32. Nonneoplastic bone marrow disorders (anaemia, leukocytosis and leukopenia, thrombocytopenia)

Page created on March 19, 2019. Not updated since.


Anaemia is defined as a reduction in the oxygen-transporting capacity of the blood, usually due to a decrease in the total RBC mass. Here are the approximate normal lab values related to RBCs:

Haemoglobin (Hb) 130 – 170 g/L
Haematocrit (Hct) 40 – 50 %
RBC count 4.2 – 5.6 x 106/ µL
Reticulocyte count 0.5 – 1.5 %
Mean corpuscular volume (MCV) 80 – 95 fL
Mean corpuscular haemoglobin (MCH) 25 – 35 pg
Mean corpuscular haemoglobin concentration 33 – 35 g/dL
RBC distribution width (RDW) 11.5 – 14.5%

Reticulocytes are immature RBCs. These account for only around 1% of all RBCs in the peripheral blood. The reticulocyte count is an important measure of the rate of production of RBCs.

The RDW measurement shows the range of variation of MCV in a sample; i.e. how many RBCs that are either too large or too small. Too high RDW is called anisocytosis, meaning that the size of the RBCs is more variable than normal.

Anaemia causes symptoms like pallor, fatigue and weakness. Depending on the cause can other symptoms occur, like jaundice or haemochromatosis occur.

Anaemias can be classified according to their cause:

  • Blood loss
    • Acute blood loss
    • Chronic blood loss
  • Reduced production of RBCs
    • Reduced proliferation
      • Aplastic anaemia
      • Myelophthisic anaemia
      • Anaemia of chronic disease
    • Reduced maturation
      • Iron deficiency anaemia
      • Megaloblastic anaemia
  • Increased destruction of RBCs
    • Intrinsic RBC defects
      • Hereditary spherocytosis
      • Sickle cell anaemia
      • Thalassaemia
    • Extrinsic RBC defects
      • Autoimmune haemolytic anaemia
      • Microangiopathy haemolytic anaemia
Blood loss-related anaemia

During acute blood loss of more than 20% of the blood volume is the threat of exsanguination (hypovolaemic shock due to blood loss) and death more important than that of anaemia. If the patient survives this will the fluid content of the blood be replenished but not the RBCs. This causes haemodilution, with a resulting anaemia which is normocytic and normochromic. This stimulates EPO production, which eventually replaces the lost RBCs.

During chronic blood loss is the level of EPO chronically high, meaning that the RBC production works at an accelerated rate continuously. This requires large amounts of iron. If the person is not able to keep up the iron intake will the body’s iron stores eventually be depleted, causing iron deficiency anaemia.

Reduces RBC production

Reduced RBC production in the bone marrow can occur either if the RBC precursors aren’t proliferating like normal, or if the precursors aren’t maturing correctly.

Aplastic anaemia is a condition where the multipotent myeloid stem cells in the bone marrow are suppressed. This leads to bone marrow failure and pancytopaenia. The bone marrow is hypocellular, with more than 90% of the intertrabecular space being occupied by fat. The remaining cells are mostly lymphocytes and plasma cells.

Aplastic anaemia is idiopathic in more than half the cases. The remaining cases may be due to drugs (like chloramphenicol), hepatitis viruses, thymoma, inherited conditions (Fanconi anaemia) or irradiation. The pathomechanism may involve autoreactive T-cells that target and destroy the bone marrow cells.

Myelophthisic anaemia or simply myelophthisis is similar to aplastic anaemia, except in this case the bone marrow is replaced by primary tumors, metastasis, fibrosis, granulomatous inflammation, lipid storage disease or other lesions and not fat.

In this condition is there anaemia and thrombocytopaenia; white blood cells are less affected. Characteristically misshapen RBCs that resemble teardrops are seen in peripheral blood, together with immature white and red blood cells.

Anaemia of chronic disease is a very common cause of anaemia in hospitalized patients. Any condition that causes chronic inflammation, like chronic renal disease, rheumatoid arthritis, IBD or malignancies gives high levels of the acute phase protein hepcidin. This protein decreases the effect of EPO on the bone marrow, while reducing the intestinal absorption of iron and locking iron away inside macrophages.

Iron deficiency anaemia is the most common cause of anaemia worldwide. Iron is required for heme synthesis, and an iron deficiency therefore causes the produced RBCs to contain less haemoglobin. Iron deficiency may occur due to:

  • Decreased intake
    • Insufficient diet
  • Decreased absorption
    • Atrophic gastritis
    • IBD
    • Malabsorption syndrome
    • Coeliac disease
  • Increased demand
    • Pregnancy
    • Infancy
  • Increased loss
    • GI bleeding
    • Menorrhagia

Iron deficiency anaemia develops slowly as the iron stores take time to become depleted. Blood tests shows microcytic hypochromic anaemia with anisocytosis.

Megaloblastic anaemia is an umbrella term for folate deficiency anaemia and vitamin B12 deficiency anaemia. Both cause macrocytic hyperchromic anaemia with anisocytosis. The name “megaloblastic” comes from the presence of megaloblasts in the peripheral blood, which are large RBC precursor cells.

Folate and B12 are both involved in DNA synthesis. When either of these is deficient will the nuclear maturation and cell division that should normally occur during haematopoiesis be impaired. Many developing cells have so defective DNA that they die before maturing, which decreases the number of functioning RBCs produced. Granulocyte and thrombocyte precursors are also affected, causing patients to present with pancytopaenia.

Folate deficiency may occur in:

  • Pregnancy
  • Obesity
  • Malabsorption
  • Inadequate diet

B12 deficiency may occur in:

  • Inadequate diet
  • Autoimmune gastritis
  • Pernicious anaemia
  • Terminal ileitis (Crohn’s disease)

Pernicious anaemia does not refer to any B12 deficiency. Rather, it is an autoimmune condition where autoantibodies against gastric parietal cells causes deficiency of intrinsic factor, which then decreases the absorption of B12.

Increased RBC destruction

Increased RBC destruction or haemolytic anaemias may occur either due to intrinsic defects of the RBCs or due to extrinsic factors. Increased breakdown of RBCs means increased levels of bilirubin, which may cause symptoms like prehepatic jaundice or cholelithiasis.

Hereditary spherocytosis is a (mostly) autosomal dominant disease where some RBC membrane proteins are defective. This causes the RBCs to be more vulnerable to haemolysis and osmotic stress. The name comes from the characteristic finding of spherocytes, dark red nondeformable cells without central pallor.

These spherocytes work more or less normally, however they are sequestrated and destroyed in the spleen. Splenomegaly, anaemia and cholelithiasis are common. The clinical course if often stable but may be worsened by aplastic crises, episodes of decreased RBC production. This may be triggered by parvovirus B19 infection.

Sickle cell anaemia is the most common haemoglobinopathy. It’s a condition where the some or all the normal haemoglobin in the RBCs is replaced by an abnormal form of haemoglobin, HbS. A point mutation in the gene for the beta chain of haemoglobin is what causes this condition. Heterozygotes with this mutation have about 50% of their Hb replaced by HbS while homozygotes have only HbS.

HbS, unlike normal Hb, polymerizes when deoxygenated, which causes the RBC to take on a sickle-shape. Repeated episodes of “sickling” causes membrane damage to the RBCs, causing chronic haemolytic anaemia. The sickled cells also have increased tendency to obstruct microvessels, potentially causing ischaemic tissue damage.

Sickle cell anaemia provides some protection against infection by malaria, which is the reason that sickle cell anaemia is most common in regions of Africa where malaria is endemic.

People suffering from sickle cell anaemia may also experience aplastic crises during parvovirus B19 infection. The condition also causes splenomegaly, splenic fibrosis and increased susceptibility to pneumococcus infection.

Thalassaemias are a group of haemoglobinopathies. It involves mutations of the genes coding for the α-globin or β-globin part of haemoglobin. Our genome contains four copies (alleles) of α-globin but only two for β-globin. The severity of the thalassaemia depends on the number and type of lost (mutated) alleles. Mild forms of this condition also provide protection against malaria and therefore is more prevalent around the Mediterranean sea and in Africa.

α-thalassaemia is a spectrum of four different conditions, depending on how many of the four genes are lost:

Clinical syndrome Genotype Clinical features
Silent carrier -/α, α/α (1 allele lost) Asymptomatic
α-thalassaemia trait -/-, α/α or -/α, -/α (2 alleles lost) Asymptomatic or mild anaemia
Haemoglobin H disease -/-, -/α (3 alleles lost) Severe anaemia
Haemoglobin Barts / Hydrops foetalis -/-, -/- (4 alleles lost) Usually peripartum death

Haemoglobin H and haemoglobin Barts both have abnormally high affinity for oxygen, which makes them useless at delivering oxygen to tissues. Hydrops foetalis is a condition where fluid accumulates in fluid compartments like the peritoneal cavity, pleural cavity or pericardial cavity in the foetus. It occurs due to foetal anaemia of any cause. These foetuses may receive blood transfusions while still in the womb, which allows them to survive the birth, but if they do they’ll experience abnormal growth development later.

β is a spectrum of three different conditions. These conditions are more complicated from a genetic perspective as they don’t involve deletion of whole alleles but rather small mutations that may either reduce or abolish the synthesis of β-globin.

Clinical syndrome Genotype Clinical features
β-thalassaemia minor Heterozygous (β*/β) Asymptomatic or mild anaemia
β-thalassaemia intermedia Variable (β*/β or β**) Severe anaemia
β-thalassaemia major Homozygous (β**) Severe anaemia, regular blood transfusions required

Here β* indicates a mutated β-globin gene. The major type has more severe mutations than the intermedia type.

The reduced synthesis of β-globin causes RBCs to be hypochromic and microcytic. To compensate will α-globin be overproduced, however these α-chains will precipitate in the cells, which causes them to be unstable and prone to haemolysis. These cells die during erythropoiesis or when they are sequestrated by the spleen.

Autoimmune haemolytic anaemia (AIHA) occurs when the body begins to produce antibodies against a person’s own RBCs, causing them to lyse. It’s idiopathic in 50% of cases, but it may also be part of some other autoimmune disease like SLE. Certain drugs like penicillin and α-methyldopa may also induce this. It may also be a consequence of a B-cell lymphoma.

Antibodies bind to the RBCs and causes complement factors to bind as well, which causes the cell to lyse. The antibodies also opsonize the RBCs, so that they are phagocytosed by macrophages.

Microangiopathic haemolytic anaemia occurs when small vessels become partially obstructed or narrowed, which causes RBCs that flow through them to be damaged. This obstruction can be caused by DIC, haemolytic uraemic syndrome or thrombotic thrombocytopaenic purpura.


Erythrocytosis means the elevated RBC count in the blood. Polyglobulia means the increased Hb concentration, and polycythaemia means increased red blood cell mass.

I wish pathology department and pathophysiology department could agree on these definitions…

Polycythaemia can be either primary or secondary. Primary polycythaemia occurs in the disease polycythaemia vera, which is a neoplastic condition and will therefore be detailed in topic 34. Secondary polycythaemia has been described at length in pathophysiology, but here are some causes:

  • Cyanotic heart disease
  • Lung disease
  • Sleep apnoea syndrome
  • Renal artery stenosis
  • Drugs
  • Paraneoplastic syndrome (EPO-producing tumors like HCC or RCC)

Leukopaenia means a white cell count below 4000 cells/µL. Neutropaenia means a neutrophil count below 1500 cells/µL. Agranulocytosis means a neutrophil count below 100 cells/µL.

Leukopaenia can be caused by:

  • Reduced production
    • Aplastic anaemia
    • Myelophthisis
    • Chemotherapy
  • Increased destruction
    • Immunological damage
    • Splenomegaly
    • Overwhelming infections – these infections “consume” the WBCs by moving them from the circulation to the tissue

The neutrophils accounts for the majority of WBCs and the consequences of leukopaenia is therefore similar to those of neutropaenia:

  • Increased susceptibility to bacterial or fungal infections
  • Frequent necrotizing lesions in the oral cavity
  • Frequent airway infections

The bone marrow can be hypocellular or hypercellular, depending on the cause of the leukopaenia.


Leukocytosis means a white cell count above 10 000 cells/µL. A leukemoid reaction is a severe leukocytosis where immature WBC precursors are also present in the blood. This type of reaction may resemble a haematopoietic malignancy.

Different etiologies gives different types of leukocytosis:

  • Bacterial infection – granulocytosis
  • Viral infection – lymphocytosis
  • Allergic reaction – eosinophilia
  • Paraneoplastic syndrome
    • Hodgkin lymphoma
    • Plasma cell myeloma/multiple myeloma

Thrombocytosis means a platelet count of above 400 000/µL. It may be caused by:

  • Chronic inflammation – inflammatory cytokines stimulate thrombopoiesis
    • IBD
    • Rheumatoid arthritis
    • Tuberculosis
  • Paraneoplastic syndrome
  • Myeloproliferative diseases
  • Iron deficiency

Thrombocytopaenia means a platelet count of below 150 000/µL. It may be caused by:

  • Reduced production
    • Aplastic anaemia
    • Myelophthisis
  • Reduced survival
    • Immune thrombocytopaenia
    • Thrombotic thrombocytopaenic purpura
    • Haemolytic uraemic syndrome
    • DIC
  • Increased sequestration
    • Hypersplenism

Between approx. 30 000 – 150 000/µL is the major symptom prolonged bleeding time. Below this point however there will be spontaneous bleeding.

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31. T/NK cell lymphomas

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33. AML and MDS

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Theoretical exam topics

2 thoughts on “32. Nonneoplastic bone marrow disorders (anaemia, leukocytosis and leukopenia, thrombocytopenia)”

  1. Most anaemias you’ve mentioned are not bone marrow related! Do you think we should know them as for this topic in exam?

    1. I think they consider all types of anaemia as disorders of the bone marrow. They’re all included on the lecture, so I think they are important, yes.

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