Anaemia: Classification, Causes, Investigations and Emergency Management

Anaemia: Classification, Causes, Pathophysiology, Investigations, Treatment and Emergency Recognition

Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology

Learning objectives

• Define anaemia and explain why the laboratory threshold depends on context.
• Classify anaemia by mechanism, MCV, reticulocyte response and morphology.
• Diagnose iron deficiency, anaemia of inflammation, megaloblastic anaemia, haemoglobinopathies and haemolysis.
• Interpret CBC, reticulocytes, ferritin, transferrin saturation, haemolysis markers and blood film.
• Identify anaemia emergencies and outline safe treatment principles.

1. Definition and physiology

Anaemia means inadequate circulating red-cell haemoglobin for tissue oxygen delivery. A patient may be symptomatic with a rapidly falling haemoglobin at a level that a chronically adapted patient tolerates, so the number must be interpreted with symptoms, rate of change, cardiovascular reserve, pregnancy and comorbidity.

Physiologic response	Mechanism	Clinical consequence
Increased cardiac output	Tachycardia and increased stroke volume deliver more blood to tissues.	Palpitations, flow murmur and heart failure in vulnerable patients.
Increased 2,3-BPG	Shifts the oxygen dissociation curve to facilitate tissue unloading.	Partial compensation but does not restore oxygen content.
Increased EPO	Renal hypoxia stimulates marrow erythropoiesis.	Reticulocytosis if marrow and nutrients are intact.
Redistribution	Blood flow is prioritised to brain and heart.	Fatigue, exertional dyspnoea, dizziness and cold extremities.

2. Mechanistic classification

Mechanism	Examples	Reticulocyte response
Reduced production	Iron/B12/folate deficiency, chronic inflammation, kidney disease, endocrine disease, marrow aplasia/infiltration, myelodysplasia.	Low or inappropriately normal.
Blood loss	Trauma, gastrointestinal bleeding, heavy menstruation, obstetric haemorrhage, parasites.	Rises after several days if marrow is able to respond.
Increased destruction (haemolysis)	Immune haemolysis, malaria, sickle disease, thalassaemia, G6PD deficiency, mechanical fragmentation.	Usually high, unless marrow is suppressed or nutrients are depleted.
Mixed	Chronic kidney disease plus iron deficiency; haemolysis plus folate deficiency; inflammation plus blood loss.	May appear deceptively normal; use multiple tests.

3. Morphologic classification by MCV

Category	MCV guide	Important causes
Microcytic	Below the laboratory lower limit (often <80 fL in adults).	Iron deficiency, thalassaemia, anaemia of inflammation, sideroblastic disease, lead toxicity.
Normocytic	Usually about 80–100 fL.	Acute blood loss, haemolysis, chronic disease, kidney/endocrine disease, marrow failure.
Macrocytic	Often >100 fL.	B12/folate deficiency, alcohol/liver disease, hypothyroidism, drugs, reticulocytosis, myelodysplasia.

MCV can be misleading when two processes coexist. RDW, reticulocytes and a peripheral film often reveal a mixed disorder.

4. Clinical presentation

• General: fatigue, weakness, reduced exercise tolerance, headache, dizziness, pallor, cold intolerance and irritability.
• Cardiorespiratory: tachycardia, exertional dyspnoea, chest pain, syncope, flow murmur or heart failure.
• Iron deficiency: pica, restless legs, glossitis, angular cheilitis, koilonychia and hair loss.
• B12 deficiency: paresthesia, loss of vibration/proprioception, ataxia, cognitive change and glossitis; neurological injury can become irreversible.
• Haemolysis: jaundice, dark urine, splenomegaly, abdominal pain and pigment gallstones.
• Haemoglobinopathy: recurrent pain, jaundice, splenomegaly or functional asplenia, leg ulcers and growth delay.
• Marrow disease: fever, recurrent infection, bruising, bleeding, bone pain, lymphadenopathy or hepatosplenomegaly.

5. A practical diagnostic algorithm

1. Confirm anaemia and assess stability: vital signs, mental state, bleeding, chest pain, hypoxia, pregnancy and shock.
2. Review the trend: compare previous Hb and ask about bleeding, recent surgery, transfusion, infection, medication, diet and travel.
3. Order CBC with indices, reticulocytes and blood film.
4. Use MCV and reticulocytes together: low reticulocytes indicate underproduction; high reticulocytes indicate loss or destruction if the marrow is intact.
5. Target the cause: ferritin/iron studies; B12/folate; renal/liver/thyroid tests; haemolysis panel; stool/urine/gynaecologic assessment; malaria or parasite testing; electrophoresis/genetic testing; marrow examination when indicated.
6. Investigate occult blood loss in adults with unexplained iron deficiency, while considering local cancer and parasite prevalence.

6. Essential investigations

Test	What it shows	Interpretive cautions
Reticulocyte count/RPI	Marrow response to anaemia.	Reticulocytes rise after a delay; transfusion and mixed disease distort interpretation.
Ferritin	Iron stores; low ferritin strongly supports iron deficiency.	Acute-phase protein; inflammation or infection can make it appear normal/high.
Serum iron, transferrin/TIBC and transferrin saturation	Iron availability and binding capacity.	Diurnal variation and inflammation affect values; interpret as a pattern.
Vitamin B12 and folate	Macrocytosis and megaloblastic production.	Borderline B12 may need methylmalonic acid/homocysteine and clinical correlation.
LDH, indirect bilirubin, haptoglobin	Haemolysis pattern.	Haptoglobin is low in haemolysis but can be altered by liver disease/inflammation.
Direct antiglobulin test	Antibody/complement on RBCs in immune haemolysis.	Negative tests do not exclude every immune process.
Blood film	Cell size/shape, parasites, schistocytes, spherocytes, sickle cells, blasts.	Quality and prompt review matter in emergencies.
Haemoglobin electrophoresis/HPLC	Thalassaemia and variant haemoglobins.	Recent transfusion and iron deficiency can affect interpretation.
Renal/liver/thyroid tests	Secondary causes and treatment safety.	One abnormality rarely proves causation.

7. Iron-deficiency anaemia

7.1 Causes

• Chronic blood loss: heavy menstrual bleeding, GI ulcer/cancer/polyps, haemorrhoids, urinary or obstetric bleeding.
• Increased demand: pregnancy, infancy, adolescence and recovery after haemorrhage.
• Reduced intake: poverty, restrictive diet, malnutrition or food insecurity.
• Malabsorption: coeliac disease, bariatric surgery, achlorhydria and chronic intestinal disease.
• Parasitic blood loss, including hookworm, and repeated malaria-related haemolysis in endemic settings.

7.2 Stages and laboratory pattern

Iron stores fall first (low ferritin), then transferrin saturation falls and erythropoiesis becomes iron-restricted. Established disease produces microcytosis, hypochromia, raised RDW and a low reticulocyte response. Platelets may be reactive-high. Treating with iron without identifying ongoing bleeding is incomplete care.

7.3 Treatment principles

• Identify and control the source; treat parasites, menstrual loss, GI pathology or malabsorption.
• Use oral or intravenous iron according to severity, tolerance, absorption, urgency and local protocol; calculate the required replacement and monitor response.
• Explain adherence and common GI adverse effects; separate oral iron from interacting medicines/foods when advised.
• Recheck haemoglobin and iron stores after treatment; lack of response suggests nonadherence, ongoing bleeding, wrong diagnosis, malabsorption or mixed disease.

8. Anaemia of inflammation/chronic disease

Inflammatory cytokines increase hepcidin, which traps iron in macrophages and reduces intestinal absorption. EPO production and marrow responsiveness also fall. The pattern is often normocytic or mildly microcytic, low serum iron, low/normal transferrin and normal/high ferritin. Treat the underlying infection, inflammatory disease, kidney disease or malignancy; iron is useful only when deficiency coexists or specialist assessment supports it.

9. Megaloblastic anaemia

9.1 Vitamin B12 deficiency

Causes include pernicious anaemia, gastric surgery, ileal disease, vegan diet without supplementation, malabsorption and medicines that interfere with absorption or metabolism. DNA synthesis fails, producing macro-ovalocytes, hypersegmented neutrophils, ineffective erythropoiesis and raised LDH. Neurologic deficits can occur even without severe anaemia.

9.2 Folate deficiency

Causes include poor intake, alcoholism, malabsorption, pregnancy, haemolysis and drugs that inhibit folate metabolism. Folate deficiency produces megaloblastosis but not the classic progressive neuropathy of B12 deficiency.

10. Haemolytic anaemia

Haemolysis is premature RBC destruction. The marrow responds with reticulocytosis if able.

Mechanism	Examples	Clues
Extravascular, splenic	Warm autoimmune haemolysis, hereditary spherocytosis, some haemoglobinopathies.	Splenomegaly, jaundice, spherocytes, raised indirect bilirubin.
Intravascular	Incompatible transfusion, complement-mediated cold disease, severe mechanical injury, PNH.	Haemoglobinuria, very high LDH, low haptoglobin, renal injury.
Microangiopathic	TTP, HUS, DIC, malignant hypertension, prosthetic valves.	Schistocytes, thrombocytopenia and organ injury.
Enzyme/membrane defect	G6PD deficiency, pyruvate kinase deficiency, hereditary membrane disorders.	Trigger-related episodes, bite cells/Heinz bodies or chronic haemolysis.

Investigate drug exposure, infection (including malaria), transfusion, family history, renal function and pregnancy. Treatment depends on cause; stop an offending drug, treat infection, support renal function and involve haematology urgently in severe haemolysis.

11. Haemoglobinopathies

11.1 Sickle-cell disease

HbS polymerises during deoxygenation, deforming RBCs, causing haemolysis and vaso-occlusion. Complications include painful crises, acute chest syndrome, stroke, splenic dysfunction, priapism, renal disease and leg ulcers. Fever, chest pain, dyspnoea, neurologic deficit or severe anaemia are emergencies.

11.2 Thalassaemia

Reduced alpha- or beta-globin synthesis causes microcytosis and ineffective erythropoiesis. Trait is often mild; major disease causes severe anaemia, marrow expansion, transfusion dependence, iron overload and endocrine/cardiac complications. Do not give iron for microcytosis without evidence of iron deficiency.

12. Aplastic, marrow-infiltrative and renal anaemia

• Aplastic anaemia: hypocellular marrow causes pancytopenia; drugs, toxins, viruses, autoimmunity and inherited syndromes can be responsible. Fever or bleeding with pancytopenia is an emergency.
• Myelophthisic anaemia: marrow infiltration by fibrosis, granuloma, metastatic cancer or haematologic malignancy produces a leukoerythroblastic film and possible splenomegaly.
• Chronic kidney disease: reduced EPO, inflammation and shortened RBC survival produce predominantly normocytic anaemia. Treat iron deficiency and renal disease; EPO-stimulating therapy requires specialist risk assessment.
• Endocrine/liver disease: thyroid disease, alcohol and liver dysfunction alter production and RBC size.

13. Anaemia emergencies

Emergency	Red flags	Priorities
Acute haemorrhage	Shock, ongoing external/GI/obstetric bleeding, syncope or altered mental state.	ABCDE, control source, large-bore IV access, cross-match, balanced resuscitation and specialist/operative control.
Severe symptomatic anaemia	Chest pain, heart failure, syncope, hypoxia, confusion or haemodynamic instability.	Oxygen if hypoxic, ECG/monitoring, identify cause and consider carefully indicated transfusion; do not treat the number alone.
Acute haemolysis	Jaundice, dark urine, fever, back pain, hypotension or rapidly falling Hb.	Stop suspected transfusion/drug, send haemolysis/transfusion samples, support renal function and alert blood bank.
TTP/microangiopathy	Thrombocytopenia plus schistocytes, neurologic/renal/fever features.	Urgent haematology pathway and plasma exchange when indicated; do not delay for confirmatory assays.
Acute chest syndrome	New infiltrate, fever, chest pain, cough, hypoxia or respiratory distress in sickle disease.	Oxygen if hypoxic, analgesia, antibiotics, incentive spirometry, transfusion/exchange assessment and ICU early.
Neutropenic pancytopenia	Fever, mucositis, bleeding and low WBC/platelets.	Sepsis and bleeding protocols, cultures, immediate antibiotics and haematology involvement.

14. Transfusion principles

• Transfusion is for inadequate oxygen delivery or clinically important bleeding, not merely a low Hb; thresholds vary with symptoms, active bleeding, coronary disease, pregnancy and local guidance.
• Confirm identity, ABO/Rh compatibility and cross-match. Monitor temperature, pulse, blood pressure, respiratory status and symptoms before, during and after transfusion.
• Stop the transfusion immediately for fever, rigors, pain, dyspnoea, hypotension, urticaria or dark urine; maintain IV access with appropriate fluid and notify the blood bank.
• Repeated transfusion can cause iron overload, alloimmunisation and infection risk; use a disease-directed strategy.

15. Clinical cases

Case 1: iron deficiency in an adult

A patient has Hb 8.5 g/dL, MCV 68 fL, high RDW and low ferritin. Iron deficiency is established, but the cause still requires evaluation. Ask about menstruation, GI symptoms, diet, pregnancy, parasites, NSAIDs and malignancy risk; replace iron and treat the source.

Case 2: macrocytosis with paresthesia

Macro-ovalocytes, hypersegmented neutrophils and sensory loss suggest B12 deficiency. Test B12, folate, intrinsic-factor antibodies and malabsorption causes; begin appropriate replacement urgently because neurologic damage may become permanent.

Case 3: anaemia with schistocytes

Thrombocytopenia, renal dysfunction, confusion, raised LDH and schistocytes suggest TTP or another thrombotic microangiopathy. This requires immediate specialist treatment, not outpatient iron or simple transfusion.

16. Quick self-test

1. What are the three broad mechanisms of anaemia?
2. Why is reticulocytosis useful?
3. List five causes of microcytosis.
4. How does inflammation produce iron-restricted erythropoiesis?
5. Which deficiency can cause irreversible neurologic disease?
6. What do schistocytes indicate?
7. What is the first action when a transfusion reaction is suspected?

Answers

1. Reduced production, blood loss and increased destruction; mixed processes are common.
2. It shows whether marrow is responding to anaemia, distinguishing loss/destruction from underproduction when interpreted correctly.
3. Iron deficiency, thalassaemia, inflammation, sideroblastic anaemia and lead toxicity.
4. Hepcidin traps iron in macrophages and reduces gut absorption; cytokines also reduce EPO and marrow responsiveness.
5. Vitamin B12 deficiency.
6. Fragmentation haemolysis/microangiopathic injury, requiring urgent clinical correlation.
7. Stop the transfusion, keep IV access with appropriate fluid, assess ABCDE and notify the blood bank/medical team.

Key take-home points

• Anaemia is a sign; always identify whether production, loss or destruction is responsible.
• Use MCV, RDW, reticulocytes, film and iron/B12/folate/haemolysis studies as a connected diagnostic sequence.
• Iron deficiency requires a search for blood loss or malabsorption, not only iron replacement.
• Never miss B12 neurologic disease, haemolysis, TTP, acute chest syndrome or severe blood loss.
• Transfuse the patient with impaired oxygen delivery or active bleeding, not a laboratory number in isolation.

Selected references

• NCBI Bookshelf: Anemia
• NCBI Bookshelf: Mean Corpuscular Volume
• MedlinePlus: Anemia
• MedlinePlus: Iron-deficiency anemia
• WHO: Anaemia fact sheet
• NCBI Bookshelf: Hemolytic Anemia