Hematology Clinic Notes
OncoDesk · Haematology · A: disease notes · B: tools of the trade · C: drug classes & mechanisms · D: case list · E: literature reviewed · F: abbreviation key
Study note — verify against current guidelines + your institution's formulary before clinical decisions. Every abbreviation is spelled out on first use; full list in Part F. Heme tracks the blood counts — each line can be too low (a cytopenia) or too high (reactive, or a clonal MPN [myeloproliferative neoplasm]) — plus clotting / bleeding and the blood cancers (leukaemia, lymphoma, myeloma, MDS [myelodysplastic syndrome]).
PART A · DISEASE NOTES
Grouped by what's going wrong — each disease keeps its own section (snapshot → workup → management → watch).
▸ ANAEMIAS — too few or faulty red cells
Always start with the MCV (mean cell volume) — it sorts the causes before you order anything else. Trap: two opposing causes (e.g. iron + B12 deficiency) can cancel out → a normal MCV with a high RDW (red-cell distribution width) and a dimorphic film — don't be fooled.
| By MCV | Think of… |
|---|
| Microcytic (small) | Iron deficiency · thalassaemia (anaemia of chronic disease can be mildly microcytic too). |
| Normocytic (normal) | Anaemia of chronic disease · acute blood loss · haemolysis. |
| Macrocytic (large) | B12 / folate deficiency · alcohol · MDS (myelodysplastic syndrome) in older patients. |
Iron-deficiency anaemia (microcytic)
Snapshot. The commonest anaemia worldwide — an absolute lack of iron → small, pale cells (microcytic, hypochromic). It's a clue, not a diagnosis — always find the cause: blood loss (gastrointestinal [GI]: ulcer, cancer, NSAIDs [non-steroidal anti-inflammatory drugs], hookworm; or menstrual), malabsorption (coeliac, post-gastrectomy), increased demand (pregnancy, infancy), or poor intake. Exam clues: pica, koilonychia (spoon nails), angular cheilitis, restless legs.
Workup
Confirm it: low ferritin is the best single test (reflects stores). Ferritin is an acute-phase reactant → if the patient is inflamed it can read falsely normal; then check low transferrin saturation + high TIBC (total iron-binding capacity). Film: microcytic hypochromic cells, pencil cells, reactive thrombocytosis.
Then find the source: menstrual + dietary history; a man or a postmenopausal woman → upper endoscopy + colonoscopy; coeliac serology; urinalysis for haematuria.
Management
1. Treat the cause. 2. Oral iron first-line — ferrous sulfate / fumarate; alternate-day dosing absorbs better and is better tolerated; take with vitamin C, away from tea / calcium / PPI (proton-pump inhibitor). Response: reticulocytosis by day 5–7, haemoglobin rise ~20 g/L every 3–4 weeks; continue ~3 months past a normal haemoglobin to refill stores. 3. IV (intravenous) iron (ferric carboxymaltose, iron sucrose) if oral fails / isn't tolerated / can't absorb (CKD [chronic kidney disease], IBD [inflammatory bowel disease], a PEG [percutaneous endoscopic gastrostomy] tube, late pregnancy) — watch low phosphate. 4. Tranexamic acid for menorrhagia; transfuse only if symptomatic / cardiac.
Watch
A man or postmenopausal woman with iron deficiency = a GI cancer until proven otherwise — they need endoscopy. Failure to respond → wrong diagnosis (thalassaemia, anaemia of chronic disease), non-adherence, ongoing blood loss, or malabsorption (coeliac).
Thalassaemia (inherited, microcytic)
Snapshot. Inherited under-production of a globin chain → small, pale (microcytic, hypochromic) cells + some haemolysis. β-thalassaemia = the β-globin gene (2 copies); α-thalassaemia = the α-globin genes (4 copies — severity tracks how many are lost). Huge in this population — common across the Gulf, Mediterranean, South / Southeast Asia; the UAE runs mandatory premarital screening.
Workup
| Form | Picture |
|---|
| Trait (minor) | 1 gene (β) or 1–2 genes (α) affected. Asymptomatic, microcytosis that mimics iron deficiency; no treatment — just don't iron-overload + genetic counselling. |
| Intermedia | Moderate anaemia; occasional transfusion, not lifelong-dependent. |
| Major (β-thal major / Cooley's) | Both β genes severe → transfusion-dependent from infancy; marrow expansion + growth failure if untreated. |
| α spectrum | Silent carrier → trait → HbH disease (3 of 4 genes lost, moderate–severe) → Hb Barts / hydrops fetalis (all 4 lost — fatal in utero). |
On the blood count: very low MCV, normal / high RBC (red-cell count), Mentzer index (MCV ÷ RBC) < 13. Ferritin normal (this is what excludes iron deficiency). Film: target cells + basophilic stippling. Confirm with haemoglobin electrophoresis / HPLC (high-performance liquid chromatography) → raised HbA2 (haemoglobin A2) = β-trait; α-thalassaemia needs genetic testing. (Co-existing iron deficiency can falsely lower HbA2 — replace the iron first, then re-test.)
Management
| Form | Treatment |
|---|
| Trait | No treatment; avoid unnecessary iron; genetic counselling + partner screening before pregnancy. |
| Intermedia | Transfuse when needed; folic acid; monitor iron. |
| Major | Regular transfusion (suppresses the marrow drive) + iron chelation (deferasirox oral; desferrioxamine) to clear transfusional iron. Splenectomy if hypersplenism. Curative = allogeneic stem-cell transplant; emerging gene therapy (exagamglogene / CRISPR, betibeglogene). |
Watch
Iron overload is what kills in transfusion-dependent thalassaemia — heart failure, liver + endocrine damage; chelate and monitor ferritin + cardiac / liver MRI (T2*). Everyday trap: don't keep giving iron to a thalassaemia-trait patient who isn't iron deficient.
Haemolytic anaemia (normocytic)
Snapshot. Red cells destroyed faster than the marrow replaces them — normocytic (or macrocytic from the reticulocyte surge). Lab signature: ↑ reticulocytes, ↑ LDH (lactate dehydrogenase), ↑ unconjugated bilirubin (jaundice), ↓ haptoglobin. Intravascular (mechanical, PNH) → haemoglobinuria + very low haptoglobin; extravascular (spleen) → spherocytes.
Workup — the two-step split
First the DAT (direct antiglobulin test / Coombs): positive = immune, negative = not. Then place the mechanism:
| Group | Examples & clue |
|---|
| Immune (DAT-positive) | AIHA (autoimmune haemolytic anaemia) — warm (IgG; idiopathic, lymphoma, lupus, drugs) or cold (IgM; mycoplasma / EBV [Epstein-Barr virus], lymphoma); also transfusion reaction, haemolytic disease of the newborn. |
| Inherited | Membrane — hereditary spherocytosis; enzyme — G6PD (glucose-6-phosphate dehydrogenase) deficiency (X-linked, common in this region; haemolysis on oxidative stress — fava beans, infection, drugs); haemoglobinopathy (sickle, thalassaemia). |
| Acquired, non-immune | Microangiopathic — TTP / HUS / DIC (schistocytes); mechanical valve; PNH (paroxysmal nocturnal haemoglobinuria); malaria. |
Management
All: folic acid (high turnover); transfuse cautiously (cross-matching is harder in AIHA). Warm AIHA → corticosteroids first-line → rituximab; splenectomy / immunosuppression if refractory; treat any underlying lymphoma / lupus / drug. Cold AIHA → keep warm, avoid the cold; rituximab ± bendamustine; treat the cause. Hereditary spherocytosis → folate, splenectomy if severe. G6PD → avoid triggers (supportive). PNH → a complement inhibitor (eculizumab) + thrombosis prophylaxis.
Watch
Schistocytes + low platelets = TTP until proven otherwise (an emergency — send ADAMTS13, start plasma exchange; don't just transfuse platelets). Ask about G6PD before any oxidant drug (primaquine, nitrofurantoin, sulfonamides, rasburicase).
Anaemia of chronic disease (normocytic)
Snapshot. The "anaemia of inflammation." In chronic infection / inflammation / cancer / CKD (chronic kidney disease), hepcidin rises → iron is locked away in macrophages and poorly absorbed, the marrow's response to erythropoietin is blunted, and red-cell survival shortens. Usually normocytic, normochromic (sometimes mildly microcytic); mild–moderate and non-progressive.
Workup
The pattern vs iron deficiency: serum iron is low in both, but ferritin separates them — low = iron deficiency; normal / high = anaemia of chronic disease (iron present, just locked away). TIBC low here (high in iron deficiency); transferrin saturation low; CRP (C-reactive protein) / ESR (erythrocyte sedimentation rate) raised. Then hunt the underlying cause.
Management
Treat the underlying disease — that's the real fix; plain iron doesn't help (iron isn't what's lacking). In CKD or selected cancer cases: an ESA (erythropoiesis-stimulating agent — epoetin) ± IV (intravenous) iron — don't over-correct the haemoglobin (> ~120 g/L raises thrombosis risk). Transfuse only if symptomatic.
Watch
Iron deficiency and chronic disease often coexist — in an inflamed patient a "normal" ferritin can still hide true iron deficiency (check transferrin saturation / soluble transferrin receptor). Don't let "it's just chronic disease" mask an occult cancer or infection.
B12 & folate deficiency (macrocytic · megaloblastic)
Snapshot. Lack of B12 or folate → impaired DNA synthesis → a megaloblastic marrow → macrocytic anaemia + hypersegmented neutrophils, and if severe a pancytopenia (production is ineffective). B12 causes: pernicious anaemia (commonest), gastrectomy / atrophic gastritis, terminal-ileal disease or resection (Crohn's), vegan diet, metformin, long-term PPI (proton-pump inhibitor). Folate causes: poor diet, malabsorption (coeliac), increased demand (pregnancy, haemolysis), drugs (methotrexate, trimethoprim, anticonvulsants), alcohol.
Why pernicious anaemia happens: B12 needs intrinsic factor (made by gastric parietal cells) to be absorbed in the terminal ileum; pernicious anaemia = autoimmune loss of intrinsic factor → B12 can't be absorbed.
Workup
Low B12 / folate; raised MCV; film — oval macrocytes + hypersegmented neutrophils; raised LDH (lactate dehydrogenase) + bilirubin (ineffective erythropoiesis = haemolysis inside the marrow). Pernicious anaemia → anti-intrinsic-factor (specific) + anti-parietal-cell (sensitive) antibodies. If borderline, methylmalonic acid + homocysteine (both raised in B12 deficiency; only homocysteine in folate). Look for a co-existing iron deficiency masking the high MCV.
Management
B12 — pernicious anaemia / malabsorption → intramuscular hydroxocobalamin (loading on alternate days for ~2 weeks → then every 3 months); dietary → oral. Folate → oral folic acid. Reticulocytosis confirms response by day 5–7; treat any unmasked iron deficiency and watch low potassium as the marrow fires up.
Watch
Give B12 BEFORE / with folate — folate alone in B12 deficiency can precipitate subacute combined degeneration of the cord (irreversible — dorsal columns + corticospinal tracts: paraesthesiae, ataxia, weakness). Neuro damage can occur without anaemia — treat promptly. Pernicious anaemia → lifelong B12 + raised gastric-cancer risk + associated autoimmune disease (thyroid, vitiligo).
▸ PLATELETS & BLEEDING
Thrombocytopenia (low platelets)
Snapshot. Low platelets. Step 1 — is it real? Repeat the count + blood film to exclude pseudothrombocytopenia (clumping in the EDTA [ethylenediaminetetraacetic acid] tube — recheck in citrate). Then place the cause in one of three buckets.
Workup
| Bucket | Causes & what to check |
|---|
| Destruction / consumption | ITP (immune thrombocytopenia) — isolated low platelets, a diagnosis of exclusion. Also drug-induced; TTP (thrombotic thrombocytopenic purpura) / HUS (haemolytic uraemic syndrome) — check film for schistocytes + LDH (an emergency); DIC (disseminated intravascular coagulation) — check the coagulation screen. |
| Reduced production | Marrow failure / infiltration (leukaemia, MDS), B12 / folate deficiency. |
| Sequestration | Hypersplenism (e.g. liver disease / portal hypertension — a big spleen traps platelets). |
Secondary-cause screen: coagulation (PT [prothrombin time] / APTT [activated partial thromboplastin time]); LDH + haptoglobin + reticulocytes (for TTP); renal + liver function; viral (HIV [human immunodeficiency virus], hepatitis B & C); autoimmune (ANA [antinuclear antibody]); B12 / folate; drug review. Bone marrow only if atypical (older, other lines low, abnormal film, no response).
Management — ITP (the usual landing point)
Treat only if bleeding or platelets < 20–30 ×10⁹/L — the count alone doesn't mandate treatment. First-line: corticosteroids (prednisolone or high-dose dexamethasone) ± IVIG (intravenous immunoglobulin) when you need a fast rise (active bleeding / before a procedure). Second-line: TPO (thrombopoietin) receptor agonists (eltrombopag, romiplostim), rituximab, or splenectomy. Treat any secondary cause (HIV, hepatitis C, H. pylori, lupus, drug). Platelet transfusion only for life-threatening bleeding (they're consumed fast in ITP).
Watch
TTP and DIC are emergencies — schistocytes on film or a deranged coagulation screen changes everything; in TTP / HIT (heparin-induced thrombocytopenia) do NOT transfuse platelets unless life-threatening bleeding. ITP stays a diagnosis of exclusion.
Bleeding disorders
Snapshot. Abnormal bleeding from a defect in platelets (number or function), clotting factors, or vessels. The pattern points the way: mucocutaneous bleeding (bruising, epistaxis, gum bleeding, menorrhagia) → a platelet / VWF problem; deep bleeding (haemarthrosis, muscle haematomas) → a clotting-factor problem (haemophilia).
Workup — decode the PT / APTT
| Pattern | Points to |
|---|
| Both normal, but bleeds | VWD (von Willebrand disease) or a platelet-function defect → VWF (von Willebrand factor) antigen + activity, platelet-function tests. |
| APTT ↑, PT normal | Intrinsic pathway — haemophilia A (factor VIII), B (factor IX), or VWD (low factor VIII); also heparin, lupus anticoagulant. |
| PT ↑, APTT normal | Extrinsic — factor VII; early warfarin / vitamin-K deficiency. |
| Both ↑ | Common pathway — factor V, X, II (prothrombin), fibrinogen; or liver disease / DIC / vitamin-K deficiency. |
Mixing study (patient + normal plasma): corrects → a factor deficiency; doesn't correct → an inhibitor (acquired factor VIII, lupus anticoagulant).
Management
| Disorder | Treatment |
|---|
| VWD (commonest inherited) | Desmopressin (DDAVP) for type 1 (releases stored VWF) + tranexamic acid; VWF / factor VIII concentrate for severe / type 3. Avoid DDAVP in type 2B. |
| Haemophilia A / B | Factor VIII / IX replacement (recombinant); emicizumab prophylaxis (A); gene therapy emerging (Part E). Avoid NSAIDs / IM injections. |
| Factor V deficiency (rare) | No specific concentrate → fresh frozen plasma (± platelets, which carry factor V); tranexamic acid. |
| Acquired | Liver disease; vitamin-K deficiency (→ vitamin K); DIC (treat the cause); acquired haemophilia (immunosuppression). |
Watch
Tranexamic acid + desmopressin cover most mild mucosal bleeding / menorrhagia. Avoid aspirin / NSAIDs / IM injections in any bleeding disorder. Don't confuse factor V deficiency (bleeding) with factor V Leiden (clotting — the opposite).
▸ TOO MANY CELLS — reactive vs the MPNs
High counts — thrombocytosis, polycythaemia & the MPNs (reactive vs clonal)
Snapshot. Every cell line can be too low (a cytopenia) or too high. For a high count the one question that matters: reactive (secondary to something else — settles when the trigger is treated) or clonal (a myeloproliferative neoplasm — the marrow itself is the problem, doesn't settle, carries a lifelong thrombosis risk)?
| High line | Reactive (secondary) | Clonal (an MPN) |
|---|
| Platelets ↑ — thrombocytosis | Infection, inflammation, iron deficiency, bleeding, post-splenectomy — most high platelets are reactive. | ET (essential thrombocythaemia) — sustained high platelets; a driver mutation (JAK2 [Janus kinase 2], CALR [calreticulin], or MPL). |
| Red cells ↑ — polycythaemia / erythrocytosis | Relative (dehydration), or secondary to hypoxia, smoking, altitude, or an EPO (erythropoietin)-secreting cause. | PV (polycythaemia vera) — high haematocrit, JAK2-positive; classic itch after a hot shower + ruddy face. |
| White cells ↑ — leukocytosis | Infection, steroids, inflammation. | CML / leukaemia (see the Blood-cancers group). |
| Scarred marrow | — | MF (myelofibrosis) — marrow replaced by fibrosis → big spleen, tear-drop red cells, failing counts. |
The MPNs (PV, ET, MF) are the classic Philadelphia-negative myeloproliferative neoplasms, usually JAK2-driven. Treatment targets the clot risk, not cure: PV → venesection to keep haematocrit < 45% + low-dose aspirin; high-risk ET/PV → cytoreduction with hydroxyurea; MF → a JAK inhibitor (ruxolitinib) for spleen/symptoms, transplant in the fit.
Watch
The danger of high counts is clotting (arterial + venous) — the main cause of harm in PV / ET; always ask reactive vs clonal → check JAK2. Paradox: at very high platelets (> 1000 ×10⁹/L) you can get bleeding instead (an acquired von Willebrand defect).
▸ THROMBOSIS & ANTICOAGULATION
Thrombosis & anticoagulation
Snapshot. VTE (venous thromboembolism) = DVT (deep-vein thrombosis) + PE (pulmonary embolism). The key fork is provoked (a trigger such as surgery, immobility, long-haul travel → time-limited treatment) vs unprovoked (no trigger → consider longer / indefinite anticoagulation).
Thrombophilia / APS: a thrombophilia workup is for unprovoked, young, or recurrent clots. APS (antiphospholipid syndrome) — arterial and venous clots ± pregnancy loss; test lupus anticoagulant, anti-cardiolipin and anti-β2-glycoprotein-I antibodies. Cancer-associated thrombosis is very common (the overlap with the oncology clinic).
Watch
APS → use warfarin, not a DOAC (direct oral anticoagulant) — DOACs fail in antiphospholipid syndrome. Recurrent clot off anticoagulation = the patient likely needs it for life; recurrence on treatment → reassess adherence and dose, and look for cancer.
▸ BLOOD CANCERS — leukaemia, lymphoma, myeloma
Leukaemias
Snapshot. Cancers of the white-cell line — split acute (aggressive, marrow fills with blasts → rapid failure) vs chronic (indolent, often found on a routine count). The genetics define the disease and the drug.
| Type | Snapshot & gist of treatment |
|---|
| AML (acute myeloid leukaemia) | Adults; rapid marrow failure (low counts, bleeding, infection). Intensive chemo ± stem-cell transplant; targeted agents for FLT3 / IDH (the defining mutations). |
| ALL (acute lymphoblastic leukaemia) | Mainly children (also adults). Multi-phase chemo + CNS (central nervous system) prophylaxis; Philadelphia-chromosome-positive → add a TKI (tyrosine kinase inhibitor). |
| CML (chronic myeloid leukaemia) | Driven by BCR-ABL (the Philadelphia-chromosome fusion gene). A TKI (imatinib etc.) turns it into a near-normal-lifespan chronic condition — the classic targeted-therapy success story. |
| CLL (chronic lymphocytic leukaemia) | Older adults, often indolent (found on a high lymphocyte count). Watch-and-wait if stable; treat with a BTK (Bruton tyrosine kinase) inhibitor (ibrutinib) or venetoclax when it progresses. |
Lymphomas
Snapshot. Cancers of lymph nodes / lymphocytes. Split Hodgkin vs non-Hodgkin; the diagnosis is on a lymph-node biopsy, and many are curable.
| Type | Snapshot |
|---|
| Hodgkin lymphoma | Young adults; Reed-Sternberg cells on biopsy; highly curable. Chemo (ABVD — a 4-drug regimen) ± radiotherapy. |
| Non-Hodgkin — DLBCL (diffuse large B-cell lymphoma) | Aggressive but curable; standard is R-CHOP (rituximab + chemo). |
| Non-Hodgkin — follicular | Indolent; long survival but generally not cured — treat when symptomatic. |
| Non-Hodgkin — marginal zone / MALT | Indolent, extranodal, antigen-driven (H. pylori, Chlamydia); often localized → radiotherapy. Full section below. |
Extranodal marginal-zone lymphoma (MALT lymphoma)
Snapshot. An indolent non-Hodgkin B-cell lymphoma arising in MALT (mucosa-associated lymphoid tissue) at extranodal sites, driven by chronic antigen stimulation — a long-running infection or autoimmune process keeps B cells proliferating until a clone emerges. Usually localized, excellent prognosis; a minority transform to DLBCL (diffuse large B-cell lymphoma).
Site → trigger (the pattern): stomach → H. pylori · ocular adnexa / orbit → Chlamydia psittaci · salivary gland → Sjögren · thyroid → Hashimoto · also lung, skin. Remove the trigger and early disease can regress.
Workup
Biopsy + immunohistochemistry (CD20+, CD5−, CD10−) ± flow cytometry; the t(11;18) translocation predicts non-response to antibiotics. Labs: CBC, LDH (lactate dehydrogenase), comprehensive metabolic panel, hepatitis B + C and HIV (human immunodeficiency virus) before rituximab. Staging: PET/CT (positron-emission tomography) or contrast CT + bone-marrow biopsy; site-specific tests — H. pylori (gastric), Chlamydia psittaci (ocular). Stage by Lugano — most are localized (stage IE–IIE).
Management (per NCCN)
| Setting | Treatment |
|---|
| Remove the trigger first | Gastric → H. pylori eradication (cures many early cases); ocular, Chlamydia-positive → doxycycline (selected). |
| Localized (IE–IIE) | ISRT (involved-site radiotherapy) ~24 Gy — standard, often curative. Ocular: ultra-low-dose 4 Gy / 2 fractions is an NCCN alternative (spares the lens / lacrimal gland). Rituximab if radiotherapy is contraindicated. |
| Advanced (III–IV) | Observe if asymptomatic; treat symptomatic disease with rituximab ± chemo (bendamustine-rituximab, R-CVP, R-CHOP) ± maintenance. |
| Relapsed / refractory | Re-biopsy (exclude DLBCL transformation) → BTK (Bruton tyrosine kinase) inhibitor (zanubrutinib), lenalidomide + rituximab, or local radiotherapy. |
Watch
Histology decides the pathway — if it's DLBCL, not MALT → R-CHOP × 6 ± radiotherapy, not this. t(11;18)-positive gastric MALT won't respond to H. pylori eradication → go to radiotherapy. Orbital radiotherapy → cataract / dry eye (why the ultra-low-dose schedule is attractive).
Plasma cell & marrow disorders
Snapshot. Disorders of the plasma cell (the myeloma family) and of failing marrow output — dysplastic (MDS) or empty (aplastic). (Over-producing marrow = the MPNs — see the Too-many-cells group.)
| Disease | Snapshot |
|---|
| Multiple myeloma | Malignant plasma cells. Remember CRAB: high Calcium, Renal failure, Anaemia, Bone lesions. Not curable but very treatable — proteasome inhibitor (bortezomib), IMiD (immunomodulatory drug — lenalidomide), anti-CD38 antibody (daratumumab) ± stem-cell transplant. |
| MGUS (monoclonal gammopathy of undetermined significance) | Pre-malignant abnormal protein, no symptoms → just monitor; small yearly risk of progressing to myeloma. |
| MDS (myelodysplastic syndrome) | Marrow failure + abnormal-looking cells in older adults; low counts, risk of evolving into AML. Supportive care, hypomethylating agents, or transplant. |
| Aplastic anaemia | Empty (hypocellular) marrow → pancytopenia (all three lines low); immune-mediated, can be triggered by drugs / hepatitis. Treatable: immunosuppression (ATG [anti-thymocyte globulin] + ciclosporin) or bone-marrow transplant. |
PART B · TOOLS OF THE TRADE
The everyday language of the heme clinic — the workup toolkit, the film, the clotting screen, thrombophilia testing, transfusion.
The diagnostic toolkit (the order you reach for things)
CBC (complete blood count) + differential — which line is off (red cells, white cells, platelets)? → blood film — eyeball the cells → for any blood cancer: bone marrow aspirate + trephine biopsy (the source) → flow cytometry (names the cell type by its surface markers) → cytogenetics + molecular (the mutations that define and prognosticate — BCR-ABL, JAK2, FLT3). In heme the genetics define the disease even more than in solid tumours.
Reading the blood film — what it answers
| Finding | Points to |
|---|
| Platelet clumps | Pseudothrombocytopenia (artefact) — recheck in citrate before working up "low platelets". |
| Schistocytes (fragmented red cells) | Microangiopathy — TTP / HUS / DIC. An emergency; check LDH, reticulocytes, coagulation. |
| Blasts | Acute leukaemia — urgent. |
| Hypersegmented neutrophils | B12 / folate deficiency (megaloblastic). |
Coagulation screen — what each test means
| Test | What it reflects |
|---|
| PT (prothrombin time) / INR (international normalised ratio) | Extrinsic + common pathway; INR is how warfarin is monitored. Raised in liver disease, warfarin, DIC. |
| APTT (activated partial thromboplastin time) | Intrinsic pathway; raised in haemophilia, heparin, lupus anticoagulant. |
| Fibrinogen | The clot substrate; falls in DIC. |
| D-dimer | A clot-breakdown product; sensitive not specific (a rule-out test, not rule-in). |
Thrombophilia / APS workup — when & what
When: unprovoked, young, recurrent, or unusual-site clots (not routine after a clearly provoked DVT). What: APS (antiphospholipid syndrome) — lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein-I; inherited — protein C, protein S, antithrombin, factor V Leiden, prothrombin gene. Timing trap: an acute clot + anticoagulation distort many of these assays — confirm positives after the acute phase / off treatment.
Transfusion thresholds (typical triggers)
| Product | Usual trigger |
|---|
| Red cells | Haemoglobin < 70 g/L (< 80 if cardiac); aim to relieve symptoms, not chase a number. |
| Platelets | < 10 ×10⁹/L prophylactic; < 20–50 if bleeding or pre-procedure. Avoid in TTP unless life-threatening bleeding. |
| Fresh frozen plasma / cryoprecipitate | Active bleeding with deranged coagulation / low fibrinogen (e.g. DIC). |
PART C · DRUG CLASSES & MECHANISMS
Each class: what it is, its MOA (mechanism of action), where it's used, and the toxicities that define it.
Cytopenias & haematinic support
Corticosteroids ± IVIG (intravenous immunoglobulin) prednisolone, dexamethasone; IVIG
MOA: damp the immune destruction of platelets (and red cells). IVIG floods the reticuloendothelial system → a rapid platelet rise when you need it fast.
Use: ITP (immune thrombocytopenia) first-line; IVIG when bleeding or before a procedure / surgery; also autoimmune haemolytic anaemia.
Toxicity: steroids — glucose, mood, infection, bone loss; IVIG — infusion reactions, rare thrombosis / renal impairment.
TPO (thrombopoietin) receptor agonists eltrombopag (oral), romiplostim (injection)
MOA: mimic thrombopoietin at its receptor → tell the marrow to make more platelets. Eltrombopag also boosts overall marrow recovery.
Use: ITP second-line; aplastic anaemia (eltrombopag, added to immunosuppression).
Toxicity: thrombosis, raised liver enzymes (eltrombopag), marrow fibrosis with long use.
G-CSF (granulocyte colony-stimulating factor) filgrastim, pegfilgrastim
MOA: stimulates neutrophil production and release from the marrow.
Use: neutropenia — prophylaxis if a regimen's febrile-neutropenia risk is high, or after an episode; mobilising stem cells before transplant.
Toxicity: bone pain, splenomegaly (rare rupture).
ESAs (erythropoiesis-stimulating agents) epoetin, darbepoetin
MOA: mimic erythropoietin → drive red-cell production.
Use: anaemia of chronic kidney disease or lower-risk MDS.
Toxicity: hypertension, thrombosis — don't over-correct the haemoglobin.
Iron — oral or intravenous ferrous sulfate (oral); ferric carboxymaltose, iron sucrose (IV [intravenous])
MOA: replenish iron stores for haemoglobin synthesis.
Use: IDA (iron-deficiency anaemia); IV when oral isn't tolerated / absorbed (e.g. a PEG [percutaneous endoscopic gastrostomy] feeding tube, gut disease), given as a total-dose course.
Toxicity: oral — constipation / GI upset; IV — rare infusion / hypersensitivity reactions, low phosphate.
B12 & folate replacement hydroxocobalamin; folic acid
MOA: replace the vitamin needed for DNA synthesis in red-cell precursors.
Use: macrocytic (megaloblastic) anaemia. Give B12 first / together — folate alone in B12 deficiency can precipitate neurological damage.
Toxicity: low potassium on rapid correction; always find the cause (pernicious anaemia, diet, malabsorption).
Anticoagulation
Anticoagulants DOACs — apixaban, rivaroxaban; warfarin; heparin / LMWH (low-molecular-weight heparin)
MOA: block the clotting cascade — DOACs (direct oral anticoagulants) inhibit factor Xa or thrombin directly; warfarin blocks vitamin-K-dependent factors (monitored by INR); heparin / LMWH potentiate antithrombin.
Use: VTE (venous thromboembolism) and atrial fibrillation. DOACs first-line for most; warfarin if APS (antiphospholipid syndrome); LMWH in pregnancy and much cancer-associated thrombosis.
Toxicity: bleeding (the universal class effect). Reversal: vitamin K / prothrombin complex (warfarin), andexanet / idarucizumab (DOACs), protamine (heparin).
Marrow failure & myeloproliferation
Immunosuppression for marrow failure ATG (anti-thymocyte globulin) + ciclosporin
MOA: switch off the immune attack on the marrow so it can recover.
Use: aplastic anaemia — the alternative to bone-marrow transplant (often paired with eltrombopag).
Toxicity: infection, serum sickness (ATG); ciclosporin — renal impairment, hypertension, tremor.
Hydroxyurea (hydroxycarbamide) hydroxyurea
MOA: inhibits ribonucleotide reductase → lowers cell production; raises fetal haemoglobin in sickle cell.
Use: MPN (myeloproliferative neoplasm) — PV / ET to lower counts and clot risk; sickle-cell disease.
Toxicity: myelosuppression, mouth / leg ulcers, skin changes.
Blood-cancer targeted agents
BCR-ABL TKIs (tyrosine kinase inhibitors) imatinib, dasatinib, nilotinib
MOA: block the BCR-ABL kinase (the Philadelphia-chromosome driver) → switch off the leukaemic signal.
Use: CML (chronic myeloid leukaemia) — near-normal lifespan; Philadelphia-positive ALL.
Toxicity: cytopenias, fluid retention / pleural effusion (dasatinib), QTc (corrected QT interval) prolongation, vascular events (nilotinib).
BTK (Bruton tyrosine kinase) inhibitor ibrutinib, acalabrutinib
MOA: block Bruton tyrosine kinase, a B-cell survival signal.
Use: CLL (chronic lymphocytic leukaemia), mantle-cell lymphoma.
Toxicity: bleeding, atrial fibrillation, hypertension, infections.
BCL-2 (B-cell lymphoma-2) inhibitor venetoclax
MOA: block the anti-apoptotic protein BCL-2 → restore apoptosis (the cell's self-destruct).
Use: CLL; AML (acute myeloid leukaemia) in the unfit, with a hypomethylating agent.
Toxicity: TLS (tumour-lysis syndrome) — slow ramp-up dosing + hydration; neutropenia.
Anti-CD20 monoclonal antibody rituximab
MOA: binds CD20 on B cells → depletes them (the "R" in R-CHOP).
Use: B-cell lymphomas (DLBCL, follicular), CLL, and autoimmune disease.
Toxicity: infusion reactions, hepatitis B reactivation (screen first), infections.
Hypomethylating agents azacitidine, decitabine
MOA: demethylate DNA → re-activate silenced genes in the malignant clone.
Use: MDS (myelodysplastic syndrome); AML in patients unfit for intensive chemo.
Toxicity: cytopenias, injection-site reactions.
JAK (Janus kinase) inhibitor ruxolitinib
MOA: block the JAK signalling that drives the myeloproliferative clone.
Use: myelofibrosis (and polycythaemia vera) — shrinks the spleen, eases symptoms.
Toxicity: cytopenias, infections (including viral reactivation).
Myeloma agents bortezomib (proteasome inhibitor), lenalidomide (IMiD — immunomodulatory drug), daratumumab (anti-CD38)
MOA: three different attacks on the plasma cell — block protein recycling (proteasome), modulate the immune microenvironment (IMiD), target CD38 (antibody).
Use: multiple myeloma, in combination ± stem-cell transplant.
Toxicity: peripheral neuropathy (bortezomib), clots (IMiDs — give prophylaxis), infusion reactions + infection (daratumumab).
Gene therapy
Gene therapy for haemophilia B etranacogene dezaparvovec (Hemgenix)
MOA: a one-time intravenous AAV (adeno-associated virus) carrying a high-activity factor IX gene → delivered to the liver → the patient makes their own clotting factor (full trial in Part E).
Use: haemophilia B (factor IX deficiency) — replacing lifelong factor infusions with a single dose.
Toxicity: liver-enzyme (ALT [alanine aminotransferase]) rise in ~17% — treated with a steroid course.
PART D · CASE LIST
| Who | Diagnosis | Treatment / status | Next | To confirm ⚠ |
|---|
| 20M (cerebral palsy, PEG) | Iron-deficiency anaemia | IV iron course (weekly ×5; IV because of the feeding tube). Genetics found an LMNB1 variant | Complete course | Clarify the LMNB1↔lymphoma link (not established); CT/MRI showed no nodes — reassuring |
| Young F | Easy / spontaneous bruising, no mucosal bleed | Broad workup: platelet count + function, coagulation, autoimmune / vasculitis, rare platelet disorders | Results review | Simple easy bruising vs VWD; ask heavy periods + family history; avoid aspirin / NSAIDs (non-steroidal anti-inflammatory drugs) |
| M | Hepatitis B — "antibody positive" | Interpreting the serology | Full panel | HBsAg + anti-HBc + anti-HBs to place him: vaccinated vs past infection vs active |
| Smaah, 47F (seronegative RA [rheumatoid arthritis]) | Recurrent right-leg DVT; post-thrombotic pooling | On warfarin → stopped → re-clotted. Protein C/S + antithrombin normal, lupus anticoagulant negative, genetics not done. First DVT travel-provoked | Decide duration | Finish APS antibodies; were the recurrences travel-related? → lifelong vs situational prophylaxis; vascular review for a local vein cause |
| Abir | Hepatitis C cirrhosis + aplastic anaemia (empty marrow) | For liver transplant AND marrow transplant; on warfarin | Transplant workup | Fitness / sequencing; ?hepatitis-associated aplastic anaemia; anticoagulation tightrope in cirrhosis |
| Sudanese M | Sarcoidosis; ?lymphoma; incidental situs inversus totalis | Bone marrow biopsy NORMAL → confirms sarcoid, excludes lymphoma → case report | Collect for paper | Consent + de-identified data + chest image; screen for primary ciliary dyskinesia |
| M (mid-age, on a BP drug) | Isolated thrombocytopenia, otherwise well | Secondary-cause bloods sent (film, coagulation, viral, autoimmune, B12 / folate) | Results review | Exclude clumping (film), TTP / DIC, drug, viral, lupus → likely ITP (a diagnosis of exclusion) |
| F (orbital mass) | Extranodal marginal-zone (MALT) lymphoma — ocular adnexal / retro-orbital, biopsy-confirmed | Indolent B-cell lymphoma; staging in progress | Stage → treat | PET/CT + marrow + hep B/C/HIV + Chlamydia psittaci; localized → ISRT (24 Gy, or 4 Gy ocular); confirm it's MALT not DLBCL |
| F (dimorphic) | Mixed anaemia — low iron and low intrinsic factor; doctor queried thalassaemia | Iron deficiency + ?pernicious; MCV may read falsely normal (dimorphic) | Confirm each cause | Ferritin; Hb electrophoresis after iron repletion (HbA2 for β-thal); B12 + intrinsic-factor / parietal antibodies; Mentzer index; treat iron + IM B12 |
| F (bleeding) | Iron-deficiency anaemia (low ferritin) + ?bleeding disorder; ?factor V deficiency | ?menorrhagia as the iron-loss source; bleeding-disorder workup | Coag + bleeding workup | PT / APTT pattern; VWF antigen + activity (rule out VWD first); factor V assay; replace iron + tranexamic acid. NB factor V deficiency ≠ factor V Leiden |
| F (multisystem) | Thyroid nodule + breast lump + hypersalivation + ?seizure | ?one process — granulomatous (sarcoid) vs IgG4 vs Cowden vs separate problems | Biopsy + image | Thyroid US + FNA; breast triple assessment; MRI brain + EEG; sarcoid screen (ACE, calcium, CXR) + IgG4, exclude TB; screen Cowden / PTEN (family hx, macrocephaly, skin) |
PART E · LITERATURE REVIEWED
Key papers studied — the trial behind the practice.
Gene therapy for haemophilia B — HOPE-B 5-year final analysis (NEJM, 2025)
The drug: etranacogene dezaparvovec (Hemgenix) — a one-time IV gene therapy: an AAV5 virus carrying a high-activity ("Padua") factor IX gene → delivered to the liver → the patient's liver makes its own factor IX. Why it matters: haemophilia B (factor IX deficiency) normally needs lifelong factor infusions; this aims to fix it with a single dose.
| Outcome (over 5 years) | Result |
|---|
| Factor IX activity | Sustained ~41% (year 1) → ~36% (year 5) — turns "severe" into "mild" |
| Bleeding | ↓ ~90% (annualised bleeding 4.16 → 0.40); joint & spontaneous bleeds ↓ >90% |
| Off prophylaxis | 94% stayed completely off their regular factor infusions (only 1 restarted) |
| Safety | Main issue = liver-enzyme (ALT) rise in ~17%, treated with a steroid course; no serious treatment-related events; one suspected MDS reclassified as unrelated |
Take-home: approved (FDA 2022); a shift toward one-and-done treatment — durable and safe to 5 years. Not yet the universal standard (~$3.5M cost + eligibility limits keep it a selective option); standard factor prophylaxis remains the mainstay. Notably, pre-existing AAV5 neutralising antibodies mostly did not block the response (except at very high titre).
PART F · ABBREVIATION KEY
AAV — adeno-associated virus (gene-therapy vector)
ABVD — Hodgkin chemo regimen (4 drugs)
ADAMTS13 — the protease deficient in TTP
AIHA — autoimmune haemolytic anaemia
ALL — acute lymphoblastic leukaemia
ALT — alanine aminotransferase (liver enzyme)
AML — acute myeloid leukaemia
ANA — antinuclear antibody (autoimmune / lupus screen)
anti-HBc / anti-HBs / HBsAg — hepatitis B core antibody / surface antibody / surface antigen
APS — antiphospholipid syndrome
APTT — activated partial thromboplastin time
ATG — anti-thymocyte globulin
BCL-2 — B-cell lymphoma-2 (apoptosis protein)
BCR-ABL — the Philadelphia-chromosome fusion gene (CML)
BP — blood pressure
BTK — Bruton tyrosine kinase
CALR / MPL — MPN driver mutations (alongside JAK2)
CBC — complete blood count
CKD — chronic kidney disease
CLL — chronic lymphocytic leukaemia
CML — chronic myeloid leukaemia
CNS — central nervous system
CRAB — calcium / renal / anaemia / bone (myeloma)
CRP — C-reactive protein (inflammation)
DAT — direct antiglobulin test (Coombs)
DDAVP — desmopressin (releases von Willebrand factor)
DIC — disseminated intravascular coagulation
DLBCL — diffuse large B-cell lymphoma
DOAC — direct oral anticoagulant
DVT — deep-vein thrombosis
EBV — Epstein-Barr virus
EDTA — standard blood-tube anticoagulant (clumping artefact)
EPO — erythropoietin
ESA — erythropoiesis-stimulating agent (epoetin)
ESR — erythrocyte sedimentation rate (inflammation)
ET — essential thrombocythaemia
FLT3 / IDH — defining AML mutations
G-CSF — granulocyte colony-stimulating factor (filgrastim)
G6PD — glucose-6-phosphate dehydrogenase
GI — gastrointestinal
HbA2 — haemoglobin A2 (raised in β-thalassaemia trait)
HbH — haemoglobin H (α-thalassaemia)
HIT — heparin-induced thrombocytopenia
HIV — human immunodeficiency virus
HPLC — high-performance liquid chromatography (haemoglobin analysis)
HUS — haemolytic uraemic syndrome
IBD — inflammatory bowel disease
IDA — iron-deficiency anaemia
IMiD — immunomodulatory drug (lenalidomide)
INR — international normalised ratio (warfarin)
ISRT — involved-site radiotherapy
ITP — immune thrombocytopenia
IV — intravenous
IVIG — intravenous immunoglobulin
JAK / JAK2 — Janus kinase / its driver mutation (MPN)
LDH — lactate dehydrogenase
LMWH — low-molecular-weight heparin
MALT — mucosa-associated lymphoid tissue (lymphoma)
MCV — mean cell volume (red-cell size)
MDS — myelodysplastic syndrome
MF — myelofibrosis
MGUS — monoclonal gammopathy of undetermined significance
MPN — myeloproliferative neoplasm
NSAID — non-steroidal anti-inflammatory drug
PE — pulmonary embolism
PEG — percutaneous endoscopic gastrostomy (feeding tube)
PET — positron-emission tomography
PNH — paroxysmal nocturnal haemoglobinuria
PPI — proton-pump inhibitor
PT — prothrombin time
PV — polycythaemia vera
QTc — corrected QT interval (ECG)
RA — rheumatoid arthritis
RBC — red-cell count
RDW — red-cell distribution width (size variation)
R-CHOP — rituximab + chemo (lymphoma)
TIBC — total iron-binding capacity
TKI — tyrosine kinase inhibitor
TLS — tumour-lysis syndrome
TPO — thrombopoietin (receptor agonist)
TTP — thrombotic thrombocytopenic purpura
VTE — venous thromboembolism
VWD — von Willebrand disease
VWF — von Willebrand factor