Anaemia, fatigue and transfusion in cancer

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Anaemia in cancer may result from reduced production, blood loss, destruction or dilution, and several mechanisms commonly coexist. FBC indices and reticulocytes create the first branch: a low reticulocyte response suggests marrow, renal or nutrient failure; a high response suggests blood loss or haemolysis. A blood film can reveal leukoerythroblastosis, fragmentation, dysplasia or another haematological process that a mean cell volume cannot.

Iron interpretation is altered by inflammation. Low ferritin confirms depleted stores, but high ferritin does not guarantee available iron because hepcidin traps iron outside the marrow. Transferrin saturation, CRP, renal function and treatment context help distinguish absolute and functional deficiency. Investigate the source of iron loss, particularly gastrointestinal or gynaecological bleeding, rather than repeatedly replacing iron without a diagnosis.

Red-cell transfusion produces rapid but temporary oxygen-carrying benefit. NICE recommends a restrictive approach in stable adults, generally using 70 g/L as a threshold and 70 to 90 g/L as a target when major bleeding, acute coronary syndrome and chronic transfusion programmes do not apply. This is not a command to transfuse every patient below 70 or refuse every patient above it. Symptoms, trajectory, goals and alternatives remain decisive.

Fatigue often persists after haemoglobin correction because inflammation, cachexia, sleep, pain, depression and deconditioning remain. Exercise has the strongest general non-drug evidence when a patient is stable enough, starting below current capacity and increasing gradually. ESAs and intravenous iron belong to selected treatment contexts, not generic fatigue care. Near the end of life, estimate whether transfusion is likely to produce meaningful days of function before travel, cannulation and reaction burden outweigh benefit.

Key points

Fatigue in cancer is not synonymous with anaemia; assess bleeding, sepsis, thrombosis, heart and lung disease, endocrine toxicity, sleep, pain, mood, medicines and deconditioning.
First-line anaemia tests are FBC with indices, reticulocyte count and blood film, compared with baseline and treatment cycle to classify production failure, loss or destruction.
Iron studies require ferritin, transferrin saturation and inflammation context because cancer-associated hepcidin can produce low usable iron despite a normal or high ferritin.
Add B12, folate, renal, liver, thyroid, haemolysis, bleeding and marrow investigations according to indices, reticulocytes, film and clinical pattern.
Treat the cause: control bleeding, infection and cancer; replace iron, B12 or folate; manage renal or endocrine disease; modify marrow-toxic treatment when appropriate.
Transfusion decisions use symptoms, haemodynamic stability, rate of fall, bleeding, comorbidity, treatment intent and patient goals rather than a haemoglobin number alone.
For stable adults without major haemorrhage, acute coronary syndrome or regular transfusion needs, NICE supports a restrictive threshold around 70 g/L and a post-transfusion target of 70 to 90 g/L.
Give one red-cell unit at a time in a stable non-bleeding adult, then reassess symptoms and haemoglobin before prescribing another unit.
Use slower infusion, careful fluid balance and selected diuretic support for high circulatory-overload risk; a diuretic does not make unnecessary transfusion safe.
Check historical antibodies, special requirements and previous reactions before sampling; some haematology, transplant and purine-analogue exposures require irradiated components.
During transfusion, verify identity at the bedside and observe baseline, early and completion vital signs according to policy; stop immediately for a suspected reaction.
Intravenous iron is preferred when absolute or functional deficiency needs rapid correction and oral absorption or inflammatory blockade makes tablets ineffective, but exclude active infection and monitor hypersensitivity.
Erythropoiesis-stimulating agents may reduce transfusion in selected adults receiving chemotherapy under NICE eligibility; use the lowest effective haemoglobin goal and review thrombosis and iron availability.
For persistent cancer-related fatigue, graded aerobic and resistance exercise is first-line when safe, combined with sleep, pain, mood, nutrition and energy-conservation support.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Marrow suppression or replacement

Chemotherapy, radiotherapy, leukaemia, lymphoma and metastatic infiltration reduce red-cell production and may cause parallel neutropenia or thrombocytopenia.

Inflammation and iron restriction

Cancer cytokines raise hepcidin, trap iron in macrophages and reduce erythropoietin response, producing functional deficiency despite normal or high ferritin.

Blood loss and haemolysis

Gastrointestinal, gynaecological, urinary or tumour bleeding, surgery, phlebotomy, immune haemolysis, microangiopathy and hypersplenism shorten circulating red-cell survival.

Nutrient, renal and endocrine causes

Absolute iron, B12 or folate deficiency, kidney failure, thyroid disease, adrenal insufficiency and hypogonadism can independently drive anaemia and fatigue.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Oxygen delivery falls
Reduced haemoglobin lowers arterial oxygen content; heart rate and stroke volume rise to compensate, but coronary, pulmonary and frail patients have limited reserve.
2
Hepcidin blocks usable iron
Inflammation suppresses intestinal absorption and ferroportin release, so marrow cannot access stored iron and oral replacement may be ineffective.
3
Chemotherapy injures erythroid precursors
Cytotoxic exposure produces a delayed, cumulative fall in marrow output, modified by renal erythropoietin, prior radiation, baseline reserve and cycle interval.
4
Fatigue is multisystem
Inflammation, sleep disturbance, pain, deconditioning, mood, endocrine dysfunction, medicines and cognitive load combine with anaemia, explaining why transfusion may improve only part of the symptom.
5
Transfusion changes volume and immunity
Donor cells restore oxygen carriage rapidly but add volume, antigen and inflammatory exposure, creating circulatory overload, reactions, alloimmunisation and rare infection risk.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Reduced oxygen delivery

Exertional breathlessness, palpitations, dizziness, headache, pallor, weakness and reduced concentration become more severe with rapid fall or limited cardiopulmonary reserve.

Occult or overt bleeding

Melaena, haematemesis, haematuria, vaginal loss, bruising, abdominal distension or falling pressure requires immediate source and coagulation assessment.

Marrow infiltration

Bone pain, pancytopenia, nucleated red cells, tear-drop cells or immature myeloid cells suggests myelophthisis and may require marrow examination.

Haemolysis

Jaundice, dark urine, splenomegaly, raised LDH and bilirubin, low haptoglobin and reticulocytosis indicate accelerated destruction and an urgent cause search.

Transfusion reactionRed flag

Fever, chills, dyspnoea, wheeze, pain, rash, hypotension or dark urine during transfusion requires immediate cessation and investigation.

Multifactorial fatigue

Severe tiredness with sleep disruption, pain, mood change, muscle loss or sedation despite modest anaemia suggests several treatment targets rather than transfusion alone.

Red flags requiring action

Tachycardia, hypotension, syncope, melaena, haematemesis, brisk vaginal bleeding or expanding tumour haemorrhage requires urgent source control and major-bleeding assessment.
Chest pain, ischaemic ECG change, heart failure, resting breathlessness or hypoxia with anaemia lowers tolerance and requires urgent senior transfusion and cardiac review.
Fever, rigors, confusion or hypotension after systemic anticancer treatment is possible neutropenic sepsis even when fatigue and anaemia appear to explain weakness.
Sudden fatigue with jaundice, dark urine, back pain, rising bilirubin or falling haptoglobin suggests haemolysis and requires urgent cause and transfusion investigation.
New dyspnoea, pleuritic pain, unilateral leg swelling or disproportionate tachycardia requires cancer-associated-thrombosis assessment rather than attribution to anaemia alone.
Fever, chills, dyspnoea, wheeze, pain, hypotension, rash or dark urine during transfusion requires immediate cessation and reaction protocol.
Rapid haemoglobin fall, pancytopenia, leukoerythroblastic film or neurological bleeding suggests marrow failure, DIC, TMA or occult haemorrhage needing urgent specialist review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line FBC, indices, reticulocytes and filmFirst stepFirst line
Why
Classify anaemia by cell size, marrow response and morphological evidence of blood loss, haemolysis, dysplasia or infiltration.
Interpretation and limitations
Compare trajectory and cycle timing; normal MCV can conceal mixed iron and B12 deficiency, and a low reticulocyte response is inappropriate when anaemia is severe.
02
Iron profile with inflammation context
Why
Measure ferritin, transferrin saturation and CRP to distinguish absolute iron depletion from functional inflammatory restriction.
Interpretation and limitations
A low ferritin is specific for deficiency, while normal or high ferritin during inflammation does not exclude low available iron; investigate the bleeding source.
03
B12, folate, renal, liver and thyroid tests
Why
Identify correctable nutrient, erythropoietin, endocrine and organ contributors suggested by history, indices and treatment.
Interpretation and limitations
Interpret B12 with symptoms and medicines, and add cortisol when immunotherapy, hypotension, sodium or glucose pattern raises adrenal or pituitary toxicity.
04
Haemolysis and bleeding assessment
Why
Use bilirubin, LDH, haptoglobin, direct antiglobulin test, coagulation, stool or endoscopic and imaging tests from the phenotype.
Interpretation and limitations
Fragmentation with thrombocytopenia and renal or neurological change suggests TMA or DIC and requires urgent specialist management, not routine transfusion only.
05
Pre-transfusion group, antibody screen and special-requirement check
Why
Select compatible components and identify irradiated, antigen-negative or other requirements from history and current treatment.
Interpretation and limitations
Use correctly labelled samples and historical records; a newly identified antibody can delay supply, so contact transfusion early in active bleeding.
06
Bone marrow examination
Why
Assess unexplained persistent cytopenia, leukoerythroblastic film, suspected infiltration, myelodysplasia or haematological malignancy.
Interpretation and limitations
Obtain aspirate and trephine with cytogenetic or molecular studies as indicated; treatment timing and growth factors can alter morphology.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Infection or treatment toxicity

Sepsis, pneumonitis, myocarditis, renal injury and endocrine immune toxicity cause fatigue and breathlessness and can be immediately dangerous despite modest anaemia.

Cardiopulmonary disease or thrombosis

Heart failure, arrhythmia, pulmonary embolism, pleural fluid and lung progression can explain exercise limitation and alter transfusion risk and target.

Depression, insomnia and medicine sedation

Low mood, anxiety, sleep apnoea, opioid, antihistamine, benzodiazepine and gabapentinoid effects can produce severe fatigue without corresponding haemoglobin change.

Cachexia and endocrine disease

Muscle loss, malnutrition, hypothyroidism, cortisol deficiency, diabetes and hypogonadism impair energy, strength and concentration and require mechanism-specific care.

Deconditioning and post-treatment syndrome

Prolonged inactivity reduces aerobic capacity and strength, while persistent post-treatment fatigue may continue after blood count and cancer control improve.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01New anaemia or fatigueClassify mechanism before treating the numberFirst stepHaemoglobin falls or fatigue and breathlessness worsen during cancer care.

1Assess ABCDE danger, bleeding, infection, thrombosis, cardiopulmonary symptoms, treatment timing, nutrition, endocrine features, sleep, mood and current medicines.
2EscalationObtain FBC, reticulocytes and film, iron studies and selected renal, vitamin, thyroid, haemolysis and bleeding tests, escalating unusual multilineage patterns to haematology.
3Treat reversible causes and agree whether the immediate goal is physiological rescue, treatment completion, symptom improvement or longer-term transfusion avoidance.

02Stable transfusion decisionUse one unit and reassessA non-bleeding adult has symptomatic anaemia or falls below the appropriate restrictive threshold.

1Review symptoms, rate of fall, heart and lung reserve, fluid risk, previous reactions, antibodies, special requirements, alternatives and patient goals and obtain valid consent.
2Prescribe one compatible red-cell unit at a rate matched to circulatory risk, with identity checks and baseline and early observations and an explicit reaction plan.
3Reassess symptoms, observations and haemoglobin before any further unit and document whether benefit justifies future transfusion or cause-directed treatment should replace it.

03Suspected transfusion reactionStop first and identify the syndromeNew fever, rigors, dyspnoea, wheeze, pain, rash, hypotension or dark urine occurs during or soon after transfusion.

1Stop the component immediately, call for help, maintain intravenous access with compatible saline, reassess ABCDE and recheck patient, unit and documentation identity.
2Notify the transfusion laboratory and send the bag, repeat blood and cultures or haemolysis samples according to the reaction protocol without discarding evidence.
3Treat anaphylaxis, bacterial sepsis, haemolysis, circulatory overload or TRALI by physiology, report as required and update future component and premedication requirements.

04Persistent fatigueRebuild function across multiple causesFatigue remains after urgent disease, anaemia and metabolic abnormalities are addressed.

1Measure effect on self-care, walking, work, sleep and cognition and review pain, depression, cachexia, endocrine disease and sedating or unnecessary medicines.
2Use individualised aerobic and resistance activity below current capacity with rehabilitation, sleep, energy-conservation, psychological and nutrition support.
3Review response and cancer trajectory and reserve stimulant or short corticosteroid trials for carefully selected palliative goals with a brief stop rule.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Rapidly improves oxygen-carrying capacity when symptomatic anaemia, physiological compromise or the appropriate restrictive threshold justifies immediate benefit.

Red-cell transfusion

For a stable non-bleeding adult, transfuse one red-cell unit, usually over 90 minutes to 3 hours according to circulatory risk and local policy, then reassess clinically and check haemoglobin before another unit.

Use slower administration and careful balance in TACO risk; verify identity and special requirements and stop immediately for fever, dyspnoea, pain, rash, hypotension or dark urine.

Replaces absolute or functional iron deficiency rapidly when oral iron is ineffective, not tolerated or too slow, including selected chemotherapy-associated anaemia pathways.

Intravenous ferric carboxymaltose

Calculate iron need from weight and haemoglobin; a single adult administration may deliver up to 1,000 mg iron, not exceeding 20 mg/kg, with any further dose separated by at least 7 days under the product protocol.

Monitor hypersensitivity during and after infusion, phosphate with repeated or high-risk exposure and infection context; extravasation can stain skin and iron does not replace investigation of bleeding.

Reduces red-cell transfusion in selected symptomatic chemotherapy-associated anaemia under NICE eligibility when treatment goals and thrombotic risk support use.

Epoetin alfa during eligible chemotherapy

A licensed adult starting regimen is 150 IU/kg subcutaneously three times weekly or 450 IU/kg once weekly, adjusted or stopped by haemoglobin response, transfusion need and the current oncology protocol.

Correct iron deficiency, control blood pressure and use the lowest haemoglobin sufficient to avoid transfusion; review VTE, tumour intent and lack of response and stop when chemotherapy ends according to protocol.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cardiac and cerebral hypoxia

Severe or rapid anaemia can provoke angina, infarction, heart failure, syncope, falls, delirium and reduced kidney perfusion.

Treatment delay and functional loss

Fatigue and marrow impairment reduce performance, independence and capacity to receive chemotherapy, surgery, radiotherapy and rehabilitation.

Transfusion-associated circulatory overload

Excess volume or infusion speed causes pulmonary oedema, hypertension and hypoxia, particularly with cardiac, renal, frail or low-body-weight risk.

Immune and infectious transfusion reactions

Acute haemolysis, febrile, allergic, anaphylactic, bacterial contamination, TRALI and delayed alloantibody reactions vary in timing and require exact investigation.

ESA thrombosis and tumour concern

Erythropoiesis-stimulating agents increase venous and arterial thrombotic risk and are restricted to selected chemotherapy-associated anaemia with conservative haemoglobin goals.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend haemoglobin, indices and reticulocytes against chemotherapy cycle, bleeding and treatment changes rather than reacting to an isolated value.
During transfusion, record baseline, early and completion observations and reassess any new fever, dyspnoea, pain, rash, pressure or urine change immediately.
After each unit, reassess symptoms, heart and lung signs, fluid balance and haemoglobin before prescribing another unit.
During intravenous iron, observe for hypersensitivity and monitor haemoglobin, ferritin, transferrin saturation and phosphate at an interval matched to product and exposure.
During ESA therapy, review haemoglobin at protocol intervals, blood pressure, thrombosis symptoms, iron availability and whether transfusion need is actually falling.
For fatigue, follow a patient-valued outcome such as walking, self-care, work or time out of bed alongside sleep, pain, mood and medicine burden.
Near end of life, document duration and magnitude of previous transfusion benefit before repeating travel and cannulation burdens automatically.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Ferritin is an acute-phase protein

A reassuring concentration during inflammation can coexist with severe iron restriction, making transferrin saturation and clinical context essential.

One unit is a therapeutic trial

In a stable patient it permits symptom and volume reassessment and avoids the inherited habit of prescribing two units automatically.

Fatigue can outlive anaemia

Inflammation, deconditioning and sleep or mood disruption explain why a normal haemoglobin does not invalidate severe cancer-related fatigue.

Transfusion thresholds are exceptions aware

Major bleeding, acute coronary syndrome and chronic transfusion dependence need different targets, while symptoms and trajectory remain relevant in every group.

TACO risk begins before the unit

Age, low weight, heart or kidney failure and positive fluid balance should change necessity, number, rate and post-unit reassessment before infusion starts.

ESA benefit is delayed

It cannot rescue acute symptomatic anaemia and should stop when inadequate response or completed chemotherapy removes a meaningful transfusion-avoidance goal.

11Common pitfallsFrequent interpretation and management errors.

01
Calling all cancer fatigue anaemia and missing sepsis, thrombosis, endocrine toxicity or heart failure.
02
Using MCV alone and missing mixed iron, B12 and inflammatory disease.
03
Interpreting high ferritin as proof of adequate available iron during inflammation.
04
Transfusing from a haemoglobin number without symptoms, trajectory, comorbidity or goals.
05
Prescribing two units automatically to a stable non-bleeding adult.
06
Using a diuretic to justify an unnecessary transfusion in circulatory-overload risk.
07
Failing to stop a transfusion immediately when a reaction is suspected.
08
Starting ESA for rapid rescue or without reviewing iron and thrombotic risk.
09
Recommending rest alone for fatigue and accelerating deconditioning.
10
Repeating end-of-life transfusion despite no meaningful benefit from the preceding unit.