For education and revision only. Not individual medical advice; check current NICE/BNF and local guidance before clinical use. Clinical safety and terms.
🩸 Haematology anatomy, physiology and pharmacology -blood carries oxygen (red cells), fights infection (white cells) and stops bleeding (platelets and clotting factors). Most blood problems are too few cells, too many cells, abnormal cells, or a clotting system that bleeds or clots too easily. The commonest haematology drugs in everyday practice are iron, anticoagulants, antiplatelets and blood products -all high-risk if used wrongly.
Your four questions for every drug: How does it work? What is it used for? What are the important side effects and safety issues? What does it interact with, and how is it monitored?
Bone Marrow and Blood Cell Production
Where blood is made:
Fetus -yolk sac (first weeks), then liver and spleen (mid-pregnancy), then bone marrow (from about 5 months).
Children -marrow in almost all bones.
Adults -mainly the axial skeleton: pelvis, sternum, vertebrae, ribs, skull and the ends of the femur and humerus. Marrow samples (aspirate and trephine) are taken from the posterior iliac crest.
Extramedullary haematopoiesis -liver and spleen start making blood again when the marrow fails or is overworked (myelofibrosis, thalassaemia) → hepatosplenomegaly.
Stem cells -a small number of haematopoietic stem cells make all blood cells; they can renew themselves (the basis of stem cell transplantation):
Lymphoid line -B cells, T cells and natural killer cells.
Growth factors control production -erythropoietin (kidney -red cells), thrombopoietin (liver -platelets), G-CSF (neutrophils), interleukins. Several are given as drugs.
Scale -the marrow makes about 200 billion red cells a day; it can increase output several-fold (e.g. after bleeding or in haemolysis -rising reticulocytes).
Marrow failure (aplastic anaemia, leukaemia, infiltration by cancer or fibrosis, chemotherapy, drugs, B12 or folate deficiency) → pancytopenia -anaemia, infections and bleeding.
Leucoerythroblastic film (immature red and white cells in the blood) -suggests marrow infiltration (metastatic cancer, myelofibrosis, TB) or severe stress.
Position -left upper quadrant under the 9th–11th ribs; not normally palpable. An enlarged spleen grows towards the right iliac fossa, has a notch, moves with breathing, you can't get above it, and it is dull to percussion (unlike a kidney).
Functions:
Red pulp -filters old and damaged red cells; removes inclusions from red cells (after splenectomy -Howell–Jolly bodies, target cells and raised platelets).
White pulp -immune responses, especially against encapsulated bacteria (pneumococcus, meningococcus, Haemophilus influenzae type b).
Stores about a third of platelets -so a big spleen lowers the platelet count (hypersplenism).
Preventing infection after splenectomy or in hyposplenism (UKHSA Green Book):
Vaccines -pneumococcal, Hib/MenC, MenACWY, MenB, yearly influenza (and COVID-19) -ideally 2 weeks before planned splenectomy or 2 weeks after.
Antibiotic prophylaxis (phenoxymethylpenicillin, or a macrolide if allergic) -at least for the first years and lifelong in high-risk patients; a stand-by course for fever.
Alert card; warn about severe malaria when travelling and infection from dog bites (Capnocytophaga).
Overwhelming post-splenectomy infection -fever in an asplenic patient is an emergency -IV antibiotics immediately.
Splenic rupture -trauma, or with minor trauma in infectious mononucleosis (avoid contact sport for several weeks) -referred pain to the left shoulder tip (Kehr's sign).
Cortex -B cells in follicles (germinal centres -where antibodies are refined).
Paracortex -T cells.
Medulla -plasma cells and macrophages.
Lymphadenopathy -infection (tender, recent), inflammation (sarcoid, autoimmune), cancer spread (hard, fixed), lymphoma (rubbery, painless, often large; Hodgkin's nodes may hurt after alcohol). Red flags -node over 2 cm, persisting over 6 weeks, supraclavicular, with weight loss, night sweats or fever (NICE NG12).
Important nodes -left supraclavicular (Virchow's) node -gastric and other abdominal cancers (Troisier's sign); axillary -breast cancer, arm infections; inguinal -legs, perineum, anus below the dentate line.
Thymus -where T cells mature and learn to ignore the body's own tissues; large in children, shrinks with age. Thymoma is linked to myasthenia gravis, pure red cell aplasia and low antibodies.
MALT (mucosa-associated lymphoid tissue) -in the gut (Peyer's patches), airways and elsewhere; gastric MALT lymphoma is driven by H. pylori and can regress after eradication.
Lymphocytes recirculate between blood, nodes and tissues -the reason lymphomas often involve several sites.
Plasma cells -mature B cells that make antibodies; a malignant clone causes myeloma (paraprotein, bone lesions, high calcium, kidney injury, anaemia -"CRAB").
Structure -a biconcave disc about 7–8 micrometres across, with no nucleus or mitochondria; flexible enough to squeeze through capillaries and the spleen. Lifespan about 120 days.
Membrane -supported by proteins such as spectrin and ankyrin; defects cause hereditary spherocytosis (round, fragile cells removed by the spleen -anaemia, jaundice, gallstones, splenomegaly; crises with parvovirus B19).
Energy -red cells rely on glycolysis (pyruvate kinase deficiency → haemolysis) and the pentose phosphate pathway, which makes NADPH to protect against oxidation (G6PD deficiency → haemolysis with oxidant drugs, infection, fava beans). 2,3-DPG is made here (shifts the oxygen curve right).
Haemoglobin -four globin chains, each with a haem group containing iron, which binds oxygen:
HbA (α2β2) -about 97% of adult haemoglobin.
HbA2 (α2δ2) -under about 3.5% (raised in beta-thalassaemia trait).
HbF (α2γ2, fetal) -under 1% in adults; binds oxygen more tightly. The switch from gamma to beta chains happens in the first 6 months of life -so beta-chain disorders (sickle cell, beta-thalassaemia) show up after about 3–6 months.
Red cell indices -MCV (size -the key to classifying anaemia), MCH (haemoglobin per cell), RDW (variation in size -high in iron deficiency and mixed deficiencies).
Polycythaemia -high haemoglobin and haematocrit: primary (polycythaemia vera -JAK2 mutation, low EPO) or secondary (high EPO -hypoxia, COPD, sleep apnoea, smoking, high altitude, kidney tumours, testosterone); relative (dehydration, diuretics).
Sickle cell disease (HbSS, also HbSC and HbS/beta-thalassaemia):
A single change in the beta-globin gene (glutamic acid → valine at position 6) makes HbS, which polymerises when deoxygenated → stiff sickle-shaped cells → blockage of small vessels (pain, organ damage) and haemolysis.
Sickle cell trait (HbAS) -usually no symptoms; protects against severe malaria; risk at extreme exertion, dehydration or altitude; haematuria; important in genetic counselling.
Screened for at birth (heel-prick test) and in pregnancy in England.
Thalassaemias -reduced production of globin chains (the other chain builds up and damages cells):
Alpha-thalassaemia -depends on how many of the 4 genes are lost: 1 (silent), 2 (trait -microcytosis with normal or slightly low Hb), 3 (HbH disease -moderate anaemia, splenomegaly), 4 (Hb Barts -hydrops fetalis, usually fatal before birth).
Beta-thalassaemia trait -microcytosis with a normal or high red cell count and raised HbA2; mild or no anaemia; iron studies normal -don't give iron unnecessarily.
Beta-thalassaemia major -severe anaemia from about 6 months; regular transfusions → iron overload (heart, liver, endocrine glands) needing chelation; marrow expansion (skull bossing, facial changes), splenomegaly; stem cell transplant or gene therapy can cure.
Iron deficiency vs thalassaemia trait -both microcytic; thalassaemia trait has a higher red cell count for the degree of anaemia, normal ferritin and (beta) raised HbA2. Check ferritin before haemoglobin electrophoresis (iron deficiency can lower HbA2).
Making red cells needs -erythropoietin (kidney), iron (haemoglobin), vitamin B12 and folate (DNA synthesis -deficiency causes large, immature "megaloblastic" cells), plus vitamin B6, copper, thyroid hormone and androgens.
Type
Main causes
Microcytic (MCV under 80 fL)
Iron deficiency (commonest), thalassaemia, anaemia of chronic disease (sometimes), sideroblastic anaemia (alcohol, lead, isoniazid, inherited), lead poisoning
Normocytic (MCV 80–100 fL)
Acute blood loss, anaemia of chronic disease (inflammation, cancer), CKD, haemolysis, marrow failure or infiltration, hypothyroidism, mixed deficiencies (iron plus B12)
Anaemia of chronic disease -inflammation raises hepcidin, which locks iron away in macrophages and blocks gut absorption → low serum iron with normal or high ferritin and low transferrin; often mild and normocytic.
B12 deficiency also damages nerves -peripheral neuropathy, subacute combined degeneration of the cord, memory problems, optic neuropathy -may occur without anaemia; folate deficiency doesn't cause these (but matters for neural tube defects in pregnancy).
Pernicious anaemia -autoimmune loss of intrinsic factor (intrinsic factor antibodies; parietal cell antibodies less specific); linked to other autoimmune diseases and gastric cancer risk.
Body iron -about 3–4 g, mostly (about two-thirds) in haemoglobin; the rest stored as ferritin and haemosiderin in the liver and macrophages.
Daily balance -only about 1–2 mg a day is absorbed, matching losses from skin and gut cells; menstruation, pregnancy and growth increase needs. The body has no way to excrete extra iron -so transfusions and haemochromatosis cause iron overload.
Absorption -in the duodenum, as ferrous (Fe2+) iron; helped by acid and vitamin C; reduced by tea, calcium, PPIs and coeliac disease. Iron leaves gut cells via ferroportin and travels on transferrin.
Hepcidin -the master regulator (made by the liver); it blocks ferroportin:
High in inflammation → anaemia of chronic disease; also high for about a day after an oral iron dose (the reason alternate-day or once-daily dosing absorbs better).
Low in iron deficiency and hereditary haemochromatosis (HFE C282Y -too much absorption → liver, heart, pancreas, joint and skin damage).
Iron tests:
Ferritin -the best single test; low ferritin confirms iron deficiency (under about 15–30 micrograms/L). Ferritin is an acute phase protein -it rises with inflammation, infection, liver disease and cancer, so a "normal" ferritin doesn't exclude deficiency if inflamed (deficiency still possible up to about 100).
Transferrin saturation -low (under about 20%) in iron deficiency and chronic disease; high in haemochromatosis (over about 45–50%).
TIBC (transferrin) -high in iron deficiency, low in chronic disease.
Iron deficiency anaemia is a sign, not a diagnosis -in men and postmenopausal women, investigate for GI blood loss (gastroscopy and colonoscopy, coeliac serology, urine dipstick for blood) -BSG guidance; in younger women, consider menstrual loss, diet and coeliac disease first.
Normal breakdown -old red cells are removed by macrophages in the spleen → iron is recycled; haem becomes unconjugated bilirubin (see the Gastroenterology Anatomy, Physiology and Pharmacology chapter).
Signs of haemolysis -anaemia with raised reticulocytes, raised unconjugated bilirubin (jaundice without dark urine), raised LDH, low haptoglobin (it mops up free haemoglobin), abnormal film.
Two places it happens:
Extravascular (in the spleen and liver) -hereditary spherocytosis, warm autoimmune haemolysis, sickle cell disease -splenomegaly, gallstones.
HIV, steroids, chemotherapy, lupus, severe illness, some MS drugs
Monocytes
Become macrophages; clear debris; present antigens
Chronic infection (TB), CMML, recovery from neutropenia
Hairy cell leukaemia, aplastic anaemia
Eosinophils
Parasites; allergy
Asthma, eczema, hay fever, drug reactions (DRESS), parasites (Strongyloides -screen before steroids if at risk), EGPA, Hodgkin's lymphoma, Addison's
Steroids, acute illness
Basophils
Allergy (histamine)
CML, other myeloproliferative diseases
-
Neutropenia severity -under 1.5 × 10⁹/L mild; under 1.0 moderate; under 0.5 severe (high risk of life-threatening infection).
Neutropenic sepsis -temperature over 38°C or signs of sepsis with neutrophils 0.5 × 10⁹/L or less (usually after chemotherapy) -IV broad-spectrum antibiotics within 1 hour (e.g. piperacillin–tazobactam) without waiting for the count if chemotherapy is recent (NICE).
Benign ethnic neutropenia (Duffy-null phenotype) -lower neutrophil counts (often 1.0–1.5) in many people of African and Middle Eastern ancestry, without extra infection risk -important when starting drugs like clozapine.
Blasts on a blood film -suggest acute leukaemia -same-day haematology review.
Very high white count (over 100 × 10⁹/L) -risk of leucostasis (stroke, breathlessness) -urgent haematology input.
Production -fragments of megakaryocytes in the marrow (driven by thrombopoietin from the liver); lifespan about 7–10 days; about a third are held in the spleen.
Forming a platelet plug:
Adhesion -von Willebrand factor links exposed collagen to the platelet receptor GPIb.
Activation -platelets change shape and release ADP (acts on P2Y12 receptors -blocked by clopidogrel, prasugrel, ticagrelor) and thromboxane A2 (made by COX-1 -blocked by aspirin).
Aggregation -GPIIb/IIIa receptors bind fibrinogen and link platelets together (blocked by tirofiban and eptifibatide).
Activated platelets also provide the surface where clotting factors work.
Low platelets (thrombocytopenia) -causes:
Less production -marrow failure or infiltration, chemotherapy, B12 or folate deficiency, alcohol, viral infection, drugs.
More destruction -ITP (immune), HIT, TTP and HUS, DIC, drugs (quinine, heparin, valproate), sepsis, pregnancy (gestational thrombocytopenia, HELLP).
Pooling -big spleen (portal hypertension).
Dilution -massive transfusion.
False low (pseudothrombocytopenia) -platelets clumping in the EDTA tube -check the film or repeat in a citrate tube.
Bleeding risk -usually little bleeding above 50 × 10⁹/L; spontaneous bruising and mucosal bleeding more likely under about 20–30; serious spontaneous bleeding risk under 10. For procedures -usually over about 50 for most surgery and lumbar puncture (40–50 depending on guidance), over 80 for epidurals and spinal anaesthesia, over 100 for neurosurgery and eye surgery.
Platelet-type bleeding -petechiae, purpura, bruising, gum and nose bleeding, heavy periods, oozing after procedures (versus clotting factor problems -deep muscle and joint bleeding).
High platelets (thrombocytosis):
Reactive (most) -infection, inflammation, iron deficiency, bleeding, after splenectomy, cancer.
Primary -essential thrombocythaemia and other myeloproliferative neoplasms (JAK2, CALR or MPL mutations) -clotting and bleeding risk.
The clotting cascade (classic model, used to interpret lab tests):
Extrinsic pathway -tissue factor (exposed by injury) + factor VII -the real starting point in the body; measured by the PT/INR.
Intrinsic pathway -factors XII, XI, IX and VIII -amplifies the process; measured by the APTT.
Common pathway -factors X and V → thrombin (factor II) → converts fibrinogen into fibrin; factor XIII cross-links fibrin to strengthen the clot.
Thrombin is the key enzyme -it also activates platelets and factors V, VIII and XI (positive feedback) -and is a drug target (dabigatran).
Vitamin K-dependent factors -II, VII, IX and X (and the natural anticoagulants protein C and protein S) need vitamin K to work -blocked by warfarin.
Factor VII has the shortest half-life (about 6 hours) -so the INR rises first when warfarin starts or vitamin K is lacking.
Protein C also falls quickly → a brief pro-clotting state when warfarin starts (the reason for heparin cover in VTE and the rare warfarin skin necrosis).
Natural anticoagulants (keep clotting in check):
Antithrombin -switches off thrombin and factor Xa (heparin boosts it about 1,000-fold); lost in nephrotic syndrome.
Protein C and protein S -switch off factors Va and VIIIa; factor V Leiden resists this.
Tissue factor pathway inhibitor.
Fibrinolysis -tissue plasminogen activator (tPA) turns plasminogen into plasmin, which breaks down fibrin → D-dimer (fibrin breakdown products).
Thrombolytic drugs (alteplase, tenecteplase) are forms of tPA.
Von Willebrand disease -the commonest inherited bleeding disorder; mucosal bleeding (nosebleeds, heavy periods, bleeding after dental work); vWF also carries factor VIII (so APTT may be long); desmopressin or vWF concentrate; tranexamic acid.
Haemophilia A (factor VIII) and B (factor IX) -X-linked (mainly males; female carriers may bleed); bleeding into joints (haemarthrosis) and muscles; long APTT, normal PT; factor concentrates, emicizumab (haemophilia A), gene therapy; avoid IM injections and NSAIDs.
Acquired bleeding problems -anticoagulants and antiplatelets, liver disease (fewer clotting factors and platelets -but also fewer natural anticoagulants, so clots still occur), vitamin K deficiency (malnutrition, cholestasis, antibiotics, newborns), uraemia (platelet dysfunction -desmopressin, dialysis), massive transfusion (dilution), acquired haemophilia (older people -sudden large bruises, long APTT that doesn't correct on mixing).
Disseminated intravascular coagulation (DIC) -widespread clotting uses up platelets and factors → bleeding and clotting together:
Causes -sepsis, trauma, obstetric emergencies (abruption, amniotic fluid embolism), cancer (especially acute promyelocytic leukaemia), severe pancreatitis, snake bites.
Tests -low platelets, long PT and APTT, low fibrinogen, high D-dimer, schistocytes.
Treat the cause; blood products if bleeding (platelets, FFP, cryoprecipitate).
Inherited thrombophilia -factor V Leiden (commonest -about 1 in 20 people of European descent), prothrombin gene mutation, protein C, protein S and antithrombin deficiency (rarer, higher risk). Testing rarely changes management (NICE -not routinely after a first provoked VTE).
Antiphospholipid syndrome -antibodies (lupus anticoagulant, anticardiolipin, anti-beta-2-glycoprotein I) cause venous and arterial clots and pregnancy loss; lupus anticoagulant prolongs the APTT in the lab but causes clotting in the body; treat with warfarin -DOACs are not recommended, especially in triple-positive patients (MHRA); aspirin and LMWH in pregnancy.
Acquired clotting risk -cancer (and its treatment), pregnancy and the puerperium, oestrogen (combined pill, oral HRT), surgery, immobility, obesity, inflammatory disease, nephrotic syndrome, myeloproliferative neoplasms, PNH, heparin-induced thrombocytopenia.
Warfarin, early vitamin K deficiency, early liver disease, factor VII deficiency
Normal PT, long APTT
Unfractionated heparin, haemophilia A or B, von Willebrand disease, factor XI or XII deficiency, lupus anticoagulant, acquired haemophilia
Long PT and APTT
DIC, severe liver disease, severe vitamin K deficiency or warfarin excess, massive transfusion, common pathway factor deficiencies (X, V, II, fibrinogen), DOACs (variable)
Low platelets plus long PT and APTT, low fibrinogen
DIC, massive transfusion, liver failure
Normal PT, APTT and platelets but bleeding
von Willebrand disease, platelet function disorders, antiplatelet drugs, uraemia, factor XIII deficiency, vessel wall problems (scurvy, Ehlers–Danlos, steroids)
Mixing study -mix patient plasma with normal plasma: if the long APTT corrects, a factor is missing; if it doesn't, there is an inhibitor (lupus anticoagulant, acquired haemophilia, heparin).
INR -the PT standardised for warfarin monitoring; not reliable for liver disease or DOACs.
Anti-Xa level -monitors LMWH (pregnancy, kidney disease, extremes of weight) and can measure factor Xa-inhibiting DOACs.
D-dimer -sensitive but not specific -useful to rule out VTE when clinical probability is low (Wells score); raised in infection, cancer, pregnancy, surgery, older age (age-adjusted cut-offs are used in some places).
Fibrinogen -low in DIC, massive bleeding (including postpartum haemorrhage), liver failure; give cryoprecipitate or fibrinogen concentrate if bleeding with low fibrinogen.
Viscoelastic tests (TEG, ROTEM) -bedside whole-blood clotting tests used to guide transfusion in major bleeding.
ABO system -people have naturally occurring antibodies (mainly IgM) against the A or B antigens they lack:
Giving the wrong ABO group causes immediate intravascular haemolysis (fever, loin pain, hypotension, haemoglobinuria, DIC, AKI) -usually from a patient identification error -a "never event".
Group O negative red cells -the emergency "universal donor" for red cells (O positive is often used for men and older women in emergencies).
Group AB plasma -the universal plasma donor (AB has no anti-A or anti-B).
Rhesus D -RhD-negative people make anti-D only after exposure (transfusion or pregnancy). Anti-D (IgG) crosses the placenta → haemolytic disease of the fetus and newborn in later pregnancies.
Anti-D prophylaxis for RhD-negative pregnant women -routine antenatal anti-D (around 28 weeks, unless the baby is known RhD-negative from fetal DNA testing) and after sensitising events (bleeding, trauma, procedures, delivery of an RhD-positive baby).
Other antibodies (Kell, Kidd, Duffy and others) -from previous transfusion or pregnancy; cause delayed haemolytic reactions and HDFN; patients with sickle cell disease receive extended phenotype-matched blood.
Pre-transfusion testing -group and screen (ABO, RhD and antibody screen) then crossmatch or electronic issue; two samples from separate occasions may be needed for patients without a history (to prevent wrong blood in tube).
When to transfuse red cells (NICE NG24) -restrictive thresholds in stable patients: Hb under 70 g/L (target 70–90), or under 80 g/L in acute coronary syndrome (target 80–100); one unit at a time then reassess (one unit raises Hb by about 10 g/L in an average adult). Don't transfuse for iron, B12 or folate deficiency unless severe or symptomatic -treat the cause.
Bedside safety -positive patient identification at every step, check the blood component against the wristband and prescription, observations before, 15 minutes after starting and at the end; complete each red cell unit within 4 hours of leaving storage.
Transfusion reaction
Features
Action
Acute haemolytic (ABO incompatible)
Within minutes -fever, rigors, loin or chest pain, hypotension, dark urine, DIC
Stop, keep IV line open with saline, check patient and unit identity, resuscitate, inform the lab, report (SHOT)
Febrile non-haemolytic
Fever and rigors without other features -common
Slow or pause, paracetamol; exclude haemolysis and infection
Allergic / anaphylaxis
Itch and hives (mild) / wheeze, hypotension, swelling (severe -sometimes IgA deficiency)
Antihistamine for mild; stop and treat anaphylaxis with IM adrenaline
Oral iron -ferrous sulfate 200 mg (65 mg elemental iron), ferrous fumarate or ferrous gluconate:
Once daily or on alternate days (better absorbed and tolerated than several doses a day -BSG guidance).
Side effects -nausea, abdominal pain, constipation or diarrhoea, black stools (not melaena -check if in doubt).
Absorption -better on an empty stomach or with vitamin C (orange juice); reduced by tea, coffee, calcium, antacids and PPIs.
Interactions -iron reduces absorption of levothyroxine, tetracyclines, quinolones, bisphosphonates, penicillamine and levodopa -separate by about 2–4 hours.
Response -Hb should rise by about 20 g/L in 3–4 weeks; if not, check adherence, ongoing loss, malabsorption (coeliac), wrong diagnosis. Continue for about 3 months after Hb normalises to refill stores.
Overdose -dangerous, especially in children (vomiting, GI bleeding, shock, liver failure) -TOXBASE; desferrioxamine.
IV iron (ferric carboxymaltose, ferric derisomaltose, iron sucrose) -for intolerance or failure of oral iron, malabsorption (IBD, coeliac), CKD, heart failure, need for rapid repletion (before surgery, later pregnancy):
Hypersensitivity reactions (rare but serious) -give where resuscitation is available; observe for at least 30 minutes (MHRA).
Low phosphate with ferric carboxymaltose (repeated doses -fatigue, bone pain, osteomalacia).
Skin staining if it leaks out of the vein; avoid in active infection and in the first trimester.
Vitamin B12 -hydroxocobalamin 1 mg IM:
No nerve involvement -3 times a week for 2 weeks, then every 3 months for life (pernicious anaemia).
Nerve involvement -on alternate days until no further improvement (specialist advice), then every 2 months.
Oral cyanocobalamin -for dietary deficiency (vegans) and increasingly as maintenance in some patients (check local guidance).
Give B12 before (or with) folate if both are low -folate alone can worsen nerve damage (subacute combined degeneration).
Severe megaloblastic anaemia -potassium can fall in the first days of treatment as new cells take it up -monitor.
Folic acid:
Deficiency -5 mg daily for 4 months (after checking B12).
Pregnancy -400 micrograms daily before conception until 12 weeks; 5 mg daily if higher risk (previous neural tube defect, family history, diabetes, antiseizure medicines, BMI 30 or more, sickle cell disease, thalassaemia, coeliac disease).
With methotrexate -folic acid once a week (on a different day) reduces side effects; folinic acid rescue for high-dose methotrexate or toxicity.
Chronic haemolysis (e.g. sickle cell disease, hereditary spherocytosis) -supplements are often given.
Mechanism -boosts antithrombin, inhibiting thrombin and factor Xa.
Given as an IV infusion (or SC); monitored with the APTT (or anti-Xa); short half-life (about 1–2 hours); fully reversed by protamine; not dependent on kidney excretion.
Used when bleeding risk is high, surgery or thrombolysis may be needed soon, in severe kidney failure, and in some cardiac and dialysis settings.
Act mainly on factor Xa (via antithrombin); given subcutaneously by weight; predictable -no routine monitoring.
Excreted by the kidneys -reduce dose when creatinine clearance is under 30 mL/min; check anti-Xa levels in kidney impairment, pregnancy and extremes of weight.
Safe in pregnancy (doesn't cross the placenta) -treatment and prevention of VTE in pregnancy.
Only partly reversed by protamine.
Side effects of heparins -bleeding, heparin-induced thrombocytopenia, hyperkalaemia (suppresses aldosterone -check potassium if on longer courses, with CKD or diabetes), osteoporosis (long-term UFH), injection site bruising, allergy; LMWHs are made from pork (discuss with patients for whom this matters).
Heparin-induced thrombocytopenia (HIT):
An immune reaction -antibodies against heparin–platelet factor 4 complexes activate platelets → platelet count falls by more than 50%, usually 5–10 days after starting heparin (sooner if heparin was given in the last 100 days).
Clotting, not bleeding -new venous or arterial thrombosis, skin necrosis at injection sites, reactions after IV boluses.
Assess with the 4Ts score; send HIT antibody testing.
Stop all heparin (including line flushes and heparin-coated catheters); start a non-heparin anticoagulant (argatroban, danaparoid, fondaparinux or a DOAC -specialist advice).
Don't give platelets; don't start warfarin until the platelet count has recovered (risk of limb gangrene); record as an allergy.
Fondaparinux -synthetic factor Xa inhibitor (via antithrombin); once-daily SC; VTE prophylaxis and treatment, acute coronary syndrome; kidney excretion (avoid in severe CKD); doesn't cause HIT; not reversed by protamine.
VTE prophylaxis in hospital (NICE NG89) -assess every adult on admission for VTE and bleeding risk; LMWH (e.g. enoxaparin 40 mg daily, adjusted for weight and kidney function) or fondaparinux; mechanical options (intermittent pneumatic compression -not anti-embolism stockings in acute stroke); reassess regularly.
Mechanism -blocks vitamin K epoxide reductase → the liver can't make working factors II, VII, IX and X (and proteins C and S). Full effect takes 3–5 days (factor II has a long half-life).
Uses -VTE, AF (now mainly where DOACs are unsuitable), mechanical heart valves (DOACs are contraindicated), antiphospholipid syndrome, moderate to severe mitral stenosis with AF, left ventricular thrombus (sometimes).
Targets -INR 2.5 (range 2–3) for most indications; higher (e.g. 3.0–3.5) for some mechanical valves and recurrent VTE despite good control.
Starting warfarin for VTE -overlap with heparin for at least 5 days and until the INR has been at least 2 for 24 hours (early protein C fall → clotting risk).
Interactions -INR rises (bleeding):
Enzyme inhibitors -amiodarone, fluconazole and miconazole (including oral gel), metronidazole, clarithromycin and erythromycin, ciprofloxacin, co-trimoxazole, allopurinol, cimetidine, SSRIs (fluoxetine, fluvoxamine).
Binge drinking, acute illness, diarrhoea, liver disease, hyperthyroidism, reduced vitamin K intake (poor eating), many antibiotics (gut bacteria make vitamin K).
Interactions -INR falls (clotting):
Enzyme inducers -rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort, chronic heavy alcohol use.
Vitamin K-rich foods (green leafy vegetables) in large changing amounts, enteral feeds, hypothyroidism.
Bleeding risk without INR change -aspirin, clopidogrel, NSAIDs, SSRIs, steroids (GI bleeding) -avoid or add gastroprotection.
Other side effects -bleeding (most important), rare skin necrosis (protein C deficiency, early in treatment), calciphylaxis, "purple toes".
Pregnancy -teratogenic (warfarin embryopathy -weeks 6–12; fetal bleeding later) -switch to LMWH before 6 weeks; mechanical valves in pregnancy need specialist management.
Managing a high INR (BNF / BSH -check local guidance):
Major bleeding -stop warfarin; IV vitamin K 5–10 mg; prothrombin complex concentrate (FFP only if PCC is unavailable).
INR 5–8 with minor bleeding -stop warfarin; IV vitamin K 1–3 mg; restart when INR under 5.
INR 5–8 without bleeding -withhold 1–2 doses and reduce the maintenance dose.
INR over 8 without bleeding -stop warfarin; oral vitamin K 1–5 mg; repeat if still high after 24 hours; restart when under 5.
INR over 8 with minor bleeding -stop warfarin; IV vitamin K 1–3 mg.
Surgery -usually stop warfarin 5 days before (aim for INR under 1.5); bridging with LMWH only for high clot-risk patients (e.g. mechanical mitral valve, recent VTE).
Counselling -yellow anticoagulant book, regular INR tests, consistent diet, limit alcohol, tell all prescribers and pharmacists (including for over-the-counter and herbal products), signs of bleeding.
Factor Xa inhibitors -apixaban (twice daily), rivaroxaban (once daily for AF -with food at 15 mg and 20 mg doses), edoxaban (once daily).
Direct thrombin inhibitor -dabigatran (twice daily; about 80% kidney excretion; indigestion; capsules must not be opened).
Uses -stroke prevention in non-valvular AF (first-line anticoagulants -NICE NG196), treatment and secondary prevention of DVT and PE (first-line -NICE NG158), VTE prevention after hip and knee replacement.
Advantages -fixed doses, no routine INR monitoring, fewer food and drug interactions, less brain bleeding than warfarin; fast onset and offset (missed doses quickly leave the patient unprotected).
Dosing -depends on creatinine clearance (Cockcroft–Gault, actual body weight), age, weight and interacting drugs; follow the indication-specific dose (under-dosing is a common error and raises stroke risk).
Contraindications and cautions:
Mechanical heart valves and moderate to severe mitral stenosis -use warfarin.
Severe kidney impairment -dabigatran if creatinine clearance is under 30; the others if under 15 (check the BNF).
Active bleeding, severe liver disease with coagulopathy.
Very high body weight -check current guidance (some DOACs are acceptable for VTE).
Interactions -avoid with strong CYP3A4 and P-glycoprotein inhibitors (ketoconazole, itraconazole, some HIV drugs) and inducers (rifampicin, carbamazepine, phenytoin, St John's wort -levels fall); bleeding risk with antiplatelets, NSAIDs and SSRIs; dronedarone and verapamil affect some.
Monitoring -kidney function, FBC and LFTs at baseline and at least yearly, more often in older people and CKD (e.g. every [creatinine clearance ÷ 10] months if under 60); review adherence and bleeding.
Reversal in life-threatening bleeding:
Dabigatran -idarucizumab (specific antibody); dabigatran is also removed by dialysis.
Apixaban and rivaroxaban -andexanet alfa (where available and approved for the situation) or prothrombin complex concentrate.
Plus supportive care, local measures, tranexamic acid where appropriate; note the time of the last dose.
Before procedures -stop 24–48 hours (or longer for high-bleeding-risk procedures or reduced kidney function, especially dabigatran); no bridging needed.
Aspirin -irreversibly blocks COX-1 → less thromboxane A2 for the platelet's lifetime (7–10 days):
Uses -secondary prevention of MI, stroke and peripheral arterial disease; acute coronary syndrome (300 mg loading); acute ischaemic stroke (300 mg for 2 weeks); not for primary prevention in most people.
Side effects -GI bleeding and ulcers, other bleeding, aspirin-exacerbated asthma, Reye's syndrome (avoid in under-16s except specific conditions such as Kawasaki disease), raises urate at low doses (gout); salicylate toxicity in overdose (tinnitus, hyperventilation, mixed acid–base).
P2Y12 inhibitors -block ADP receptors:
Clopidogrel -a prodrug activated by CYP2C19 (poor metabolisers and omeprazole or esomeprazole reduce its effect -use lansoprazole or pantoprazole); used after stroke, in peripheral arterial disease and with aspirin after ACS or stents.
Prasugrel -stronger; avoid with previous stroke or TIA; caution over 75 and under 60 kg.
Dual antiplatelet therapy (DAPT) -aspirin plus a P2Y12 inhibitor after ACS or coronary stents (usually 6–12 months), and for 21 days after high-risk TIA or minor stroke; higher bleeding risk -add a PPI in those at risk; never stop early after recent stents without cardiology advice (stent thrombosis).
Dipyridamole -phosphodiesterase inhibitor; with aspirin after stroke if clopidogrel isn't tolerated; headache.
GPIIb/IIIa inhibitors (tirofiban, eptifibatide) and IV cangrelor -specialist use in coronary intervention; bleeding and thrombocytopenia.
Before surgery -usually stop clopidogrel and ticagrelor 5 days and prasugrel 7 days before (discuss with cardiology if stents are recent); aspirin is often continued.
Bleeding on antiplatelets -platelet transfusion may help in severe bleeding (less effective with ticagrelor, which also affects transfused platelets).
Thrombolytics, Tranexamic Acid and Reversal Agents
Thrombolytics (alteplase, tenecteplase) -dissolve clots by activating plasminogen; for acute ischaemic stroke, STEMI (where PCI isn't available in time) and massive PE with haemodynamic compromise; major risk -bleeding (including brain); many contraindications (see the Neurology and Cardiology Anatomy, Physiology and Pharmacology chapters).
Major trauma -1 g IV over 10 minutes within 3 hours of injury, then 1 g over 8 hours (later use may be harmful).
Postpartum haemorrhage, surgery (reduces blood loss), heavy menstrual bleeding (oral), nosebleeds, dental procedures in bleeding disorders.
Not useful in GI bleeding (no benefit and more clots in a large trial).
Cautions -active thrombosis, seizures at high doses, reduce dose in kidney impairment.
Vitamin K (phytomenadione):
Newborns -IM at birth to prevent vitamin K deficiency bleeding (oral regimens are an alternative).
Warfarin reversal (IV works in about 6–12 hours; oral in about 24 hours).
Deficiency in cholestasis, malabsorption and malnutrition.
IV vitamin K can rarely cause anaphylaxis -give slowly.
Prothrombin complex concentrate (PCC) -factors II, VII, IX and X -rapid warfarin reversal in major bleeding or urgent surgery (with IV vitamin K, because PCC wears off); also used for factor Xa inhibitor bleeding.
Protamine sulfate -reverses UFH (about 1 mg for every 100 units given recently; maximum 50 mg) and partly reverses LMWH; can cause hypotension and anaphylaxis (higher risk with fish allergy, previous protamine-containing insulin, vasectomy).
Idarucizumab (dabigatran) and andexanet alfa (factor Xa inhibitors) -specific DOAC reversal agents.
Desmopressin -releases von Willebrand factor and factor VIII from blood vessel lining; for type 1 von Willebrand disease, mild haemophilia A, uraemic and some antiplatelet-related bleeding; causes hyponatraemia (restrict fluids) and loses effect with repeated doses.
Haemophilia treatments -factor VIII or IX concentrates; emicizumab (SC antibody that mimics factor VIII -prophylaxis in haemophilia A, including those with inhibitors; caution with activated PCC -thrombotic microangiopathy); bypassing agents (recombinant factor VIIa) for inhibitors; gene therapy in specialist centres.
Red cells in additive solution; stored at 2–6°C (about 5 weeks)
Symptomatic anaemia or bleeding (restrictive thresholds); exchange transfusion in sickle cell disease
Platelets
Pooled or apheresis platelets; stored at 20–24°C with agitation (about 7 days) -infection risk
Bleeding with low platelets; prevention when under 10 × 10⁹/L in marrow failure (not in ITP, TTP or HIT unless life-threatening bleeding); before procedures
Fresh frozen plasma (FFP)
All clotting factors; frozen; thawed before use
Bleeding with abnormal clotting (DIC, massive transfusion, liver disease with bleeding); TTP (plasma exchange) -not for warfarin reversal when PCC is available, nor to "correct" mildly abnormal tests before minor procedures
Cryoprecipitate
Fibrinogen, factor VIII, von Willebrand factor, factor XIII
Bleeding with low fibrinogen (under about 1.5 g/L, or under 2 g/L in obstetric haemorrhage) -DIC, massive transfusion, postpartum haemorrhage
Human albumin
Albumin (4.5% or 20%)
After large-volume paracentesis, SBP, hepatorenal syndrome, plasma exchange
Immunoglobulin
Pooled IgG
Antibody deficiency, ITP, Guillain–Barré, myasthenic crisis, Kawasaki disease, some infections (e.g. varicella or rabies exposure -specific immunoglobulins)
Anti-D immunoglobulin
Anti-RhD antibody
Preventing RhD sensitisation in RhD-negative pregnant women
Massive haemorrhage -activate the major haemorrhage protocol; give red cells with plasma (and platelets and cryoprecipitate) early in fixed ratios until lab or viscoelastic results guide; tranexamic acid; keep the patient warm; correct calcium (citrate in stored blood binds calcium); stop the bleeding (surgery, interventional radiology, endoscopy).
CMV-negative components -for intrauterine transfusion and neonates (and in pregnancy) -UK blood is leucodepleted, which reduces CMV risk for most others.
Phenotype-matched red cells -sickle cell disease, thalassaemia, patients with antibodies.
Patients who decline blood (e.g. many Jehovah's Witnesses) -respect a capacitous refusal or valid advance decision; discuss acceptable products (some accept albumin, cell salvage or clotting factor concentrates); optimise Hb before surgery (iron, ESAs), minimise blood tests, tranexamic acid.
Patient blood management -treat anaemia before planned surgery (IV iron), reduce blood loss, use restrictive thresholds and single units.
Uses -preventing neutropenia after some chemotherapy, severe chronic neutropenia, collecting stem cells from blood for transplant.
Side effects -bone pain, high white count, rare splenic rupture (left upper quadrant or shoulder pain), capillary leak.
Erythropoiesis-stimulating agents -CKD anaemia (see the Renal Anatomy, Physiology and Pharmacology chapter), some myelodysplasia and chemotherapy-induced anaemia; hypertension, thrombosis.
Uses -chronic ITP, some aplastic anaemia, raising platelets before procedures in liver disease (avatrombopag).
Eltrombopag -liver toxicity (LFTs), must be taken apart from calcium, dairy, antacids and iron (they bind it); cataracts.
Risks -thrombosis, marrow fibrosis (reticulin), rebound low platelets on stopping.
Immune thrombocytopenia (ITP) -treat if bleeding or platelets are very low (usually under about 20–30 × 10⁹/L); many children recover without treatment:
Corticosteroids -prednisolone (about 1 mg/kg for a short course) or high-dose dexamethasone.
IV immunoglobulin -rapid but temporary rise (bleeding, before surgery); side effects -headache, aseptic meningitis, thrombosis, kidney injury, haemolysis, allergic reactions.
Platelet transfusion only for life-threatening bleeding (with IVIG and steroids).
Autoimmune haemolytic anaemia -warm: prednisolone, folic acid, rituximab; cold: keep warm, rituximab, sutimlimab (complement C1s inhibitor); transfuse through a blood warmer in cold-type disease.
Complement inhibitors -eculizumab and ravulizumab (C5), pegcetacoplan (C3), iptacopan (factor B) -PNH and atypical HUS; meningococcal vaccination (and often antibiotic prophylaxis) is essential -high risk of meningococcal infection.
Hydroxycarbamide -raises fetal haemoglobin → fewer painful crises and acute chest episodes, fewer transfusions, longer life; offered to adults and children (from about 9 months) with frequent complications; side effects -marrow suppression (regular FBC), skin and nail darkening, leg ulcers; teratogenic (contraception; stop before conception -men and women).
Penicillin V prophylaxis (children, and adults often) plus vaccines for hyposplenism; folic acid is often given.
Regular transfusion or exchange -stroke prevention in children with abnormal transcranial Doppler, after stroke, some other complications.
Gene therapy (exagamglogene autotemcel) and stem cell transplant -for selected severe disease in specialist centres; some earlier new drugs (crizanlizumab, voxelotor) have been withdrawn in the UK or Europe.
Acute painful crisis (NICE CG143):
Analgesia within 30 minutes of arrival -strong opioid (e.g. morphine or diamorphine, not pethidine) for severe pain, with regular paracetamol and an NSAID if not contraindicated; reassess every 30 minutes.
Fluids (avoid overload), oxygen if hypoxic, warmth, incentive spirometry (prevents acute chest syndrome), laxatives and antiemetics with opioids.
Acute chest syndrome (new chest X-ray changes with chest pain, fever, hypoxia) -antibiotics (including atypical cover), oxygen, transfusion or exchange transfusion; involve haematology and critical care early.
Transfusion -avoid raising Hb above about 100 g/L with simple transfusion (thicker blood → more sickling); extended phenotype-matched blood; watch for hyperhaemolysis.
Iron chelation (iron overload from transfusions -thalassaemia, sickle cell disease, myelodysplasia):
Desferrioxamine -SC infusion over 8–12 hours on most nights; eye and hearing toxicity (yearly checks), Yersinia infection (stop if fever with abdominal pain or diarrhoea), slowed growth in children.
Deferasirox -oral once daily; kidney and liver toxicity (monitor creatinine, urine protein and LFTs), GI upset, rash.
Deferiprone -oral three times daily; agranulocytosis (weekly FBC; stop if fever or infection), joint pains, zinc deficiency.
Monitor iron load with ferritin and MRI (heart T2* and liver iron).
Venesection (removing blood):
Hereditary haemochromatosis -weekly at first until ferritin is about 50 micrograms/L, then maintenance.
Polycythaemia vera -to keep haematocrit under 0.45; plus low-dose aspirin; hydroxycarbamide or interferon (pregnancy) for high-risk patients; ruxolitinib (JAK inhibitor) if resistant.
Essential thrombocythaemia -aspirin for most; hydroxycarbamide (or anagrelide -palpitations, headache, heart failure; interferon in pregnancy) in high-risk patients.
How it works -kills rapidly dividing cells, so it also harms fast-growing normal tissues: marrow, gut lining, hair follicles, gonads. Drugs are combined (different mechanisms and toxicities) and given in cycles (allowing normal cells to recover).
Common side effects:
Marrow suppression -lowest counts ("nadir") usually about 7–14 days after treatment → infection, bleeding, anaemia.
Neutropenic sepsis -the most important emergency -IV antibiotics within 1 hour.
Nausea and vomiting -prevent with 5-HT3 antagonists, NK1 antagonists and dexamethasone (see the Gastroenterology Anatomy, Physiology and Pharmacology chapter).
Mucositis, diarrhoea, hair loss, fatigue, infertility (offer sperm or egg storage before treatment), second cancers later.
Extravasation of vesicant drugs (anthracyclines, vinca alkaloids) -tissue necrosis -stop, follow the extravasation policy.
Tumour lysis syndrome -rapid breakdown of cancer cells (high-grade lymphomas, acute leukaemias, especially with high white counts or bulky disease) releases potassium, phosphate and uric acid → high potassium, high phosphate, low calcium, high urate, AKI, arrhythmias, seizures:
Prevention -IV fluids; allopurinol (low–moderate risk) or rasburicase (high risk -breaks down uric acid; contraindicated in G6PD deficiency -haemolysis and methaemoglobinaemia).
Treatment -fluids, treat hyperkalaemia, rasburicase, dialysis if needed.
Specific drug toxicities:
Anthracyclines (doxorubicin, daunorubicin) -cardiotoxicity (cumulative dose -echocardiogram before and during), red urine.
Vincristine -peripheral neuropathy, constipation and ileus; fatal if given intrathecally (given in a mini-bag, never in a syringe near intrathecal drugs).
Cyclophosphamide and ifosfamide -haemorrhagic cystitis (mesna, hydration); ifosfamide encephalopathy.
Methotrexate -marrow suppression, mucositis, liver, lung and kidney toxicity; folinic acid rescue after high doses; glucarpidase for toxic levels with kidney failure.
Purine analogues (fludarabine, cladribine) and bendamustine -profound immunosuppression -irradiated blood for life, PCP prophylaxis.
Infection prophylaxis in intensive treatment -antivirals (aciclovir), co-trimoxazole (PCP), antifungals (posaconazole -many interactions); screen for hepatitis B before rituximab and chemotherapy.
⚠️ Safety Pearl: A patient who has had chemotherapy in the last 6 weeks and feels unwell or has a temperature of 38°C or more has neutropenic sepsis until proven otherwise. Give IV antibiotics within 1 hour; don't wait for the blood count.
Anticoagulants, antiplatelets, NSAIDs, SSRIs and SNRIs (especially with NSAIDs or anticoagulants), steroids (GI), ibrutinib, herbal products (ginkgo, fish oil -minor)
Thrombosis
Combined pill, oral HRT, tamoxifen and raloxifene, thalidomide and lenalidomide, ESAs, JAK inhibitors, asparaginase, tranexamic acid (if pre-existing clot risk), testosterone (via polycythaemia), antipsychotics, steroids, ponatinib
Methaemoglobinaemia
Dapsone, prilocaine and benzocaine, nitrates and nitrites, rasburicase, primaquine
Sideroblastic anaemia
Isoniazid (pyridoxine), linezolid, chloramphenicol, alcohol, lead
1. A 78-year-old man on warfarin for AF is given clarithromycin and fluconazole for a chest infection and oral thrush. A week later he has blood in his urine. INR 9.2. BP and Hb are stable. Answer: Over-anticoagulation from enzyme-inhibitor interactions, with minor bleeding.
Stop warfarin; give IV vitamin K 1–3 mg; recheck INR the next day; restart warfarin when INR is under 5.
If bleeding becomes major -IV vitamin K 5–10 mg and prothrombin complex concentrate.
Review interacting drugs; consider whether a DOAC is suitable for him; investigate haematuria once stable (anticoagulation can unmask a bladder cancer).
2. A 66-year-old woman is on enoxaparin after a knee replacement. On day 8 her platelets have fallen from 260 to 90 × 10⁹/L and she has a new swollen calf with a DVT on ultrasound. Answer: Probable heparin-induced thrombocytopenia with thrombosis.
Calculate the 4Ts score (high); send HIT antibody tests; stop all heparin, including flushes.
Start a non-heparin anticoagulant (e.g. argatroban, or fondaparinux or a DOAC per haematology advice); don't give platelets.
Delay warfarin until platelets recover; record heparin allergy prominently.
3. A 72-year-old man has tiredness. Hb 92 g/L, MCV 71 fL, ferritin 6 micrograms/L. He takes omeprazole. He has no GI symptoms. Answer: Iron deficiency anaemia -must be investigated for GI cancer.
Urgent referral for gastroscopy and colonoscopy (or CT colonography if unsuitable); coeliac serology; urine dipstick for blood.
Start oral iron once daily (or alternate days); omeprazole reduces absorption -review need; IV iron if oral fails or isn't tolerated.
Expect Hb to rise by about 20 g/L in 3–4 weeks; continue for 3 months after it normalises.
4. An 84-year-old woman on apixaban for AF falls and hits her head. CT shows an acute subdural haematoma. Her last apixaban dose was 3 hours ago. Answer: Life-threatening bleeding on a factor Xa inhibitor.
Stop apixaban; urgent reversal -andexanet alfa (if available and approved locally) or prothrombin complex concentrate; neurosurgical referral.
Check FBC, clotting, kidney function (and an anti-Xa level if available); control blood pressure.
Later -multidisciplinary decision about restarting anticoagulation (stroke risk versus re-bleeding), falls assessment.
5. A 28-year-old man with Burkitt lymphoma starts chemotherapy. Next day: K 6.8 mmol/L, phosphate 3.1, adjusted calcium 1.75, urate high, creatinine 240 (baseline 80). He is G6PD deficient. Answer: Tumour lysis syndrome with AKI.
Treat hyperkalaemia (IV calcium gluconate if ECG changes, insulin–glucose); aggressive IV fluids with urine output monitoring.
Rasburicase is contraindicated (G6PD -haemolysis and methaemoglobinaemia) -use allopurinol; early renal referral for dialysis.
Only treat low calcium if symptomatic (calcium with high phosphate can deposit in tissues); cardiac monitoring.