Continuing Education Activity

Pure red cell aplasia (PRCA) is a rare disorder characterized by a reduction or absence of red blood cell precursors in the bone marrow, resulting in severe anemia. The bone marrow fails to produce mature red blood cells, leading to symptoms such as fatigue, weakness, pallor, and shortness of breath. PRCA may be congenital or acquired, primary or secondary. Prognosis can vary depending on the underlying cause and how well the patient responds to treatment.

PRCA diagnosis can be challenging due to its rarity, diverse presentations, and possible causes. Despite the difficulties, healthcare providers can effectively diagnose this condition by systematically evaluating the patient's medical history, conducting appropriate tests, and ruling out other potential causes of anemia.

This activity for healthcare professionals enhances learners' proficiency in evaluating and managing PRCA. Valuable insights equip learners to collaborate effectively with an interprofessional team caring for patients affected by this illness.

Objectives:

• Identify the signs and symptoms suggestive of pure red cell aplasia.

• Create a clinically guided diagnostic plan for a patient with possible pure red cell aplasia.

• Differentiate the management options available for pure red cell aplasia to develop therapeutic plans for patients diagnosed with this condition.

• Collaborate effectively with an interprofessional team in formulating short- and long-term care plans for patients with pure red cell aplasia.

Introduction

Pure red cell aplasia (PRCA) is a rare disorder that presents with anemia from failure of erythropoiesis. This condition is characterized by normocytic, normochromic anemia with associated reticulocytopenia and absent or infrequent erythroblasts in the bone marrow.[1][2][3] PRCA is distinct from aplastic anemia in having intact platelet and leukocyte precursors. Thus, PRCA has normal platelet and leukocyte numbers and morphology in the peripheral blood.

Kaznelson first described PRCA in 1922.[4] The congenital or inherited form of PRCA, also called "Diamond-Blackfan syndrome," was first described by Joseph in 1936 and subsequently by Diamond and Blackfan in 1938.[5] PRCA's thymoma association led to the discovery of the autoimmune mechanisms producing this rare disease. PRCA has also been the object of much laboratory research due to the condition's association with parvovirus B19 in patients with sickle cell disease. However, PRCA's rarity makes it difficult to conduct interventional trials. Thus, most PRCA treatment recommendations are based on retrospective studies or anecdotal case reports.

The Hematopoietic Process and Erythrocyte Formation

All cells in the peripheral blood and some solid tissues, eg, osteoclasts, arise from hematopoietic stem cells. Hundreds of billions of blood cells can form daily from a stem cell pool of only 100,000. Hematopoietic stem cells can undergo self-renewal and differentiation, allowing continuous blood cell regeneration and maintenance.

Blood cells appear in the 3rd week of embryonic development in the yolk sac. By the 3rd month, hematopoietic stem cells translocate from the yolk sac to the liver, the main site of blood cell production until the antenatal period. In the 4th month, hematopoietic stem cells start to populate various bone marrow sites. At birth, all skeletal marrow sites are hematopoietically active, replacing the liver and becoming the only blood cell source. The marrow remains red and hematopoietically active until puberty. By age 18, about half of the marrow spaces become fatty and inactive, and the only active sites remaining are found in the skull, vertebrae, sternum, ribs, pelvis, and proximal humeral and femoral epiphyses.

The hematopoietic cells arise from a pluripotent progenitor, which forms the common myeloid and lymphoid stem cell lines. Thrombopoietin and interleukin-11 (IL-11) commit some stem cells to become the common precursors for erythroid, megakaryocytic, and basophilic cells. Erythropoietin (EPO) promotes differentiation to proerythroblasts, which undergo several functional changes before becoming reticulocytes and mature erythrocytes. Red blood cells (RBCs) contain hemoglobin and are specialized to deliver oxygen from the alveoli to the peripheral tissues. 

Etiology

Pure red cell aplasia can either be inherited or acquired. Diamond-Blackfan or Blackfan-Diamond syndrome is the most widely studied congenital PRCA type.[6] Meanwhile, acquired PRCA can arise from various causes, including the following:

• Autoimmune or collagen disorders: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease
• Leukemias
• Lymphoproliferative disorders:
  • Chronic lymphocytic leukemia (CLL) (common)
  • Large granular lymphocytic leukemia (LGL) (common)
  • Hodgkin disease
  • Non-Hodgkin lymphoma
  • Multiple myeloma
  • Castleman disease
  • Waldenstrom macroglobulinemia
• ABO-incompatible stem cell transplant
• Solid tumors:
  • Thymoma (strongly associated)
  • Breast
  • Biliary
  • Gastric
  • Lung
  • Thyroid
  • Renal cell
  • Carcinoma of unknown origin 
• Viruses:
  • Parvovirus B19 (most common); can lead to transient aplastic crises
  • HIV
  • Human T-cell leukemia-lymphoma virus-1 (HTLV-1), Epstein-Barr virus (EBV)
  • Hepatitis A, B, C, and E
  • Cytomegalovirus (CMV)
• Bacterial infections: group C streptococcus, tuberculosis, bacterial sepsis
• Drugs: recombinant human EPO (rhEPO) is the most commonly implicated pharmacologic agent in PRCA
• Pregnancy
• Riboflavin deficiency
• Idiopathic: primary acquired PRCA [7][8]

Understanding the underlying cause of PRCA is crucial for determining treatment strategies. In many cases, addressing the underlying condition or discontinuing offending medications can lead to improvement or resolution of PRCA. However, management may require ongoing monitoring and treatment to prevent complications and maintain stable blood counts.

Epidemiology

PRCA is a rare disorder. The condition has no definitive incidence or prevalence estimates in the general population. However, congenital PRCA or Diamond-Blackfan syndrome's incidence is approximately 5 to 7 cases per 1 million live births. According to the U.K. Diamond-Blackfan Anaemia Registry, 67% of individuals with this condition had macrocytosis at presentation, 13% were anemic at birth, and 72.5% had presented by age 3 months.[9]

Pathophysiology

PRCA is a highly heterogeneous disease, both clinically and pathologically. The discussion below explains the pathophysiologic mechanisms giving rise to various forms of this condition.

Congenital PRCA (Diamond-Blackfan Anemia)

Congenital PRCA or Diamond-Blackfan Anemia (DBA) is currently recognized as a disease of ribosomal biogenesis. Initial theories about the origins of this disorder included T-cell mediation, humoral mechanisms, and defective bone marrow microenvironment. However, these theories were all discarded with the discovery of defective ribosomal genes and the success of allogeneic stem cell transplants in patients with congenital PRCA, respectively.[10]

Sporadic cases are most common (55%-60%), followed by cases with autosomal dominant inheritance (up to 40% or 50%). Rare instances of autosomal recessive inheritance, defined as the presence of siblings with DBA born to unaffected consanguineous parents, have been reported.[11]

The first gene identified belonged to a Swedish patient who carried a balanced translocation between chromosomes X and 19.[12] The disease is equally prevalent in both sexes, essentially ruling out chromosome X's role. Subsequent linkage analyses involving European families identified chromosome 19q13 as the site involved in DBA's pathophysiology.[13]

In 1999, the first DBA-associated mutation was identified in the ribosomal protein S19 (RPS19) gene responsible for encoding a protein that assists in ribosome assembly.[14] Most mutations were whole-gene mutations, translocations, or truncations, and all led to haploinsufficiency and, consequently, RPS19 behaving like a dominant gene. Subsequently, 19 other ribosomal protein (RP) mutations were identified using whole exome or genome sequencing and comparative genomic hybridization or single nucleotide polymorphism array. Of 80 RP genes, 20 mutations have been implicated in the development of congenital PRCA. However, RPS19, RPL5, RPS26, RPL11, RPL35a, and RPS 24 account for 70% of the mutations.

The murine and zebrafish DBA models have identified lethal RP homozygosity mutations. Some non-RP genes like TSR-2, GATA1, and EPO genes have also been found. However, the debate about their role in DBA or DBA-like disease pathophysiology remains.[15][16][17] 

Transient Aplastic Crisis and Parvovirus B19 Infection

A transient aplastic crisis occurs when the blood has a high parvovirus B19 concentration. The virus has an affinity for the progenitor erythroid cells because of their P antigen, which acts as the virus' entry receptor into the cell.[18] Both in vitro and in vivo experiments have demonstrated the virus' ability to target and lyse the erythroid line, especially the late progenitor cells, thus inhibiting erythropoiesis. Pronormoblast differentiation arrest is characteristic.

Typically, neutralizing antibodies (immunoglobulin G or IgG) develop quickly in a patient with acute infection. Although a phase of reticulocytopenia may occur, anemia does not manifest unless RBC survival is curtailed. Parvovirus B19 infection can induce a transient aplastic crisis in patients with inherited hematological disorders like thalassemia, sickle cell disease, and hereditary spherocytosis. Thrombocytopenia and neutropenia are also well-documented in such patients. However, aplastic crises occur only once throughout life owing to humoral immunity.[19]

Transient aplastic crisis increases the frequency of fever, acute chest syndrome, pain, and acute sequestration crises in children with sickle cell disease. The viral levels tend to be extremely high in such patients but unaccompanied by antibody formation, thus distinguishing this condition from fifth disease (erythema infectiosum). Up to 75% of patients with sickle cell disease get infected with parvovirus by the age of 20 years. However, most of these patients are utterly asymptomatic despite parvovirus infection.[20]

Note that transient aplastic crisis is distinct from fifth disease, which is characterized by IgM antibodies against the virus and low to undetectable viral levels. Additionally, the symptoms of arthritis, arthralgia, and "slapped cheek appearance" occur in fifth disease due to the antibody-virus immune complex. Parvovirus B19 can also precipitate hemophagocytic syndrome, which usually has a favorable outcome.[21]

Transient Erythroblastopenia of Childhood

Transient erythroblastopenia of childhood (TEC) is a poorly understood entity, though parvovirus B19 is the most commonly implicated virus in this condition.[22]  Transient erythroblastopenia of infancy (TEBI) is a variant that affects mainly infants. Reports pointing to other viruses exist, but these reports do not demonstrate consistent causation.[23] IgG- and T-cell-mediated mechanisms appear to play a role in TEC's pathophysiology. One study showed that reduced T-cell numbers led to a dramatic increase in erythroid colony-forming units.[24]

Drugs that can cause PRCA can also give rise to TEC via a hapten-based mechanism. The serum antibody can act against the erythroid precursors only on exposure to the offending medication.[25][26]

PRCA with Autoimmune Disorders

Immune-mediated erythropoietic failure is central to PRCA seen in patients with autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, autoimmune hemolytic anemia, acquired hypogammaglobulinemia, autoimmune polyglandular syndrome, and thymoma. Laboratory evidence clearly shows the existence of both antibody-mediated and cell-mediated mechanisms of red cell erythropoiesis inhibition.[27] Immunoglobulin fractions from patients have been shown to inhibit heme synthesis and red cell progenitors in vitro.[28] Further credence to autoimmune-mediated mechanisms comes from secondary acquired PRCA responding to treatments like plasmapheresis and anti-CD20 therapies.

EPO-Associated Antibodies Causing PRCA

New reports of EPO-associated PRCA were published in the literature around the turn of the 21st century.[29][30][31] The most common link between anti-EPO antibodies and PRCA was rhEPO administration to patients on renal dialysis. The peak incidence in 2011 was associated with a specific epoetin alfa product's formulation change. Past epidemiological studies showed that prefilled syringes' rubber-stop leachates and certain stabilizers caused antibody formation. PRCA became rare when these issues were addressed.[32]

Although rhEPO and native EPO glycosylation sites are different, the antibody consistently targets the protein moiety's conformational epitopes and not those of the sugar moiety. Research has identified a few HLA types that correlate with increased immunogenicity against EPO. A study revealed that the allele frequency of HLA-DRB1*9 was 12.5% in cases as compared to 1.2% in controls (P = 002).[33]

ABO-Incompatible Transplant-Associated PRCA

Using donors mismatched at the major ABO locus leads to the development of target-specific antibodies and, consequently, delayed erythroid precursor engraftment or even PRCA later in life.[34] The specific targets are still not recognized in such patients.

PRCA Associated with Lymphoproliferative Disorders

CLL is the most frequently associated lymphoproliferative disease with PRCA. Erythropoiesis suppression is more frequently attributed to a T-cell- rather than an antibody-mediated mechanism. Signal transducer and activator of transcription three (STAT3) gene mutations, leading to clonal cytotoxic CD8+ cell activation and erythropoiesis suppression, have been identified in patients with PRCA.[35][36] Research also revealed that lymphocytes from patients diagnosed with idiopathic PRCA and PRCA secondary to CLL, LGL, thymoma, lymphoid malignancies, EBV, and HTLV-1 suppressed erythropoiesis in colony assays. 

Researchers suggest several mechanisms whereby T-cells reduce erythropoiesis. Such mechanisms may involve T-helper-cell-mediated antibody production, major histocompatibility complex- (MHC-) restricted or unrestricted red cell progenitor recognition, or MHC-unrestricted cytotoxicity. T-cells have also been shown to downregulate the inhibitory responses of natural killer cells and cause lysis of erythroid colony-forming units.

Persistent Parvovirus B19 Infection

Intrinsic humoral immunity is responsible for parvovirus B19 infection resolution within 1 to 2 weeks. Patients with immunodeficiency secondary to viruses (HIV), drugs (chemotherapy, immunosuppressive drugs), or congenital causes cannot mount an antibody response against the virus. Persistent infection arises, damaging the erythroid progenitor cells and leading to chronic red cell aplasia.

Parvovirus can be transmitted transplacentally in the mid-trimester, thus damaging the fetal liver's erythroid progenitors and producing severe red cell aplasia and hydrops fetalis. Affected infants rescued with timely red cell infusions can still develop persistent congenital PRCA or dyserythropoietic anemia.[19]

PRCA as a Myelodysplasia Manifestation

NRAS point mutation activation and RPS-14 gene loss lead to PRCA in patients with myelodysplastic syndrome (MDS), particularly those with 5q deletion.[37] MDS-induced PRCA differs from immune-mediated marrow failure. Burst-forming units-erythroid are intact in immune-mediated marrow failure but not in MDs.

Drugs Causing PRCA

The drugs listed below have been implicated in drug-induced PRCA. The mechanism appears to be IgG-mediated in patients receiving diphenylhydantoin and rifampin.

• Diphenylhydantoin
• Sulfa and sulfonamide drugs
• Azathioprine
• Allopurinol
• Isoniazid
• Rifampin
• Procainamide
• Ticlopidine
• Ribavirin
• Penicillamine

Histopathology

The peripheral blood smear demonstrates normocytic normochromic anemia with reticulocytopenia. The white cell and platelet counts are normal in number and morphology.

The histological picture seen on bone marrow examination depends on the cause of PRCA. Complete or near erythroblast absence, ie, less than 1% erythroblasts on marrow differential count, in an otherwise normal marrow is a characteristic of autoimmune PRCA (see Image. Bone Marrow Biopsy of a Patient with Refractory Autoimmune Pure Red Cell Aplasia). A few erythroblasts or basophilic erythroblasts are occasionally present, but their number never exceeds 5% of the differential count.

The marrow examination of patients with B19 parvovirus infection typically reveals large proerythroblasts with vacuolated cytoplasm and pseudopodia (giant pronormoblasts), though this is not a diagnostic finding.[19] Lymphoid aggregation with plasmacytosis and lymphocytosis points to an inflammatory reaction. Any signs of hypercellularity, ringed sideroblasts, or dysplastic features extending beyond one cell line suggest a myelodysplastic variant of PRCA or MDS itself. Moreover, the virus is often detected at extremely high levels (greater than 10¹² genome copies per milliliter) during acute infection.

History and Physical

No signs or symptoms are specific to PRCA. However, patients typically present with anemia and its associated symptoms, such as generalized fatigue, decreased exercise tolerance, palpitations, and, in patients with poor cardiac function, presyncope or syncope. The history may provide a clue about the possible underlying cause of PRCA. For example, recent drug exposure, pregnancy, or an autoimmune condition may be reported.

Physical examination findings are also nonspecific. Pallor is a feature in all patients. A thorough skin exam is necessary to look for erythema infectiosum, which signifies recent parvovirus B19 infection. Children may develop the classic facial rash (slapped-cheek appearance) and reticular trunk and limb rash. The systemic examination may reveal swollen lymph nodes, hepatomegaly, splenomegaly, and joint tenderness. None of these signs or symptoms are diagnostic of PRCA, though they may provide vital clues when establishing etiology.

Diamond-Blackfan syndrome is associated with physical anomalies in 40% of infants with DBA.[38] Craniofacial dysmorphism and thumb abnormalities are classic in DBA. Short stature, urogenital abnormalities, web neck, skeletal, and cardiac defects may also present in patients with DBA.[39] A classic description is that of Cathie: “tow-colored hair, snub nose, wide-set eyes, thick upper lips, and an intelligent expression.”[40] Likewise, Aase and Smith described the triphalangeal thumb abnormality accompanying anemia in DBA.[41]

Evaluation

Isolated anemia and reticulocytopenia in the presence of normal white cell and platelet counts suggest PRCA. A review of the peripheral smear is the first step in evaluating PRCA. Further evaluation is pursued to determine the degree of anemia and specific PRCA etiology and rule out other diagnoses.

• Tests for evaluating the degree of anemia include the following:
• Complete blood count with differential: low hemoglobin and hematocrit along with normal leukocyte and platelet counts and a markedly reduced reticulocyte count strongly support the diagnosis of PRCA
• EPO level: a high level usually accompanies anemia
• Type and cross: to prepare for pure red blood cell transfusion
• Peripheral blood tests to determine the PRCA etiology include the following:
• Tests that help determine the presence of an autoimmune condition, such as antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid arthritis antibody
• Viral studies, including Parvovirus B19, viral hepatitis A, B, C, and E, HIV, EBV, CMV, and HTLV-1 [42]
• Flow cytometry of peripheral blood cells to rule out malignant clonal cells
• T-cell gene rearrangement, which may accompany thymoma-induced PRCA
• Modalities to determine the presence of a plasma cell disorder, such as quantitative immunoglobulins, free κ and λ light chains, serum electrophoresis, and immunofixation
• Pregnancy test
• Bone marrow testing should include the following:
• Cytogenetics
• Flow cytometry
• T-cell gene rearrangement
• Tests to determine iron overload:[43]
• Ferritin level, which increases as transfusions increase
• Iron level, which should be high in iron-overloaded states
• Total iron-binding capacity, which should be low in iron overload
• Hepatic and renal panel to monitor liver and kidney function and help in choosing a suitable iron chelator
• Liver magnetic resonance imaging to determine the liver iron concentration

Diamond-Blackfan syndrome is associated with increased erythrocyte adenosine deaminase activity. However, critical challenges exist in performing this test, and exceptionally few labs perform the assay worldwide. Notably, only one lab performs this test in the US. Moreover, the erythrocyte adenosine deaminase assay must be performed only in patients who have not had RBC transfusions. The test must also be performed only on a fresh blood sample or, at most, stored at 4 °C only for a few days.[44]

Treatment / Management

PRCA management consists of supportive treatment and interventions addressing the condition's underlying cause. Genetic factors giving rise to congenital PRCA cannot be corrected. However, hematopoietic stem cell transplantation (HSCT) may be considered in some patients. Meanwhile, acquired PRCA often has an identifiable source, though not all are easy to treat. 

Regardless of the etiology, supportive care measures usually include blood transfusions, EPO-stimulating agents, and iron supplementation to manage anemia and maintain stable hemoglobin levels. Close monitoring by healthcare providers is essential to assess treatment response, manage complications, and adjust regimens as needed.

Congenital PRCA

Untreated congenital PRCA results in severe anemia, leading to congestive heart failure and death. Glucocorticoid use, blood transfusion, and allogeneic stem cell transplant are the mainstays of treatment in children.

Glucocorticoids

Corticosteroids were the first drugs that proved to be efficacious in children with DBA. Children who present at an older age, have a normal platelet count, and report a family history of PRCA respond better to steroids. Children who are born prematurely or present at a younger age are poor responders.[45]

Prednisone is typically started at 2 mg/kg daily in 3 to 4 divided doses. A response occurs in approximately two-thirds of the patients who receive steroids. Reticulocyte recovery is typically noted within 1 to 4 weeks, followed by a rise in hemoglobin. An adequate response is a hemoglobin level above 9 g/dL without transfusion. A meaningful response should occur within a few weeks of starting high-dose steroids. Steroid treatment is deemed a failure when even a partial response does not occur within 4 weeks of starting steroids. Steroid weaning should start once a partial response is achieved. A low-dose maintenance regimen of 0.5 to 1 mg/kg daily or on alternate days may be used to maintain remission if this dose does not compromise growth. Eventually, patients may only need very low prednisone doses, sometimes only 2 to 3 times a week.

Response patterns vary. Some patients experience a prompt recovery and apparent cure. Others either become treatment-refractory after multiple successful treatments or are completely unresponsive. A second attempt at steroids can be made 12 to 18 months after initial unresponsiveness. Chronic transfusions must be started on steroid-refractory individuals.

The long-term effects of steroids include growth retardation, cushingoid facies, hypertension, diabetes, and cataract formation. Patients treated with high-dose steroids must receive prophylaxis for Pneumocystis jirovecii.

All attempts should be made to give live vaccines before starting steroid therapy. However, once the therapy starts, live vaccines should only be administered when clinically warranted, like if the patient lives in an endemic area.

Red cell transfusions

RBC transfusion is mainly used in acutely symptomatic and steroid-refractory patients. The risks of chronic RBC transfusion are more manageable than long-term high-dose steroid use. However, frequent transfusions may result in hemosiderosis, alloimmunization, and antibody formation. Iron chelation should start early in patients requiring frequent or more than 10 to 20 blood transfusions, usually before age 2. The goal is to reach a hemoglobin level of 7 to 9 g/dL, which should be maintained for normal growth and sexual development. The median life expectancy of children compliant with red cell transfusions and iron chelation is 30 to 40 years, but it is shorter for noncompliant individuals.

HSCT

Transfusion dependence remains the most frequent indication for pursuing HSCT in patients with DBA. Blood may come from an HLA-matched relative or alternative donor transplant.[46] Younger patients who receive matched sibling donor allogeneic HSCT for DBA have a survival rate greater than 90%. Since 2000, registry data have shown an 80% survival rate with allogeneic unrelated donor HSCT.

Reduced-intensity and nonmyeloablative regimens are options for adult patients with iron overload or significant organ toxicity. A history of chronic transfusion reduces the success of HSCT due to iron overload. Iron overload reduction must be aggressively pursued after HSCT.

Other therapies

Immunosuppressive therapy with agents like IL-3, high-dose methylprednisolone, cyclosporine, and prolactin induction by metoclopramide has not gained much success. Gene transfer in vitro, which has the potential to correct RSP19, has shown promise but remains in the experimental stage.[47]

Acquired PRCA

Acquired PRCA is either primary or secondary. Primary-acquired PRCA is idiopathic, while secondary-acquired PRCA arises from an identifiable source. Depending on the specific etiology, treatment strategies may include immunosuppressive therapy, antiviral medications, discontinuing or modifying offending medications, and managing associated conditions such as thymoma or malignancies. Supportive care measures such as blood transfusions and EPO-stimulating agents may be necessary to treat anemia and improve symptoms.

Primary acquired PRCA 

The treatment approach for primary acquired PRCA is similar to immune-mediated PRCA. The interventions aim to suppress the abnormal immune response and stimulate RBC production. Corticosteroids, such as prednisone, are often used as first-line therapy to suppress the immune system. Other immunosuppressive medications, such as cyclosporine or azathioprine, may be considered in refractory cases. Some patients may also respond to therapies such as intravenous immunoglobulin (IVIG) or rituximab, which target specific components of the immune system.[64]

Transient PRCA

Transient PRCA is a self-limited condition that may arise from parvovirus B-19 infection or an autoimmune reaction. In individuals with transient PRCA due to parvovirus B-19 infection, humoral immunity is responsible for containing the infection and symptom resolution. Immunity develops within 2 weeks and is lifelong, thus preventing reinfecton. IVIG at 2 g/kg divided over 5 days corrects parvovirus-induced PRCA in 93% of patients with persistent infection. However, up to 42% relapse within 4.3 months.[48] IVIG has a small but significant renal tubular acidosis and thrombosis risk.[49]

TEBI and TEC are conditions without a clear cause, though viral infections, immune mechanisms, drug sensitivity, and maternal antibodies have been implicated in their development. TEBI and TEC resolve within a few weeks, but anemia may persist for months. Any drug suspected of causing these conditions should be withdrawn. Transfusion support may be necessary for a brief period.

Immune-mediated PRCA in adults

Cyclosporine, with or without concurrent corticosteroids, has emerged as the first choice of treatment for this condition, with a response rate as high as 75%. Cyclosporine is a natural cyclic polypeptide immunosuppressant used alone or combined with prednisone for treating PRCA. This medication may be tried in treatment-refractory cases. A reasonable starting dose is 6 mg/kg daily, with or without prednisone at 30 mg/day, to target a trough level of 150 to 250 ng/mL. A slow cyclosporine taper may be considered once hemoglobin levels normalize. However, maintenance doses may be necessary to maintain remission. 

Corticosteroids were the first-line therapy for PRCA before the discovery of cyclosporine. The first series of patients with PRCA who received treatment with steroids reported a response rate of 37%, with a median duration of response at 2.5 weeks. Since then, other reports have recorded a response rate between 30 and 60%. However, the relapse rate after steroid treatment was as high as 80% after tapering and subsequent withdrawal. Most of the patients who relapsed after steroid withdrawal responded again to immunosuppressive therapy. The best responses were achieved in patients who received cytotoxic agents along with corticosteroids.[50]

Cytotoxics have been used primarily in cyclosporine-refractory patients. Cyclophosphamide is the most studied cytotoxic agent. This alkylator is particularly effective in patients with LGL-induced PRCA. Either cyclophosphamide or methotrexate can be used in combination with steroids. Cytotoxic drug tapering may start upon achieving a hematologic response. Cyclophosphamide treatment should not exceed 6 months, as this drug may cause the development of a secondary malignancy. Cyclophosphamide can induce longer remissions compared to cyclosporine. However, the relapse rates are high following cyclophosphamide withdrawal. Switching to cyclosporine for maintenance after achieving a hematological response with cytotoxics has never been tested in clinical trials but has been suggested.

Tacrolimus provides effective immunosuppression, which can be useful in managing PRCA. However, a few reports have identified tacrolimus as a drug causing PRCA.[51][52]

Antithymocyte globulin treatment produces a 50% response rate in PRCA when used at the same dose as aplastic anemia. Rituximab (anti-CD20) and alemtuzumab (anti-CD52) have demonstrated efficacy in patients with PRCA. Rituximab is primarily used in patients with a lymphoproliferative disorder and has shown efficacy in treating PRCA associated with an underlying lymphoproliferative disorder.[53] The IL-1 receptor monoclonal antibody daclizumab is effective in approximately 40% of patients.[54]

IVIG, plasma exchange, and allogeneic stem cell transplant are other modalities for immune-mediated PRCA in adults. Splenectomy, androgens, and EPO are not recommended despite a few case reports describing success with these modalities. 

Thymoma-associated PRCA

The utility of thymoma resection is unclear, although this procedure is mandatory in patients with thymoma-associated PRCA. Only a third of patients experience remission after surgery, and most of them continue to have some degree of anemia throughout their lives. Many patients develop PRCA after thymoma resection. Cyclosporine is the treatment of choice in patients with thymoma-associated PRCA.[55][56]

PRCA associated with incompatible stem cell transplants

The persistence of anti-donor isohemagglutinins targeting donor RBC and erythroid precursors beyond 2 months is an ominous sign. The likelihood of spontaneous remission decreases beyond this period. Immunosuppressive regimen adjustment, donor-leukocyte infusion, plasma exchange, and rituximab have been used.[57]

PRCA due to rhEPO antibodies

PRCA from rhEPO antibodies is rare. A few reports have suggested rechallenging with subcutaneous or intravenous rhEPO once antibodies become undetectable in the blood. However, this approach has resulted in PRCA recurrence. The first line of treatment for this condition is immunosuppression with cyclosporine A, with or without corticosteroids. The emergence of biosimilars in the European and US market may circumvent this issue.[58]

Treating Iron Overload from Chronic Transfusions

Iron overload may arise from chronic blood transfusions and injure multiple organs. Chelation is the definitive treatment for this complication. The choice of chelating agent must be based on patient factors.

• Deferoxamine: used at a dose of 40 to 60 mg/kg/d subcutaneously or infused over 8 to 12 hours per night and 4 to 7 nights per week. This medication is not routinely recommended due to the availability of oral formulations. Deferoxamine can still be used IV over 24 hours in patients with severe cardiac iron overload and cardiomyopathy. 
• Deferasirox: administered at 20 to 30 mg/kg/d orally; may cause visual or hearing impairment.
• Deferiprone: dosed at 80 to 100 mg/kg/d orally. Agranulocytosis is a significant adverse effect, though this treatment is highly effective in patients with cardiac iron deposition.

Early detection and treatment of iron overload are essential to prevent complications. Vigilance is necessary to manage iron overload and its associated complications effectively.

Differential Diagnosis

Any patient presenting with anemia and reticulocytopenia requires evaluation for PRCA. The low reticulocyte count helps differentiate PRCA from hemolytic anemia, which features isolated anemia with reticulocytosis. A thorough history and judicious use of diagnostic tests can help differentiate conditions presenting with anemia.

PRCA variants may be differentiated from each other based on etiology. These conditions may also be distinguished from other clinical entities based on presentation.

• Diamond Blackfan syndrome is associated with craniofacial and thumb abnormalities in most patients, though not all these symptoms are seen in every patient. Fetal hemoglobin elevation, increased erythrocyte adenosine deaminase activity, and finding the ribosomal mutation on DNA analysis help establish a diagnosis. Fanconi anemia must be ruled out using cytogenetic analysis and clastogenic stress.
• TEC demonstrates self-recovery. The condition can present at birth or at an older age. TEBI is hard to differentiate from inherited PRCA in infants due to the onset age. However, spontaneous recovery is more consistent with TEBI than congenital PRCA.
• Inherited PRCA is hard to distinguish from acquired PRCA when the condition first manifests in adulthood. 
• Aplastic anemia and acute lymphoblastic leukemia should be ruled out when concomitant neutropenia is present. A bone marrow examination can help rule these conditions out. 

Prognosis

The prognosis of PRCA varies depending on several factors, including the underlying cause, condition severity, age of onset, and treatment response. Patients who respond well to immunosuppressive therapy may achieve remission and maintain stable blood counts. However, some cases of PRCA may be refractory to treatment or may relapse after initial remission.

Inherited PRCA

Patients who respond well to steroids and can get weaned off this treatment can have a normal life span. Meanwhile, steroid-refractory individuals dependent on chronic transfusions are likely to develop organ toxicity secondary to iron overload. The median life expectancy of these patients is 30 to 40 years. Patients who receive HSCT at a younger age have better outcomes than individuals who have had chronic transfusions and received HSCT at an older age.

Acquired PRCA 

A Japanese consortium reported the long-term follow-up results of patients with PRCA in Japan, which gave some insight into the long-term prognosis of patients with acquired PRCA.[48] 

The life span of patients with acquired PRCA is significantly shorter than the general population. Meanwhile, the life expectancies of patients with different PRCA etiologies, ie, LGL, thymoma, and idiopathic PRCA, do not differ significantly.

Infection and organ failure are the most common causes of death in patients with PRCA, not the progression of the underlying disease. This finding further stresses close monitoring and prompt management of complications, eg, infection from immunosuppression and iron overload from repeated blood transfusions. Iron chelation in a cohort of patients with aplastic anemia showed improvement in hematopoiesis.[49] 

Maintenance with cyclosporine is essential for most patients to prevent relapses. Patients who respond to steroids have a median survival of 12 years. By comparison, a study found that 95% of individuals who responded well to cyclosporine A were alive after a 14-year follow-up. The median survival for these patients is unknown but may be longer based on this finding.

Overall, the prognosis of PRCA depends on individual factors. Regular monitoring and follow-up are crucial to detect any complications or relapses early and adjust treatment as needed.

Complications

Children diagnosed with DBA are predisposed to cancer. This risk is lower than in patients with Fanconi anemia but still higher than in the general population of the same age group. International registries report an increased incidence of both solid and liquid malignancies in patients with DBA. Acute myeloid leukemia is the most common hematologic malignancy, while osteogenic sarcoma is the most frequently diagnosed solid organ tumor in children with DBA.

Chronic anemia can lead to growth retardation and poor psychomotor development in children. Severe anemia can also lead to hyperdynamic circulation, which increases cardiac work. Individuals with preexisting cardiac conditions have an increased heart failure risk due to chronic anemia.

Premature labor and abnormally low birth weight are possible consequences of anemia during pregnancy. Increased maternal and fetal mortality have also been reported. Overall, anemia can cause low energy, constant fatigue, and a generally poor quality of life.[50]

Patients with PRCA who receive chronic transfusions often develop iron overload and related toxicities. Immunosuppressive therapy with cyclosporine or chronic steroid therapy can lead to myelosuppression and, consequently, opportunistic infections. Corticosteroid use, whether as short-term high-dose therapy or long-term maintenance therapy, correlates with multiple adverse events.[51]

Deterrence and Patient Education

Measures that may help prevent PRCA or its complications include the following:

• Genetic counseling must be offered to families affected by congenital PRCA.
• Infection avoidance may be accomplished by frequent sanitation, good hygiene, and avoiding close contacts with infections that can increase PRCA risk.
• Toxin exposure minimization: healthy lifestyle habits such as eating a balanced diet, avoiding polluted areas, and refraining from smoking and drinking can help reduce exposure to toxins that may cause PRCA
• Early HSCT must be performed in individuals with congenital PRCA to avoid the complications of immunosuppressive therapy and chronic blood transfusions.
• Regular patient follow-up must be maintained to prevent underlying disease and treatment complications.

Patients should be counseled regarding PRCA's recurrent nature and the need for long-term therapy. Patients should be educated on the importance of seeking medical help immediately if they develop new symptoms, either from the treatment or PRCA.

Pearls and Other Issues

PRCA is a rare pathology that presents as a congenital or acquired disease. A few pearls to keep in mind regarding this condition are as follows:

• The most common finding in PRCA is isolated anemia with reticulocytopenia. Bone marrow examination shows under 1% erythroblasts.
• Diamond-Blackfan anemia is the most common form of inherited PRCA. Craniofacial and thumb abnormalities are frequent but not present in all patients. 
• Steroids, chronic transfusion therapy, and HSCT are the most effective modalities for managing patients with Diamond-Blackfan syndrome. HSCT must be considered early in patients with congenital PRCA.
• Transient PRCA most commonly results from parvovirus B19 infection. Recovery is spontaneous, and immunity to parvovirus is lifelong. One must remember that parvovirus infection-related PRCA differs from fifth disease, where the IgM antibody against the virus is at play.
• Immunocompromised individuals cannot develop humoral immunity against parvovirus, thus leading to chronic infection and relapsing PRCA.
• Acquired PRCA is both antibody-mediated and T-cell-mediated. 
• The most common lymphoproliferative diseases associated with PRCA are CLL and LGL. 
• Many drugs are associated with acquired PRCA, which must be discontinued before starting therapy for the condition.
• Cyclosporine is the most effective drug for PRCA, as it has the highest response rates. Cyclosporine maintenance prevents PRCA relapse, which usually occurs when stopping the medication completely. 
• Steroids are an effective alternative to cyclosporine, though these medications produce lower response rates and higher relapses. Steroids are usually combined with cyclosporine to optimize their benefits. 
• Chronic RBC transfusions correlate with iron overload and hemosiderosis. Iron chelation should start early in the course of treatment.

Patients with PRCA require long-term monitoring to assess treatment response, detect relapses, and manage complications.

Enhancing Healthcare Team Outcomes

PRCA is a rare disorder with serious consequences if not treated appropriately. An interprofessional approach helps optimize outcomes for affected individuals.

Primary care physicians are typically the first providers patients consult about symptoms suggestive of anemia or other hematologic disorders. These professionals coordinate care, facilitate referrals to specialists, and manage comorbidities that may affect PRCA treatment. Hematologists play a central role in diagnosing and treating PRCA. These experts oversee the evaluation of patients with suspected PRCA, interpret laboratory tests and bone marrow biopsies, develop individualized treatment plans, prescribe immunosuppressive therapy, monitor treatment response, and manage complications from the condition itself or the interventions. Immunologists may be involved if the etiology of PRCA is possibly autoimmune. These specialists may assist in selecting immunosuppressive medications and manage complications from such treatments.

Laboratory specialists perform laboratory tests essential for diagnosing and monitoring PRCA, ensuring accuracy in reporting the results. In cases of suspected genetic PRCA or when a family history of PRCA is present, genetic counselors can provide information about the condition's inheritance pattern, genetic testing options, and the implications for family members.

Nurses administer medications, monitor patients, help educate patients and families about the condition, and coordinate care. Pharmacists can review medication regimens, educate patients about the proper use of immunosuppressive drugs and iron chelators, and monitor for potential drug interactions and adverse effects. Nutritionists or dietitians can provide guidance on dietary modifications to manage iron overload or optimize nutritional intake in patients with PRCA. Social workers provide support and assistance to patients and their families in managing the emotional, practical, and financial aspects of living with a chronic condition like PRCA.

Close monitoring and early intervention are essential for the timely treatment of PRCA-related complications. By working collaboratively as an interprofessional team, healthcare providers can provide holistic care for patients with PRCA.