Pathology

Interpreting Liver Function Tests (LFTs): Patterns, Causes, Algorithms and Emergency Findings Study level: Clinical medicine, emergency medicine and clinical chemistry | Topic: Liver tests Core concept: A “liver function test” panel contains markers of hepatocellular injury, cholestasis and synthetic function. ALT/AST show injury, ALP/GGT suggest cholestasis, bilirubin describes excretory handling, and albumin/INR reflect synthetic function (with important non-liver influences). Interpret the pattern, severity, trend and patient—not an isolated number. Learning objectives Identify what each common liver panel test measures and what it cannot prove. Classify results as hepatocellular, cholestatic or mixed using the R-ratio concept. Interpret bilirubin, albumin, INR, ALP, GGT, ALT and AST together. Build a stepwise differential and investigation plan. Recognise acute liver failure, cholangitis, severe drug injury and other emergencies. 1. The liver panel: injury versus function Test What it reflects Important limitations ALT Leakage from hepatocytes; relatively liver-specific. Can rise in muscle/other disease; magnitude does not equal functional failure. AST Hepatocyte and muscle injury; mitochondrial and cytosolic enzyme. Less liver-specific; also rises in skeletal/cardiac muscle and haemolysis. ALP Bile-duct/ductular injury and cholestasis; also bone, placenta and intestine. Physiologically higher in children, pregnancy and healing bone. GGT Supports hepatobiliary source of an elevated ALP; inducible enzyme. Alcohol and many drugs raise it; isolated GGT is nonspecific. 5′-nucleotidase Alternative confirmation of hepatic ALP source. Less available; does not identify the exact cause. Total/direct bilirubin Heme breakdown, hepatic uptake/conjugation and biliary excretion. Fractionation is essential; haemolysis and fasting also alter levels. Albumin Longer-term hepatic protein synthesis and nutrition/inflammation. Long half-life; low in renal/GI loss, inflammation and malnutrition. PT/INR Short half-life clotting-factor synthesis and vitamin K status. Also altered by warfarin, vitamin K deficiency, DIC and anticoagulants. Total protein/platelets Globulins and portal-hypertension/marrow clues. Supportive, not specific. 2. Classify the biochemical pattern 2.1 R-ratio Use the upper limit of normal (ULN) for the laboratory: R = (ALT ÷ ALT ULN) ÷ (ALP ÷ ALP ULN) Hepatocellular: R ≥5; ALT/AST predominate. Mixed: R >2 and <5. Cholestatic: R ≤2; ALP/GGT and often bilirubin predominate. Patterns can evolve. In severe hepatocellular injury, aminotransferases may fall as hepatocytes are lost while INR/bilirubin worsen; a falling ALT is not automatically recovery. 3. Hepatocellular pattern 3.1 Common causes Cause Clues Initial tests Viral hepatitis Exposure, fever, malaise, jaundice, very high ALT/AST. HAV IgM, HBsAg/anti-HBc IgM, HCV antibody/RNA; HEV where relevant. Drug-induced liver injury (DILI) New medicine, supplement or dose change; variable latency. Full medication timeline, exclusion of viral/autoimmune/obstructive causes. Ischemic/hypoxic hepatitis Shock, hypoxia, cardiac failure; abrupt very high AST/ALT and LDH. Haemodynamics, lactate, LDH, ECG/echo and renal tests. Autoimmune hepatitis Female predominance, other autoimmunity, high IgG. ANA, ASMA, anti-LKM where appropriate, IgG and specialist assessment. Metabolic fatty liver/MASH Obesity, diabetes, dyslipidaemia; mild chronic ALT elevation. Metabolic profile, ultrasound/elasticity and fibrosis risk assessment. Wilson disease Young patient, neuropsychiatric symptoms, haemolysis or acute liver failure. Ceruloplasmin, urinary copper, slit-lamp exam and specialist testing. Muscle injury Myalgia, weakness, trauma, seizures or strenuous exercise; AST often prominent. Creatine kinase, renal function and urine. 3.2 AST:ALT ratio An AST:ALT ratio above about 2 supports alcohol-associated liver disease in the right context, but it is neither sensitive nor specific. AST predominance also occurs in cirrhosis, muscle injury and advanced mitochondrial injury. 4. Cholestatic pattern 4.1 Intrahepatic versus extrahepatic Extrahepatic obstruction: gallstones, pancreatic/ampullary cancer, biliary stricture, cholangitis or postoperative injury. Intrahepatic cholestasis: sepsis, drug injury, primary biliary cholangitis, primary sclerosing cholangitis, infiltrative disease, pregnancy-related cholestasis. 4.2 Diagnostic sequence Confirm hepatic source of ALP with GGT or 5′-nucleotidase and repeat if unexpected. Ask about jaundice, pale stool, dark urine, itch, fever, RUQ pain, drug exposure and inflammatory bowel disease. Perform ultrasound first in many settings to assess ducts, gallstones, liver texture and portal flow. If ducts are dilated, escalate to MRCP/CT/endoscopic assessment and urgent intervention when cholangitis/obstruction is likely. If ducts are not dilated, consider autoimmune cholestatic disease, DILI, sepsis, infiltrative disease and pregnancy-related causes. 4.3 Cholangitis emergency Fever/rigors, RUQ pain and jaundice suggest ascending cholangitis; hypotension and altered mental state indicate severe disease. Start sepsis management, cultures and antibiotics per local protocol, urgent imaging and biliary drainage consultation. 5. Bilirubin interpretation Pattern Mechanism Examples Unconjugated predominant Overproduction or impaired conjugation. Haemolysis, Gilbert syndrome, neonatal physiology, ineffective erythropoiesis. Conjugated predominant Hepatocyte excretion failure or obstruction. Hepatitis, cholestasis, obstruction, sepsis, drug injury. Mixed Combined hepatocellular and biliary dysfunction. Severe hepatitis, advanced cirrhosis and mixed DILI. Urine bilirubin is present when conjugated bilirubin is water-soluble. Dark urine with pale stools and itch suggests cholestasis, whereas isolated unconjugated hyperbilirubinaemia without liver injury suggests haemolysis or impaired conjugation. 6. Synthetic function and severity INR/PT: rises quickly when clotting-factor synthesis is impaired. An unexpectedly prolonged INR may also reflect vitamin K deficiency, warfarin, DIC or anticoagulant contamination. Albumin: low albumin suggests chronic disease or nonhepatic loss; normal albumin does not exclude acute liver failure. Glucose: hypoglycaemia is a severe hepatic failure warning, especially with encephalopathy. Ammonia: may support encephalopathy assessment but correlates imperfectly with severity; treat the patient, not the number alone. Platelets/spleen: thrombocytopenia and splenomegaly support portal hypertension but have many other causes. 7. Acute liver failure: emergency recognition Acute liver failure is rapid severe hepatic injury with coagulopathy and encephalopathy in a person without established cirrhosis. It requires urgent specialist/transplant-centre discussion. Jaundice plus confusion, asterixis, drowsiness or coma. Rising INR/PT, hypoglycaemia, metabolic acidosis, renal injury or lactate elevation. Very high aminotransferases from acetaminophen/toxin, viral hepatitis or ischemia; the cause may be clinically silent initially. Urgent actions: ABCDE, bedside glucose, stop hepatotoxic drugs, contact a liver unit, test for acetaminophen and viral/autoimmune causes, manage cerebral oedema/sepsis/renal failure and avoid unnecessary procedures. 8. Interpreting common combinations Pattern Likely considerations Next step ALT/AST high, ALP mild, bilirubin variable Hepatitis, ischemia, DILI, autoimmune hepatitis, muscle injury. Repeat/trend, medication and exposure history, viral/autoimmune tests, CK and ultrasound. ALP/GGT high with direct bilirubin Obstruction, cholangitis, cholestatic DILI, PBC/PSC. Ultrasound, urgent assessment if pain/fever, cholangiography when indicated. Isolated ALP high, GGT normal Bone growth/disease, fracture, vitamin D disorders, pregnancy. Bone-specific ALP/other tests and clinical evaluation. Isolated GGT high Alcohol, enzyme-inducing drugs, metabolic disease.

Blood Cross-Matching: Pre-Transfusion Compatibility Testing, Antibody Screening and Emergency Release Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology and transfusion medicine Core concept: Cross-matching is the final compatibility check between a recipient and a specific donor unit. It complements ABO/Rh typing and antibody screening; it does not replace correct patient identification, historical antibody review or bedside verification. Learning objectives Explain the difference between type-and-screen, antibody screen, cross-match, DAT and IAT. Describe serologic and electronic cross-match workflows. Recognise clinically significant antibodies and incompatible results. Manage emergency-release blood while testing is incomplete. Prevent wrong-blood-in-tube and wrong-patient errors. 1. The pre-transfusion testing pathway Clinical request: specify component, urgency, indication, special processing and anticipated number of units. Correct specimen: collect and label a patient sample at bedside using two identifiers; include transfusion/pregnancy history. ABO/Rh(D) typing: test patient RBC antigens and confirm with plasma reverse grouping. Antibody screen: incubate patient plasma with reagent group O screening cells expressing common antigens. Antibody identification: if screen is positive, test a panel to determine specificity and clinical significance. Donor-unit selection: choose ABO/Rh-compatible, antigen-negative and specially processed units. Cross-match: test recipient plasma against donor RBCs, electronically or serologically according to policy. Bedside check: independently verify patient, unit, group, compatibility, expiry and special requirements immediately before administration. 2. Key tests and terminology Test/term What it does Clinical meaning ABO/Rh typing Identifies RBC antigens using forward/reverse grouping and anti-D testing. Prevents major ABO/Rh incompatibility. Antibody screen (IAT) Detects unexpected IgG antibodies in patient plasma using reagent screening cells. Predicts delayed/acute haemolysis and guides antigen-negative selection. Antibody identification panel Maps reaction pattern against cells with known antigen profiles. Determines whether anti-K, anti-E, anti-Jka or another antibody is present. Major cross-match Recipient plasma + donor RBCs. Detects antibodies that would attack transfused RBCs; the essential final compatibility test. Minor cross-match Donor plasma + recipient RBCs. Historically used with whole blood; less relevant for modern packed RBCs but plasma compatibility remains important. Electronic cross-match Validated computer check using current ABO/Rh and negative antibody screen/history. Fast and safe only when all system criteria are met. Immediate-spin cross-match Rapid ABO incompatibility check at room temperature. Insufficient alone if clinically significant antibodies are present. AHG/antiglobulin cross-match Incubation with antihuman globulin detects IgG-mediated reactions. Required when antibody screen/history is positive or policy demands it. DAT (direct antiglobulin test) Detects IgG/complement already coating patient RBCs in vivo. Useful in autoimmune/drug haemolysis and transfusion reactions. IAT (indirect antiglobulin test) Detects antibodies in plasma that can bind reagent/donor RBCs in vitro. Used for antibody screening and compatibility testing. 3. Clinically significant antibodies Most clinically important alloantibodies are IgG, react at 37°C/AHG phase and can cause extravascular haemolysis or HDFN. Common significant systems include Rh (D, C, c, E, e), Kell, Kidd, Duffy and selected MNS antibodies. Anti-A and anti-B are usually IgM/complement-activating and cause severe immediate intravascular haemolysis when incompatible. Some antibodies become undetectable over time; a historical antibody remains clinically relevant even if the current screen is negative. Cold-reactive antibodies may be clinically insignificant at body temperature, but laboratory interpretation is essential because some complement-reactive antibodies are dangerous. 4. What an incompatible cross-match means Pattern Possible explanation Action ABO mismatch Wrong group, sample error, reagent issue or major clerical problem. Stop, repeat patient typing and investigate identity; do not release the unit. Positive screen + incompatible donor unit Donor expresses the target antigen. Select antigen-negative unit and perform antiglobulin cross-match. Positive screen + apparently compatible panel Autoantibody, low-incidence antigen, dosage effect or multiple antibodies. Reference laboratory, adsorption/genotyping and specialist consultation. Panagglutination Warm autoantibody, cold interference, drug antibody or contamination. DAT, autocontrol, pre-warm technique and specialised work-up. Recent transfusion/mixed field Two RBC populations, donor cells, stem-cell transplant or weak subgroup. Review history, genotype where useful and avoid relying on phenotype alone. 5. Specimen collection and validity Use two identifiers and label the tube at the bedside immediately after collection. Record date/time, collector identity, pregnancy/transfusion history and current antibody status. Many services limit a pre-transfusion sample to about 72–96 hours when the patient has been recently transfused or pregnant because new antibodies can develop; local policy governs expiry. Reject haemolysed, clotted, unlabeled, mislabeled or insufficient samples; redraw rather than guessing. Do not draw from a line containing blood or IV medication unless the laboratory has an approved technique. 6. Electronic and serologic cross-match 6.1 Electronic cross-match A validated system checks that the patient has a compatible historical and current ABO/Rh result, a negative antibody screen and no unresolved clinically significant antibody. It reduces delays and manual error but fails if records are incomplete, the sample is invalid or the patient has a current/historical antibody. 6.2 Serologic cross-match Recipient plasma is incubated with donor RBCs and tested through the required phases, including antihuman globulin when IgG antibodies are possible. A visible or instrument-detected reaction indicates incompatibility until resolved. 6.3 Cross-match is not a bedside substitute A compatible laboratory result cannot protect a patient if the wrong unit is attached to the wrong patient. Bedside identity checks must be repeated immediately before transfusion. 7. Emergency-release blood In exsanguinating haemorrhage, do not delay life-saving RBCs for full testing. Obtain a correctly labeled pre-transfusion sample before release whenever feasible. Blood bank may issue uncrossmatched group O or group-specific RBCs under emergency policy; select Rh strategy according to age, sex, pregnancy potential, inventory and local guidance. Continue ABO/Rh typing, antibody screen and cross-match in parallel. Switch to fully compatible antigen-negative units as soon as available, and document the emergency rationale. Emergency release increases risk but is safer than allowing a patient to exsanguinate. The decision should be communicated clearly and recorded. 8. Special scenarios Warm autoimmune haemolytic anaemia: panreactive autoantibody may make all units appear incompatible; transfusion is based on clinical need, after excluding alloantibodies with specialist methods. Sickle cell disease/thalassaemia: use extended phenotype/genotype matching and historical antibody review to reduce alloimmunisation. Pregnancy: screen for anti-D, anti-c, anti-K and other antibodies; coordinate maternal and fetal monitoring. Stem-cell transplant: ABO mismatch does not always preclude transplant, but component selection is specialised and may change

Blood Grouping: ABO, Rh(D), Antigens, Antibodies, Testing and Clinical Significance Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology and transfusion medicine Core concept: Blood grouping identifies red-cell antigens and the naturally occurring or immune antibodies in plasma. Correct ABO/Rh testing protects the patient from acute haemolysis, while antibody screening and antigen matching address clinically significant non-ABO systems and pregnancy-related risk. Learning objectives Explain ABO antigen inheritance and naturally occurring antibodies. Describe forward and reverse grouping, Rh(D) testing and antibody screening. Apply red-cell and plasma compatibility principles. Recognise blood-group discrepancies, weak D, Bombay phenotype and mixed-field reactions. Explain Rh alloimmunisation and haemolytic disease of the fetus/newborn. 1. Antigens and antibodies A red-cell antigen is a genetically determined surface structure that may be recognised as foreign. A plasma antibody binds a specific antigen and can activate complement, cause agglutination or promote phagocytosis. A person normally lacks the ABO antigen(s) they do not express and may have the corresponding antibody. ABO group RBC antigen(s) Expected plasma antibodies A A Anti-B B B Anti-A AB A and B Neither anti-A nor anti-B O Neither A nor B Anti-A and anti-B ABO antibodies are mainly IgM and activate complement strongly, so an incompatible RBC transfusion can cause rapid intravascular haemolysis. ABO antibodies may also include IgG components and vary with age, illness and immune status. 2. ABO genetics and biochemistry The H gene creates the H substance on which A or B transferases act. The A allele adds N-acetylgalactosamine; the B allele adds galactose; O generally produces an inactive transferase. A and B are codominant; O is recessive. Genotype and phenotype are not always interchangeable because rare variants exist. Secretor status determines whether soluble ABO substances appear in saliva and other secretions. The rare Bombay (Oh) phenotype lacks H substance, so routine typing may appear group O but anti-H prevents safe transfusion with ordinary O blood; compatible Bombay units are required. 3. How blood grouping is performed 3.1 Forward (cell) grouping Patient red cells are mixed separately with anti-A, anti-B and often anti-A,B reagents. Agglutination indicates the corresponding antigen on the RBC surface. 3.2 Reverse (serum/plasma) grouping Patient plasma is mixed with known A1 and B reagent cells. Agglutination indicates the corresponding antibody in plasma. Reverse grouping confirms forward grouping and helps detect errors or weak/absent antibodies. Forward result Reverse result Interpretation Anti-A positive, anti-B negative A1 cells negative, B cells positive Group A. Anti-A negative, anti-B positive A1 cells positive, B cells negative Group B. Anti-A and anti-B positive A1/B cells negative Group AB. Anti-A and anti-B negative A1/B cells positive Group O. 3.3 Rh(D) typing Patient cells are tested with anti-D reagent. A positive result is Rh(D)-positive; a negative result is Rh(D)-negative under the laboratory method. Weak D or partial D variants may require additional testing and specialist interpretation, especially in pregnancy and transfusion. 4. ABO/Rh compatibility 4.1 Red-cell compatibility Recipient Usually compatible RBC groups Reason A positive A positive/negative or O positive/negative, after testing. Recipient anti-B must not meet B antigen. B positive B positive/negative or O positive/negative, after testing. Recipient anti-A must not meet A antigen. AB positive ABO/Rh-compatible units; often broadest RBC receiving options. No anti-A/anti-B, but other antibodies still matter. O negative O negative RBCs preferred. Anti-A/anti-B in plasma; Rh-negative recipient needs Rh-negative red cells. “Universal donor” and “universal recipient” are emergency shorthand, not substitutes for a full type-and-screen/cross-match. O-negative supply is limited and should be reserved according to local policy. In life-threatening bleeding, uncrossmatched group O or group-specific blood may be released by the blood bank while testing continues. 4.2 Plasma compatibility For plasma, the donor’s antibodies matter. AB plasma lacks anti-A and anti-B and is broadly compatible as donor plasma; group O plasma contains both antibodies and is not universal plasma. The exact product choice follows the blood bank’s policy, especially in massive transfusion. 5. Rh system and alloimmunisation Rh proteins are inherited membrane antigens; D is the most immunogenic. Unlike ABO antibodies, anti-D is not naturally present. It develops after exposure through transfusion or fetomaternal haemorrhage. Anti-D is usually IgG, crosses the placenta and can cause fetal/neonatal haemolysis. Rh-negative pregnant patients require antenatal antibody screening and prophylaxis with anti-D immunoglobulin according to local obstetric protocol after sensitising events and at recommended gestations. Once immune anti-D is present, prophylaxis does not remove it; monitor the pregnancy and fetus with specialist care. 6. Other clinically important blood-group systems System Clinical significance Kell Highly immunogenic; anti-K can cause severe transfusion reactions and haemolytic disease of the fetus/newborn. Kidd Antibodies may become undetectable and cause delayed haemolysis after re-exposure. Duffy Anti-Fya/Fyb can cause transfusion reactions and HDFN; Duffy-null phenotype has malaria relevance. MNS Some antibodies are clinically significant, especially after repeated exposure. Lewis/P systems Often less clinically significant, but interpretation depends on antibody class, temperature and patient context. Patients with chronic transfusion needs, multiple antibodies or haemoglobinopathy may require extended phenotype/genotype matching to reduce alloimmunisation. 7. Blood-group discrepancy A discrepancy is any conflict between forward and reverse grouping, current and historical result, or expected and observed reaction. Never release routine blood until resolved unless an emergency-release protocol is authorised. Cause Clue Action Clerical/identification error Unexpected result or mismatch with history. Stop, redraw correctly labelled sample and investigate identity. Weak/missing antibodies Newborn, elderly, immunosuppressed or hypogammaglobulinaemic patient. Use extended testing and specialist interpretation. Weak/variant antigen Weak or mixed-field forward reaction. Repeat with alternate reagents, anti-A1 lectin or reference laboratory. Recent transfusion/transplant Two RBC populations or mixed-field agglutination. Review transfusion/transplant history; genotype may help. Cold autoantibody/rouleaux Panagglutination or pseudoagglutination. Warm technique, saline replacement or specialised testing. Rare phenotype (e.g., Bombay) Appears O but reacts with anti-H or has unexpected antibodies. Reference laboratory and rare-donor search. 8. Haemolytic disease of the fetus and newborn (HDFN) Maternal IgG crosses the placenta and destroys fetal RBCs when maternal antibodies target fetal antigens. Anti-D is classic, but anti-c, anti-K and other antibodies can be severe. Screening: maternal ABO/Rh type and antibody screen early in pregnancy and at recommended intervals. Risk assessment: identify

Complications of Blood Transfusion: Acute Reactions, Delayed Effects and Emergency Management Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology and transfusion medicine Safety rule: Any new fever, rigors, rash, dyspnoea, pain, hypotension, dark urine, bleeding or anxiety during or after transfusion may be a transfusion complication. Stop the transfusion first, assess ABCDE, recheck identity and notify the blood bank. Never restart a suspect unit casually. Learning objectives Classify acute, delayed, immune and nonimmune transfusion complications. Recognise haemolytic, febrile, allergic, septic, TRALI and TACO presentations. Explain delayed haemolysis, alloimmunisation, iron overload and transfusion-associated GVHD. Apply a stepwise investigation and emergency response. Prevent complications through patient selection, component modification and haemovigilance. 1. Classification by timing Timing Examples Clinical significance During/within 24 hours Acute haemolysis, febrile reaction, urticaria/anaphylaxis, bacterial sepsis, TRALI, TACO, hypotension, citrate toxicity and hypothermia. May progress to shock, respiratory failure, DIC or cardiac arrest. Days to weeks Delayed haemolysis, post-transfusion purpura, alloimmunisation and some infections. Falling Hb, jaundice, thrombocytopenia or difficulty finding compatible blood. Months to years Iron overload, transfusion-transmitted infection, chronic GVHD and repeated alloantibody formation. End-organ injury and complex future transfusion support. 2. Acute immune reactions 2.1 Acute haemolytic transfusion reaction (AHTR) Usually caused by ABO-incompatible RBCs from identification or clerical error. Recipient IgM activates complement, causing intravascular haemolysis, cytokine release, vasodilation, DIC and renal tubular injury. Other clinically significant antibodies can also cause reactions. Symptoms: fever, rigors, flushing, chest/back/flank pain, dyspnoea, nausea, anxiety/impending doom, hypotension, bleeding and dark urine. Signs/tests: haemoglobinuria, raised LDH/indirect bilirubin, low haptoglobin, positive DAT, rising creatinine, hyperkalaemia and DIC. Immediate care: stop transfusion, maintain IV access with compatible fluid, verify identity, notify blood bank, send blood/unit/urine samples, support shock and renal function, monitor potassium and coagulation. 2.2 Febrile non-haemolytic transfusion reaction (FNHTR) A temperature rise of at least 1°C or fever with chills/rigors during or soon after transfusion, usually from cytokines or antibodies to donor leukocytes. It is a diagnosis of exclusion: bacterial contamination and haemolysis must be ruled out before attributing fever to FNHTR. 2.3 Allergic and anaphylactic reactions Mild: isolated urticaria, pruritus or flushing due to donor plasma proteins. Severe: bronchospasm, angioedema, hypotension or shock; IgA-deficient recipients with anti-IgA are a classic risk group. Management: stop and assess. Mild isolated symptoms may receive an antihistamine under policy; anaphylaxis requires immediate IM adrenaline, airway/oxygen support and fluid resuscitation. 3. Acute nonimmune reactions Complication Mechanism/causes Clinical clues TRALI Donor antibodies/mediators activate recipient neutrophils, causing noncardiogenic pulmonary oedema. Acute hypoxia, bilateral infiltrates and respiratory distress during or within hours, without primary circulatory overload. TACO Rapid or excessive volume in a patient with limited cardiac/renal reserve. Dyspnoea, hypertension, raised JVP, pulmonary oedema, positive fluid balance and response to diuresis. Septic transfusion reaction Bacterial contamination, especially platelets stored at room temperature. High fever, rigors, vomiting, hypotension, shock and DIC. Mechanical haemolysis Improper warming, freezing, pressure pumps, small needles or incompatible IV solutions. Pink/red plasma, haemoglobinuria and falling Hb without expected antibody findings. Nonimmune haemolysis Overheating, hypotonic fluids, contaminated line or damaged unit. Haemolysis with negative immune work-up; inspect equipment and unit. Hypothermia Rapid infusion of cold components. Arrhythmia, coagulopathy, impaired oxygen unloading and worsened shock. Citrate toxicity Citrate chelates ionised calcium during rapid/massive transfusion. Perioral tingling, hypotension, tetany, QT prolongation and arrhythmia. Hyperkalaemia Potassium leakage from stored RBCs, amplified by renal failure/rapid massive transfusion. Weakness, ECG changes, ventricular arrhythmia or cardiac arrest. Air embolism Improper pressure/catheter handling, rare with standard systems. Sudden dyspnoea, chest pain, neurologic deficit or cardiovascular collapse. 4. Delayed immune complications 4.1 Delayed haemolytic transfusion reaction An antibody titre falls below detection after an earlier exposure, then rises days to weeks after re-exposure. Extravascular haemolysis causes an unexpected Hb fall, jaundice, fever or dark urine. Repeat antibody screen, DAT, bilirubin, LDH, haptoglobin and blood film; notify the blood bank so future units are antigen-negative. 4.2 Alloimmunisation Recipients form antibodies to RBC, platelet or HLA antigens after transfusion or pregnancy. Alloimmunisation can cause delayed haemolysis, platelet refractoriness, haemolytic disease of the fetus/newborn and difficulty finding compatible units. Use extended phenotype/genotype matching in chronically transfused patients. 4.3 Post-transfusion purpura Rare severe thrombocytopenia occurs about 5–10 days after exposure, often in previously sensitised individuals. It may cause mucosal, GI or intracranial bleeding; urgent haematology assessment and IVIG are typical specialist therapies. 4.4 Transfusion-associated GVHD Viable donor T cells engraft and attack recipient skin, gut, liver and marrow, causing fever, rash, diarrhoea, hepatitis and pancytopenia days to weeks later. Mortality is high. Prevention is irradiation of cellular components for defined high-risk recipients and directed donations. 5. Transfusion-transmitted infections Donation screening and pathogen-reduction reduce but do not eliminate risk. Possible agents include HIV, hepatitis B/C, malaria, syphilis, bacteria, parasites and emerging viruses. A recipient with unexplained fever, hepatitis, haemolysis or sepsis after transfusion requires investigation and haemovigilance reporting. Maintain traceability of donor unit and recipient samples. 6. Iron overload and chronic complications Repeated RBC transfusions deposit iron in liver, heart, pancreas and endocrine organs. Monitor cumulative exposure, ferritin and organ iron (MRI where available) in chronic transfusion disorders. Iron chelation is specialist-directed; adherence and renal/hepatic safety monitoring are essential. Chronic transfusion also increases alloimmunisation, transfusion dependence, venous access complications and infection exposure. 7. Massive-transfusion complications Problem Why it occurs Monitoring/prevention Dilutional coagulopathy Loss/dilution of platelets and factors. Balanced components; serial fibrinogen, PT/aPTT, platelets and viscoelastic tests. Hypocalcaemia Citrate binds ionised calcium. Serial ionised calcium and protocol-guided calcium replacement. Hyperkalaemia Stored RBC potassium and tissue injury. ECG/electrolytes; use appropriate products and treat hyperkalaemia. Hypothermia Large volumes of cold blood/fluid. Active warming and blood warmers where approved. Acidosis then alkalosis Shock/lactate initially; citrate metabolism later. Serial blood gases; treat perfusion rather than bicarbonate reflexively. TACO High volume/rate in limited cardiac/renal reserve. Slow targeted transfusion, fluid balance and diuretic strategy when appropriate. TRALI Inflammatory lung injury from donor mediators. Recognise early, avoid unnecessary plasma and report to blood service. 8. Universal emergency response Stop the transfusion immediately. Keep the IV line open with compatible fluid through new tubing if required. Assess airway, breathing, circulation, disability, exposure, temperature,

Indications for Blood Transfusion and Patient Blood Management Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology and transfusion medicine Core principle: Transfuse when the expected benefit—restoring oxygen delivery or haemostasis—outweighs the risks. A haemoglobin or platelet number is a decision aid, not an automatic prescription. Consider symptoms, bleeding rate, physiology, comorbidity, procedure risk, alternatives and the patient’s values. Learning objectives Decide when red cells, platelets, plasma, cryoprecipitate or factor concentrates are indicated. Apply restrictive, symptom-guided transfusion thresholds safely. Manage acute haemorrhage, obstetric bleeding, children, pregnancy, chronic anaemia and haemoglobinopathies. Use patient blood management (PBM) to prevent avoidable transfusion. Recognise when a low laboratory value is not an indication and when delay is dangerous. 1. The three questions before prescribing What physiologic deficit exists? Oxygen-carrying capacity, platelet plug, fibrinogen or multiple clotting factors? How urgent is it? Active haemorrhage/shock requires simultaneous resuscitation and source control; stable anaemia allows diagnosis and alternatives. What is the smallest effective intervention? One component, one unit or a targeted factor may be safer than broad whole-blood exposure. Situation Transfusion decision Stable, nonbleeding anaemia Investigate and treat cause; consider red cells when symptoms or oxygen delivery impairment persist despite alternatives. Active major haemorrhage Activate a major-haemorrhage protocol, give balanced components/whole blood per local policy and control the source urgently. Isolated abnormal INR without bleeding Usually not an indication for plasma; treat the cause or use targeted reversal when appropriate. Low platelet count without bleeding Prophylactic platelet decisions depend on cause, trend, infection, fever and procedure risk; do not transfuse reflexively. 2. Red-cell transfusion 2.1 Major indications Acute blood loss with shock, ongoing bleeding or inadequate oxygen delivery. Severe symptomatic anaemia: syncope, myocardial ischemia, heart failure, hypoxia, confusion or severe exertional intolerance attributable to anaemia. Perioperative or obstetric blood loss when oxygen delivery cannot be maintained by haemostasis and fluid/blood-conservation measures. Chronic transfusion-dependent disorders such as thalassaemia major, selected marrow failure and sickle-cell indications under a specialist programme. Exchange transfusion or red-cell exchange for selected severe sickle complications or neonatal conditions under specialist protocols. 2.2 Thresholds as decision aids For stable, nonbleeding adults, many guidelines consider a restrictive strategy around Hb 7 g/dL (70 g/L), with a higher trigger around 8 g/dL (80 g/L) in selected patients with cardiovascular disease or major surgery. These are not universal rules: symptoms, active ischemia, chronic adaptation, pregnancy, altitude, ongoing bleeding and local policy modify the decision. In a shocked patient, do not wait for a haemoglobin that may initially appear falsely reassuring. 2.3 One-unit reassessment In a stable adult without active bleeding, prescribe one red-cell unit, reassess symptoms and vital signs, and repeat Hb before another unit when appropriate. A typical adult unit raises Hb by roughly 1 g/dL (10 g/L), but the response varies with bleeding, body size and fluid balance. 3. Platelet transfusion Clinical situation Common educational threshold/goal Important caveat Stable, nonbleeding hypoproliferative thrombocytopenia Consider prophylaxis at <10 × 109/L. Fever, sepsis, rapid fall, DIC and procedures may require different targets. Clinically significant bleeding Often target >50 × 109/L for major bleeding. Treat the cause; platelet transfusion may be ineffective in immune destruction or TTP. Neurosurgery/critical CNS or eye bleeding Many protocols target >100 × 109/L. Consult neurosurgery/haematology; thresholds vary by procedure and evidence. Invasive procedure Often target >50 × 109/L for high-risk procedures. Low-risk procedures may need less; local policy governs. ITP, TTP or HIT Do not give routinely for the count alone. Reserve for life-threatening bleeding or urgent procedure with specialist advice. Platelet refractoriness requires assessment of post-transfusion increments, fever/sepsis, splenic sequestration and HLA/HPA antibodies; HLA-selected or crossmatched platelets may be needed. 4. Plasma transfusion 4.1 Appropriate indications Clinically significant bleeding with multiple coagulation-factor deficiency. Major haemorrhage with documented or anticipated factor depletion according to protocol. Urgent procedure with significant coagulopathy when a targeted factor or reversal agent is unavailable or unsuitable. Plasma exchange replacement in selected thrombotic microangiopathy (specialist protocol). 4.2 Inappropriate uses Volume expansion or hypoalbuminaemia alone. Correction of a mildly prolonged INR in a nonbleeding patient. Routine reversal when vitamin K, PCC or a specific antidote is the indicated treatment. Low fibrinogen when cryoprecipitate/fibrinogen concentrate is the targeted product. Plasma has substantial volume and can cause allergy, TRALI and TACO. Reassess coagulation and clinical bleeding rather than chasing a laboratory number. 5. Cryoprecipitate and fibrinogen replacement Clinically significant bleeding with low fibrinogen, especially in obstetric haemorrhage, trauma, DIC or massive transfusion. Fibrinogen targets commonly lie around 1.5–2.0 g/L in active major bleeding, but the goal and product depend on local protocol and viscoelastic results. Use fibrinogen concentrate or cryoprecipitate according to availability, indication and specialist guidance. Do not use cryoprecipitate as a general treatment for anaemia or isolated prolonged PT/aPTT. 6. Major haemorrhage 6.1 Activation criteria Activate a major-haemorrhage pathway for shock with ongoing bleeding, rapidly falling haemoglobin, uncontrolled obstetric/trauma/surgical haemorrhage or anticipated massive transfusion. Do not wait for laboratory confirmation when the patient is exsanguinating. 6.2 Priorities Call the haemorrhage team, assign roles and obtain large-bore access or intraosseous access. Control the source: pressure, tourniquet, pelvic binder, surgery, endoscopy, uterine intervention or interventional radiology. Give balanced red cells/plasma/platelets or whole blood according to local protocol; tailor once laboratory/viscoelastic results return. Monitor temperature, ionised calcium, potassium, pH, lactate, Hb, platelet count, PT/aPTT and fibrinogen. Prevent hypothermia, hypocalcaemia and acidosis; avoid excessive crystalloid dilution. Reassess after each cycle and stop protocol when bleeding is controlled and physiology is restored. 7. Special populations 7.1 Obstetric haemorrhage Postpartum haemorrhage can deteriorate rapidly. Prepare group-and-screen early in high-risk pregnancy, use a major-haemorrhage pathway, monitor fibrinogen and treat uterine atony, retained tissue, genital tract injury or coagulopathy. Maternal resuscitation takes priority; involve obstetrics, anaesthesia, haematology and blood bank. 7.2 Children and neonates Calculate volume by weight and use paediatric/neonatal components; avoid adult assumptions. Consider prematurity, small circulating volume, congenital heart disease, bilirubin, potassium and CMV/GVHD product requirements. Use dedicated paediatric transfusion and monitoring protocols; confirm consent and parental/guardian communication. 7.3 Sickle-cell disease Transfusion may be indicated for acute stroke, acute chest syndrome, splenic sequestration, severe

Blood Transfusion: Components, Indications, Blood Groups, Cross-Matching, Administration and Complications Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology and transfusion medicine Core concept: Transfusion is the controlled administration of whole blood or a selected blood component to restore oxygen-carrying capacity, haemostasis or circulating volume. It is a clinical treatment with benefits and risks—not a routine response to an abnormal laboratory value. Correct patient identification, compatibility testing, monitoring and rapid recognition of reactions are as important as choosing the component. Learning objectives Describe whole blood, red-cell, platelet, plasma and cryoprecipitate components. Choose a component according to the physiologic deficit and indication. Explain ABO/Rh compatibility, antibody screening and cross-matching. Perform safe bedside administration and monitoring. Recognise acute and delayed transfusion reactions and initiate emergency management. Apply patient-blood-management principles and know when specialist advice is required. 1. Why transfusions are given Blood products replace a specific missing function: Deficit Preferred component Purpose Reduced oxygen-carrying capacity or major red-cell loss Red-cell concentrate (packed RBCs) or whole blood in selected massive-haemorrhage settings. Increase haemoglobin and oxygen delivery. Low platelet number or function with bleeding/procedure risk Platelet concentrate. Improve primary haemostasis. Multiple clotting-factor deficiency with bleeding Fresh frozen plasma (FFP) or pathogen-reduced plasma. Replace soluble coagulation factors. Low fibrinogen Cryoprecipitate or fibrinogen concentrate according to local availability. Restore fibrin formation and factor VIII/vWF/factor XIII content. Specific factor deficiency Purified factor concentrate or targeted therapy. More precise replacement with less volume. Plasma volume alone: crystalloid or balanced resuscitation fluids—not plasma—are usually used for volume replacement when coagulation factors are not deficient. 2. Blood components 2.1 Red-cell concentrate Red-cell units contain concentrated erythrocytes with most plasma removed. They improve oxygen delivery but do not correct thrombocytopenia or isolated clotting-factor deficiency. Risks include haemolysis, alloimmunisation, circulatory overload, hyperkalaemia, hypothermia and iron accumulation after repeated transfusion. 2.2 Platelets Platelets may be pooled from whole-blood donations or collected by apheresis. Indications depend on bleeding, procedure risk, platelet function and the cause of thrombocytopenia. Platelet refractoriness can result from HLA antibodies, consumption, sepsis, splenomegaly or nonimmune destruction. 2.3 Plasma Plasma contains multiple clotting factors and is used for clinically significant bleeding or urgent invasive procedures with documented or strongly suspected factor deficiency. It is not a general “volume expander”; unnecessary plasma exposes patients to allergy, TRALI and circulatory overload. 2.4 Cryoprecipitate/fibrinogen replacement Cryoprecipitate is rich in fibrinogen, factor VIII, vWF and factor XIII. Use local thresholds and clinical bleeding context. Fibrinogen concentrate offers standardised dosing where available. 2.5 Whole blood Whole blood provides red cells, plasma and platelets in one unit and may be used in major haemorrhage or resource-limited settings under an approved protocol. Component therapy is usually more targeted and reduces unnecessary exposure. 3. Indications and patient blood management Transfuse for active major haemorrhage, symptomatic anaemia with impaired oxygen delivery, or clinically important coagulopathy/thrombocytopenia—not the laboratory value alone. Assess haemodynamics, bleeding rate, cardiac/respiratory reserve, pregnancy, sepsis, chronic adaptation and planned procedure. Correct reversible causes first when safe: bleeding source, iron/B12/folate deficiency, hypothermia, hypocalcaemia and anticoagulant effect. Use a restrictive, single-unit reassessment approach for stable nonbleeding adults where consistent with local guidelines; reassess symptoms and repeat Hb rather than automatically ordering multiple units. In massive haemorrhage, activate the local major-haemorrhage protocol early; give balanced red cells, plasma and platelets, monitor calcium/temperature/acid-base and control the source surgically or obstetrically. 4. Blood groups and compatibility 4.1 ABO system Group RBC antigen Plasma antibody Key rule for red cells A A Anti-B Can receive A or O RBCs if compatible. B B Anti-A Can receive B or O RBCs if compatible. AB A and B No anti-A/anti-B Can receive ABO-compatible RBCs; AB plasma is broadly compatible for plasma donation. O No A/B Anti-A and anti-B O RBCs can be used in emergencies when group is unknown, subject to local policy; O plasma is not universal. ABO-incompatible RBCs can cause rapid complement-mediated intravascular haemolysis, shock, kidney injury, DIC and death. Clerical identification errors remain a major preventable cause. 4.2 Rh(D) and other antigens Rh(D)-negative recipients may form anti-D after exposure through transfusion or pregnancy. Rh matching is especially important for people with pregnancy potential and those requiring repeated transfusion. Other systems—Kell, Kidd, Duffy and MNS—can cause delayed haemolytic reactions and require antigen-negative, phenotype-matched units in selected patients. 5. Pre-transfusion testing Clinical prescription: specify component, indication, urgency, dose/number of units and special requirements (irradiated, leukoreduced, washed, CMV-safe or antigen-negative). Patient identification: use two identifiers; label the blood sample at bedside. A wrong-blood-in-tube error can be fatal. ABO/Rh typing: determine recipient group and confirm historical records. Antibody screen: detect clinically significant unexpected antibodies from previous transfusion or pregnancy. Cross-match: test recipient plasma against donor red cells, electronically or serologically according to laboratory policy. Compatibility report: verify unit number, group, expiry, special processing and visual appearance before release. If a life-threatening haemorrhage cannot wait, emergency-release blood may be issued under local policy. Obtain a pre-transfusion sample before giving it whenever possible, document the emergency and switch to fully compatible units as soon as testing permits. 6. Special products Product modification Why used Examples/precautions Leukoreduced Reduces febrile reactions, CMV transmission risk and HLA alloimmunisation. Common standard in many services; does not prevent every reaction. Irradiated Prevents transfusion-associated GVHD by inactivating donor lymphocytes. Stem-cell transplant, selected immunodeficiencies and directed donations; follow local indications. Washed Removes most plasma proteins. Recurrent severe allergic reactions or IgA-related anaphylaxis under specialist advice. CMV-reduced-risk Reduces transfusion-transmitted CMV risk. Use according to recipient risk and national policy. Antigen-negative/phenotype-matched Prevents alloantibody reactions. Patients with existing antibodies, chronic transfusion or haemoglobinopathy. 7. Safe bedside administration Confirm consent, indication, allergies, baseline observations and IV access; use a dedicated blood administration set with a filter. At the bedside, independently verify patient identity, unit number, ABO/Rh, cross-match status, expiry, component and special requirements. Inspect the unit for clots, unusual colour, leaks or haemolysis; do not use a damaged or questionable unit. Record temperature, pulse, respiratory rate, blood pressure and oxygen saturation before starting. Begin slowly while observing closely during the initial period; increase only according to patient

Other Blood Disorders: White-Cell, Platelet, Red-Cell Excess, Marrow and Coagulation Disorders Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology Core concept: Blood disorders may affect cell number, cell function, haemoglobin, marrow production or coagulation. A high or low count is a clue, not a diagnosis. Confirm the result, review the blood film and interpret it with bleeding, thrombosis, infection, organ dysfunction and medication history. Learning objectives Classify leukocyte, platelet, erythrocyte and coagulation abnormalities. Distinguish reactive changes from clonal marrow disease. Recognise thrombocytopenia, thrombocytosis, neutropenia, leukocytosis and polycythaemia. Explain common bleeding disorders, disseminated intravascular coagulation and thrombophilia. Recognise haematologic emergencies and select first investigations. 1. A pattern-based approach Pattern First questions Urgent danger One abnormal cell line Is the change reactive, drug-related, immune, nutritional or clonal? Severe neutropenia, critical thrombocytopenia, symptomatic polycythaemia. Two or three cytopenias Marrow failure/infiltration, hypersplenism, infection, drug or nutritional deficiency? Sepsis, haemorrhage, acute leukaemia. High counts Dehydration/stress/infection versus myeloproliferative neoplasm. Leukostasis, thrombosis, hyperviscosity. Bleeding Platelet-type mucosal bleeding or coagulation-factor deep bleeding? Intracranial, airway, retroperitoneal or obstetric bleeding. Thrombosis Provoked versus unprovoked; arterial versus venous; malignancy or antiphospholipid syndrome? Stroke, pulmonary embolism, limb or mesenteric ischemia. 2. White-cell disorders 2.1 Leukocytosis Leukocytosis is an age-adjusted increase in total WBC count. Identify the lineage and look at the smear before assuming infection. Pattern Common reactive causes Clonal/other causes Neutrophilia Bacterial infection, inflammation, stress, smoking, corticosteroids, tissue necrosis. Chronic myeloid leukaemia, other myeloproliferative neoplasms, severe leukemia. Lymphocytosis Viral infection, pertussis, recovery from infection. Chronic lymphocytic leukaemia, lymphoproliferative disorders. Eosinophilia Helminths, allergy, asthma, drug reaction. Clonal eosinophilic neoplasm, Hodgkin lymphoma, selected solid tumours. Monocytosis Chronic infection, inflammatory disease, recovery from neutropenia. Chronic myelomonocytic leukaemia. Basophilia Allergy/inflammation, rarely reactive alone. Strong clue to myeloproliferative neoplasm, especially CML. 2.2 Leukopenia and neutropenia Causes include viral infection, sepsis, drugs (especially chemotherapy, antithyroid agents and some antibiotics), autoimmune disease, nutritional deficiency, marrow failure and hypersplenism. Calculate the ANC; severity and duration determine infection risk. Mild neutropenia: may be transient; review trend and cause. Severe/prolonged neutropenia: fever is an emergency even without localising signs. Examination: inspect mouth, skin, perianal area, lungs, catheter sites and abdomen; avoid unnecessary rectal examination in profound neutropenia. Investigations: repeat CBC/film, cultures, medication review, viral testing, B12/folate/copper, autoimmune tests and marrow examination when persistent. 3. Platelet disorders 3.1 Thrombocytopenia Platelets below the laboratory reference threshold (often <150 × 109/L) may reflect decreased production, increased destruction/consumption, sequestration or dilution. Mechanism Examples Clues Pseudothrombocytopenia EDTA-dependent platelet clumping. Unexpected isolated low count; clumps on film; repeat in citrate. Reduced production Marrow failure, leukemia, chemotherapy, alcohol, B12/folate deficiency, viral disease. Other cytopenias, abnormal film or low reticulocytes. Immune destruction ITP, drug-induced thrombocytopenia, HIV, SLE, post-transfusion. Often isolated thrombocytopenia; large young platelets. Consumption DIC, TTP/HUS, severe sepsis, HELLP, massive haemorrhage. Schistocytes, organ injury, abnormal coagulation in DIC. Sequestration/dilution Hypersplenism, liver disease, massive transfusion/fluids. Splenomegaly or dilution context. Platelet-type bleeding produces petechiae, purpura, epistaxis, gum bleeding and menorrhagia. Deep muscle/joint bleeding is more typical of coagulation-factor deficiency. Always ask about antiplatelet drugs, anticoagulants and herbal products. 3.2 Thrombocytosis Reactive thrombocytosis follows infection, inflammation, iron deficiency, surgery, trauma or splenectomy. Clonal thrombocytosis (essential thrombocythaemia) is a myeloproliferative neoplasm; JAK2, CALR or MPL mutations may be present. Very high counts can paradoxically cause bleeding through acquired von Willebrand dysfunction while also increasing thrombosis risk. 4. Polycythaemia (erythrocytosis) Polycythaemia is an increased red-cell mass; a high Hb/Hct may also reflect reduced plasma volume (relative erythrocytosis). Type Causes Clues/tests Relative Dehydration, diuretics, stress erythrocytosis. Volume depletion; correct hydration and repeat. Secondary appropriate Chronic hypoxia from lung disease, cyanotic heart disease, sleep apnoea or high altitude. Low oxygen saturation, smoking/carboxyhaemoglobin; EPO usually high. Secondary inappropriate Renal/hepatic tumours, exogenous EPO or androgen use. High EPO without hypoxia; image when indicated. Primary/clonal Polycythaemia vera, usually JAK2-driven myeloproliferative neoplasm. Low EPO, leukocytosis/thrombocytosis, splenomegaly, aquagenic pruritus, erythromelalgia. Hyperviscosity causes headache, visual symptoms, dizziness, hypertension and thrombosis. Sudden neurologic deficit, chest pain, limb ischemia or abdominal pain is an emergency. 5. Marrow and blood cancers 5.1 Leukaemia Leukaemia is malignant proliferation of haematopoietic precursors. Acute disease has blasts and rapid marrow failure; chronic disease may be indolent but can transform. Acute leukaemia: fatigue/pallor, infection, bruising/bleeding, bone pain, lymphadenopathy, hepatosplenomegaly and blasts. CML: marked leukocytosis with left shift, basophilia and splenomegaly; BCR-ABL1 testing confirms. CLL: persistent clonal B lymphocytosis, lymphadenopathy, recurrent infection and autoimmune cytopenias. Investigations: urgent CBC/film, flow cytometry, marrow aspirate/biopsy, cytogenetics and molecular testing. 5.2 Lymphoma and plasma-cell disorders Lymphomas present with persistent lymphadenopathy, B symptoms (fever, drenching night sweats, weight loss), extranodal masses or cytopenias. Myeloma causes bone pain/lytic lesions, renal impairment, hypercalcaemia and anaemia; serum/urine electrophoresis, free light chains and marrow testing are used. 6. Coagulation and bleeding disorders 6.1 Primary versus secondary haemostasis Defect Typical bleeding Examples Platelet/vWF (primary) Mucosal bleeding, petechiae, immediate bleeding after injury, menorrhagia. ITP, aspirin effect, von Willebrand disease. Coagulation factors (secondary) Deep muscle/joint bleeding, delayed post-procedure bleeding, large haematomas. Haemophilia A/B, vitamin K deficiency, liver disease. Mixed consumption Bleeding and thrombosis together. DIC, severe liver failure, TTP/HUS. 6.2 Screening tests PT/INR: extrinsic/common pathways; prolonged in warfarin effect, vitamin K deficiency, liver disease and factor VII deficiency. aPTT: intrinsic/common pathways; prolonged in haemophilia, heparin effect, lupus anticoagulant and some inhibitors. Fibrinogen and D-dimer: consumption/fibrinolysis pattern; D-dimer is sensitive but nonspecific. Platelet count and film: thrombocytopenia, clumping or schistocytes. Mixing study and factor assays: distinguish factor deficiency from inhibitors when PT/aPTT is prolonged. 6.3 High-yield disorders Von Willebrand disease: inherited quantitative/qualitative vWF defect; mucosal bleeding and menorrhagia; check vWF antigen/activity and factor VIII. Haemophilia A/B: X-linked factor VIII/IX deficiency; recurrent haemarthroses and deep bleeding. CDC guidance emphasises factor replacement, with prophylaxis for many patients. Vitamin K deficiency/antagonism: prolonged PT first; causes include malabsorption, antibiotics, liver disease and warfarin. Liver failure: reduced clotting-factor production, thrombocytopenia and altered anticoagulants; INR alone does not perfectly predict bleeding. DIC: systemic thrombin generation consumes platelets and factors, causing simultaneous microvascular thrombosis and bleeding. Thrombophilia: inherited or acquired tendency to thrombosis, including antiphospholipid syndrome, factor V Leiden and malignancy-associated clotting. 7. Haematologic emergencies

Anaemia: Classification, Causes, Pathophysiology, Investigations, Treatment and Emergency Recognition Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology Core concept: Anaemia is a reduction in haemoglobin or red-cell mass sufficient to impair oxygen delivery for the patient’s age, sex, pregnancy status, altitude and physiologic context. It is a sign, not a final diagnosis. The central questions are: is the marrow failing to produce cells, are cells being lost, or are they being destroyed prematurely? 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 Confirm anaemia and assess stability: vital signs, mental state, bleeding, chest pain, hypoxia, pregnancy and shock. Review the trend: compare previous Hb and ask about bleeding, recent surgery, transfusion, infection, medication, diet and travel. Order CBC with indices, reticulocytes and blood film. Use MCV and reticulocytes together: low reticulocytes indicate underproduction; high reticulocytes indicate loss or destruction if the marrow is intact. 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. 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,

Introduction to Hematology: Blood, Hematopoiesis, Cells, Laboratory Tests and Emergency Interpretation Study level: Clinical medicine, emergency medicine and pathology | Topic: Hematology Core concept: Hematology is the study of blood, blood-forming organs, blood cells, haemostasis and diseases of these systems. A complete blood count (CBC), blood film, reticulocyte count and targeted coagulation tests turn the physiology of blood into clinically actionable information—but results must always be interpreted with the patient, the specimen quality and the laboratory’s reference interval. Learning objectives Describe the composition and functions of whole blood and plasma. Explain adult and fetal hematopoiesis and the roles of marrow, liver, spleen, thymus and lymph nodes. Identify the morphology and functions of erythrocytes, leukocytes and platelets. Interpret the main components of a CBC, differential count, red-cell indices, reticulocytes and blood film. Recognise patterns that suggest anaemia, infection, marrow failure, haemolysis, leukaemia or thrombocytopenia. Collect blood correctly and identify urgent hematologic emergencies. 1. What is blood? Blood is a specialised connective tissue that circulates through arteries, veins and capillaries. It transports oxygen, carbon dioxide, nutrients, hormones, heat, drugs and metabolic waste; provides immune surveillance; maintains acid–base, fluid and electrolyte balance; and prevents blood loss through haemostasis. Component Approximate proportion Major functions Plasma About 55% of blood volume. Water, electrolytes, albumin, clotting proteins, immunoglobulins, nutrients, hormones and waste transport. Red blood cells (erythrocytes) Most of the cellular volume; haematocrit varies with sex, age, pregnancy and altitude. Oxygen delivery through haemoglobin; carbon-dioxide transport and buffering. White blood cells (leukocytes) Small fraction of blood volume. Innate and adaptive immunity, inflammation and tissue repair. Platelets Cell fragments derived from megakaryocytes. Primary haemostasis, clot formation, vascular repair and inflammatory signalling. 2. Plasma and its proteins Water: solvent and major determinant of circulating volume and viscosity. Albumin: maintains oncotic pressure and transports bilirubin, fatty acids, calcium and many drugs. Globulins: immunoglobulins, complement, transport proteins and acute-phase proteins. Fibrinogen and clotting factors: form fibrin and support coagulation; most are synthesised in the liver. Electrolytes and buffers: sodium, chloride, bicarbonate, calcium and phosphate influence cell function and coagulation. Serum: plasma after clotting, so it lacks fibrinogen and some clotting factors. This distinction matters when choosing a specimen. 3. Hematopoiesis Hematopoiesis is the continuous production of mature blood cells from self-renewing multipotent haematopoietic stem cells (HSCs). In adults it occurs mainly in the red marrow of the pelvis, vertebrae, ribs, sternum and proximal long bones. 3.1 Developmental sites Life stage Major site Embryo Yolk sac initially, then fetal liver and spleen. Late fetus/newborn Most bones contain active red marrow. Childhood Marrow gradually converts from red to fatty yellow marrow in long-bone shafts. Adult Axial skeleton and proximal humerus/femur; liver and spleen can resume extramedullary hematopoiesis in severe demand or marrow disease. 3.2 Lineage commitment and growth factors HSCs give rise to a common myeloid progenitor and common lymphoid progenitor. Erythropoietin (EPO), produced mainly by renal peritubular cells in response to hypoxia, increases erythroid production. Thrombopoietin (TPO), produced largely by the liver, regulates megakaryocyte and platelet production. G-CSF promotes neutrophil production and release; GM-CSF supports granulocyte and monocyte lineages. Interleukins coordinate proliferation, differentiation and survival; the marrow microenvironment provides stromal signals and niches. 3.3 Marrow response principles Increased demand can increase production if stem cells, nutrients and marrow architecture are intact. A high reticulocyte response suggests preserved erythropoiesis; an inappropriately low response suggests inadequate production. Marrow infiltration, fibrosis, cytotoxic drugs, nutritional deficiency and kidney disease can blunt compensation. 4. Red blood cells and haemoglobin 4.1 Structure and function Mature erythrocytes are flexible, anucleate biconcave discs with a large surface area and no mitochondria. Their membrane and cytoskeleton allow passage through capillaries; haemoglobin binds oxygen reversibly and carries some carbon dioxide. The average red-cell lifespan is about 120 days, after which senescent cells are removed by splenic and hepatic macrophages. 4.2 Haemoglobin Adult haemoglobin HbA is predominantly alpha-2 beta-2; HbA2 and fetal HbF are minor fractions after infancy. Oxygen affinity is shifted by pH, carbon dioxide, temperature and 2,3-BPG (the Bohr effect), allowing unloading in metabolically active tissues. Iron cycles between ferrous and ferric states; haem synthesis requires iron, pyridoxine and functioning mitochondria, while globin production depends on intact genes and protein synthesis. 4.3 Erythropoiesis requirements Healthy erythropoiesis requires iron, vitamin B12, folate, protein, EPO, thyroid and marrow function. Iron is absorbed mainly in the duodenum and transported by transferrin; B12 absorption requires intrinsic factor and an intact terminal ileum. Folate is absorbed in the small intestine and is rapidly depleted when demand is high. 5. White blood cells Cell Morphology/function Clinical interpretation Neutrophils Multilobed nucleus; rapid phagocytosis and killing of bacteria/fungi. Neutrophilia in infection, stress, steroids and inflammation; neutropenia raises bacterial/fungal sepsis risk. Lymphocytes T cells, B cells and NK cells; adaptive memory and cytotoxicity. Lymphocytosis in many viral infections; lymphopenia in HIV, steroids, malnutrition and severe illness. Monocytes/macrophages Large cells that enter tissue and become macrophages or dendritic cells. Chronic inflammation, tissue repair and phagocytosis; monocytosis may indicate infection or marrow disease. Eosinophils Bilobed nucleus and red-orange granules; parasite defence and allergic inflammation. Eosinophilia in helminths, drug reactions, asthma and some neoplasms. Basophils Granules containing histamine and heparin; IgE-associated responses. Basophilia can occur in myeloproliferative disease and allergic states. 6. Platelets and primary haemostasis Platelets are anucleate fragments shed from megakaryocytes. Vascular injury exposes collagen and von Willebrand factor (vWF). Platelets adhere through glycoprotein receptors, activate, release ADP/thromboxane and aggregate through glycoprotein IIb/IIIa-fibrinogen bridges. Coagulation then generates thrombin and fibrin to stabilise the platelet plug. Platelet count reflects quantity, not necessarily function. Thrombocytopenia causes petechiae and mucosal bleeding; severe spontaneous bleeding risk rises as the count falls, but clinical context matters more than a single threshold. Thrombocytosis may be reactive (infection, inflammation, iron deficiency, splenectomy) or clonal. Platelet dysfunction can occur with aspirin, uraemia, inherited disorders and antiplatelet medicines despite a normal count. 7. The complete blood count (CBC/FBC) A CBC measures the number and selected physical properties of red cells, white cells and platelets. It is a screening and monitoring test, not a final diagnosis. Parameter Meaning Common

Primary and Secondary Immunodeficiency Diseases: Classification, Infection Patterns, Diagnosis and Emergency Care Study level: Clinical medicine, emergency medicine and pathology | Topic: Immunopathology Core concept: Immunodeficiency is failure of one or more immune components, causing susceptibility to infection, malignancy and sometimes autoimmunity or allergy. Primary immunodeficiencies are usually genetic and may present in infancy or adulthood; secondary immunodeficiencies are acquired and are much more common, including HIV, malnutrition, malignancy, organ failure and immunosuppressive therapy. Learning objectives Define immunodeficiency and distinguish primary from secondary causes. Match recurrent-infection patterns to defects in antibodies, T cells, phagocytes and complement. Recognise important primary disorders: SCID, X-linked agammaglobulinaemia, CVID, selective IgA deficiency, DiGeorge syndrome, CGD, leukocyte adhesion deficiency and complement deficiency. Explain secondary immunodeficiency due to HIV, drugs, malnutrition, malignancy, protein loss, asplenia and chronic disease. Choose first-line investigations and interpret basic immunology results. Manage sepsis and opportunistic infection urgently while planning prophylaxis, replacement therapy and specialist referral. 1. Definition and consequences An immunodeficiency is inadequate quantity or function of immune cells, antibodies, complement or innate defence pathways. The defect may be quantitative (too few cells/proteins), qualitative (cells present but dysfunctional), or both. Consequence Why it occurs Clinical examples Recurrent infection Failure to recognise, contain or clear microbes. Otitis, sinusitis, pneumonia, skin abscess, meningitis, chronic diarrhoea. Unusual organisms Missing immune pathway permits opportunistic pathogens. Pneumocystis, invasive fungi, mycobacteria, chronic mucocutaneous Candida. Severe or prolonged infection Weak response, poor vaccine protection or delayed clearance. Persistent viral disease, recurrent sepsis, failure to thrive. Autoimmunity/inflammation Immune dysregulation and defective tolerance may coexist with infection susceptibility. Cytopenias, enteropathy, granulomas, lupus-like features. Malignancy Reduced immune surveillance and chronic viral stimulation. Lymphoma, EBV-related disease, HPV-associated cancers. 2. Primary versus secondary immunodeficiency Feature Primary (inborn) Secondary (acquired) Cause Pathogenic variant affecting immune development/function. Infection, medication, malnutrition, malignancy, organ disease, protein loss or ageing. Onset Infancy, childhood or adulthood depending on residual function. Any age; often follows a new exposure or illness. Family history May show consanguinity, affected siblings or male relatives. Usually absent unless the cause is inherited malnutrition or disease. Reversibility Often chronic; some are curable with haematopoietic stem-cell transplant or gene therapy. May improve when the cause is treated, though HIV and some drug-related deficits persist. Examples SCID, X-linked agammaglobulinaemia, CVID, CGD, DiGeorge. HIV, corticosteroids, chemotherapy, diabetes, nephrotic syndrome, splenectomy. 3. Match the immune component to the infection pattern Defective component Typical organisms and sites Clues B cells/antibodies Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus), Giardia; sinopulmonary and GI infections. After maternal IgG wanes; poor vaccine antibody responses; small/absent tonsils in severe B-cell defects. T cells Viruses, fungi, protozoa and intracellular bacteria; chronic mucocutaneous Candida. Thrush, chronic diarrhoea, severe viral disease, failure to thrive and opportunistic infection. Combined T and B cells Broad spectrum, including live vaccine organisms. Very early severe infection, lymphopenia, absent thymic shadow or persistent diarrhoea. Neutrophils/phagocytes Staphylococcus, Gram-negative bacteria and Aspergillus; deep skin/liver/lung abscesses. Delayed cord separation, poor pus, periodontal disease, recurrent abscesses or poor wound healing. Complement Neisseria (terminal complement), encapsulated bacteria (C3), immune-complex/autoimmune disease. Recurrent meningococcal disease or lupus-like illness. Asplenia Encapsulated bacteria, especially pneumococcus, meningococcus and Hib. Rapid overwhelming sepsis; Howell–Jolly bodies on blood film. 4. Primary immunodeficiency categories and high-yield disorders 4.1 Severe combined immunodeficiency (SCID) SCID is a group of disorders with profound T-cell dysfunction and severe impairment of cellular and humoral immunity. Causes include X-linked common-gamma-chain defects (often T−B+NK−), adenosine deaminase deficiency (often T−B−NK−), JAK3 defects, RAG defects and others. Presentation: infections in the first months of life, persistent oral thrush, chronic diarrhoea, pneumonia, failure to thrive and opportunistic infections. Laboratory pattern: severe lymphopenia, low T-cell numbers/function, abnormal mitogen responses and variable B/NK cells; newborn T-cell receptor excision circle screening helps detection. Emergency: fever or respiratory symptoms require immediate assessment; avoid live vaccines, especially BCG or rotavirus where relevant. Definitive treatment: urgent specialist referral for haematopoietic stem-cell transplantation, enzyme replacement for selected ADA deficiency or approved gene therapy pathways. 4.2 X-linked agammaglobulinaemia (Bruton disease) BTK mutation blocks B-cell maturation. Affected boys develop profoundly low B cells and immunoglobulins after maternal IgG declines. Recurrent otitis, sinusitis, pneumonia and enteroviral infection; tonsils and lymph nodes may be small. Diagnosis: low all immunoglobulin classes, markedly reduced CD19/20 B cells and genetic confirmation. Management: regular immunoglobulin replacement, prompt antibiotics, vaccination planning and avoidance of live vaccines without specialist advice. 4.3 Common variable immunodeficiency (CVID) CVID is heterogeneous, usually presenting later with low IgG plus low IgA and/or IgM and poor antibody responses despite adequate B-cell numbers. Recurrent sinopulmonary infection, bronchiectasis, chronic Giardia, autoimmune cytopenias, enteropathy, granulomas and lymphoma risk. Diagnosis requires exclusion of secondary causes, quantitative immunoglobulins and vaccine-response assessment. Management: immunoglobulin replacement, airway care, antibiotic treatment/prophylaxis when indicated and surveillance for lung disease, autoimmunity and malignancy. 4.4 Selective IgA deficiency The most common clinically recognised primary antibody deficiency. Many patients are asymptomatic; others develop recurrent mucosal infection, allergies, coeliac disease or autoimmune disease. Low/absent IgA with normal IgG/IgM after the appropriate age and exclusion of secondary loss. Rare transfusion reactions to anti-IgA antibodies; alert the transfusion service if prior reaction occurred. 4.5 DiGeorge syndrome / 22q11.2 deletion Thymic hypoplasia causes variable T-cell deficiency, with congenital heart disease, hypocalcaemia from parathyroid hypoplasia, characteristic facies and developmental/psychiatric features. Assess calcium, ECG, cardiac anatomy, lymphocyte subsets and T-cell function. Live vaccine decisions depend on T-cell function; involve immunology. 4.6 Chronic granulomatous disease (CGD) Defective NADPH oxidase impairs the respiratory burst, so phagocytes cannot kill catalase-positive organisms effectively. Organisms: Staphylococcus aureus, Serratia, Burkholderia, Nocardia and Aspergillus. Presentation: recurrent pneumonia, lymphadenitis, liver/skin abscesses, osteomyelitis and granulomatous bowel or urinary obstruction. Diagnosis: neutrophil oxidative burst (DHR) testing and genetic confirmation. Management: prolonged targeted antimicrobial treatment, prophylaxis, interferon-gamma in selected settings and stem-cell transplantation for severe disease. 4.7 Leukocyte adhesion deficiency Defective integrin-mediated adhesion prevents neutrophils from leaving blood vessels. Typical clues are delayed umbilical-cord separation, omphalitis, recurrent skin/mucosal infection, severe periodontitis, poor wound healing and little or no pus despite high neutrophil counts. 4.8 Complement deficiency Defect Pattern C3 deficiency Severe recurrent pyogenic infection and immune-complex disease. C5–C9 deficiency Recurrent