Mednotes

L02 Blood Introduction to Anaemias

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aliasesL02 Blood Introduction to Anaemias

16 min read

Overview

This lecture introduces anaemia: what it is, how it is recognised clinically and from the blood count, and the two complementary ways of classifying it (by red cell size/morphology and by underlying cause). It then works through the main categories in turn - microcytic (iron deficiency, thalassaemias, anaemia of inflammation), macrocytic (megaloblastic and non-megaloblastic), normocytic (renal, post-haemorrhagic, marrow disease), and haemolytic anaemias - before closing on anaemia as part of pancytopenia and pointers to self-study cases.

Defining and recognising anaemia

  • Anaemia = a reduced haemoglobin (Hb) level relative to what is normal for the person’s age, sex (hormonal effects) and physiological state (e.g. pregnancy).
  • NZ adult reference ranges: female 115-155 g/L, male 130-175 g/L.
  • Severity by Hb: mild >~100 g/L, moderate 70-100 g/L, severe <70 g/L.
  • Symptoms (what the patient experiences): often none if mild; weakness, fatigue; shortness of breath; palpitations (“heart racing”); feeling cold; if coexisting vascular disease - angina (ischaemic heart pain), claudication (ischaemic leg pain).
  • Signs (clinical examination): pallor of mucous membranes; increased pulse rate; in severe anaemia, heart failure; if vascular disease coexists, myocardial ischaemia on ECG/exercise test; confusion from inadequate oxygen delivery.

Classifying anaemia

Two classifications are used together, and they answer different questions.

By the blood count (descriptive, guides next tests, not a cause-based classification):

  • Is Hb normal / reduced / raised → normal / anaemia / polycythaemia?
  • Are the cells microcytic / normocytic / macrocytic (by MCV, reference range 80-99 fL)?

By aetiology (cause):

  • Increased loss or destruction: blood loss followed by haemodilution (e.g. acute trauma, surgery); haemolysis (increased rate of red cell breakdown), which can be inherited (membrane, enzyme, some Hb abnormalities) or acquired (antibodies, drugs, heart valves, etc.).
  • Impaired red cell production: disturbed maturation of erythroblasts from deficiencies (iron, folate, vitamin B12) or globin gene abnormalities; or disturbances of bone marrow/stem cell proliferation (wide variety of causes).

Combined (morphology x aetiology) table:

  • Reduced production, microcytic: iron deficiency, thalassaemias.
  • Reduced production, normocytic: anaemia of renal disease, malignancy, bone marrow disease.
  • Reduced production, macrocytic: megaloblastic anaemia, liver disease, alcohol, (myelodysplasia).
  • Anaemia of inflammation spans microcytic/normocytic, with a tendency to microcytosis.
  • Increased loss/destruction, normocytic: haemolytic anaemias (inherited - membrane, enzyme, thalassaemia, HbS; acquired - autoimmune, immune drug-related, drugs) and acute bleeding with haemodilution. No entries listed for microcytic/macrocytic in this row.

The reticulocyte count: reticulocytes are 1-2 day old red cells just released from the marrow, still containing RNA and other organelles. When bleeding or abnormal red cell destruction occurs, EPO stimulates the marrow and the reticulocyte count rises; if the marrow itself is not working (e.g. drugs, cancer), the reticulocyte count is low. Automated analysers use a fluorescent dye to count reticulocytes; a manual retic stain shows the RNA as blue granular/reticular material inside the cell. Normal reticulocyte count: 20-100 x10^9/L (1-2%).

Haemoglobin and the “bag of haemoglobin” concept

  • Iron + protoporphyrin = haem; haem + globin peptides = haemoglobin.
  • HbA is a tetramer of 4 globin chains (2 alpha, 2 beta), each carrying one haem group with a central iron atom.
  • A mature red cell is essentially a skeleton, a few enzymes, and a large amount of haemoglobin. If less Hb is produced during maturation, the cell ends up smaller and paler - this is the basis of microcytic, hypochromic anaemias.

Microcytic anaemias

Cells contain less haemoglobin than normal. Three main causes:

  • Iron deficiency: unable to make normal amounts of Hb.
  • Thalassaemias: reduced production of alpha or beta globin protein.
  • Anaemia of inflammation: iron becomes unavailable to the red cells.
    All three produce a reduced amount of haemoglobin per cell and small red cells.

Iron deficiency

  • The most common cause of anaemia; it is not itself a disease but a laboratory sign reflecting either blood loss or poor iron absorption.
  • Red cells normally obtain iron from bone marrow macrophages; immature (nucleated) red cells cluster around an iron-rich macrophage. Lack of iron stores leads to small, pale red cells.
  • Laboratory picture: microcytic (low MCV on the analyser), hypochromic (low MCH, or pale cells microscopically).
  • Ferritin is the best test of iron stores; ferritin is usually <20 ug/L in iron deficiency anaemia.
  • Response to iron therapy: red cell volume histograms can show a bimodal (“double population”) pattern as a new population of larger, well-filled red cells appears alongside the old microcytic population.

Thalassaemias

  • A family of genetic diseases causing reduced production of either the alpha or beta globin chain of haemoglobin, varying in severity; produce microcytic anaemia with iron stores usually normal or raised. Blood films can show target cells (central dark “bullseye” dot).
  • Normal globin genetics: two alpha genes (alpha2, alpha1) on chromosome 16 pair with beta, delta or gamma genes on chromosome 11 to form HbA (majority), HbA2 (<3.5%, alpha+delta) and HbF (<1%, alpha+gamma).
  • Alpha thalassaemia: deletion of one or more of the alpha globin gene copies on chromosome 16. Reduced alpha chain production means excess beta chains form abnormal beta tetramers (HbH), and excess gamma chains form abnormal gamma tetramers (Hb Barts).
  • Beta thalassaemia: mutation in the beta globin gene on chromosome 11, reducing/abolishing its contribution to HbA. Compensatory increased pairing of alpha chains with delta and gamma genes occurs, raising HbA2 (>3.5%) and HbF (>1%) - i.e. relatively more delta and gamma expression.

Anaemia of inflammation (anaemia of chronic disease)

  • Normocytic or microcytic depending on severity; mild to moderate anaemia.
  • Main cause: lack of iron availability (low serum iron), caused by liver release of the peptide hepcidin, which reduces release of iron from stores (liver cells and macrophages of marrow, liver, spleen).
  • Does not respond to iron therapy; resolves if the underlying condition is adequately treated.
  • Mechanisms: (1) iron stores are sequestered in macrophages and unavailable for transfer to red cells, and gut iron absorption is decreased, producing a “functional iron deficiency” with reduced availability to maturing erythroblasts and a tendency to microcytosis depending on severity; (2) a minor contribution from reduced marrow response to erythropoietin.
  • Hepcidin pathway: hepcidin (produced by the liver, acts as a bacterial killer) shuts down ferroportin (the iron export channel) at two sites - the macrophage (blocking release of recycled iron from senescent erythrocytes) and the enterocyte (blocking intestinal iron absorption) - so iron cannot reach transferrin (apo-Tf) for delivery to erythroblasts.
  • Supporting experiment (Elin, Blood 1977): young volunteers (19-24) given endotoxin plus the fever-inducing drug etiocholanolone showed serum iron plummet within a few hours, reaching a low point around 12 hours, with partial recovery by 24 hours, versus stable controls - demonstrating that inflammation acutely lowers serum iron and iron supply to erythroblasts.
  • Example causes: rheumatoid arthritis (autoimmune arthritis), inflammatory bowel disease, severe chronic or untreated infection (lung abscess, osteomyelitis, endocarditis), some cancers. Rationale: the body responds as if fighting bacterial infection and tries to starve the bacteria of iron.
  • Other causes of anaemia commonly coexist with anaemia of inflammation: bleeding (common); iron deficiency and inflammation together (e.g. cancer, IBD); reduced EPO or response to EPO; shortened red cell survival from toxic waste products in chronic liver/renal disease. Neutrophil and platelet counts may be elevated (inflammation and/or bleeding); CRP is raised.
  • C-reactive protein (CRP): produced by the liver in acute and chronic inflammation, rises rapidly (hours), part of innate immune mechanisms. Used diagnostically: very high in acute severe bacterial infection; only mildly raised in viral infection; elevated in inflammatory states (arthritis, Crohn disease, etc.); mild-to-moderate rise in some cancers, acute tissue injury, etc.

Macrocytic anaemias

Megaloblastic anaemia (folate or B12 deficiency)

  • Folate and vitamin B12 are needed for nucleic acid (thymidine) synthesis; deficiency delays maturation in the marrow, producing the megaloblastic appearance of erythroblasts and macrocytic red cells with hypersegmented neutrophils in the blood film.
  • Folate deficiency is now very rare due to food fortification.
  • Vitamin B12 deficiency is usually due to autoimmune destruction of stomach cells.
  • Case example: 55-year-old alcoholic with a very poor diet - MCV raised (109-114 fL vs ref 80-99), MCH raised (37-38 pg vs ref 27-33), Hb reduced (105-124 g/L vs ref 115-155), serum B12 normal (524 pmol/L, ref 170-600) but serum folate low (4.1 nmol/L, ref >6.0) - low serum folate consistent with deficiency, prompting consideration of dietary intake, excess alcohol and malabsorption.

Non-megaloblastic macrocytic anaemias

  • Liver disease/alcohol: abnormal or delayed erythropoiesis in the marrow.
  • Increased red cell production (haemolytic anaemias or response to blood loss): reticulocytes are 20-30% larger than mature red cells, so a very high reticulocyte count itself causes macrocytosis.
  • Case example: 22-year-old male, Hb 90 g/L three weeks earlier, now Hb 111 g/L (ref 130-175), MCV 109 fL (ref 80-99), reticulocyte count markedly raised at 246 x10^9/L (ref 10-100) - illustrating that reticulocytosis raises MCV even as Hb partly recovers.

Normocytic anaemias

A large, heterogeneous group; common and important causes include:

  • Anaemia of renal failure (lack of EPO).
  • Acute blood loss followed by haemodilution.
  • Bone marrow disease (sometimes macrocytic).
  • Anaemia of inflammation (sometimes microcytic).
  • Haemolytic anaemias (sometimes macrocytic).

Anaemia after haemorrhage

  • Bleeding reduces blood volume, lowering blood pressure in venules/capillaries and producing net movement of fluid from tissues into vessels.
  • Blood volume is restored by the kidneys (retaining salt and water) or by IV fluid replacement, which further dilutes the circulation.
  • Net result: haemoglobin concentration falls mostly within the first 24 hours, with the fall complete by around 72 hours (this is dilutional, not a true drop in red cell mass).

Anaemia of renal disease

  • Normocytic; mainly due to reduced erythropoietin (EPO) production by small, diseased kidneys, giving reduced erythropoiesis. Without kidneys, Hb can fall to 50-60 g/L. Responds to EPO injections.
  • Some contribution from toxic waste products (“uraemic”) shortening red cell survival.
  • Flip side - EPO abuse by athletes: creates a dangerous rise in Hb and blood viscosity, risking clots (stroke, myocardial infarct, venous thrombosis); between 1987 and 1990, when athletes began using EPO, 20 young Belgian and Dutch cyclists died.

Haemolytic anaemias

  • Reduced red cell survival in the circulation, ranging in severity from no anaemia to severe anaemia.
  • The marrow responds by increasing red cell production, producing reticulocytosis (raised reticulocyte count). Reticulocyte RNA stains blue on a normal film - this is called polychromasia.
  • Because reticulocytes are 20-30% larger than mature red cells, MCV is often increased in severe haemolysis due to the larger proportion of young red cells.
  • Examples: autoimmune haemolytic anaemia (red cells coated in autoantibodies, ingested by splenic macrophages, with large polychromatic reticulocytes on film); hereditary spherocytosis (genetic red cell membrane defect causing loss of membrane, spherocyte formation, and removal in the splenic filter); malaria (red cells parasitised, with haemolysis occurring once the parasite matures).
  • Main tests for haemolysis: blood count and blood film examination; reticulocyte count; bilirubin (breakdown product from recycled haem); haptoglobin (a protein that mops up free haemoglobin from old/haemolysed red cells - gets used up in haemolysis, so levels become very low).

Anaemia as part of pancytopenia

If the bone marrow is not functioning, all major marrow cell lines fall together: haemoglobin, platelets and neutrophils - pancytopenia. This most commonly occurs after chemotherapy or in patients with advanced cancer involving the bone marrow (e.g. breast cancer, prostate cancer, blood cancers). A case example contrasted marrow infiltrated with sheets of metastatic breast cancer cells against normal marrow architecture (fatty spaces interspersed with haematopoietic cells and bony trabeculae).

Self-test

  1. Define anaemia and give the NZ adult reference ranges for haemoglobin in females and males.
  2. Describe how anaemia severity is graded by haemoglobin level.
  3. Distinguish the two ways anaemia is classified from the blood count versus by aetiology, and explain why the blood count classification is not an aetiological one.
  4. Describe the two broad aetiological categories of anaemia (from the classification by cause) and give at least two examples under each.
  5. Explain what a reticulocyte is and how the reticulocyte count behaves in (a) bleeding/haemolysis and (b) marrow failure.
  6. List the three causes of microcytic anaemia given in the lecture and state what they have in common in terms of red cell haemoglobin content.
  7. Describe the steps by which iron deficiency leads to small, pale red cells, and state which laboratory test best reflects iron stores and its typical cut-off in iron deficiency.
  8. Distinguish alpha thalassaemia from beta thalassaemia in terms of the underlying genetic change and the resulting abnormal haemoglobins/tetramers.
  9. Describe the steps of the hepcidin-ferroportin pathway that produce anaemia of inflammation.
  10. A patient has a normocytic/microcytic anaemia that does not respond to iron therapy, with a raised CRP. What is the likely diagnosis and why does iron therapy not help?
  11. Explain why folate and vitamin B12 deficiency cause macrocytic anaemia, and state the most common underlying causes of each deficiency mentioned in the lecture.
  12. Explain why a very high reticulocyte count can itself cause macrocytosis even without B12/folate deficiency.
  13. List the common causes of normocytic anaemia given in the lecture.
  14. Describe the mechanism by which acute haemorrhage leads to a falling haemoglobin concentration over the following 24-72 hours.
  15. Describe the mechanism of anaemia in renal failure, including how low Hb can go in the absence of kidneys and why EPO abuse by athletes is dangerous.
  16. Describe the steps by which haemolysis leads to reticulocytosis and, in severe cases, macrocytosis.
  17. Distinguish autoimmune haemolytic anaemia, hereditary spherocytosis and malaria in terms of the mechanism of red cell destruction.
  18. List the main laboratory tests used to investigate suspected haemolysis and what each detects.
  19. Define pancytopenia and explain why it occurs when the bone marrow is not functioning, giving an example of a cause.
  20. A 55-year-old with heavy alcohol use and a poor diet has a raised MCV, normal serum B12, and low serum folate. Explain the likely diagnosis and mechanism.

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