem cell transplant (HSCT), medication, viral infection such as parvovirus B19, thymoma, or pregnancy) (table 1). Some cases of primary PRCA may eventually behave like a myelodysplastic syndrome (MDS). (See 'Classification' above.)

●Presentation – The typical presentation is insidious, with most individuals lacking signs and symptoms of anemia until the reduction in hemoglobin and hematocrit becomes quite severe, often to a hematocrit of <10 percent. Other than signs and symptoms of anemia and/or findings associated to an underlying condition, most individuals lack specific physical findings. The anemia is normochromic and normocytic with a dramatically reduced (or absent) reticulocyte count. The bone marrow is normocellular with absent or extremely rare erythroid precursors. (See 'Clinical features' above.)

●Evaluation and diagnosis – Laboratory testing includes complete blood count (CBC) and reticulocyte count. Bone marrow is performed in all cases. The diagnosis is confirmed when there is normochromic, normocytic anemia, absolute reticulocyte count <10,000/microL, normal white blood cell (WBC) and platelet count (in the absence of a concurrent disorder such as chronic lymphocytic leukemia [CLL]), and normocellular bone marrow with <1 percent erythroblasts or proerythroblasts and basophilic erythroblasts totaling <5 percent of nucleated cells. Additional testing to determine the cause is described above. (See 'Evaluation' above.)

●Differential diagnosis – The differential diagnosis of acquired PRCA includes myelodysplastic syndrome (MDS), sideroblastic anemia, and, rarely, Diamond-Blackfan anemia (DBA) and transient erythroblastosis of childhood. (See 'Differential diagnosis' above and "Overview of causes of anemia in children due to decreased red blood cell production".)

●Management

•Transfusions – Transfusions are given as needed. (See 'Overview of management' above and 'Transfusions' above.)

•Immunosuppression for primary PRCA – A brief period of observation is appropriate for spontaneous remission. Therapy is generally initiated if anemia and severe reticulocytopenia persist for ≥1 month or if transfusions are required on ≥2 separate occasions. Immunosuppressive therapy with cyclosporine A and/or a glucocorticoid are typical first-line therapies. Therapy can be readministered for relapse. Refractory disease can be treated with oral cyclophosphamide plus prednisone or azathioprine plus prednisone; sirolimus is also a reasonable choice. Other therapies may also be effective. (See 'Immunosuppression' above and 'Refractory disease' above.)

•Treat the underlying cause for secondary PRCA – Specific therapies are available for myeloid or lymphoid malignancies and for ABO-incompatible HSCT. Drug discontinuation may be indicated for implicated drugs. Persistent parvovirus infection may respond to intravenous immune globulin (IVIG). Thymoma can be resected. (See 'Interventions for specific conditions' above.)

●Prognosis – Prognosis in PRCA is generally good, with most series reporting survival >10 to 20 years. Common causes of death include complications of the underlying disorder (infection and organ failure), especially in individuals with relapsed or refractory disease. (See 'Prognosis' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.