Anaemia and Blood Disorders

TL;DR. Anaemia means too little haemoglobin to carry oxygen adequately, and it affects roughly 1.9 billion people, making it the most common blood disorder on earth by an enormous margin. The single most important thing about it is that anaemia is a finding, not a diagnosis: the question is never "do you have anaemia" but "why". Iron deficiency causes about half of it worldwide, and while the answer in a menstruating woman is usually obvious, the same finding in a man or a postmenopausal woman means bleeding from somewhere in the gut until proven otherwise, and a meaningful proportion of those turn out to be colorectal cancer. Treating the anaemia without finding the cause is one of the more consequential shortcuts in medicine.

Key takeaways

• Roughly 1.9 billion people are anaemic, and iron deficiency is the leading cause. It is the most common nutritional deficiency in the world.
• Anaemia is a clue, not an endpoint. Iron deficiency in a man or a postmenopausal woman requires investigation of the gut, not just iron tablets.
• B12 deficiency causes nerve damage that becomes permanent if left long enough, and the neurological damage can appear before the anaemia does.
• Alternate-day iron dosing absorbs better than daily dosing, because a dose triggers a hormone that blocks absorption for about 24 hours. This reverses decades of standard practice.
• Ferritin is the best single test for iron stores and is falsely raised by inflammation, which is the commonest reason iron deficiency is missed.
• Von Willebrand disease is the commonest inherited bleeding disorder, affecting up to 1 percent of people, and it is frequently undiagnosed in women who consider heavy periods normal.

What anaemia is

In short: Not enough haemoglobin to deliver oxygen, defined by a threshold that differs by sex, and always a symptom of something else.

Haemoglobin is the oxygen-carrying protein in red blood cells (Chapter 4). Anaemia is a concentration below the population threshold:

The most useful first step is the size of the cells (mean corpuscular volume, on every blood count), because it sorts the causes immediately:

Iron deficiency anaemia

In short: The commonest cause worldwide, and the one where finding the reason matters more than the treatment.

Why it happens

Iron is lost from the body only slowly, about 1 mg a day, and there is no mechanism for excreting excess. So deficiency means either insufficient intake, poor absorption, increased need, or blood loss, and blood loss is the one that matters clinically.

The rule worth remembering: iron deficiency anaemia in a man of any age, or in a woman after menopause, is gastrointestinal bleeding until proven otherwise, and warrants endoscopic investigation of both upper and lower gut. A meaningful proportion turn out to have a cancer, and it is one of the more common presentations of colorectal cancer.

What it feels like

Fatigue, breathlessness on exertion, pallor, palpitations, headache, and poor concentration are the familiar ones. Two are more specific and worth knowing:

• Pica: craving non-food substances, classically ice (pagophagia), also soil or chalk. It is oddly specific to iron deficiency and resolves with treatment.
• Restless legs syndrome: an irresistible urge to move the legs, worse at rest and at night. Iron deficiency is a common and treatable cause, and checking ferritin in restless legs is standard (Chapter 57).

Also: brittle spoon-shaped nails, hair loss, cracks at the corners of the mouth, and a sore smooth tongue. Symptoms depend more on how fast the anaemia developed than on how severe it is; a slow decline over months is tolerated remarkably well.

Testing

Ferritin is the storage protein and the best single measure of iron stores. Its trap is that it is also an acute phase protein, rising with any inflammation, infection, liver disease, or malignancy. So a normal ferritin in someone with inflammation does not exclude iron deficiency, and transferrin saturation or a CRP alongside it helps interpret the result. This is the single most common reason iron deficiency is missed.

Treatment

Oral iron, and here the standard advice changed. Taking iron triggers a rise in hepcidin, a hormone that blocks further iron absorption for roughly 24 hours. So a second dose the same day, or even the next morning, is poorly absorbed.

Trials found that alternate-day dosing, once daily, absorbs a greater fraction than daily or twice-daily dosing and causes fewer side effects. Many guidelines have moved to once daily or alternate-day dosing as a result. Taking it with vitamin C helps; taking it with tea, coffee, calcium, or antacids does not.

Expect a haemoglobin rise of about 10 g/L in 2 to 4 weeks, and continue for about 3 months after haemoglobin normalises to refill stores.

Intravenous iron is used when oral iron is not tolerated, not absorbed (inflammatory bowel disease, after bariatric surgery), or when correction needs to be fast. Modern preparations allow full replacement in one or two infusions with a low rate of reactions.

Transfusion is reserved for haemoglobin that is dangerously low or for symptomatic patients, and restrictive transfusion thresholds (typically 70 to 80 g/L in stable patients) produce outcomes as good as or better than liberal ones, which was a significant and counterintuitive finding.

B12 and folate deficiency

In short: Large red cells, and in the case of B12, nerve damage that becomes permanent if you wait.

Both vitamins are needed for DNA synthesis, so without them dividing cells in the marrow enlarge and fail to mature properly, producing large red cells and a low count.

Vitamin B12 is found almost exclusively in animal foods and requires a stomach protein called intrinsic factor for absorption in the terminal ileum. Causes of deficiency:

The neurological damage is the reason this matters. B12 deficiency causes subacute combined degeneration of the spinal cord: numbness and tingling starting in the feet, loss of position sense, unsteady gait, and, if prolonged, permanent weakness and cognitive impairment. Critically, neurological damage can occur before or without anaemia, so a normal blood count does not exclude it, and treatment reverses recent damage and not established damage.

Folate deficiency produces the same blood picture without the neurological damage. It matters most in pregnancy, where deficiency causes neural tube defects, which is why supplementation before conception and flour fortification exist (Chapter 63).

Don't be confused: never treat a large-cell anaemia with folate alone before excluding B12 deficiency. Folate will correct the blood count while the neurological damage from B12 deficiency continues silently and becomes permanent. Check both.

Anaemia of chronic disease

In short: The body deliberately hides iron from itself during chronic inflammation, and giving iron does not fix it.

The second most common anaemia worldwide, seen in chronic infection, autoimmune disease, cancer, and chronic kidney disease.

The mechanism is elegant and inconvenient. Inflammation raises hepcidin, which locks iron inside storage cells and blocks absorption from the gut. Evolutionarily this makes sense: bacteria need iron, so hiding it is a defence. The consequence is a mild-to-moderate anaemia with plenty of iron in the body and none available to the marrow.

Ferritin is therefore normal or high while functional iron is low, which is exactly the trap described above. Treatment is treating the underlying disease. In chronic kidney disease specifically, the additional problem is loss of erythropoietin production (Chapter 23), treated with erythropoiesis-stimulating agents plus iron, targeting a haemoglobin deliberately below normal because full correction increased strokes and deaths in trials.

Haemolytic anaemias

In short: Red cells destroyed faster than they are made, from inherited defects, immune attack, or mechanical damage.

Haemolysis produces anaemia plus jaundice (from the breakdown pigment), dark urine, an enlarged spleen, and, over years, pigment gallstones.

Bone marrow failure

In short: The factory itself failing, producing shortages of all three cell lines at once.

Aplastic anaemia is failure of the marrow to produce red cells, white cells, and platelets. It is rare, often autoimmune, sometimes drug-induced or viral, and it presents with the triad of anaemia, infection, and bleeding. Treatment is immunosuppression or stem cell transplantation.

Myelodysplastic syndromes are a group of disorders in which the marrow produces defective cells, mostly in older adults, and a proportion progress to acute leukaemia.

Marrow infiltration by leukaemia, lymphoma, myeloma, or metastatic cancer crowds out normal production (Chapter 25).

When there is too much

In short: Excess red cells thickens the blood and raises clot risk, and the causes divide into appropriate and inappropriate.

Polycythaemia means a raised red cell count. It is appropriate when driven by low oxygen (chronic lung disease, sleep apnoea, high altitude, smoking, cyanotic heart disease), where the body is doing the right thing. It is inappropriate in polycythaemia vera, a bone marrow disorder driven by a mutation in the JAK2 gene, which raises the risk of clots and strokes and is treated by regular venesection (removing blood) plus aspirin.

Either way, thicker blood flows less well and clots more readily, which is why polycythaemia is worth finding.

Bleeding and clotting disorders

In short: Two families, one bleeding too easily and one clotting too readily, and the commonest inherited bleeding disorder is routinely missed in women.

Bleeding too easily

Heavy menstrual bleeding is the presentation to take seriously. It affects a large minority of women, is the commonest cause of iron deficiency, and in a meaningful proportion reflects an undiagnosed bleeding disorder. It is also highly treatable, with options from tranexamic acid to hormonal treatments to a hormonal intrauterine device, which typically reduces bleeding by 70 to 95 percent.

Clotting too readily

Thrombophilia describes an increased tendency to clot, whether inherited (Factor V Leiden, prothrombin gene mutation, protein C or S deficiency, antithrombin deficiency) or acquired (antiphospholipid syndrome, cancer, pregnancy, oestrogen-containing contraception, immobility). These are the underlying causes of venous thromboembolism, covered in Chapter 56.

What the person can do

In short: Get the cause found, take iron correctly, and know when heavy periods or fatigue are worth investigating.

• Insist on knowing the cause. "You are anaemic, here is some iron" is an incomplete answer, especially in a man or a postmenopausal woman.
• Take iron on alternate days, with vitamin C or orange juice, away from tea, coffee, calcium, and antacids. Expect dark stools, which is harmless, and constipation, which is manageable.
• Do not self-treat with iron indefinitely. Iron overload is real, and men and postmenopausal women have no route to excrete excess.
• If you are vegan, take B12. This is not a preference; it is a requirement.
• Get heavy periods assessed rather than tolerated. Practical markers: flooding through protection, passing clots larger than a coin, needing to change protection hourly, or bleeding more than 7 days.
• Get investigated for coeliac disease if iron deficiency recurs without an obvious cause.
• If you donate blood regularly, particularly if you menstruate, ask about your ferritin rather than only your haemoglobin.
• Know the red flags: anaemia with weight loss, change in bowel habit, blood in stool, or difficulty swallowing needs urgent investigation.

Sources and notes

Global anaemia prevalence of approximately 1.9 billion: WHO and Global Burden of Disease estimates. Haemoglobin thresholds: WHO. Alternate-day iron dosing and hepcidin: Moretti et al., Blood, 2015, and Stoffel et al., Lancet Haematology, 2017. Restrictive transfusion thresholds: TRICC, TRISS, and subsequent trials; Carson et al., Cochrane review. B12 neurological damage preceding anaemia: Lindenbaum et al., NEJM, 1988. Anaemia of chronic disease and hepcidin: Weiss and Goodnough, NEJM, 2005. Erythropoiesis-stimulating agent targets: CHOIR and CREATE trials. Von Willebrand disease prevalence: Rodeghiero et al., with clinically significant disease considerably rarer than laboratory prevalence. Hormonal intrauterine device and menstrual blood loss reduction: multiple randomised trials. G6PD deficiency distribution: WHO and malaria genetics literature.

Open questions. Optimal ferritin thresholds for diagnosing iron deficiency in the presence of inflammation are not agreed, and different guidelines use different cut-offs. Whether treating iron deficiency without anaemia improves fatigue is supported by some trials and not others.

Next: three organs that determine how you experience the world, and that between them cause more disability than almost anything else in this book. 👉