Production

Overview of Thrombocytopenia due to Decreased Production

Definition: A type of thrombocytopenia (low platelet count) resulting from a decreased rate of platelet production by megakaryocytes in the bone marrow. The bone marrow simply isn’t making enough platelets
Key Feature: The bone marrow is hypoactive (producing too few megakaryocytes) or ineffective (megakaryocytes are present but are not producing enough platelets). This can often be identified with a bone marrow aspirate and biopsy
Reticulated Platelets: Reticulated platelets, also known as immature platelets, are newly released platelets that contain RNA. A low count can correlate with a decreased rate of platelet production
Etiology: Can be caused by a variety of factors, including bone marrow disorders, infections, medications, and nutritional deficiencies
General Mechanisms:
- Damage or destruction of megakaryocytes (the platelet precursor cells in the bone marrow)
- Impaired megakaryocyte proliferation and differentiation
- Disruption of thrombopoietin (TPO) signaling

Specific Causes of Thrombocytopenia due to Decreased Production

Bone Marrow Failure or Infiltration
- Aplastic Anemia:
  - Definition: Bone marrow failure characterized by pancytopenia (decreased RBCs, WBCs, and platelets) and a hypocellular bone marrow
  - Pathophysiology: Damage to or destruction of hematopoietic stem cells (HSCs) in the bone marrow, leading to reduced production of all blood cell lines, including megakaryocytes
  - Causes:
    - Acquired:
      - Idiopathic (most common) - thought to be autoimmune in many cases
      - Drug-induced (e.g., chloramphenicol, sulfonamides, NSAIDs)
      - Chemical exposure (e.g., benzene)
      - Radiation exposure
      - Infections (e.g., parvovirus B19, EBV, HIV)
      - Autoimmune disorders
    - Inherited:
      - Fanconi anemia
      - Dyskeratosis congenita
  - 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: Low
    - Bone Marrow Examination: Hypocellular marrow with decreased or absent hematopoietic cells (including megakaryocytes)
    - Flow cytometry: May show decreased or abnormal hematopoietic stem cells
  - Clinical Features:
    - Symptoms of anemia (fatigue, weakness, pallor)
    - Symptoms of thrombocytopenia (bleeding, bruising)
    - Symptoms of neutropenia (increased susceptibility to infections)
  - Treatment:
    - Supportive Care:
      - Transfusions (RBCs and platelets) to alleviate symptoms
      - Antibiotics to treat infections
    - Immunosuppressive Therapy:
      - Antithymocyte globulin (ATG)
      - Cyclosporine
    - Hematopoietic Stem Cell Transplantation (HSCT):
      - Potentially curative option, especially for younger patients with matched donors
- Myelodysplastic Syndromes (MDS):
  - Definition: A group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplasia in one or more cell lines, and a variable risk of progression to acute myeloid leukemia (AML)
  - Pathophysiology:
    - Genetic mutations impair the differentiation and maturation of hematopoietic cells, leading to cytopenias and dysplasia
    - Dysplastic megakaryocytes may have abnormal morphology and decreased platelet production
  - Causes:
    - Acquired mutations in hematopoietic stem cells
    - Risk factors: Advanced age, exposure to certain chemicals or radiation, prior chemotherapy or radiation therapy
  - Laboratory Findings:
    - CBC: Cytopenias (anemia, thrombocytopenia, leukopenia)
    - Peripheral Blood Smear: Dysplastic features in one or more cell lines
      - Abnormal megakaryocytes (e.g., micromegakaryocytes, hypolobated megakaryocytes)
      - Large platelets, abnormal granulation
    - Bone Marrow Examination:
      - Hypercellular or hypocellular marrow with dysplasia in one or more cell lines
      - Increased megakaryocytes with abnormal morphology
    - Cytogenetic Analysis: Chromosomal abnormalities are common (e.g., deletion 5q)
  - Clinical Features:
    - Symptoms of anemia (fatigue, weakness, pallor)
    - Bleeding and bruising due to thrombocytopenia
    - Increased susceptibility to infections due to neutropenia
  - Treatment:
    - Supportive care: Transfusions, growth factors
    - Hypomethylating Agents: Azacitidine and decitabine
    - Lenalidomide: Used for MDS with deletion 5q
    - Hematopoietic Stem Cell Transplantation (HSCT): Potentially curative
- Bone Marrow Infiltration:
  - Metastatic Cancer: Cancer cells from solid tumors can infiltrate the bone marrow, crowding out normal hematopoietic cells, including megakaryocytes
  - Lymphoma: Infiltration of the bone marrow by lymphoma cells can suppress megakaryopoiesis
  - Myeloma: Infiltration of the bone marrow by plasma cells in multiple myeloma can suppress megakaryopoiesis
  - Laboratory Findings:
    - CBC: Cytopenias (including thrombocytopenia)
    - Peripheral Blood Smear: May show abnormal cells (e.g., tumor cells, lymphoma cells)
    - Bone Marrow Examination: Evidence of infiltration by malignant cells
Infection
- Viral Infections:
  - HIV: Can directly infect and damage megakaryocytes, leading to decreased platelet production
  - Parvovirus B19: Can transiently suppress erythropoiesis and, less commonly, thrombocytopoiesis
  - Other viral infections (e.g., EBV, CMV) can also cause thrombocytopenia through various mechanisms
- Bacterial Infections:
  - Sepsis: Severe systemic infection can lead to bone marrow suppression and decreased platelet production
Nutritional Deficiencies
- Vitamin B12 Deficiency:
  - Impaired DNA synthesis affects megakaryocyte maturation and platelet production
- Folate Deficiency:
  - Impaired DNA synthesis affects megakaryocyte maturation and platelet production
- Iron Deficiency Anemia:
  - Severe iron deficiency can impair megakaryopoiesis and platelet production
Medications
- Chemotherapy: Cytotoxic agents can damage megakaryocytes and suppress platelet production
- Alcohol: Chronic alcohol abuse can impair megakaryopoiesis
- Thiazide Diuretics: Can cause thrombocytopenia in some individuals

Key Laboratory Findings

Complete Blood Count (CBC):
- Thrombocytopenia (platelet count < 150 x 10^9/L)
- May see other cytopenias (anemia and/or leukopenia), depending on the underlying cause
Peripheral Blood Smear:
- Decreased number of platelets
- May see normal or abnormal platelets (depending on the cause)
- May see other abnormal cells (e.g., blasts, tumor cells, dysplastic cells)
Reticulocyte Count:
- In cases of isolated thrombocytopenia, the reticulocyte count will be normal
- If there is concurrent anemia, the reticulocyte count will help to classify the anemia:
  - High reticulocyte count: Suggests increased RBC destruction or blood loss
  - Low reticulocyte count: Suggests decreased RBC production
Bone Marrow Aspiration and Biopsy:
- Essential for evaluating the cause of thrombocytopenia
- Assess cellularity of the bone marrow
- Evaluate megakaryocyte number and morphology
- Rule out bone marrow disorders (e.g., aplastic anemia, MDS, bone marrow infiltration)
Other Tests:
- Vitamin B12 and Folate Levels: To rule out nutritional deficiencies
- HIV Testing: To rule out HIV-associated thrombocytopenia
- HepC Testing: To rule out HepC-associated thrombocytopenia
- Parvovirus B19 PCR: To rule out parvovirus B19 infection
- Antinuclear Antibody (ANA) Testing: To evaluate for autoimmune disorders

Key Terms

Thrombocytopenia: Decreased platelet count
Megakaryocytes: Bone marrow cells that produce platelets
Aplastic Anemia: Bone marrow failure with pancytopenia and hypocellular marrow
Myelodysplastic Syndromes (MDS): Clonal hematopoietic stem cell disorders with ineffective hematopoiesis and dysplasia
Pancytopenia: Deficiency of all blood cell lines (RBCs, WBCs, platelets)
Hypocellular: Decreased cellularity in the bone marrow
Dysplasia: Abnormal cell development or maturation
Thrombopoietin (TPO): Hormone that stimulates platelet production

Destruction

Pseudo