• Decreased bone marrow production or bone marrow failure
• Clonal disorders of haematopoiesis
• Increased non-immune-mediated destruction or sequestration
• Immune-mediated destruction of blood cells.

Etiologies

Pancytopenia With Hypocellular Bone Marrow

• Acquired aplastic anemia Inherited aplastic anemia (Fanconi anemia and others)
• Some myelodysplasia syndromes
• Rare aleukemic leukemia (acute myelogenous leukemia)
• Some acute lymphoblastic leukemias
• Some lymphomas of bone marrow

Hypocellular Bone Marrow ± Cytopenia

• Q fever
• Legionnaires disease
• Mycobacteria
• Tuberculosis* Pancytopenia in tuberculosis only rarely is associated with a hypocellular bone marrow at biopsy or autopsy. Marrow failure in the setting of tuberculosis is almost always fatal; exceptional patients probably had underlying myelodysplasia or acute leukemia.
• Anorexia nervosa, starvation
• Hypothyroidism

Pancytopenia With Cellular Bone Marrow

• Primary bone marrow diseases

  • Myelodysplasia syndromes
  • Paroxysmal nocturnal hemoglobinuria
  • Myelofibrosis
  • Some aleukemic leukemias
  • Myelophthisis
  • Bone marrow lymphoma
  • Hairy cell leukemia

• Secondary to systemic diseases

  • Systemic lupus erythematosus, Sjögren syndrome
  • Hypersplenism
  • Vitamin B 12 , folate deficiency (familial defect)
  • Overwhelming infection
  • Alcohol
  • Brucellosis
  • Ehrlichiosis
  • Sarcoidosis
  • Tuberculosis and atypical mycobacteria

Decreased bone marrow production

After birth, the bone marrow is the site of production of RBCs, WBCs, and immature platelets. Once the cells are made they are released into the peripheral circulation. For this process to occur, adequate haematopoietic stem cell activity is required along with a functional bone marrow stromal environment. In addition, the high proliferative rate of the marrow requires adequate nutritional status, particularly vitamin B12 and folic acid, and trace amounts of other elements.

• Chemotherapy is a common cause of transient pancytopenia, although this rarely presents a diagnostic dilemma, most commonly resolving within 1 to 2 weeks. Some regimens are associated with significantly longer periods of pancytopenia. The most common cause of transient pancytopenia in all age groups is cytotoxic chemotherapy and radiotherapy.
• Although most cases of megaloblastic anaemia cause a macrocytic anaemia without leukopenia or thrombocytopenia, severe megaloblastic anaemia can result in pancytopenia. Megaloblastic anaemia most commonly arises from deficiency of vitamin B12 (e.g., pernicious anaemia, an autoimmune condition where autoantibodies interfere with the function of intrinsic factor, which is required for absorption of vitamin B12 within the GI tract). Less commonly, B12 deficiency is caused by dietary deficiency (in vegans) or by malabsorption in the gut.
• Folic acid deficiency, almost always dietary in origin, also results in megaloblastic anaemia.
• Infiltration of the bone marrow is a common cause of pancytopenia and commonly results from malignant disease. In general, the infiltrate is cellular and may be of haematological origin (e.g., acute myeloid and lymphoblastic leukaemia, myeloma, non-Hodgkin's lymphoma, hairy cell leukaemia, chronic lymphocytic leukaemia, and myelofibrosis) or non-haematological malignancies (e.g., breast, lung, kidney, prostate, and thyroid). In children, pancytopenia can be caused by neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, and retinoblastoma.
• Lysosomal storage disorders (e.g., Gaucher's disease) can infiltrate the marrow, resulting in pancytopenia. The infiltrate may be largely reticulin fibrosis, which is also associated with malignant conditions. Gaucher's disease patients may have massive splenomegaly and functional hypersplenism in addition to infiltration of the bone marrow.
• Rarer causes of pancytopenia arising from decreased bone marrow production of blood cells include anorexia nervosa, transfusion-associated graft-versus-host disease in immunosuppressed patients, and heavy metal poisoning (e.g., arsenic). Infections such as HIV have also been associated with pancytopenia secondary to underproduction (see further below), as has parvovirus in individuals with specific predisposing conditions (most prominently sickle cell anaemia).

Clonal disorders of haematopoiesis

• Myelodysplasia (MDS) is a common acquired clonal disorder of haematopoietic cells, characterised by ineffective and dysplastic haematopoiesis and a propensity for evolution to acute myeloid leukaemia. The bone marrow may be either hypercellular or hypocellular. In both cases there is commonly peripheral blood pancytopenia. In addition to decreased or inadequate production of blood cells within the marrow, there is sometimes an immune-mediated mechanism contributing to the peripheral blood pancytopenia in MDS.
• Paroxysmal nocturnal haemoglobinuria (PNH) is a rare (1-2 cases per million general population) acquired clonal disorder of haematopoietic cells, caused by somatic mutation of the X-linked phosphatidylinositol glycan A gene and resulting in deficient expression of glycosylphosphatidylinositol-anchored proteins. PNH is clinically characterised by intravascular haemolysis and thrombosis, and evolution of pancytopenia is common (probably arising from a combination of decreased bone marrow production secondary to acquired defects in haematopoietic stem cells and cell destruction). There is an overlap in clinical and laboratory features between PNH patients and those with idiopathic aplastic anaemia (IAA).

Paroxysmal Nocturnal Hemoglobinuria (PNH)