Anaemia: A Comprehensive Clinical Review

Definition

Anaemia is a clinical sign of an underlying pathological process, not a disease in itself. It is most commonly defined by the World Health Organization (WHO) using a quantitative threshold: a haemoglobin (Hb) concentration below a specified value (2, 3). For adults in Malaysia, this is a haemoglobin level of less than 13.0 g/dL for men and less than 12.0 g/dL for non-pregnant women (1). For pregnant women, a single, practical cut-off of less than 11.0 g/dL is used throughout all trimesters in local antenatal care settings (3).

Physiologically, anaemia represents a reduced oxygen-carrying capacity of the blood, leading to a state of tissue hypoxia that drives the condition's clinical manifestations (5). It's important to recognise that Hb concentration can be influenced by plasma volume. For instance, in pregnancy or fluid overload states, a "relative anaemia" can occur due to haemodilution, where the red cell mass is normal but the plasma volume is expanded. Conversely, in states of dehydration, the Hb level may be falsely elevated, masking a true underlying anaemia.

Epidemiology

Anaemia is a major public health problem in Malaysia, with a national prevalence in adults estimated to be around 24%, affecting millions (24). The burden is disproportionately high in specific vulnerable groups. Data from the National Health and Morbidity Survey (NHMS) 2022 revealed a severe public health crisis among children aged 6-59 months, with an anaemia prevalence of 46.5% (4). This has profound implications for neurodevelopment and physical growth. Pregnant women also face a persistently high burden, with prevalence rates between 29% and 43%, largely due to Iron Deficiency Anaemia (IDA) and poor compliance with supplementation (7). This increases the risk of maternal morbidity, preterm birth, and low birth weight infants. The elderly and indigenous (Orang Asli) communities are also severely affected, with prevalence rates in some Orang Asli children reaching as high as 80%, often due to a complex interplay of malnutrition and parasitic infections like hookworm (36).

A consistent and clinically significant finding in Malaysia is the ethnic disparity in anaemia prevalence. Multiple studies confirm a distinct pattern: Malaysian Indians have the highest rates, followed by Malays, with the lowest rates observed in the Chinese community (23, 24). The reasons are multifactorial, likely involving a higher prevalence of vegetarian diets (affecting iron and B12 intake) and potentially a different genetic predisposition to certain anaemias within the Indian community. This establishes Indian ethnicity as a key non-modifiable risk factor that must be considered in clinical assessment.

Pathophysiology

All anaemias arise from one of three fundamental mechanisms, and sometimes a combination: impaired red blood cell (RBC) production, increased RBC destruction (haemolysis), or blood loss (6).

1. Impaired RBC Production (Hypoproliferation): This is the most common mechanism.

   • Substrate Deficiency: In Iron Deficiency Anaemia (IDA), a lack of iron impairs haem synthesis, leading to small (microcytic) and pale (hypochromic) RBCs (1). In Vitamin B12 and folate deficiency, impaired DNA synthesis causes "ineffective erythropoiesis," where abnormal precursors (megaloblasts) undergo apoptosis within the marrow, and the few that survive are large (macrocytic) (16).

   • Globin Chain Defect: In thalassaemia, a quantitative defect in globin chain synthesis leads to a profound imbalance. The excess, unpaired globin chains precipitate within RBC precursors, causing oxidative damage and premature death within the bone marrow. This massive ineffective erythropoiesis is the primary driver of the severe anaemia seen in transfusion-dependent thalassaemia (17).

   • Marrow Failure/Suppression: In Anaemia of Chronic Disease (ACD), inflammatory cytokines (especially IL-6) stimulate the liver to produce hepcidin. Hepcidin blocks iron release from macrophages and absorption from the gut, creating a "functional" iron deficiency where iron is present in the body but unavailable for erythropoiesis (13). In aplastic anaemia, the bone marrow stem cells themselves are destroyed, leading to pancytopenia.

2. Increased RBC Destruction (Haemolysis): This occurs when the RBC lifespan (normally 120 days) is significantly shortened.

   • Intrinsic Defects: These are defects within the RBC itself. In G6PD deficiency, common in Malaysia, a lack of the G6PD enzyme renders cells vulnerable to oxidative damage from triggers like certain drugs (sulphonamides, dapsone), infections, or fava beans, leading to acute haemolysis (12, 22).

   • Extrinsic Factors: Here, a normal RBC is destroyed by an external force. This includes autoimmune haemolytic anaemia, where antibodies target RBCs, or microangiopathic haemolytic anaemia (MAHA), where RBCs are physically sheared by fibrin strands in the microvasculature (e.g., in TTP or DIC) (6).

3. Blood Loss: This can be acute or chronic.

   • Acute: From trauma or massive haemorrhage, the immediate threat is hypovolemic shock, not anaemia itself. The Hb only drops after several hours as fluid shifts into the vascular space (15).

   • Chronic: This is the most common cause of IDA in adults. Slow, persistent bleeding from sources like heavy menstruation or an occult gastrointestinal lesion (e.g., NSAID-induced ulcer, colorectal cancer) gradually depletes the body's iron stores (5).

Clinical Presentation

The clinical presentation depends on the severity and acuity of the anaemia, as well as the patient's underlying cardiorespiratory reserve.

• Diagnostic Clues: The presence of pica (craving for non-nutritive substances like ice, or pagophagia) is a highly specific symptom of iron deficiency, thought to be related to central nervous system dysfunction from iron depletion (1). Jaundice and dark, tea-coloured urine are cardinal signs of haemolysis, caused by the rapid breakdown of haemoglobin into bilirubin and the presence of haemoglobin in the urine (12). Symmetrical peripheral neuropathy (numbness and tingling) and gait instability are distinct features of Vitamin B12 deficiency, resulting from defective myelin synthesis in the spinal cord, and can occur even before anaemia develops (16).

• Common Symptoms (>50%): The most frequent complaints are non-specific and related to tissue hypoxia, including pervasive fatigue, lethargy, generalised weakness, and exertional dyspnoea (1, 5).

• Less Common Symptoms (10-50%): These include palpitations, headaches, dizziness, and light-headedness, which are compensatory responses to maintain cerebral perfusion (5).

• ⚠️ Red Flag Signs & Symptoms: Angina, significant dyspnoea at rest, postural dizziness, confusion, or signs of heart failure (e.g., peripheral oedema) indicate severe, symptomatic anaemia where the body's compensatory mechanisms are failing, requiring immediate assessment and potential stabilisation.

Complications

Severe or prolonged anaemia can lead to significant multi-system complications. Chronic tissue hypoxia forces the heart to increase its output to maintain oxygen delivery, which can lead to a sustained hyperdynamic state, left ventricular hypertrophy, and eventually high-output cardiac failure (9). In patients with pre-existing coronary artery disease, the increased demand and reduced oxygen supply can precipitate angina or myocardial infarction. The neurological complications of untreated Vitamin B12 deficiency, including subacute combined degeneration of the spinal cord, can be irreversible, leaving patients with permanent gait and sensory deficits (48). In pregnancy, severe anaemia is associated with poor maternal and fetal outcomes, including an increased risk of preterm delivery, low birth weight, and even maternal mortality.

Prognosis

The prognosis of anaemia is entirely dependent on its underlying cause and the ability to treat it effectively. For nutritional anaemias like IDA or B12 deficiency, the prognosis is excellent with appropriate replacement therapy and management of the root cause (e.g., stopping blood loss). For patients with transfusion-dependent thalassaemia, the prognosis has been transformed by regular transfusions and diligent iron chelation therapy, which prevents fatal iron overload, though it remains a lifelong condition requiring multidisciplinary care (65). For anaemia associated with malignancy or aplastic anaemia, the prognosis is tied to the outcome of the primary disease and its response to treatment like chemotherapy or transplantation.

Differential Diagnosis

• Microcytic Anaemia (IDA vs. Thalassaemia Trait): This is the most critical differential in the Malaysian context. Iron Deficiency Anaemia is suggested by a history of bleeding or poor diet and supported by a high Red Cell Distribution Width (RDW) and a low serum ferritin (1, 65). In contrast, a thalassaemia trait should be strongly considered in any Malaysian patient with microcytic anaemia, particularly if they are of Malay, Chinese, or Kadazan-Dusun ethnicity. It is less likely if there is no family history, and points against it include a normal HbA2 level on haemoglobin analysis and a response to iron therapy (which would only occur if there was co-existent iron deficiency) (17, 65). The Mentzer Index (MCV/RBC count) can be a useful clue; a value <13 suggests thalassaemia, while >13 suggests IDA.

• Macrocytic Anaemia (Megaloblastic vs. Non-Megaloblastic): Vitamin B12 deficiency is a key differential, especially in older adults, long-term metformin users, or strict vegans. The presence of neurological symptoms and hypersegmented neutrophils on the blood film strongly supports this diagnosis (16, 49). Consider chronic liver disease or hypothyroidism as differentials, especially if there are other clinical stigmata. Points against a megaloblastic cause include the absence of hypersegmented neutrophils and normal B12/folate levels (1). In an older patient with other cytopenias, Myelodysplastic Syndrome (MDS) is a crucial differential to exclude.

Investigations

A stepwise approach is crucial, guided by the initial Full Blood Count (FBC).

Immediate & Bedside Tests

• Full Blood Count (FBC): This is the mandatory first step to confirm anaemia and classify it by Mean Corpuscular Volume (MCV). An MCV < 80 fL suggests microcytic, 80-100 fL normocytic, and > 100 fL macrocytic anaemia (1). The FBC is essential for assessing severity and identifying other cytopenias (the action), which could indicate a bone marrow failure syndrome like aplastic anaemia or leukaemia, requiring urgent haematology consultation (the rationale).

Diagnostic Workup

• First-Line Investigations:

  • Peripheral Blood Film (PBF): This is a high-yield test that provides invaluable morphological clues to guide further testing (the action). It can reveal features like the elliptical "pencil cells" of IDA, the target cells and prominent basophilic stippling of thalassaemia, or the pathognomonic hypersegmented neutrophils of megaloblastic anaemia, which are critical for differentiating common local causes (the rationale) (1, 16).

  • Iron Studies (for microcytic anaemia): A low serum ferritin (<30 µg/L) is diagnostic for IDA, as it directly reflects depleted body iron stores (the rationale), confirming the need for iron replacement and investigation of the underlying cause (the action) (8). In the presence of inflammation (ACD), ferritin is an acute phase reactant and can be falsely normal; a level <100 µg/L in this context may still indicate co-existent IDA.

  • Haemoglobin Analysis (for microcytic anaemia): This is mandatory to diagnose or exclude thalassaemia, a high-prevalence condition in Malaysia (the action). An elevated HbA2 level (>4.0%) on HPLC or electrophoresis is diagnostic for β-thalassaemia trait, preventing misdiagnosis as IDA (the rationale) (65).

  • Reticulocyte Count (for normocytic anaemia): This is the key test to differentiate between causes. A high count indicates the bone marrow is responding appropriately to RBC loss from haemolysis or acute bleeding (the rationale), prompting a haemolysis screen (LDH, bilirubin, haptoglobin, DAT) (the action). A low count signifies inadequate bone marrow production, pointing towards chronic disease or marrow failure (the rationale) (15).

• Gold Standard:

  • Bone Marrow Aspiration & Biopsy: This is the definitive investigation for unexplained pancytopenia or suspected bone marrow failure syndromes like aplastic anaemia or leukaemia. It provides a direct histological diagnosis by assessing cellularity, morphology, and iron stores (the rationale), which is essential for guiding specific, often intensive, treatment (the action) (5).

• Monitoring & Staging:

  • Serial FBCs: These are performed to monitor the patient's response to treatment, such as iron therapy (the action), as the rate of haemoglobin rise (typically 1 g/dL every 2-3 weeks) and reticulocyte response (within 7-10 days) directly reflect the efficacy of the intervention (the rationale) (68).

Management

The foundational principle is to treat the underlying cause, not just the number. The modern approach is guided by the principles of Patient Blood Management (PBM), which aims to optimise the patient's own red cell mass, minimise blood loss, and avoid unnecessary transfusions.

Management Principles

The management of anaemia focuses on correcting the underlying disorder, replenishing deficient stores, alleviating symptoms, and improving quality of life, using transfusion as a last resort.

Acute Stabilisation (The First Hour)

• Circulation: In a patient with severe symptomatic anaemia (e.g., angina, heart failure) or haemodynamic instability from bleeding, secure two large-bore IV cannulas. The decision to transfuse should be based on clinical symptoms, not just a haemoglobin value (the action), to urgently improve oxygen-carrying capacity and prevent end-organ damage (the rationale) (75). The standard approach is to transfuse a single unit of packed red cells and then clinically reassess. This avoids the risks of fluid overload and other complications associated with multi-unit transfusions.

Definitive Therapy

• Iron Deficiency Anaemia:

  • First-Line Treatment: Oral ferrous fumarate or sulfate, providing 100-200 mg of elemental iron daily, is the standard treatment (8). Patients should be counselled to take it on an empty stomach with Vitamin C to maximise absorption (the action), which is necessary to correct the deficiency and replenish stores (the rationale) (42). To mitigate common GI side effects, strategies include starting with a lower dose or using an alternate-day regimen, which may improve both tolerance and absorption.

  • Second-Line/Escalation: Intravenous (IV) iron is indicated for patients intolerant to oral iron, those with malabsorption (e.g., IBD, post-gastrectomy), or when a rapid correction is needed (40). IV iron is significantly underutilised in Malaysia; its use can prevent unnecessary blood transfusions and rapidly restore iron levels (the action), which is critical for patients with severe symptoms or ongoing losses. Newer formulations like ferric carboxymaltose allow for a total dose infusion in a single session, greatly improving convenience (the rationale) (25, 72).

• Megaloblastic Anaemia:

  • Vitamin B12 Deficiency: Initial treatment is typically parenteral hydroxocobalamin 1000 mcg IM to rapidly replenish stores, especially if neurological symptoms are present (the action), bypassing any potential malabsorption and preventing irreversible neurological damage (the rationale) (48). Crucially, always rule out or co-treat B12 deficiency before giving folic acid alone. Administering folate in the face of B12 deficiency will correct the anaemia but mask the diagnosis, allowing devastating neurological damage to progress silently.

  • Folate Deficiency: Treatment is with oral folic acid 5 mg daily (16).

• Thalassaemia: Management of transfusion-dependent thalassaemia should follow the Malaysian MOH CPG (2024), focusing on regular, leucodepleted blood transfusions to maintain a pre-transfusion Hb of 9.0-10.0 g/dL and meticulous iron chelation therapy to prevent fatal iron overload. Splenectomy may be considered for hypersplenism causing escalating transfusion needs, and hematopoietic stem cell transplantation (HSCT) remains the only curative option (65).

Supportive & Symptomatic Care

This includes dietary advice to improve intake of iron-rich foods, patient education on their condition, and ensuring adherence to treatment. For patients with ACD, managing the underlying inflammation is the primary supportive measure.

Key Nursing & Monitoring Instructions

• Monitor for signs of severe anaemia: tachycardia (>100 bpm), hypotension (SBP <90 mmHg), or increasing dyspnoea.

• For patients on oral iron, monitor for and manage GI side effects like constipation or nausea, which are major barriers to compliance.

• For patients receiving a blood transfusion, perform baseline observations and monitor closely during the first 15 minutes for any signs of an acute reaction (fever, rigors, back pain, tachycardia, hypotension). Continue hourly monitoring thereafter.

• Inform the medical officer if a transfused patient develops new symptoms or if a stable patient's systolic BP drops below 90 mmHg.

Long-Term Plan & Patient Education

The long-term plan involves addressing the root cause of the anaemia (e.g., treating the source of bleeding with endoscopy, managing menorrhagia). Patients must be educated on the importance of long-term compliance, especially for lifelong conditions like pernicious anaemia or thalassaemia. For IDA, therapy should continue for 3-6 months after the haemoglobin normalises to fully replenish iron stores (target ferritin >50 µg/L) and prevent early relapse (40).

When to Escalate

A house officer must call for help in specific situations.

• Call Your Senior (MO/Specialist) if:

  • The patient is haemodynamically unstable (shock) or has severe end-organ symptoms (e.g., angina, heart failure, new confusion).

  • The diagnosis is uncertain after initial investigations, especially if multiple cell lines are affected (pancytopenia).

  • There are features on the blood film suggestive of a haematological malignancy (e.g., blasts).

  • The patient fails to respond to appropriate first-line treatment (e.g., Hb does not rise with a compliant course of oral iron).

• Referral Criteria:

  • Refer to a Haematologist for suspected leukaemia, aplastic anaemia, complex haemolytic anaemias, or for initiation and management of thalassaemia care.

  • Refer to a Gastroenterologist for investigation of occult GI bleeding (OGDS/colonoscopy) in any male or post-menopausal female with unexplained IDA.

  • Refer to a Gynaecologist for management of heavy menstrual bleeding causing IDA.

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