HAEMATOLOGY

Comprehensive Study Notes

Anaemia · Polycythaemia · Haemoglobinopathies · Leukaemia

Lymphoma · Myeloma · Coagulation · Blood Groups

Everything you need — explained clearly, completely.

 1. ANAEMIA

Definition
Anaemia is defined as a reduction in haemoglobin (Hb) concentration below the normal range for the
patient's age and sex, leading to reduced oxygen-carrying capacity of the blood. It is a symptom, not a
diagnosis — the underlying cause must always be found.

Normal Haematological Values

Parameter Adult Male Adult Female Children (approx.)

Haemoglobin (Hb) 13.5 – 17.5 g/dL 11.5 – 15.5 g/dL 11.0 – 16.0 g/dL

RBC Count 4.5 – 5.5 × 10¹²/L 3.8 – 4.8 × 10¹²/L 3.8 – 5.2 × 10¹²/L

Haematocrit/PCV 40 – 52% 36 – 48% 35 – 45%

Remember: Hb values vary slightly between laboratories. The key is knowing that Males > Females
due to the effect of androgens stimulating erythropoiesis, and females lose iron monthly through
menstruation.

Classification of Anaemia

A. By MCV (Red Cell Size) — Most Clinically Useful

Type MCV Key Causes

Microcytic (small cells) < 80 fL Iron deficiency, Thalassaemia, Sideroblastic anaemia,

Anaemia of chronic disease (sometimes)

Normocytic (normal size) 80 – 100 fL Acute blood loss, Haemolytic anaemia, Aplastic anaemia,
Renal failure, Early mixed deficiency

Macrocytic (large cells) > 100 fL B12 deficiency, Folate deficiency, Liver disease,
Hypothyroidism, Drugs (methotrexate, hydroxyurea)

B. By Pathophysiological Mechanism
1. Decreased RBC Production (Hypoproliferative)

• Iron deficiency — most common worldwide; inadequate dietary intake, chronic blood loss (GI bleed,
heavy menstruation), malabsorption
• Megaloblastic anaemia — deficiency of Vitamin B12 or Folate impairs DNA synthesis; RBCs are large
and immature (megaloblasts)
 • Aplastic anaemia — bone marrow failure; all cell lines reduced (pancytopenia); causes include
autoimmune destruction, radiation, chemicals
• Anaemia of chronic disease — inflammatory cytokines suppress erythropoietin and iron utilisation;
seen in TB, rheumatoid arthritis, malignancy
• Renal anaemia — kidneys produce insufficient erythropoietin (EPO)
2. Increased RBC Destruction (Haemolytic Anaemia)

RBCs are destroyed faster than the marrow can replace them. Evidence includes raised bilirubin
(jaundice), raised LDH, reduced haptoglobin, reticulocytosis.

• Intrinsic (inside the cell): Sickle cell disease, Thalassaemia, G6PD deficiency, Hereditary
spherocytosis
• Extrinsic (outside the cell): Autoimmune haemolysis, Malaria, Mechanical heart valves, Transfusion
reactions
3. Blood Loss

• Acute: trauma, surgery, ruptured ectopic pregnancy

• Chronic: peptic ulcer, hookworm infestation, heavy menstrual bleeding

Clinical Features of Anaemia

Symptoms and signs arise from tissue hypoxia and compensatory mechanisms:

System Features

General Fatigue, weakness, pallor (conjunctiva, palm, nail beds, tongue)

Cardiovascular Palpitations, tachycardia, dyspnoea on exertion, angina (if pre-existing

IHD), high-output cardiac failure if severe

CNS Headache, dizziness, tinnitus, fainting, difficulty concentrating

Specific to Iron Deficiency Koilonychia (spoon nails), angular stomatitis, glossitis, dysphagia
(Plummer–Vinson syndrome), pica

Specific to B12 Deficiency Subacute combined degeneration of spinal cord: peripheral neuropathy,
ataxia, loss of proprioception
 2. POLYCYTHAEMIA (Erythrocytosis)

Polycythaemia is an increase in the total red cell mass, resulting in elevated Hb (>17.5 g/dL in males;
>15.5 g/dL in females) and raised haematocrit (>52% M, >48% F). Blood becomes viscous, increasing the
risk of thrombosis.

Primary Polycythaemia (Polycythaemia Vera — PV)

This is a myeloproliferative neoplasm — a clonal disorder of a bone marrow stem cell that autonomously
overproduces RBCs (and often platelets and WBCs too), independent of erythropoietin.

• Cause: Mutation in the JAK2 gene (JAK2 V617F) found in >95% of cases — this is the hallmark of PV
• EPO level: LOW or undetectable (the marrow does not need the signal — it produces on its own)
• Features: Plethoric (red) face, hypertension, splenomegaly, pruritus (especially after hot bath — due
to histamine from excess basophils), headache, thrombosis (stroke, DVT, PE, Budd-Chiari syndrome)
• Treatment: Venesection (phlebotomy), low-dose aspirin, hydroxyurea, JAK inhibitors (ruxolitinib)

Secondary Polycythaemia
Excess RBC production is a physiological or pathological response to elevated EPO. The bone
marrow is normal but being driven harder.

Cause Mechanism

High altitude living Chronic hypoxia → kidney senses low O■ → secretes more EPO
→ more RBCs

Chronic lung disease (COPD, Persistent hypoxaemia stimulates EPO

fibrosis)

Cyanotic congenital heart disease Right-to-left shunt → chronic hypoxaemia → compensatory

erythrocytosis

Obstructive sleep apnoea Intermittent nocturnal hypoxia stimulates EPO

Renal cell carcinoma / renal cysts Inappropriate (non-physiological) EPO secretion by tumour

Hepatocellular carcinoma Ectopic EPO production

Smoking (carboxyhaemoglobin) CO binds Hb → reduces O■ delivery → EPO rises

Key Distinction: In PRIMARY (PV) — EPO is LOW. In SECONDARY — EPO is HIGH. This single
test distinguishes the two.
 3. HAEMOGLOBINOPATHIES

Haemoglobinopathies are inherited (genetic) disorders affecting the structure or production of

haemoglobin. Normal adult haemoglobin (HbA) consists of two alpha (α) and two beta (β) globin chains.
Mutations in these chains cause disease.

Common Abnormal Haemoglobins

Haemoglobin Mutation Clinical Significance

HbS Glutamic acid → Valine at position 6 of Causes Sickle Cell Disease; polymerises
β-chain under low O■

HbC Glutamic acid → Lysine at position 6 of Milder haemolysis; HbCC mild, HbSC
β-chain moderate sickling

HbE Glutamic acid → Lysine at position 26 of Common in SE Asia; HbEE is mild;

β-chain HbE/β-thalassaemia can be severe

SICKLE CELL DISEASE (HbSS)

Genetics
Autosomal recessive. Both parents carry the HbS gene. If both parents are carriers (HbAS trait), each
pregnancy has a 25% chance of HbSS (disease), 50% HbAS (trait), 25% HbAA (normal).

Pathophysiology
• HbS is structurally abnormal — under conditions of low O■, acidosis, dehydration, or cold, HbS
molecules polymerise into long rigid fibres
• These fibres distort the RBC into the characteristic sickle (crescent) shape
• Sickled cells are: (1) rigid and inflexible — they block small vessels (vaso-occlusion causing painful
crises), (2) fragile — they haemolyse rapidly (haemolytic anaemia), and (3) recognised as abnormal —
removed by the spleen (leading to functional hyposplenism)
• Repeated splenic infarction from sickling eventually destroys the spleen (auto-splenectomy) →
patient is susceptible to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae,
Neisseria meningitidis)

Clinical Manifestations

Crisis/Complication Explanation

Vaso-occlusive (Painful) Crisis Sickled cells block capillaries → ischaemia → severe

bone/joint/chest/abdominal pain. Triggered by infection, dehydration,
cold, hypoxia
Crisis/Complication Explanation

Acute Chest Syndrome Vaso-occlusion in pulmonary vasculature + infection → fever, chest

pain, hypoxia; life-threatening

Stroke Cerebrovascular occlusion → common in children with HbSS

Splenic Sequestration Sudden massive pooling of blood in spleen → acute severe anaemia,
shock (especially in young children)

Aplastic Crisis Parvovirus B19 infects erythroid precursors → sudden drop in RBC
production → severe anaemia

Haemolytic Crisis Accelerated RBC destruction → worsening anaemia, jaundice

Chronic Organ Damage Avascular necrosis of femoral head, retinopathy, renal failure, leg
ulcers, priapism

Management of Sickle Cell Disease

1. Proper Hydration

Dehydration raises the concentration of HbS within the red cell, accelerating polymerisation and sickling.
Patients must maintain excellent oral hydration daily and receive IV fluids during crises. Adequate
hydration reduces blood viscosity and dilutes HbS concentration, directly reducing sickling episodes.

2. Hydroxyurea (Hydroxycarbamide)

The most important disease-modifying drug in sickle cell disease. Hydroxyurea is a cytotoxic agent that
works by reactivating fetal haemoglobin (HbF) production. HbF does not sickle and when present in
significant amounts, dilutes HbS within the red cell, reducing polymerisation. Benefits include: reduced
frequency and severity of painful crises, reduced acute chest syndrome, reduced hospitalisation, possible
reduction in stroke risk, and improved survival. It also has mild myelosuppressive effects so blood counts
must be monitored.

3. Blood Transfusion

• Simple transfusion: raises Hb and improves O■ delivery — used in aplastic crisis, severe anaemia,
pre-operatively
• Exchange transfusion: patient's HbSS blood is replaced with HbA donor blood — reduces HbS% —
used in acute chest syndrome, stroke, priapism, before major surgery
• Regular transfusion: children with high stroke risk (detected on Transcranial Doppler) receive monthly
transfusions to keep HbS < 30%
• Risk: iron overload with chronic transfusion — needs chelation therapy (desferrioxamine or
deferasirox)
4. Bone Marrow (Haematopoietic Stem Cell) Transplant

The only curative treatment. Diseased stem cells are destroyed with chemotherapy/radiotherapy
(conditioning) and replaced with healthy donor stem cells (from an HLA-matched sibling ideally). The
donor's stem cells repopulate the marrow and produce normal HbA. Limitations include the need for a
compatible donor, risk of graft-versus-host disease, treatment-related mortality, and high cost. Increasingly
successful in children; gene therapy trials are ongoing.

Other Supportive Measures

• Folic acid supplementation — increased red cell turnover means increased folate demand
• Penicillin V prophylaxis — for life in asplenic patients to prevent pneumococcal sepsis
• Vaccinations — pneumococcal, Hib, meningococcal, flu vaccine
• Analgesia during crises — NSAIDs, opioids (morphine), warmth, rest
• Avoid triggers — cold, dehydration, high altitude, excessive exercise, infection
 4. LEUKAEMIA

Leukaemia is a malignant clonal proliferation of haematopoietic (blood-forming) cells in the bone

marrow. Abnormal cells accumulate and crowd out normal blood cell production, leading to anaemia,
bleeding, and infection.

Classification
Type Cell of Origin Onset / Key Feature

Acute Lymphoblastic Lymphoid precursor Most common childhood cancer;

Leukaemia (ALL) (lymphoblast) responds well to chemo

Acute Myeloid Leukaemia Myeloid precursor More common in adults; aggressive; Auer
(AML) (myeloblast) rods on smear

Chronic Lymphocytic Mature B lymphocyte Most common adult leukaemia; indolent;

Leukaemia (CLL) smudge cells on smear

Chronic Myeloid Leukaemia Myeloid stem cell Philadelphia chromosome t(9;22);

(CML) BCR-ABL gene; imatinib is treatment

Clinical Features (General)

• Anaemia (↓RBC) — fatigue, pallor, dyspnoea
• Infections (↓functional WBCs) — fever, recurrent/unusual infections
• Bleeding / bruising (↓platelets / thrombocytopenia) — petechiae, purpura, mucosal bleeds
• Organomegaly — hepatomegaly, splenomegaly, lymphadenopathy
• Bone pain — marrow expansion
• Hyperviscosity symptoms in very high WBC counts — headache, visual disturbance

Diagnosis requires bone marrow biopsy and immunophenotyping (flow cytometry) to classify the
exact type. The full blood count (FBC) will show anaemia, thrombocytopenia, and markedly
elevated WBC with many blast cells.
 5. LYMPHOMA

Lymphomas are malignancies of lymphocytes (B cells, T cells, or NK cells) that typically arise in lymph
nodes but can involve any organ with lymphoid tissue. Unlike leukaemia (primarily bone marrow/blood),
lymphomas form solid tumour masses.

Hodgkin Lymphoma (HL)

Feature Detail

Hallmark cell Reed–Sternberg (RS) cell — large binucleated cell with prominent
'owl-eye' nucleoli; derived from B cells; essential for diagnosis

Typical age Bimodal: young adults (15–35) and elderly (>55); relatively rare

Presentation Painless cervical or supraclavicular lymphadenopathy, B symptoms (fever

>38°C, drenching night sweats, >10% weight loss in 6 months),
mediastinal mass

Alcohol-induced pain Classic but uncommon: alcohol causes pain at the site of lymph node
involvement — highly specific for HL

Spread Orderly, contiguous spread node-to-node (unlike NHL)

Staging Ann Arbor staging I–IV

Treatment Highly curable — ABVD chemotherapy ± radiotherapy; >85% cure rate in

early stages

Non-Hodgkin Lymphoma (NHL)

NHL is a heterogeneous group of >60 different lymphoid malignancies. Most are B-cell origin (85%).
Spread is non-contiguous (skips lymph node stations). More common than HL.

Feature Detail

Common types Diffuse Large B-Cell Lymphoma (DLBCL) — most common aggressive;
Follicular Lymphoma — most common indolent; Burkitt Lymphoma; Mantle
Cell Lymphoma; T-cell lymphomas

Presentation Lymphadenopathy (non-tender), systemic B symptoms, extranodal disease

(GI tract, skin, brain, bone marrow)

Associations EBV (Burkitt, post-transplant), H. pylori (gastric MALT), HIV (primary CNS
lymphoma), HTLV-1 (T-cell lymphoma)
Feature Detail

Treatment Depends on subtype: R-CHOP (rituximab + chemotherapy) for DLBCL;

watch-and-wait for indolent follicular; stem cell transplant for relapsed
disease

Key Difference — HL vs NHL: • HL: RS cells present, orderly spread, younger patients, usually
curable • NHL: No RS cells, non-contiguous spread, older patients, more variable prognosis
 6. MULTIPLE MYELOMA

Multiple myeloma is a malignancy of plasma cells (terminally differentiated B lymphocytes that normally
produce antibodies). Malignant plasma cells accumulate in the bone marrow and secrete a monoclonal
immunoglobulin (M protein or paraprotein), causing widespread organ damage.

Pathophysiology
Abnormal plasma cells secrete large amounts of one type of immunoglobulin (most commonly IgG or IgA).
They also secrete cytokines that activate osteoclasts, causing bone destruction. Normal antibody
production is suppressed (immunoparesis), leaving the patient vulnerable to infections.

Clinical Features — CRAB Criteria

CRAB Feature Mechanism

C Hypercalcaemia Osteoclast activation breaks down bone → calcium released into

blood → nausea, vomiting, confusion, constipation, polyuria

R Renal failure Light chains (Bence Jones proteins) damage tubules;

hypercalcaemia; amyloid deposition; recurrent infections

A Anaemia Marrow infiltration by plasma cells crowds out normal erythropoiesis

B Bone pain / Bone lesions Osteolytic (punched-out) lesions on X-ray — skull, spine, ribs, long
bones; pathological fractures; spinal cord compression

Additional features: Recurrent bacterial infections (immunosuppression), hyperviscosity syndrome

(headache, visual changes, bleeding — due to excess paraprotein), peripheral neuropathy.

Diagnosis: Serum protein electrophoresis (M spike), bone marrow biopsy (>10% plasma cells), skeletal
survey X-rays, urine for Bence Jones proteins.

Treatment: Not usually curable. Chemotherapy (bortezomib-based regimens), autologous stem cell
transplant in eligible patients, bisphosphonates (to protect bone), novel agents (thalidomide, lenalidomide,
daratumumab).
 7. PLATELETS & COAGULATION

Platelets
• Normal platelet count: 150,000 – 400,000 per µL (150–400 × 10■/L)
• Produced by megakaryocytes in the bone marrow
• Role in primary haemostasis: adhere to damaged vessel wall (via vWF), then aggregate to form a
platelet plug (primary clot)
• Thrombocytopenia: < 150 × 10■/L — risk of spontaneous bleeding below 20 × 10■/L
• Thrombocytosis: > 400 × 10■/L — risk of thrombosis

Bleeding Time vs Clotting Time

Parameter Bleeding Time (BT) Clotting Time (CT)

Definition Time for bleeding to stop from a Time for blood to clot in a glass tube
standardised small skin puncture after collection

Normal Range 2 – 7 minutes (Duke method: 4 – 10 minutes (Lee–White method in

earlobe/fingertip) glass tube)

What it tests Primary haemostasis — platelet Secondary haemostasis — the

function and vessel integrity coagulation cascade (clotting factors)

Prolonged by Thrombocytopenia, platelet function Clotting factor deficiencies

disorders (e.g. vWD, aspirin use), (haemophilia), liver disease,
vascular disorders anticoagulant drugs (heparin,
warfarin), DIC

Clinical use Assesses platelet plug formation Assesses clotting factor activity;
largely replaced by APTT and PT

Important distinction: Bleeding time reflects platelet + vessel function (primary haemostasis).
Clotting time reflects coagulation factor function (secondary haemostasis). A patient can have
prolonged CT with a normal BT (haemophilia) or prolonged BT with normal CT (aspirin therapy).

Why is Fibrinogen NOT a Serum Protein?

This is a classic question. Serum is the fluid that remains after blood has clotted and the clot has been
removed. During clotting, thrombin converts fibrinogen → fibrin. Fibrin forms the structural mesh of the
clot. When the clot is removed, fibrinogen has been consumed in forming the clot — so it is absent from
serum.
Plasma, on the other hand, is obtained by preventing clotting (using anticoagulants such as EDTA or
citrate) before the blood cells are spun down. Because clotting never occurred, fibrinogen is still present in
plasma.

Memory trick: Plasma = blood without cells (clotting prevented) → CONTAINS fibrinogen Serum =
plasma without clotting factors (clot formed and removed) → NO fibrinogen

Causes of Prolonged Bleeding Time

1. Thrombocytopenia (reduced platelet count)

Fewer platelets means the primary platelet plug forms inadequately or not at all. Causes of
thrombocytopenia:

• Decreased production: aplastic anaemia, bone marrow infiltration (leukaemia, lymphoma, myeloma),
megaloblastic anaemia, viral infections (HIV, EBV)
• Increased destruction: Immune Thrombocytopenic Purpura (ITP) — antibodies destroy platelets;
Thrombotic Thrombocytopenic Purpura (TTP); DIC; drug-induced (heparin-induced thrombocytopenia
— HIT; quinine)
• Sequestration: hypersplenism — spleen sequesters and destroys platelets
2. Thrombocytosis — Paradoxically, extreme thrombocytosis (>1000 × 10■/L) can also cause
bleeding!

At very high platelet counts, abnormal platelet function can occur, and large multimers of von Willebrand
factor (vWF) are absorbed onto the excess platelets and degraded, causing acquired vWD and thus a
bleeding tendency despite a high count.

3. Platelet Function Disorders

• Von Willebrand Disease (vWD) — most common inherited bleeding disorder; vWF is needed for
platelet adhesion; its deficiency → prolonged BT
• Aspirin/NSAIDs — inhibit COX → reduce thromboxane A■ → impair platelet aggregation
• Glanzmann's thrombasthenia — absent GPIIb/IIIa receptor → platelets cannot aggregate
• Bernard–Soulier syndrome — absent GPIb receptor → platelets cannot adhere to vWF
• Uraemia — uraemic toxins impair platelet function

Causes of Prolonged Clotting Time

Clotting time is prolonged when coagulation factors are deficient or inhibited:

• Haemophilia A (Factor VIII deficiency) or B (Factor IX deficiency)

• Liver disease — most coagulation factors are synthesised in the liver; liver failure → reduced
production
• Vitamin K deficiency — Factors II, VII, IX, X, and Proteins C & S are vitamin K-dependent; deficiency
(malnutrition, malabsorption, warfarin therapy) → prolonged clotting
• Disseminated Intravascular Coagulation (DIC) — massive consumption of clotting factors
 • Anticoagulant therapy — heparin (inhibits thrombin and Factor Xa), warfarin (inhibits vitamin
K-dependent factors), direct oral anticoagulants (DOACs)
• Massive transfusion — dilution of clotting factors with stored blood (which is deficient in factors)

Can Liver Disease Affect Bleeding/Clotting? — YES, Both!

The liver is the factory for haemostasis. Liver disease affects coagulation in multiple ways:

Effect Mechanism

↓ Clotting factors Liver synthesises Factors I, II, V, VII, VIII (partly), IX, X, XI, XII — liver
failure → reduced production → prolonged PT and APTT

↓ Vitamin K factors Liver is necessary for vitamin K utilisation and activation of factors II, VII,
IX, X

↓ Fibrinogen Reduced synthesis → less fibrin clot formation → prolonged PT, BT, and
CT

Thrombocytopenia Portal hypertension → splenomegaly → hypersplenism → platelet

sequestration in spleen → low platelet count → prolonged BT

↓ Anticoagulant proteins Liver also makes Protein C, Protein S, and antithrombin — their reduction
can paradoxically cause thrombosis

Dysfibrinogenaemia Abnormal fibrinogen structure impairs clot formation

NET RESULT: Liver disease typically causes a BLEEDING tendency — patients can have bruising,
GI bleeding (varices), and clotting studies are often deranged. The PT is the most sensitive
indicator of liver synthetic function.
 8. HAEMOPHILIA

Haemophilia is an X-linked recessive inherited bleeding disorder caused by deficiency of a specific

clotting factor. Because it is X-linked, it almost exclusively affects males (XY). Females with one defective
X chromosome are carriers (usually asymptomatic) and can pass the gene to sons.

Feature Haemophilia A Haemophilia B Haemophilia C

Deficient Factor Factor VIII (8) Factor IX (9) Factor XI (11)

Inheritance X-linked recessive X-linked recessive Autosomal recessive

(affects both sexes
equally)

Prevalence 1 in 5,000 males; most 1 in 30,000 males; also Rare; more common
common called Christmas disease in Ashkenazi Jews

Affected test APTT prolonged; PT APTT prolonged; PT APTT prolonged; PT

normal normal normal

Severity classification Mild >5%, Moderate Same classification Generally milder

1–5%, Severe <1% applies bleeding
Factor VIII activity

Treatment Recombinant Factor VIII Recombinant Factor IX Fresh Frozen Plasma

concentrate; concentrate (FFP); Factor XI
desmopressin (DDAVP) concentrate
in mild cases

Clinical Features of Haemophilia A & B

• Haemarthrosis (bleeding into joints — knee, elbow, ankle) — the hallmark; leads to joint damage and
arthropathy over time
• Deep muscle haematomas — particularly iliopsoas muscle, which can compress the femoral nerve
• Prolonged bleeding after cuts, dental extractions, or surgery
• Intracranial haemorrhage — serious complication even from minor head trauma
• No petechiae or purpura (these are platelet disorders); no prolonged bleeding time (platelets are
normal)

Key point: In haemophilia, the PRIMARY platelet plug forms normally (BT normal, platelet count
normal). The problem is in SECONDARY haemostasis — the clot cannot be properly reinforced by
fibrin because of the missing factor. Hence APTT is prolonged but PT is normal (APTT tests the
intrinsic pathway where VIII and IX operate).
 9. BLOOD GROUPING & RHESUS SYSTEM

ABO Blood Group System

Discovered by Karl Landsteiner (1901). Blood group is determined by the presence or absence of
antigens (agglutinogens) on the RBC surface, and naturally occurring antibodies (agglutinins) in the
plasma.

Blood RBC Antigen Plasma Antibody Can Donate To Can Receive

Group From

A A antigen Anti-B A, AB A, O

B B antigen Anti-A B, AB B, O

AB A and B antigens None AB only A, B, AB, O

(Universal
Recipient)

O Neither A nor B Anti-A and Anti-B A, B, AB, O O only

(Universal Donor)

Universal Donor = Group O (no antigens to trigger reaction in recipient) Universal Recipient =
Group AB (no antibodies to react against donor antigens) Anti-A and Anti-B antibodies are naturally
occurring — present from birth without prior exposure to blood.

Adverse Effects of Mismatched Blood Transfusion

When incompatible blood is transfused, the recipient's pre-formed antibodies bind to the donor RBC
antigens, triggering an acute haemolytic transfusion reaction (AHTR):

1. Agglutination

Antibodies (IgM class in ABO incompatibility) cross-link donor RBCs together, causing clumping
(agglutination). These agglutinated clumps block small blood vessels, particularly in the kidneys, leading to
renal ischaemia and acute kidney injury.

2. Haemolysis

The antigen-antibody complexes on the RBC surface activate the complement cascade → membrane
attack complex (MAC) punches holes in the RBC membrane → intravascular haemolysis. Released
haemoglobin is toxic to the renal tubules → acute tubular necrosis → acute renal failure. Free
haemoglobin turns urine red/dark (haemoglobinuria). Bilirubin rises → jaundice.

3. Shock

Cytokines released during the immune reaction cause massive vasodilation and increased vascular
permeability → distributive (anaphylactic/haemolytic) shock. Patients develop: fever, rigors (chills),
hypotension, tachycardia, back/loin pain, chest pain, flushing, urticaria. In severe cases: DIC (from
released thromboplastins from lysed cells) → further bleeding paradox. Mortality is significant if not caught
early.

IMMEDIATE ACTION if transfusion reaction suspected: STOP the transfusion immediately →

maintain IV access with normal saline → inform the blood bank → send blood samples and the unit
for analysis → manage shock and renal failure.
 10. RHESUS (Rh) SYSTEM

The Rhesus system is the second most important blood group system. It is based on the presence or
absence of the D antigen (RhD) on the RBC surface.

• Rh positive (Rh+): RhD antigen present — ~85% of the population

• Rh negative (Rh−): RhD antigen absent — ~15% of the population
• Unlike ABO antibodies, anti-D antibodies are NOT naturally occurring — they only develop after
exposure to Rh+ blood (sensitisation)
• Sensitisation occurs through: incompatible blood transfusion, or fetomaternal haemorrhage during
pregnancy/delivery in an Rh− mother carrying an Rh+ baby

Rhesus Incompatibility in Transfusion

If an Rh− person receives Rh+ blood (first time): No immediate reaction but they become sensitised →
produce anti-D antibodies. On second exposure to Rh+ blood → brisk haemolytic transfusion reaction.
Therefore, always transfuse Rh-compatible blood.

Haemolytic Disease of the Newborn (HDN)

Also called erythroblastosis fetalis. This occurs when an Rh− mother carries an Rh+ fetus (father is
Rh+ and the gene is inherited by the baby).

Mechanism:

Event What Happens

First Pregnancy Fetal RhD+ RBCs leak into maternal circulation (usually at delivery, but also
at miscarriage, amniocentesis, antepartum haemorrhage). Mother is
sensitised → produces IgG anti-D antibodies. First baby is usually
unaffected.

Subsequent Pregnancy Mother's memory B cells rapidly produce large amounts of IgG anti-D. IgG
(unlike IgM) can cross the placenta. Anti-D crosses → attacks fetal RhD+
RBCs → haemolysis in the fetus.

Effects on Fetus/Neonate Haemolytic anaemia in fetus → fetus compensates by producing immature

RBCs (erythroblasts) extramedullary (liver, spleen) → hepatosplenomegaly.
Severe: hydrops fetalis (generalised oedema from heart failure and
hypoalbuminaemia). Bilirubin accumulates → neonatal jaundice (can't cross
placenta; rises after birth) → kernicterus (bilirubin deposits in brain causing
brain damage).

Prevention of HDN — Anti-D Immunoglobulin (RhoGAM)

An Rh− mother is given an injection of anti-D immunoglobulin (passive antibody) at 28 and 34 weeks
gestation and within 72 hours of delivery. The injected anti-D destroys any fetal Rh+ RBCs that entered the
maternal circulation before the mother can mount her own immune response and form memory cells. This
prevents sensitisation, protecting future pregnancies.

Treatment of HDN:
• Antenatal: Serial fetal anaemia monitoring (Doppler of middle cerebral artery), intrauterine transfusion
(Rh− blood) if severe
• Postnatal: Phototherapy (for jaundice — light converts bilirubin to water-soluble isomers), exchange
transfusion (replaces bilirubin-laden blood with fresh Rh− blood in severely affected neonates)
 11. PROTHROMBIN TIME (PT) & APTT

The Coagulation Cascade — Brief Overview

Haemostasis (stopping bleeding) has two main phases. Primary haemostasis = platelet plug. Secondary
haemostasis = coagulation cascade that reinforces the plug with fibrin. The cascade has two pathways
converging on a common pathway:

• Extrinsic Pathway: Triggered by tissue factor (TF) released from damaged tissue → activates Factor
VII → activates Factor X
• Intrinsic Pathway: Triggered by contact with damaged vessel collagen → activates XII → XI → IX →
VIII → activates Factor X
• Common Pathway: Factor X + Va → prothrombinase complex → converts prothrombin (II) →
thrombin → converts fibrinogen → fibrin clot

Prothrombin Time (PT)

Feature Detail

What it measures Extrinsic pathway + common pathway (Factors VII, X, V, II, I/fibrinogen)

Normal range 10 – 14 seconds (varies by lab)

INR International Normalised Ratio = standardised PT ratio; normal INR ~1.0–1.2;

therapeutic range for warfarin ~2.0–3.0

Prolonged in Warfarin therapy (inhibits vitamin K-dependent factors including VII), Liver
disease (VII has shortest half-life — PT is earliest indicator), Vitamin K
deficiency, Factor VII deficiency, DIC, Common pathway factor deficiencies

Clinical use Monitor warfarin therapy (via INR), assess liver synthetic function
(synthesises clotting factors), screen for coagulopathy pre-operatively

Activated Partial Thromboplastin Time (APTT)

Feature Detail

What it measures Intrinsic pathway + common pathway (Factors XII, XI, IX, VIII, X, V, II,
I/fibrinogen)

Normal range 25 – 40 seconds (varies by lab)

Feature Detail

Prolonged in Haemophilia A (↓Factor VIII) and B (↓Factor IX) — MOST IMPORTANT,

Heparin therapy (heparin enhances antithrombin which inactivates thrombin
and Xa, IXa), vWD (vWF carries and protects Factor VIII), Lupus
anticoagulant (paradoxically prolongs APTT in vitro but causes thrombosis in
vivo), DIC (consumes all factors), Common pathway factor deficiencies

Clinical use Diagnosis and monitoring of haemophilia, monitoring of unfractionated

heparin (UFH) therapy, screening for intrinsic pathway disorders, mixing
studies to identify factor deficiencies vs inhibitors

Test Pathway Tested Prolonged in

PT / INR Extrinsic + Common Warfarin, liver disease, Vit K deficiency,

Factor VII deficiency, DIC

APTT Intrinsic + Common Haemophilia A/B, heparin, vWD, DIC,

lupus anticoagulant

Both PT and APTT Common pathway or both DIC, liver disease, Factors I, II, V, X
prolonged pathways deficiency, massive transfusion

Thrombin Time (TT) Fibrinogen → Fibrin step Heparin, hypofibrinogenaemia, DIC

only

Quick Summary Table for Exam: Haemophilia A/B: APTT ↑, PT normal, BT normal, platelets normal
Warfarin: PT ↑ (INR ↑), APTT usually normal or mildly ↑ Heparin (UFH): APTT ↑, PT normal or
mildly ↑ Liver disease: PT ↑, APTT ↑, BT ↑ (thrombocytopenia), fibrinogen ↓ DIC: PT ↑, APTT ↑,
BT ↑, platelets ↓, fibrinogen ↓, D-dimers ↑ vWD: BT ↑, APTT mildly ↑ (if severe), PT normal,
platelets normal

These notes cover all topics as discussed in class. Review each section carefully, understand
mechanisms — not just facts — and you will have everything you need.