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What's Covered (Navigation Guide)

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• IDA: pencil cells + absent Prussian blue iron on BM - pathognomonic; ferritin is the earliest and most sensitive test
• Megaloblastic: macro-ovalocytes + hypersegmented neutrophils on PBS; giant metamyelocytes + megaloblasts on BM; MMA elevated in B12 deficiency only
• Sickle Cell: GAG→GTG (Glu→Val) in β-globin codon 6; HbSS on electrophoresis; Howell-Jolly bodies = autosplenectomy
• Haemolytic: elevated reticulocytes + low haptoglobin = hallmark; schistocytes = MAHA; spherocytes = HS/AIHA; Heinz bodies = G6PD
• Morphological classification: Microcytic hypochromic (IDA, thalassaemia), Normocytic normochromic (aplastic, haemolytic), Macrocytic (megaloblastic, liver disease)

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COMPLICATIONS OF ANAEMIAS

Reference: Harsh Mohan's Textbook of Pathology | Robbins Basic Pathology

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1. COMPLICATIONS OF IRON DEFICIENCY ANAEMIA (IDA)

A. Haematological Complications

1. Severe microcytic hypochromic anaemia - Hb may fall to <5 g/dL in chronic neglected cases
2. Thrombocytosis - reactive; can predispose to thromboembolic events
3. Impaired immune function - iron is required for lymphocyte proliferation and neutrophil killing; increased susceptibility to infections
4. Thrombocytopenia - in very severe, long-standing IDA (rare)

B. Cardiovascular Complications

1. High-output cardiac failure - compensatory increased cardiac output to maintain O₂ delivery → eventually leads to:
   • Cardiomegaly
   • Palpitations, tachycardia
   • Cardiac failure (especially in elderly or those with pre-existing cardiac disease)
2. Angina pectoris - reduced O₂-carrying capacity worsens ischaemia in those with coronary artery disease

C. Neurological / Neuromuscular Complications

1. Fatigue, weakness, lethargy - due to reduced O₂ to muscles
2. Reduced cognitive function and poor concentration - iron required for dopamine synthesis and myelination
3. In children: impaired psychomotor development and intellectual disability - most significant long-term complication in paediatric IDA
4. Headache, dizziness, tinnitus, syncope
5. Restless legs syndrome (RLS) - iron deficiency in CNS dopaminergic pathways
6. Breath-holding spells in infants

D. Epithelial/Mucosal Complications (Specific to IDA)

1. Koilonychia (spoon-shaped nails) - flattening and concavity of nails; brittle nails
2. Angular cheilitis (angular stomatitis) - painful cracks at corners of mouth
3. Glossitis (atrophic glossitis) - smooth, beefy red, painful tongue; loss of papillae
4. Pharyngeal/oesophageal web - Plummer-Vinson syndrome (Patterson-Kelly syndrome): triad of IDA + glossitis + postcricoid web → dysphagia; premalignant (predisposes to postcricoid carcinoma)
5. Gastric atrophy - reduced gastric acid secretion (further impairs iron absorption - vicious cycle)
6. Pica - craving for non-food substances (ice = pagophagia; clay = geophagia; starch = amylophagia)

E. Pregnancy Complications

1. Intrauterine growth restriction (IUGR)
2. Preterm labour and low birth weight
3. Increased maternal mortality (especially peripartum haemorrhage in severe anaemia)
4. Post-partum depression
5. Impaired foetal brain development

F. Growth and Development (Paediatric)

1. Poor growth and short stature
2. Reduced exercise tolerance and physical performance
3. Increased susceptibility to lead poisoning (pica behaviour + increased GI lead absorption in iron deficiency)

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2. COMPLICATIONS OF MEGALOBLASTIC ANAEMIA

A. Haematological Complications

1. Pancytopenia - severe anaemia + leucopenia + thrombocytopenia in advanced disease
2. Increased bleeding tendency - thrombocytopenia → purpura, mucosal bleeding, menorrhagia
3. Increased infection risk - leucopenia + impaired neutrophil function
4. Ineffective erythropoiesis → haemolysis → pigment gallstones (bilirubin stones)
5. Haemolytic component - intramedullary destruction

B. Neurological Complications (B12 Deficiency ONLY)

1. Subacute Combined Degeneration (SCD) of the Spinal Cord - the most serious complication:
   • Demyelination of posterior columns (dorsal columns) → loss of vibration sense, proprioception, sensory ataxia, positive Romberg's sign
   • Demyelination of lateral (corticospinal) columns → upper motor neurone signs - spasticity, hyperreflexia, extensor plantar response (Babinski sign)
   • Demyelination of peripheral nerves → glove-and-stocking sensory loss, absent ankle jerks (mixed UMN+LMN picture)
   • Can occur without anaemia (neurological disease may precede haematological changes, especially if folate supplementation given)
2. Cognitive impairment and dementia - "megaloblastic madness": memory loss, confusion, psychosis, depression; reversible if treated early
3. Optic atrophy - rare; tobacco-alcohol amblyopia
4. Peripheral neuropathy - paresthesiae (pins and needles), numbness in hands and feet
5. Autonomic neuropathy - postural hypotension, impotence, bladder/bowel dysfunction

Critical: Folate treatment in undiagnosed B12 deficiency will correct anaemia but allow neurological damage to progress - the most dangerous pitfall. Always test B12 before prescribing folate.

C. Gastrointestinal Complications

1. Glossitis - smooth, sore, beefy-red tongue (Hunter's glossitis / atrophic glossitis)
2. Angular cheilitis
3. Anorexia, weight loss, malabsorption - GI epithelial cell DNA synthesis impaired
4. Diarrhoea - malabsorption due to villous atrophy
5. Increased risk of GI malignancy - pernicious anaemia patients have 2-3x increased risk of gastric carcinoma (due to chronic atrophic gastritis + achlorhydria + bacterial overgrowth → carcinogenic N-nitroso compounds)
6. Gastric carcinoid tumours - elevated gastrin in pernicious anaemia → ECL cell hyperplasia → carcinoid

D. Cardiovascular Complications

1. Hyperhomocysteinaemia - B12/folate deficiency → elevated homocysteine → endothelial damage → increased risk of atherosclerosis, coronary artery disease, stroke, DVT/PE
2. Cardiac failure from severe anaemia
3. High-output state

E. Obstetric Complications (Folate Deficiency in Pregnancy)

1. Neural tube defects (NTDs) - most important: anencephaly, spina bifida, encephalocele (folate required in first 28 days of neural tube closure - often before pregnancy recognised)
2. Spontaneous abortion and recurrent miscarriage
3. Placental abruption and pre-eclampsia
4. Preterm birth and low birth weight
5. Cleft palate

F. Associated Autoimmune Complications (Pernicious Anaemia)

1. Associated with other autoimmune diseases: Hashimoto's thyroiditis, Addison's disease, Type 1 diabetes, vitiligo
2. Gastric carcinoma risk (as above - 2-3x increased)

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3. COMPLICATIONS OF MACROCYTIC ANAEMIA

A. From Macrocytic Anaemia Itself

1. Cardiovascular: High-output cardiac failure, tachycardia, cardiac failure
2. Neurological: Fatigue, dizziness, syncope, poor concentration
3. If megaloblastic: All neurological and GI complications of megaloblastic anaemia (see above)

B. Complications Specific to Alcoholic Macrocytosis

1. Alcoholic liver disease (hepatitis → cirrhosis → liver failure) - the macrocytosis here is a marker of alcohol excess
2. Alcoholic cardiomyopathy
3. Wernicke-Korsakoff syndrome (thiamine deficiency from alcoholism)
4. Peripheral neuropathy
5. Pancreatitis (acute and chronic)
6. Portal hypertension → oesophageal varices → GI haemorrhage (worsens anaemia)

C. Complications Specific to Hypothyroid Macrocytosis

1. Myxoedematous coma (if untreated hypothyroidism progresses)
2. Associated autoimmune B12 deficiency (Hashimoto's + PA association)
3. Cardiovascular: Pericardial effusion, atherogenic dyslipidaemia

D. MDS-Associated Macrocytosis

1. Transformation to Acute Myeloid Leukaemia (AML) - the most feared complication; 10-40% of MDS cases transform
2. Progressive pancytopenia → life-threatening infections, bleeding

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4. COMPLICATIONS OF SICKLE CELL ANAEMIA

A. Acute Complications (Crises)

1. Vaso-occlusive (Painful) Crisis - Most common crisis

• Acute ischaemic pain in bones, joints, chest, abdomen
• Hand-foot syndrome (dactylitis) - swelling and pain in hands/feet; often the first manifestation in infants (6 months-2 years)
• Precipitated by infection, dehydration, cold, hypoxia, stress, acidosis

2. Acute Chest Syndrome (ACS) - Leading cause of death

• Fever + chest pain + pulmonary infiltrate + hypoxia + new chest X-ray opacity
• Caused by: fat embolism (from bone marrow infarction), infection (Chlamydia, Mycoplasma, Streptococcus pneumoniae, viruses), in-situ sickling in pulmonary vasculature
• Can progress to acute respiratory failure
• Single most common cause of death in SCD

3. Aplastic Crisis

• Caused by Parvovirus B19 infection → infects erythroid progenitors → transient arrest of erythropoiesis for ~7-10 days
• Severe, sudden-onset anaemia with reticulocytopenia (absence of reticulocytes - distinguishes from haemolytic crisis)
• Life-threatening in SCD (already anaemic baseline); may require transfusion
• Self-limiting; confers lifelong immunity

4. Haemolytic Crisis (Hyperhemolytic Crisis)

• Sudden acceleration of haemolysis → rapid fall in Hb
• Often precipitated by G6PD deficiency (common co-inheritance in same ethnic populations), infections
• Hyperhemolytic syndrome: can be transfusion-associated (transfused AND native RBCs destroyed)

5. Sequestration Crisis

• Sudden pooling/trapping of large volumes of blood in the spleen (in young children) or liver
• Rapidly enlarging, tender spleen/liver + sudden fall in Hb + hypovolaemic shock
• Most common in children aged 5 months-5 years (before autosplenectomy)
• Potentially fatal within hours - true haematological emergency
• Management: urgent blood transfusion; splenectomy after recurrence

B. Chronic/Systemic Organ Complications

1. Spleen

• Repeated infarctions → progressive autosplenectomy by age 5-10 years
• Resulting functional asplenia → high susceptibility to encapsulated bacteria:
  • Streptococcus pneumoniae (most common - risk of overwhelming sepsis = pneumococcal septicaemia)
  • Haemophilus influenzae
  • Neisseria meningitidis
  • Salmonella (unique to SCD - causes osteomyelitis unusually; Salmonella typhi bacteraemia)
• Requires prophylactic penicillin (from 2 months of age) and pneumococcal/meningococcal/Hib vaccinations

2. Bone and Joints

• Avascular necrosis (osteonecrosis) of femoral head (most common) and humeral head - due to medullary infarction
• Osteomyelitis - Salmonella spp. (uniquely common in SCD) and Staphylococcus aureus
• "Hair on end" appearance on skull X-ray (marrow hyperplasia eroding cortex)
• Frontal bossing - skull expansion due to marrow hyperplasia
• Pathological fractures
• Periostitis and cortical thinning
• Growth retardation in children

3. Neurological

• Stroke (cerebrovascular accident) - occurs in ~10% of patients by age 20; due to large vessel vasculopathy (intimal hyperplasia, thrombosis)
• Ischaemic stroke most common in children; haemorrhagic stroke in adults
• Silent cerebral infarcts - occur in ~35% and cause cognitive impairment
• Seizures
• Transient ischaemic attacks (TIAs)
• Management: chronic transfusion programme (maintains HbS <30%) reduces stroke risk

4. Lung (Chronic)

• Pulmonary hypertension - from repeated episodes of ACS, chronic haemolysis (free Hb scavenges NO → vasoconstriction), thromboemboli
• Progressive right heart failure (cor pulmonale)
• Chronic restrictive lung disease

5. Kidney

• Haematuria - papillary ischaemia; even in sickle cell trait
• Renal papillary necrosis - infarction of renal papillae → haematuria, renal colic, tubular dysfunction
• Hyposthenuria - inability to concentrate urine (ischaemia of renal medulla/vasa recta); early and universal finding; nocturia, enuresis
• Sickle nephropathy - progressive chronic kidney disease → ESRD (significant cause of mortality in adults)
• Nephrotic syndrome - membranoproliferative pattern

6. Eye

• Proliferative sickle retinopathy - neovascularization (sea-fan pattern), vitreous haemorrhage, retinal detachment → blindness
• Non-proliferative changes - salmon-patch haemorrhages, black sunburst lesions
• More common in HbSC than HbSS

7. Liver and Gallbladder

• Gallstones (cholelithiasis) - pigment (bilirubin) stones from chronic haemolysis; in >30% of adults with SCD
• Cholecystitis, ascending cholangitis
• Sickle cell hepatopathy - hepatomegaly from RBC sequestration, iron overload, hepatitis (from transfusions)
• Acute hepatic sequestration - sudden RBC trapping

8. Cardiovascular

• Cardiomegaly - chronic high-output state from anaemia
• Pulmonary hypertension → right ventricular failure
• Sudden cardiac death
• Iron overload cardiomyopathy in heavily transfused patients

9. Genitourinary

• Priapism - painful, prolonged, unwanted erection due to vascular occlusion in corpora cavernosa
  • Stuttering priapism: recurrent, brief (<3 hours) episodes
  • Major priapism (>4 hours): urological emergency; if untreated → erectile dysfunction (fibrosis of cavernosa)
• Risk of impotence is high in adult men

10. Dermatological

• Chronic leg ulcers (malleolar ulcers) - over medial and lateral malleoli; caused by ischaemia, venous stasis, poor healing; very painful, slow to heal, recurrent

11. Growth and Development

• Growth retardation and delayed puberty
• Nutritional deficiencies (zinc, folate)
• Psychosocial complications - depression, anxiety, school absenteeism, reduced quality of life

12. Transfusion Complications (in multiply-transfused patients)

• Iron overload (haemosiderosis) → cardiomyopathy, hepatic cirrhosis, endocrine failure (diabetes, hypogonadism, hypothyroidism)
• Alloimmunisation to RBC antigens → haemolytic transfusion reactions
• Infection transmission (HIV, hepatitis B/C - historical)

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5. COMPLICATIONS OF HAEMOLYTIC ANAEMIA

A. Complications Common to All Haemolytic Anaemias

1. Gallstones (Cholelithiasis)

• Chronic haemolysis → excess bilirubin production → precipitation as calcium bilirubinate (pigment) stones
• Can cause: biliary colic, acute cholecystitis, ascending cholangitis, pancreatitis, obstructive jaundice
• Even in children with HS, gallstones may form by age 10

2. Aplastic Crisis

• Parvovirus B19 - most common cause; infects erythroid progenitors → temporary cessation of erythropoiesis → sudden, severe anaemia with reticulocytopenia
• Life-threatening in chronic haemolytic anaemias (already compensating at maximum)
• Self-limiting (~10-14 days); managed with transfusion support

3. Folate Deficiency (Megaloblastic Change)

• Chronic high erythroid turnover demands large amounts of folate
• Folate stores depleted → superimposed megaloblastic anaemia → worsening of anaemia
• Prophylactic folic acid 5 mg/day is given routinely in chronic haemolytic anaemias

4. Iron Overload (Haemosiderosis)

• Mainly from repeated blood transfusions (each unit deposits ~250 mg iron)
• Also: increased intestinal iron absorption due to elevated erythropoiesis drive
• Target organs: Heart (cardiomyopathy - most lethal), liver (cirrhosis), pancreas (diabetes mellitus), endocrine glands (hypogonadism, growth failure, hypothyroidism)
• Management: iron chelation (desferrioxamine, deferasirox, deferiprone)

5. Extramedullary Haemopoiesis

• Chronic severe haemolysis → marrow hyperplasia overflows to extramedullary sites
• Spleen, liver (hepatosplenomegaly)
• Paravertebral masses (chest X-ray finding)
• Skull: "hair on end" radiological appearance (especially in thalassaemia and SCD)
• Facial deformity: frontal bossing, maxillary hyperplasia ("chipmunk facies") in severe thalassaemia

6. Splenomegaly and Hypersplenism

• Massive splenomegaly → hypersplenism → pancytopenia (RBC, WBC, platelet sequestration)
• Risk of splenic rupture (spontaneous or traumatic)
• Splenic infarction (in rapidly enlarging spleens)

7. Chronic Jaundice

• Persistent unconjugated hyperbilirubinaemia → jaundice, icteric sclerae
• Bilirubin may deposit in skin

B. Complications Specific to Autoimmune Haemolytic Anaemia (AIHA)

1. Life-threatening haemolysis - particularly in warm AIHA; Hb can fall precipitously
2. Steroid side effects - first-line treatment is corticosteroids; long-term use causes Cushing's syndrome, osteoporosis, diabetes, hypertension, cataracts
3. Splenectomy complications - second-line treatment; post-splenectomy sepsis from encapsulated organisms
4. Thromboembolic events - AIHA associated with hypercoagulable state; DVT, PE
5. Evans syndrome - simultaneous AIHA + immune thrombocytopenic purpura (ITP) → severe anaemia + thrombocytopenia + bleeding
6. Underlying disease progression - secondary AIHA (from SLE, CLL, lymphoma) - the primary disease may itself progress
7. Haemoglobinuria - renal tubular damage from free haemoglobin; acute tubular necrosis → acute kidney injury

C. Complications Specific to G6PD Deficiency

1. Neonatal jaundice - severe in neonates; can cause kernicterus (bilirubin encephalopathy → permanent brain damage, deafness, athetoid cerebral palsy)
2. Acute haemolytic episodes triggered by:
   • Drugs (primaquine, dapsone, nitrofurantoin, aspirin in large doses, chloroquine)
   • Favism (fava beans - Vicia faba)
   • Infections (any febrile illness)
   • Naphthalene (mothballs)
3. Haemoglobinuria → "Blackwater fever" (especially with primaquine + malaria)
4. Chronic non-spherocytic haemolytic anaemia in rare severe enzyme variants

D. Complications Specific to Hereditary Spherocytosis (HS)

1. Gallstones (in up to 50% of adults with HS)
2. Aplastic crisis (parvovirus B19)
3. Haemolytic crisis (during infections)
4. Megaloblastic crisis (folate depletion)
5. Post-splenectomy complications:
   • Post-splenectomy sepsis (encapsulated bacteria)
   • Thrombocytosis → thromboembolic risk
   • Atherosclerosis (cholesterol from excess Hb breakdown)
6. Leg ulcers (rare)

E. Complications Specific to MAHA (TTP/HUS)

1. Acute kidney injury (AKI) - hallmark of HUS (thrombotic microangiopathy in renal microvasculature); may progress to chronic renal failure
2. Neurological dysfunction - hallmark of TTP: confusion, seizures, focal deficits, stroke (from cerebral microthrombi)
3. Cardiac involvement - myocardial microinfarcts
4. Bowel ischaemia (in STEC-HUS from E. coli O157:H7 - bloody diarrhoea triggers)
5. DIC-related bleeding - in DIC-associated MAHA
6. Thrombotic microangiopathy → multi-organ failure if untreated

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SUMMARY TABLE: COMPLICATIONS AT A GLANCE

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