Hypoproliferative

Overview of Hypoproliferative Anemias

Definition: A group of anemias characterized by a decreased production of red blood cells (RBCs) by the bone marrow. This is due to a problem with the bone marrow’s ability to produce RBCs, despite adequate nutrients (like iron, vitamin B12, and folate)
Hallmark: A low reticulocyte count (corrected reticulocyte count or reticulocyte production index) in the setting of anemia. This indicates that the bone marrow is not responding appropriately to the anemia by increasing RBC production
Key Feature: Reduced erythropoiesis (RBC production) in the bone marrow
Classification:
- Primary Bone Marrow Disorders: Intrinsic problems within the bone marrow itself (e.g., aplastic anemia, myelodysplastic syndromes)
- Secondary Causes: Extrinsic factors that suppress erythropoiesis (e.g., chronic kidney disease, endocrine disorders, anemia of chronic disease)

Key Concepts

Reticulocyte Response: In a normal, healthy individual with anemia, the bone marrow should respond by increasing RBC production, leading to an elevated reticulocyte count. In hypoproliferative anemias, this response is absent or inadequate
Bone Marrow Examination: A bone marrow aspiration and biopsy is often essential for diagnosing hypoproliferative anemias, as it provides direct information about the cellularity and maturation of the bone marrow
Exclusion of Other Causes: It’s important to rule out other causes of anemia (e.g., blood loss, hemolysis, nutritional deficiencies) before diagnosing a hypoproliferative anemia

Causes of Hypoproliferative Anemias

Primary Bone Marrow Disorders:
- Aplastic Anemia (AA):
  - Definition: Bone marrow failure characterized by pancytopenia (decreased RBCs, WBCs, and platelets) and a hypocellular bone marrow
  - Etiology: Can be acquired (idiopathic, autoimmune, drug-induced, radiation-induced, infection-related) or inherited (e.g., Fanconi anemia)
  - Pathophysiology: Damage to or destruction of hematopoietic stem cells (HSCs) in the bone marrow, leading to reduced production of all blood cell lines
  - Clinical Features:
    - Anemia (fatigue, weakness, pallor)
    - Thrombocytopenia (bleeding, bruising)
    - Neutropenia (increased susceptibility to infections)
  - Laboratory Findings:
    - CBC: Pancytopenia (low HGB, HCT, RBC count, WBC count, and platelet count)
    - Peripheral Blood Smear: Normocytic, normochromic RBCs; absence of abnormal cells
    - Reticulocyte Count: Very low (hallmark finding)
    - Bone Marrow Examination: Hypocellular marrow with decreased or absent hematopoietic cells
    - Flow cytometry: May show decreased or abnormal hematopoietic stem cells
  - Treatment:
    - Supportive care:
      - Transfusions (RBCs and platelets) to alleviate symptoms
      - Antibiotics to treat infections
    - Immunosuppressive Therapy:
      - To suppress the autoimmune attack on bone marrow stem cells
      - Antithymocyte globulin (ATG)
      - Cyclosporine
    - Hematopoietic Stem Cell Transplantation (HSCT):
      - Potentially curative option, especially for younger patients with matched donors
      - Involves replacing the patient’s damaged bone marrow with healthy stem cells from a donor
- Myelodysplastic Syndromes (MDS):
  - Definition: A group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia (AML)
  - Etiology: Acquired mutations in hematopoietic stem cells
    - Risk factors: Advanced age, exposure to certain chemicals or radiation, prior chemotherapy or radiation therapy
  - Pathophysiology: Dysplastic (abnormal) development of one or more myeloid cell lines (RBCs, WBCs, platelets), leading to cytopenias and increased risk of AML
  - Clinical Features:
    - Anemia (fatigue, weakness, pallor)
    - Thrombocytopenia (bleeding, bruising)
    - Neutropenia (infections)
  - Laboratory Findings:
    - CBC: Cytopenias (anemia, thrombocytopenia, leukopenia)
    - Peripheral Blood Smear: Dysplastic features in one or more cell lines
      - RBCs: Oval macrocytes, hypochromia, basophilic stippling
      - Neutrophils: Pseudo-Pelger-Huët anomaly (bi-lobed neutrophils), hypogranulation
      - Platelets: Large platelets, abnormal granulation
    - Reticulocyte Count: Low or normal (inappropriately low for the degree of anemia)
    - Bone Marrow Examination: Hypercellular or hypocellular marrow with dysplasia in one or more cell lines
    - Cytogenetic Analysis: Chromosomal abnormalities (e.g., deletion 5q, trisomy 8) are common
  - Treatment:
    - Supportive care:
      - Transfusions to manage anemia and thrombocytopenia
      - Growth factors (e.g., erythropoietin, G-CSF) to stimulate blood cell production
      - Antibiotics to treat infections
    - Hypomethylating Agents:
      - Azacitidine and decitabine: Improve hematopoiesis and reduce the risk of AML transformation
    - Lenalidomide:
      - Used for patients with MDS with deletion 5q
    - Hematopoietic Stem Cell Transplantation (HSCT):
      - Potentially curative option for younger patients with high-risk MDS
- Pure Red Cell Aplasia (PRCA):
  - Definition: Selective destruction of erythroid precursors in the bone marrow, leading to severe anemia with a marked decrease in reticulocytes
  - Etiology:
    - Acquired:
      - Autoimmune: Antibodies against erythroid precursors or erythropoietin
      - Infections: Parvovirus B19 infection (especially in patients with chronic hemolytic anemias)
      - Drug-induced: Certain medications (e.g., erythropoietin, immunosuppressants)
      - Thymoma: Tumor of the thymus gland
    - Inherited: Diamond-Blackfan anemia
  - Pathophysiology:
    - Autoantibodies or cytotoxic T cells target and destroy erythroid precursors (CFU-Es and proerythroblasts) in the bone marrow
    - Parvovirus B19 directly infects and destroys erythroid precursors
  - Clinical Features:
    - Severe anemia
    - Absence of other cytopenias (normal WBC and platelet counts)
  - Laboratory Findings:
    - CBC: Severe anemia with normal WBC and platelet counts
    - Peripheral Blood Smear: Normocytic, normochromic RBCs; absence of abnormal cells
    - Reticulocyte Count: Very low (near zero)
    - Bone Marrow Examination: Normal cellularity with a marked decrease or absence of erythroid precursors
    - Antibody Testing: May detect antibodies against erythroid precursors or erythropoietin
    - Parvovirus B19 PCR: To detect parvovirus B19 infection
  - Treatment:
    - Treat Underlying Cause:
      - Discontinue offending medications
      - Treat infections (e.g., parvovirus B19)
      - Remove thymoma (if present)
    - Immunosuppressive Therapy:
      - Corticosteroids
      - Cyclosporine
    - Intravenous Immunoglobulin (IVIG):
      - May be used in parvovirus B19-related PRCA
    - Blood Transfusions:
      - To manage severe anemia
    - Erythropoiesis-Stimulating Agents (ESAs):
      - May be effective in some cases, especially if EPO levels are low
Secondary Causes of Hypoproliferative Anemia:
- Chronic Kidney Disease (CKD):
  - Decreased erythropoietin (EPO) production by the kidneys
  - Uremic toxins can also suppress erythropoiesis
  - Treatment:
    - Erythropoiesis-stimulating agents (ESAs)
    - Iron supplementation
- Endocrine Disorders:
  - Hypothyroidism: Decreased thyroid hormone can reduce erythropoiesis
  - Hypopituitarism: Decreased production of hormones that stimulate erythropoiesis (e.g., growth hormone, androgens)
  - Treatment: Hormone replacement therapy
- Anemia of Chronic Disease/Inflammation:
  - Chronic inflammation leads to increased hepcidin production, which impairs iron release and reduces erythropoiesis
  - Treatment:
    - Treat underlying inflammatory condition
    - Erythropoiesis-stimulating agents (ESAs) (use cautiously)
- Nutritional Deficiencies (Less Common Cause of Hypoproliferative Anemia):
  - Severe protein-calorie malnutrition
  - Scurvy (vitamin C deficiency)
  - These deficiencies primarily affect RBC maturation but can also impair erythropoiesis
  - Treatment: Correct the underlying nutritional deficiency

Key Laboratory Findings in Hypoproliferative Anemias

Complete Blood Count (CBC):
- Anemia (low HGB and HCT)
- MCV: Can be normocytic, microcytic, or macrocytic, depending on the underlying cause
Peripheral Blood Smear:
- RBC morphology: Usually normocytic and normochromic, but may show abnormalities depending on the cause (e.g., oval macrocytes in MDS)
Reticulocyte Count:
- Low (hallmark finding)
Iron Studies:
- Variable, depending on the underlying cause
Serum Erythropoietin (EPO) Level:
- May be low, normal, or elevated, depending on the underlying cause
Bone Marrow Examination:
- Essential for diagnosis
- Cellularity: Can be hypocellular (aplastic anemia) or normocellular/hypercellular (MDS)
- Maturation: May show dysplastic features (MDS) or a selective decrease in erythroid precursors (PRCA)
- Cytogenetics: To detect chromosomal abnormalities in MDS
- Special stains and flow cytometry: To evaluate for specific abnormalities

Key Terms

Hypoproliferative Anemia: Anemia due to decreased red blood cell production
Aplastic Anemia: Bone marrow failure with pancytopenia and hypocellular marrow
Myelodysplastic Syndromes (MDS): Clonal hematopoietic stem cell disorders with ineffective hematopoiesis
Pure Red Cell Aplasia (PRCA): Selective destruction of erythroid precursors in the bone marrow
Reticulocyte Count: Measure of new red blood cell production
Bone Marrow Examination: Aspiration and biopsy to assess the cellularity and maturation of blood cell precursors
Erythropoietin (EPO): Hormone that stimulates red blood cell production
Cytopenia: Deficiency of blood cells (e.g., anemia, neutropenia, thrombocytopenia)
Dysplasia: Abnormal cell development

Acquired Hemolytic

Acute Hemorrhage