CLINICAL

HAEMATOLOGY NOTES

THIRD EDITION
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Table Of Contents:

What’s included: Ready-to-study anatomy, physiology and pathology notes of the Haematological (Hematological)
System presented in succinct, intuitive and richly illustrated downloadable PDF documents. Once downloaded, you
may choose to either print and bind them, or make annotations digitally on your iPad or tablet PC.

Anatomy & Physiology Notes:
- BLOOD: AN OVERVIEW
- HAEMATOPOIESIS
- RED BLOOD CELLS
- HAEMOSTASIS/HEMOSTASIS
- THE ROLE OF BLOOD IN THE IMMUNE SYSTEM
- BLOOD GROUPS, TRANSFUSION & BLOOD PRODUCTS

Pathology Notes:
- ANAEMIAS
o IRON DEFICIENCY ANAEMIA (Microcytic)
o ANAEMIA OF CHRONIC Inflammatory DISEASE (Microcytic/Normocytic)
o THALASSAEMIAS
o SICKLE CELL ANAEMIA
o MACROCYTIC ANAEMIA
o “HA” - HAEMOLYTIC ANAEMIA
o HAEMOLYTIC DISEASE OF THE NEWBORN
o APLASTIC ANAEMIA (Ie. MARROW FAILURE)
- POLYCYTHAEMIA
- HAEMOCHROMATOSIS
- MYELODYSPLASTIC (PRELEUKAEMIC) SYNDROMES
- MULTIPLE MYELOMA
- LEUKAEMIAS
o ALL - ACUTE LYMPHOBLASTIC LEUKAEMIA
o AML - ACUTE MYELOID LEUKAEMIA
o CLL - CHRONIC LYMPHOCYTIC LEUKAEMIA
o CML - CHRONIC MYELOID LEUKAEMIA
- LYMPHOMAS
o HODGKIN’S LYMPHOMA (15%)
o NON-HODGKIN’S LYMPHOMAS (85%)
- BLEEDING DISORDERS
- THROMBOTIC DISORDERS
- DRUGS FOR HAEMOSTASIS:
o ANTI-COAGULANTS
o ANTI-PLATELET DRUGS
o THROMBOLYTICS




























BLOOD: AN OVERVIEW

 BLOOD: AN OVERVIEW

An Introduction To Blood:
• The main transport medium of the body
• 8% of body weight
• A special type of Connective Tissue (living cells suspended in a non-living matrix)
• More dense than water
• 5x more viscous than water
• pH beween 7.35 & 7.45
• 37.4 degrees Celsius
• Average adult blood volume = 5L (women); 5.5L (men)

Blood Functions:
• Distribution:
o Oxygen
o Metabolic Waste
o Hormones
• Regulation:
o Temperature
o Maintaining pH in body tissues.
o Fluid volume in Circulatory System
• Protection:
o Preventing blood loss – clotting
o Preventing infection

Blood Components:
• Mixture of Cellular & Liquid Elements
• In a Centrifuged Sample:
o Red Blood Cells (Erythrocytes) sink to the bottom (heaviest)
§ Normally 45%+/- of the total blood-volume (a measure known as the Hematocrit)
o White Blood Cells (Leukocytes) & Platelets form the “Buffy Coat” in the middle.
o A layer of plasma ‘floats’ on top. (Mostly water)

• Plasma:
o Mostly water (90%)
o Contains 100’s of dissolved nutrients/gases/hormones/wastes/ions/protein
o 5-7% protein:
§ Albumin – blood carrier
§ Globulin – mainly immunoglobulins
§ Fibrinogen – part of a clotting protein
o Predominant Ions: Na+, K+, Ca2+, Mg2+, Cl-, HCO3-
• Serum:
o The fluid, noncellular portion of blood that remains after coagulation; lymphatic fluid.
o Serum is equivalent to plasma without its clotting elements.
• Cells:
o Red Blood Cells: AKA: Erythrocytes - carry oxygen around the body
o White Blood Cells: AKA: Leukocytes: (leuko = white)
§ Granulocytes: (due to cytoplasmic granules)[are polymorphonuclear – Multilobed Nucleus]
• 60% Neurtophils - Responsible for fighting bacterial infections & some cancers
• 3% Eosinophils - Responsible for fighting parasitic infections & also allergic reactions
• 0.5% Basophils - Responsible for allergic reactions
§ Non-Granulocytes:
• 5% Monocytes - 2 functions:
o Replenish resident macrophages and dendritic cells under normal states
• 30% Lymphocytes - Constantly circulating -Responsible for innate immune response
(T-cells, B-cells & NK-cells)
o T-Lymphocytes: Responsible for Cell-Mediated immune response.
o B-Lymphocytes: Responsible for Humoral immune response by producing
antibodies.
o Platelets: From fragmented Megakaryocytes – Responsible for Clotting.




























HAEMATOPOIESIS

 HAEMATOPOIESIS
(Yes, we know some countries spell it ‘Hematopoiesis’ :P)
Haematopoiesis:
- What is it?
o = ‘The Formation of Cells in the Blood from Pluri-Potent Stem Cells’
- Why is it important?
o Blood cells don’t live forever
o Blood cells get used up/killed/broken down/sacrificed constantly.
o The body needs a way to balance this blood cell turnover with new production
o Also need to be able to produce MORE of a CERTAIN blood cell type under different physiological
conditions:
§ Eg. High altitude hypoxia à Relative polycythemia
§ Eg. Bacterial Infection à Neutrophilia
§ Eg. Parasitic Infection à Eosinophilia
- Where does it occur?
o In Foetal Life: Takes place in the Yolk Sac/Liver/Spleen/&Bone Marrow.
o After Birth: Takes place only in the Bone Marrow (Medullary Cavity)
§ Ie. The Bone Marrow is generally the only source of new blood cells.
§ Usually confined to axial skeleton (pelvis & spine) & long bones (Femur & Humerus).
§ However, the remaining Fatty Marrow, Liver & Spleen can resume their “extramedullary
haematopoietic” roles in Times of Need.

ALL Blood Cells Start As Haematopoietic Stem Cells:
- Haematopoiesis starts with PluriPotent Stem Cells in the bone marrow.
- Stem Cells are Self-renewing
- Cell Lineages:
o Myeloid Stem Cells:
§ Erythroid:
• Proerythroblast à Reticulocyte à RBCs
§ Granulocytic:
• Myeloblasts à Neutrophils
• Eosinophilic Myeloblast à Eosinophils
• Basophilic Myeloblast à Basophils
§ Monocytic:
• Monoblast à Macrophages
§ Megakaryocytic:
• Megakaryoblasts à Megakaryocytes à Platelets
o Lymphoid Stem Cells:
§ Lymphocytic:
• B-Lymphoblasts à B-Cells
• T-Lymphoblasts à T-Cells
• NK Cells
- Considerable amplification:
o Ie. 1 Stem Cell can produce 10,000,000 blood cells after only 20 divisions.
- Leukemias & Lymphomas can result from defective haematopoietic stem cell lines;
o Sometimes treated with total body irradiation to kill all defective stem cell lineages, à Then
replace/regenerate the stem cell pool with a bone marrow transplant.

Haematopoietic Growth Factors:
- Pluripotent Stem Cells are capable of becoming any type of cell.
- Therefore, they need certain growth factors to direct their differentiation.
o Eg. Various Interleukins (IL’s)
o Eg. Colony Stimulating Factors (CSF’s)
o Eg. Thrombopoietin (TPO)
o Eg. Erythropoetin (EPO)
- There are many growth factors, and unlimited combinations which could direct differentiation.
o (Generally, committing these combinations to memory is outside the scope of a medical student)
- Functions of these Growth Factors:
o Control Growth & Differentiation
o Can Stimulate Cell Maturation
o Can Suppress Apoptosis
o Can Affect the Function of Mature, Non-Dividing Cells.

 - Normal Blood Smears:
o RBCs:
§ Most of the RBCs are round, have central pallor (due to being thinner at their centre).
§ RBC’s size is comparable to a small lymphocyte
o Other Cells:
§ Neutrophils
§ Basophils
§ Eosinophils
§ Lymphocytes
§ Monocytes/Macrophages (Monocytes in Blood, Macrophages in Tissues)
§ Platelets

- System for Looking at Blood Smears:
o (Usually performed by specialist pathologists; not general medical practitioners)
o 1. RBC – Assess Size, Colour, Shape.
o 2. WBC – Number, Types
o 3. Platelets – Number, Size, Distribution
o 4. Abnormalities – Parasites, Abnormal Cells (Eg. Sickle/Infected/Schistocytes/Blasts/Atypical/Etc.)

 - Causes of Abnormal White Cell Counts:
o (NB: Philia = Too Many)
o (NB: Penia = Too Few)




























RED BLOOD CELLS

 RED BLOOD CELLS

ERYTHROPOIESIS:
- Erythropoiesis = Process of Red Blood Cell Formation
o Responsible for 1012 new erythrocytes each day
o Finely Regulated
- A similar sequence of Amplification & Maturation.
o Pluripotent Stem Cells à Pronormoblast (aka. Proerythroblast)
o Pronormoblasts à progressively smaller Normoblasts (aka. Erythroblasts)
o Normobloasts à Reticulocytes
o Reticulocytes à Mature into Erythrocytes
o Reticulocytes circulate in peripheral blood (1-2 days) before maturing in the Spleen
- Presence of Nuclei/Organelles:
o As erythrocyte precursors mature, they gain haemoglobin & lose nuclear material
o “Blasts” = Large, Nucleated RBC Progenitors + Organelles
o “Reticulocytes” = Smaller, Non-Nucleated RBC Progenitors (No organelles; just remnants)
- Note: Presence of Blasts & Reticulocytes in Peripheral Blood means ↑↑Erythropoiesis:
o In a normal smear, less than 1% of RBCs are Reticulocytes
o Ie. NORMALLY, All progenitors are in the marrow ONLY, except for the Erythrocyte
o To view Reticulocytes, you need “Methylene Blue Stain”.
o Excess Reticulocytes can indicate Anaemia (ie. The body’s effort to compensate for lack of O2)
o Severe Anaemia can result in immature nucleated RBC’s in the blood (not good)

ERYTHROPOIETIN:
- Erythropoiesis is regulated by the Hormone ‘Erythropoietin’
- Produced by the PeriTubular Interstitial Cells of the Kidneys. (Also produced by liver <10%)
o Erythropoietin Production – regulated by Oxygenation of Tissues in Kidneys.
o Therefore Production INCREASES when:
§ Body is Anaemic
§ Haemoglobin isn’t giving up O2 normally (eg. CarbonMonoxide Poisoning)
§ Atmospheric [O2] is low
§ Damage to Renal Circulation (ie. Ischemia of Kidney)
o Production DECREASES when:
§ Tissue Oxygenation is Normal.

Requirements for Erythropoiesis & Haemoglobin Formation:
- The Marrow requires other precursors for effective erythropoiesis: eg.
o Metals:
§ Iron – essential for Haemoglobin synthesis
§ Cobalt
o Vitamins:
§ Especially Vit. B12 - necessary for normal DNA synthesis
§ Folate - necessary for normal DNA synthesis
§ Vit. C
§ Vit. E
§ Vit. B6
§ Thiamine
§ Riboflavin
§ Pantothenic Acid
o Amino Acids:
§ For the production of cell proteins
o Hormones:
§ Erythropoietin
§ Androgens
§ Thyroxine
§ Interleukin-3
§ GM-CSF (Granulocyte & Macrophage – Colony Stimulating Factor)
HAEMOGLOBIN:
- Functions:
o To carry O2 to tissues
o To Return CO2 from tissues à Lung
o Storage pool of Iron. (65% of bodily Iron is in Haemoglobin)
- Constituents:
o Made up of the protein Globin bound to the red Haem (heme) pigment.
o Most common Adult Haemoglobin Molecule = Hb‘A’
o Globin consists of 4 Polypeptide Globulin chains – each with its own Haem Group.
§ 2 Alpha
§ 2 Beta
o Haem Molecules (Groups)....containing:
§ Protoporphyrin:
• Combines with iron in the Ferrous (Fe2+) State to form Haem.
§ 1x Iron atom in its centre:
• Each Iron atom can combine with 1x molecule of Oxygen....therefore:
o 1x Haemoglobin molecule can transport 4x molecules of Oxygen

- Oxygen Loading:
o In lungs
o O2 diffuses into blood à into erythrocytes à binds to Iron Molecules in Haemoglobin.
o Haemoglobin à Becomes OxyHaemoglobin:
§ Assumes a new 3D shape
§ Becomes Ruby Red
- Oxygen UnLoading:
o In Tissues
o O2 detaches from Iron Molecules in Haemoglobin à Out of RBC, into blood à O2 into Tissue
o OxyHaemoglobin à Becomes DeOxyHaemoglobin:
§ Resumes its former 2D shape
§ Becomes Dark Red.
- CO2 Transport:
o CO2 binds to Globin’s Amino Acids ...Rather than on the Haem Group.

HAEMOGLOBIN – OXYGEN DISSOCIATION CURVE:
- Oxygen exchange operates between 95% Saturation (Arterial Blood) & 70% Saturation (Venous Blood)
- P50 = Partial Pressure of O2 at which Haemoglobin is ½ saturated with O2. (Approx 26 mmHg)
- As the curve shifts to the right, O2 is given up More Readily to the Tissues.
- During CO2 Unloading in the lungs, the curve shifts to the left, à O2 uptake increases.

ERYTHROCYTE METABOLISM:
- *RBC’s don’t have Mitochondria, so they’re forced to generate energy via anaerobic pathways:
o Embden-Meyerhof Pathway:
§ Glucose metabolised to produce ATP
o Pentose-Phosphate Pathway (aka. Hexose Monophosphate Shunt):
§ Glucose metabolised to produce NADPH
§ NADPH – used by Methaemoglobin Reductase to maintain Iron in Ferrous Form (Fe2+)
§ Iron in the Ferric Form is useless because it doesn’t bind oxygen. à Leads to Oxidative Stress

Embden-Meyerhof Pathway Shows the Pentose Phosphate Pathway
(Aka. Hexose Monophosphate Shunt).
ERYTHROCYTE DEATH:
- Average Erythrocyte Lifespan: 120 Days
- Beyond 100 Days:
o Glycolysis slows
o ATP levels decline
o Membrane becomes less flexible
- Dying Cells – Removed by Macrophages in Spleen & Liver
o Iron is reused:
§ à Transported back to Bone Marrow (bound to Transferrin)
§ à Stored as Ferritin in Bone Marrow.
o Protoporphyrin (Haeme minus the Iron) is Metabolized:
§ Protoporphyrin à Bilirubin à Conjugated in Liver à Excreted in Bile à Faeces.



























HAEMOSTASIS/HEMOSTASIS:

 HAEMOSTASIS/HEMOSTASIS:

What is Haemostasis?
- Literally means “Blood Halting”....i.e. Stopping Bleeding
- When a blood vessel is broken, Haemostasis is responsible for ‘plugging’ the hole.
o Without Haemostasis, we would ‘bleed-out’ from even the smallest cuts.
- The Haemostatic Response is Fast, Localised & Finely Regulated.
o Involves a chain reaction of 12 Blood Coagulation FACTORS (Procoagulants)
o Plus Fibrin Stabilising Factor (FSF)
o Also involves some other substances released by platelets and injured tissue cells.
- Results in a stable ‘Platelet Plug’ (clot) at the site of injury.

Important Components of Haemostasis:
- Endothelial Cells:
o = Simple Squamous Epithelium that Lines the blood vessels
o (Plus Small amount of Smooth Muscle around outside)
o Important For:
§ Barrier between intra/extra vascular tissues
§ Regulate/mediate inflammation – facilitate movement of leukocytes
• Leukocytes must be able to migrate from intra-extra vascular sites.
§ Fluid Distribution – can change permeability à Fluid (Plasma) can exit to Interstitial Space
§ Angiogenesis:
• Formation of new vessels
• Or Vessel Repair.
o Role in Haemostasis:
§ Promote Plug Formation & Coagulation when injured:
• Pro-Platelet Effects:
o Exposure of SubEndothelial Collagen
o Produce Von Willebrand Factor (the glue)
• Pro-Coagulant Effects:
o Exposure of Tissue Factor à Triggers Extrinsic P-way of Coag. Cascade.
• Anti-Fibrinolytic Effects: (pro-fibrin deposition)
o Blocks the Tissue Plasminogen Activator.
§ Inhibits Plug Formation & Coagulation when intact:
• Anti-Platelet Effects:
o Nitric Oxide
• Anti-Coagulant Effects:
o Heparin
o & Thrombomodulin
• Fibrinolytic Effects:
o Tissue Plasminogen Activator

(Important Components of Haemostasis – Continued)
- Platelets:
o Produced in bone marrow: From Megakaryocytes
§ Fragment into many platelets
§ 4000 platelets/megakaryocyte

o Production Stimulated by Thrombopoietin (produced by Liver & Kidneys)
o Functions:
§ Central role in Haemostasis
§ Form platelet-plugs at vascular injury.

(Important Components of Haemostasis – Continued)
- Coagulation Factors (Cascade):
o Role: To stabilise primary platelet plug
§ Protects plug from being washed away by flowing blood
o Dependant on Coagulation Factors
§ Mainly produced in liver; (Some severe liver diseases à clotting deficiencies)
o Has an Intrinsic, Extrinsic, & Common Pathway
§ (See simplified diagram below; explained in more detail later)

(Simplified; Explained in detail later)

- Plasminogen/Plasmin (Responsible for Fibrinolysis):
o Clots aren’t permanent solutions to vessel injuries.
o :. Fibrinolysis removes un-needed clots after healing has occurred...by:
§ Blocking Coagulation Cascade:
§ & By Breaking Down Fibrin:

 3 PHASES OF HAEMOSTASIS:

PHASE 1. PRIMARY HAEMOSTASIS:
- a) Vascular Spasms:
o Vasoconstriction: The immediate response to vessel damage.
o Triggered by:
§ Local Neural Pain-Reflexes
§ Chemicals released by: Endothelial Cells & Platelets
§ Direct Smooth Muscle Injury
o Significantly reduces blood lossà allows time for Platelet-Plug Formation & Clotting.
o Most effective in smaller vessels.
- b) Primary Platelet Plug Formation:
o Platelets form a ‘plug’ à Temporarily seals the break in vessel wall
o Platelets normally flow smoothly through an undamaged vessel.....HOWEVER....
o When vessel is damaged à Sub-Endothelial Collagen is exposed....
§ Platelets (+ Von Willebrand Factor [glue]) adhere strongly to the Collagen Fibres...
• Platelets Activate à Conformational Change à
o Swell
o Form Spiked Processes
o Become ‘Sticky’.
• à Primary Platelet-Plug ‘Sandwich’:

Surface Glycoproteins on Platelets
Von Willebrand Factor
Sub-Endothelial Collagen

- c) Platelet Aggregation:
o Once attached, Platelets à Activated à Release Several Chemicals:
(Platelet Activation & Secretion Enhanced by Thrombin)
§ Serotonin: Vasoconstrictor
§ ADP: Potent Platelet-Aggregating Agent
§ Calcium (Factor IV): A cofactor that Activates other Inactive Pro-Coagulation Factors.
:. Important in Coagulation
§ Thromboxane A2: Vasoconstrictor
Potent Platelet-Aggregating Agent
o Initiates a Positive Feedback Cycle à Activates & Attracts more & more Platelets.
§ Within 1min, a platelet plug is built à further reduces blood loss.
- d) Platelet-Plug Localisation:
o Prostacyclin:
§ A Prostaglandin Produced by Intact Endothelial Cells.
§ A Strong Inhibitor of Platelet Aggregation

PHASE 2. SECONDARY HAEMOSTASIS:
- a) Coagulation Cascade:
o Coagulation (i.e. Blood ‘Clotting’): Where Blood; Liquid à Gel
§ = Series of enzymatic conversions of Inactiveà Active Coagulation Factors.
o Intrinsic Pathway:
§ àTriggered by Exposed Sub-Endothelial Collagen
§ All factors needed for clotting are in the blood
o Extrinsic Pathway:
§ àTriggered by Exposed Tissue Factor (Factor III)

àà
o Common Pathway:
§ Both Pathways eventually lead to Activation of Factor-X
• 1. Activated Factor-X combines with other factorsà
• 2. Prothrombin Activator is formed...
• 3. Prothrombin Activator; converts the plasma-protein: Prothrombin à Thrombin.
- b) Fibrin Deposition:
o 4. Thrombin Catalyses Conversion & Deposition of FibrinogenàFibrin
§ Also +Ve Feedback on Coag. Cascade (Amplification of ProThrombin Activation)
o 5. Fibrin Mesh à+ Active Factor-XIII à Stabilises the Platelet-Plug à Seals the hole
§ Primary Platelet Plug + Mesh à Secondary Platelet Plug.
- c) Regulation:
o ProCoagulants (Clotting Factors):
§ Factors enhancing clot-formation (Factors I – XIII)
§ Most are plasma proteins (inactive) made by the liver
§ These factors Dominate in Damaged-Vessels
o AntiCoagulants:
§ Factors inhibiting clot-formation
§ These factors Dominate in Undamaged-Vessels.
- d) Coagulation Localisation:
o Activation of Coagulation Factors is Restricted to Sites of Exposed PhosphoLipids:
§ I.e. Phospholipids on platelet membranes
§ Platelet Phospholipids are exposed by Platelet-Activation
o Anticoagulants: See Above
§ Tissue Factor Pathway Inhibitor:
• (Inhibits Extrinsic Pathway)
• à Inactivates Factor-Xa
• à Inhibits [Factor-VIIa – Tissue Factor Complex]
§ Thrombomodulin:
• à Blocks Coagulation Cascade
• à Binds Thrombin – Fibrinogen can’t convert to Fibrin
o à Then Activates Protein-C
§ Protein C & Protein S:
• àCombine to Inactivate Factor-Va & Factor-VIIIa.
§ Antithrombin (+ Heparin):
• àInhibits Thrombin
• àInhibits Factor-Xa & Factor-XIa


The coagulation system is ‘irreducibly complex’

PHASE 3. FIBRINOLYSIS:
- Clots aren’t permanent solutions to vessel injuries.
- :. Fibrinolysis removes un-needed clots after healing has occurred...by:
- Blocking Coagulation Cascade:
o Thrombomodulin:
§ Blocks Thrombin from activating Fibrinogen :. No Fibrin Deposition
- & By Breaking Down Fibrin:
o Via a Fibrin-Digesting Enzyme: Plasmin à Degrades fibrin & :. The clot as well.
§ Plasmin: Produced when Plasminogen is activated.
§ Plasminogen is initially incorporated into a forming clot à Remains inactive until clot forms.
§ Plasminogen Activation: (once clot is formed)
• Endothelial Cells: secrete Tissue Plasminogen Activator (tPA)
• Activated Factor XII: also Activates Plasminogen
• Thrombin: also Activates Plasminogen
o Results in Fibrin Degradation Products (FDP’s):
§ Eg. D.Dimer
§ Can be measured in the blood
§ Tested to see whether there has been excessive blood clotting

RECAP:



























THE ROLE OF BLOOD IN THE IMMUNE SYSTEM

 THE ROLE OF BLOOD IN THE IMMUNE SYSTEM
(Basic Summary; More Detail in our Immunology/Rheumatology Subject)

The Immune System:
- The immune system is more a functional system rather than an anatomical or organ-based system.
- Consists of:
o a diverse array of molecules
o -and trillions of immune cells (especially lymphocytes).
o These molecules & immune cells inhabit lymphoid tissues & circulate in body fluids.
- Functions to protect the body from:
o Most infectious microorganisms
o Cancer cells
o Transplanted organs
o Grafts
o Any other foreign material
- Can act directly – by cell attack
- Can act indirectly – by releasing mobilising chemicals & antibody molecules.

Terminology:
- Pathogen: microorganism that is able to cause disease
- Pathogenicity: the ability of a microorganism to cause disease.
- Virulence: the degree of pathogenicity.
- Opportunistic pathogens: bacteria which cause disease in a compromised host.
- Normal flora: harmless bacteria consistently associated with the host.
- Infection: when an organism (incl. Normal flora) breaches a body surface.
o Note: Infection Doesn’t necessarily lead to disease; Depends on:
§ Route of entry
§ Number of pathogens
§ Immune status of host

Basic Diagram of the Immune System:
- Note that there is an External Barrier, An Innate Immune Response & an Adaptive Immune Response

 INNATE VS ADAPTIVE IMMUNE SYSTEM

INNATE (NON-SPECIFIC) IMMUNE SYSTEM:
- Features:
o Already in place at birth.
o Is always prepared
o Responds within minutes
- Role:
o Protects the body from all foreign substances.
o Are often sufficient to ward off invading pathogens single-handedly.
o Essentially, it exists to reduce the workload of the adaptive system.
st
- 1 Line of Defence: Surface Barriers:
o Role: Prevents Entry of Pathogen
§ Skin
• Stratified
• Heavily keratinised

§ Mucous membranes
• Lysozyme: enzyme found in saliva & tears àdestroy bacteria.
• Sticky Mucus: in digestive & respiratory tracts àtraps bacteria.
• Cilia – nasal & respiratory àsweep bacteria into mouthàswallowed.
• Acid secretion: skin, vagina, stomach àkills microbes.

- 2nd Line of Defence: Internal Defences:
o Role: Prevents Spread of Pathogen If Surface Barriers are Breached
§ Macrophages – Large phagocytic cells

•
§ Granulocytes – possess cytoplasmic granules
• Neutrophils –they release toxic chemicals into the extracellular fluid, killing both the
target and themselves. (kamikaze)
• Eosinophils – another type of white blood cell – kill parasitic worms.
• Basophils – important in allergic reactions

•
§ Fever
• When exposed to foreigners, leukocytes & macrophages secrete pyrogens à
increases the body’s thermostat.
• Increases metabolic rate, kills microbes, speeds up repair.
§ Natural Killer cells
• Police the body in blood & lymph
• Can lyse & kill cancer cells & virus-infected cells
• Target all cells that lack ‘self’ surface receptors (non-specific)
• Kill by latching onto invaders and inducing apoptosis.
• Also secrete potent chemicals that promote inflammation
§ Antimicrobial proteins
• Either attack microbes directly or reduce their reproductive ability.
• –‘Interferons’ & ‘compliment’
§ Inflammation
• In response to physical trauma/intense heat/bad chemicals/infection.
• Prevents spread of damaging agents to nearby tissue
• Disposes of cell debris & pathogens
• Sets stage for repair.
• Characterised by heat, redness, pain & swelling
ADAPTIVE (SPECIFIC)IMMUNE SYSTEM:
- Think of the Adaptive Immune System as “The body’s elite special forces” – with high-tech weapons.
- Features:
o >It is Specific: recognises particular pathogens/antigens
o >It is Systemic: immunity isn’t restricted to initial infection site
o >It has Memory Adaptive responses are called into action as ‘reinforcements’
- Roles:
o Tremendously amplifies the inflammatory response.
o Attack specific foreign substances – incl. Antigens and abnormal body cells
o mounts stronger attacks on previously encountered pathogens.
- The body’s 3rd line of defence (Humoral & Cellular Immunity):
o a) HUMORAL IMMUNITY (aka. Antibody-mediated immunity) -Immunity can be transferred from
person-person via serum
§ B Cells (B-Lymphocytes)
• Make antibodies against soluble antigens.
§ Antibodies (Immunoglobulins):
• Circulate freely in blood & lymph
• Neutralises bacteria/toxins/& viruses àmarks for destruction by phagocytes or
compliment.

 >>>>Humoral Immunity Continued

(Note: Once the body has Memory B-Cells from the first immune response, the immune reaction to the second
exposure is much quicker and has a higher antibody yield. Is the primary mechanism behind vaccines)
 o b) CELLULAR IMMUNITY -Immunity can be transferred from person-person via blood cells
§ Antigen causes activation of macrophages, NK-cells, T-lymphocytes & cytokines
• Macrophages & NK-Cells – destroy intracellular pathogens
• T Cells (T-Lymphocytes) – induce apoptosis of body cells with viruses/intracellular
bacteria/cancerous traits.
• Cytokines are secreted – enhance inflammatory response and/or activate other
lymphocytes/macrophages.
§ Activated cells destroy infected/foreign cells.

The Whole Immune System Summary:



























BLOOD GROUPS, TRANSFUSION & BLOOD PRODUCTS.

 BLOOD GROUPS, TRANSFUSION & BLOOD PRODUCTS.

BLOOD GROUP ANTIGENS:
- There are ≈400 known RBC Antigens.
- We are only concerned with 2 categories; the ABO & Rh Antigens.
- 1. ‘ABO’ Blood Group Antigens:
o Sugar Chains emanating from the RBC membrane
o Determines the ‘A/B/AB/O’ blood types.
§ A-Antigen
§ B-Antigen
§ A & B-Antigens
§ H-Antigen (O-Type)

o Exist due to 3 allelic genes (A, B & O)

§ A & B alleles can show CoDominance (AB-Type)
§ A & B alleles are Dominant over the ‘O’ allele.
§ Homozygous ‘OO’ is dominant over A or B alleles.

- 2. ‘Rh’ (Rhesus/Rh-D) Blood Group Antigens:
o Membrane-Bound protein on RBC.
o Presence/Absence of the Rh’D’-Gene determines +ve/-ve blood type.
§ Presence of RhD à Positive
§ Absence of RhD à Negative

o Relevance in Transfusions:
§ Rh-Positive Patients: Can receive either Rh-Positive OR Rh-Negative Blood
§ Rh-Negative Patients: Should ONLY receive Rh-Negative Blood (except in extreme
emergencies and Rh-Negative blood is unavailable)
o Relevance in Pregnancy:
§ If the mother is Rh-Negative, but the foetus is (potentially) Rh-Positive à
• à ‘Rh-Incompatibility’
• (If father is Rh-Positive or father’s Rh-status is unknown)
§ Normally, maternal and foetal blood don’t mix, but sometimes a sensitizing event can occur,
causing foetal blood to contact maternal blood.
• Eg. Abdominal trauma during pregnancy
• Eg. Amnioscentesis
• Eg. Miscarriage
• Eg. Ectopic pregnancy
• Eg. Chorionic illus sampling
• Eg. Bleeding during pregnancy
§ If Rh-Negative mother gets sensitized to Rh-Positive Foetus à
• à Mother’s immune system produces Rh-Antibodies
• à Rh-Antibodies Cross the placenta
• à Enter foetal bloodstream à Attack foetal RBC’s à Haemolytic Anaemia
§ Note: You can prevent an Rh-Negative mother from being sensitized by administering Rh-
Immunoglobulin (aka: Anti-D-Antibodies) at strategic times during the pregnancy.

BLOOD GROUP ANTIBODIES:
- Anti-A / Anti-B Antibodies:
o Are Naturally-Occurring Antibodies:
§ Ie. Present at birth.
§ Ie. Do not require an immune-sensitizing event
o Are Immunoglobulins of type:
§ IgM type antibodies
o Are Present In plasma of people who lack the corresponding Antigen.
§ Eg. A-type individual will have ‘Anti-B’ Antibodies (against B-Antigens).
§ Eg. B-Type individual will have ‘Anti-A’ Antibodies (against A-Antigens)
§ Eg. O-type individual will have ‘Anti-A’ & ‘Anti-B’ Antibodies.
o If Antibodies contact their respective Antigen, A Haemolytic Reaction may occur.
o Clinical significance:
§ Determines a patient’s ABO-compatibility when receiving transfusions.

- Anti-D Antibodies:
o Are Immune Antibodies:
§ Ie. Produced following an immune-sensitizing event
• Eg. Via transfusion ...or
• Eg. Trans-Placental Passage
o Are Immunoglobulins of type:
§ IgG type antibodies
§ Note: Only IgG-Ab’s are capable of trans-placental passage.
o Most Important IgG = the ‘Rh-Antibody’ (Anti-D)
o Clinical Significance:
§ Determines a foetus’ risk of Haemolytic Disease of the Newborn.
§ Determines a patient’s absolute ability to receive a Rh-Positive transfusion.

ANTIGLOBULIN TEST (COOMB’S TEST):
- 2 Clinical Blood Tests – Direct & Indirect
o Direct (DAT):
§ Detect if antibodies or complement have bound to RBC surface antigens in vivo.
§ Used clinically when immune-mediated hemolytic anemia (antibody-mediated destruction of
RBCs) is suspected.
§ A Positive Result àmeans an immune mechanism is attacking the patient's RBC's.

o Indirect (IDAT):
§ Detects antibodies against RBCs present in the patient's serum.
§ Serum is extracted from the blood, and is incubated with RBCs of known antigenicity.
§ If agglutination occurs, the indirect Coombs test is positive.
§ It is used to detect very low concentrations of antibodies present in a patient's
plasma/serum prior to a blood transfusion.
§ In antenatal care, the IAT is used to screen pregnant women for antibodies that may cause
haemolytic disease of the newborn.

BLOOD DONATION PROCESS:
- 1. Blood Donation:
o Donors carefully selected:
§ Healthy
§ 18-65yrs
§ Minimum Hb Level (not anaemic)
§ No infection
§ No Meds/Drugs
o Frequency: 2-3times/year
o Volume: 450mL (A Pint)
- 2. Collection:
o Can be stored for 5-6 weeks
o Stored in PVC Bag
o With Anticoagulants:
§ Citric Acid
§ Na
§ Sodium Phosphate (NaH2PO4)
o Additive Solution:
§ Adenine – for ATP production
§ Glucose – to feed Glycolysis
§ Saline – maintain isotonic
o Bags are refrigerated – NOT FROZEN – Freezing would crystalise cells àlysis.
- 3. Lab Screening:
o HIV
o Hep B/C
o HTLV (Leukaemia Virus)
o CMV (Cytomegalovirus)
o Syphilis
- 4. Serology Tests:
o ABO Typing:
§ By Addition of Antibodies ‘A’ & ‘B’ to blood sample.
• If Type-A: Reacts if ‘A-Antibodies’ added.
• If Type-B: Reacts if ‘B-Antibodies’ added.
• If Type-AB: Reacts if ‘A’ or ‘B-Antibodies’ added.
• If Type-O: No reaction with addition of either ‘A’/’B’.
§ Reaction = Agglutination of RBCs. (Not Clotting)
o Rh-D Typing:
§ By Addition of Antibody-‘D’ to blood sample
• If Positive: Agglutination Reaction
• If Negative: No Reaction
§ Reaction = Agglutination of RBCs. (Not Clotting)
o Rh C & E Typing
o Screening for serum RBC Antibodies
- 5. Quality Assurance Tests:
o Whole Blood Volume
o RBC Concentrate – (Packed Cell Volume)
o Platelet Concentrate
o Fresh Frozen Plasma Volume
§ Factor VIII Concentration
o Sterility Testing
- 6. Pre-Transfusion Tests:
o Recipient’s Blood is Typed.
o Cross-Matching:
§ Testing Donor-RBC’s against serum of patient.
§ Ie. Mixing the 2 blood samples (recipient & donor) – check for reaction.
o To ensure donor-recipient compatibility.
o Still a slight possibility of mismatch even between ‘compatible’ patients (due to other RBC Antigens)
Blood Products:
- --Whole Blood:
o Cells/Platelets
o Plasma
o Reason For Transfusion:
§ Acute Blood Loss
- Packed Red Blood Cells:
o RBC’s
o Reasons for Transfusion of RBCs:
§ Mainly to Quickly improve O2 Delivery to Tissues.
• Expect a rise of 10g/L of Haemoglobin Per Unit of Blood (450mL)
§ Egs of Eligable Recipients:
• Acute Blood Loss
• Preoperative
• Anaemias
• Renal failure
• Bone Marrow Failure
• Septicaemia
• Haemolytic Disease of the Newborn.
- Granulocyte Concentrates:
o White Blood Cells (leukocytes)
o Reason For Transfusion:
§ Supportive Therapy for Neutropenia (Low White Cell Count)
§ Eg. Pts following radiotherapy.
- Platelet Concentrate:
o Platelets
o Reasons For Transfusion:
§ Severe Thrombocytopenia
§ Severe Bone-Marrow Failure (Ie. Acute Leukaemia)
§ Myelotoxic Chemotherapy
- --Plasma:
o Blood proteins
o Clotting Factors
o Reasons For Transfusion:
§ Replacement of Coagulation Factors
§ Eg. Haemophilia & other Bleeding Disorders.
- Cryoprecipitate:
o Clotting Factors
o Fibrinogen
o Reasons For Transfusion:
§ Used To Control Clotting Disorders.
§ Factor VIII & Fibrinogen:
• Treatment of Haemophilia
§ Factor IX & Prothrombin:
• Treatment of Factor IX Deficiency
• Treatment of Christmas Disease.
- Cryosupernatant:
o Albumin
o Immunoglobulins
o Reasons For Transfusion:
§ Used as ‘Volume Expanders’ – in Hypovolumic Shock
§ Albumin:
• Volume Expander
• To Treat HypoAlbuminaemia – eg. Burns/Renal Patients.
§ Immunoblobulins:
• Treatment of Immunocompromised Patients


Artificial Oxygen Carriers as RBC Substitutes:
- Technologies that are being developed to replace red blood cell transfusions.
o Benefits:
§ Eliminates risk of transfusion complications
§ Overcomes the problem of donor deficiency
- Eg. Haemoglobin-Based Oxygen Carriers:
o Direct infusion of Hb molecules
o However, when Hb is taken out of the RBC, it tends to break apart, and it also loses its oxygen
affinity.
o To overcome this problem, Hb is inserted into liposomes to mimic the red blood cells.

BLOOD TRANSFUSIONS:
- What is it?
o Involves the infusion of blood from a donor to a recipient
o Compatibility between Donor RBC Antigens & Recipient Plasma Antibodies Essential.
o If incompatible – haemolytic reaction may occur.
- Universal Donor:
o O-Negative
§ No A or B Antigens
§ No Rh-D Antigens
- Universal Recipient:
o AB-Positive
§ No anti-A or anti-B Antibodies
§ No anti-Rh-D Antibodies
- Group Specific Blood Vs. Cross Matched Blood:
o Group Specific = Blood of any ‘Type’ (ABO,Rh) that’s compatible with the Recipient. (20mins)
o Cross Matched = Complex Pre-Transfusion Testing for Compatibility across all Blood Types. (1hr)
- In Emergency Situations:
o In emergencies, there’s often no time to do a blood group or do a full cross match, so O-Neg is given.

COMPLICATIONS OF BLOOD TRANSFUSION:
- Immediate Complications:
o Immunological:
§ Haemolytic Reaction - Fever, Tachycardia, Hypotension, Shock
• Reaction à Intravascular Haemolysis
• Ie. Rapid Destruction of RBCs à Reduced O2-Carrying Capacity
o Involving ABO Antibodies = Life threatening
o Involving Rh Antibodies = Less severe
• Managed by Maintaining BP & Renal Perfusion (by giving Plasma & Diuretics)
§ Pyrogenic Reaction – Fever
• Due antibodies formed after previous sensitisation (Transfusion/Pregnancy)
§ Allergic Reactions.
• Triggered by IgE Antibodies (covered more in 4th year)
• May result in Anaphylactic Shock

o Non-Immunological:
§ Bacterial Contamination
§ Circulatory Overload à Left Ventricular Failure
§ Hyperkalaemia – Excess Blood K+
§ Clotting Abnormalities

- Delayed Complications:
o Immunological:
§ Delayed Haemolytic Reactions
§ Alloimmunisation - development of antibodies in response to alloantigens (antigens derived
from a genetically dissimilar animal of the same species)
§ Graft-Versus-Host-Disease – Where immune cells in the transfused blood recognizes the
recipient as "foreign" and mounts an immunologic attack.

o Non-Immunological:
§ Infectious Disease – eg. HIV, Hep-B/C, Bacteria, Parasites
§ Iron Overload - accumulation of iron in the body – Affects liver, heart & endocrine glands.
• Occurs in people who rely on Regular RBC Transfusion.
• Eg. Renal patients – lack erythropoietin.
• Excessive transfusion à Iron overload.



























ANAEMIAS

 ANAEMIAS

General:
- Definition = “Decreased haemoglobin concentration in blood”
o May be Low Hb
o OR low Hematocrit/Packed Cell Volume.
o Anaemia = generally less than 100g/L
- Normal Hb Range:
o (Normal Hb Concentration depends on age/sex/geographical location.)
o 13 - 16g/dl (male) (130-160g/L)
o 11.5 - 16g/dl (Female) (115-160g/L)

Aetiologies:
- Decreased Production (Fe/Folate/B12 Deficiency incl.Pernicious/Chronic Disease/Aplastic)
- Blood Loss (Haemorrhage/Hookworm/Menorrhagia)
- Destruction/Abnormality of RBCs (Haemolytic/Microangiopathy/G6PD/Sickle/Thalassaemia/Spherocytosis)
- Spurious (Increased Plasma Volume – Eg. Pregnancy/Fluid Overload)

Morphologies:
- Size Classifications:
o Microcytic: Small - Reduced MCV
o Normocytic: Normal MCV
o Macrocytic: Large – Increased MCV
- Staining/Colour:
o Normal RBCs stain well – (Normochromic)
o Anaemic cells stain lightly - (Hypochromic)

Microscopy (Blood Films):
- Iron Deficiency Anaemia:
o Hypochromic RBCs - Increased Central Pallor
o Microcytic
o Pencil Cells (RBCs with a single sharp edge)

- Megaloblastic Anaemia:
o Oval Macrocytic RBCs
o Hypersegmented Neutrophils
o Normochromic

- Warm Antibody (IgG) Autoimmune Haemolytic Anaemia:

o Microspherocytes (Small, RBCs with No Central Pallor)
o Evidence of Haemolysis (Reticulocytes, Nucleated RBCs, Schistocytes)

- Cold Antibody (IgM) Autoimmune Haemolytic Anaemia:

o Agglutination of RBCs (Ugly clumping of) @ <20oC
o May agglutinate in peripheries @ cold temperatures àRaynaud’s Phenomenon

- Oxidative Haemolysis (Eg. G6P Deficiency):

o (Affects cell fluidity, Hb Condenses)
o Bite Cells (RBCs) – Macrophages take bites out of RBCs
§ NB: an Indication for Splenectomy.
o Blister Cells (RBCs)
o Irregularly contracted microspherocytes
Clinical Features of Anaemia:
- May be Asymptomatic
- General Anaemia Symptoms:
o Fatigue, Headaches & Faintness
o Exertional Dyspnoea
o Exertional Angina
o Intermittent Claudication
- General Anaemia Signs:
o Pallor (Mucosal/Facial/Palmar Crease)
o Tachycardia
o Systolic Flow Murmur (Hyperdynamic Circulation)
o Cardiac Failure
- Some Signs Specific to Different Types of Anaemia:
o Koilonychia (Spoon-shaped nails) – Iron Deficiency
o Glossitis – Iron/B12 Deficiency
o Jaundice – Haemolytic Anaemia
o Splenomegaly – Haemolytic Anaemia, Leukaemia, Lymphoma
o Bone Pain/Deformities – Thalassemia Major, Myeloma
o Leg Ulcers – Sickle Cell

Investigations:
- Mean Cell Haemoglobin Concentration (MCHC):
o The average concentration of haemoglobin in a given volume of blood.
o Derived from the measurement of haemoglobin and the haematocrit.
§ Haemoglobin value = amount of haemoglobin in a volume of blood while the hematocrit is
the ratio of the volume of red cells to the volume of whole blood.) The normal range for the
MCHC is 32 - 36%.
- Mean Cell Haemoglobin (MCH):
o The average amount of haemoglobin in the average RBC.
o Derived from the measurement of haemoglobin and the red cell count.
§ The haemoglobin value = amount of haemoglobin in a volume of blood
§ The red cell count = number of red blood cells in a volume of blood.)
o The normal range for the MCH is 27 - 32 picograms.
- Mean Cell Volume (MCV):
o Average size of RBC
o Described as:
§ Microcytic (smaller than normal)
§ Normal
§ Macrocytic (larger than normal)

- Iron Studies Interpretation:


Differential Diagnosis of Anaemia – Based on Microscopic Features (Mean Cell Volume & Reticulocytes):
Microscopic Features: Differential Diagnoses: Further Lab Evaluation:
Anaemia Iron Deficiency Iron Studies, Fe-Binding, Ferritin
Low MCV (Microcytic) Anaemia of Chronic Disease/Inflammation Blood Film (Pencil Cells = IDA)
Low Retics Sideroblastic Anaemia
Thalassemias A & B
Lead Poisoning
Anaemia Megaloblastic (B12/Folate Deficiency) Serum B12
High MCV (Macrocytic/ - Eg. Pernicious Anaemia RBC Folate Levels
Megaloblastic) - Eg. Coeliac Disease/Short bowel Blood Film (Macroovalcytes,
Alcohol Abuse Pancytopenia)
Liver Disease Marrow Biopsy
Myelodysplastic Syndromes or Leukaemia (Dysplasia/Neoplasia)
High Retics? = Bleeding, Haemolysis.
Anaemia Acute Blood Loss Blood Smear
Normal MCV Primary Bone Marrow Failure Iron Studies, Fe-Binding, Ferritin
- Aplastic Anaemia/Drugs/Chemo Kidney, Thyroid, Liver Function Tests
- Leukaemia Cortisol Levels
- Myelodysplastic Syndromes EPO Levels
Secondary Bone Marrow Failure
- Uraemia
- Endocrine Disorder
- HIV/AIDS
- Anaemia of Chronic Disease
Haemoglobinopathies (Sickle/Thalassemia)
Haemolysis – Immune/Mech/Toxic.
Renal Failure
Pregnancy (Spurious)
Anaemia Bleeding – Blood Loss (Internal/External) Blood Film – nRBC, spherocytes,
High Reticulocyte Count Haemolysis – Immune/Mech/Toxic. parasites
Bilirubin/Haptoglobin (Haemolysis)
Coombe’s (Direct & Indirect)
G6PD screen.


IRON DEFICIENCY ANAEMIA (Microcytic):
- (Most common type of Anaemia)
- Aetiology:
o Chronic blood loss à MOST common cause of Iron Deficiency
§ (Eg. Parasitic Worm Infestation, Malignancy, Menorrhagia, GI Ulcers)
o Increased Need (Over-Demand):
§ Pregnancy, Rapid Growth (children)
o Poor diet / poor absorption:
§ Malnutrition (↓Greens & Meat)
§ Malabsorption, intestinal surgery, gastric atrophy.
- Pathogenesis:
o Iron is a fundamental constituent of Haemoglobin
o Therefore Iron deficiency à↓Haemoglobin Synthesis (&↓RBC Production) àAnaemia.
- Morphology – Blood Film:
o Microcytic (↑Divisions of Progenitors) (↓MCV)
o Hypochromic (↑Central Pallor of RBCs) (↓Hb Content)
o + An-Isocytosis (variations in size)
o + Poikilocytosis (Variations in shape)
o + Some “Pencil Cells”. (RBCs with one Sharp Edge)

- Clinical Features:
o Symptoms & Signs:
§ General Anaemia Symptoms:
• Fatigue, Headaches & Faintness
• Exertional Dyspnoea
• Exertional Angina
• Intermittent Claudication
• (Incl. Exacerbations of CVS/REsp problems in Elderly – Eg. Claudication & Angina)
§ General Anaemia Signs:
• Pallor (Mucosal/Facial/Palmar Crease)
• Tachycardia
• Systolic Flow Murmur (Hyperdynamic Circulation)
• Cardiac Failure (Eg. Pedal Oedema)
§ Signs Specific to Iron Deficiency Anaemia:
• (All due to cytochrome oxidase functional deficiency – Which requires iron to work)
• **Atrophic Glossitis (Atrophy of Papillae of tongue)
• *Angular Cheilitis/Stomatitis
• *Koilonychia (Spoon Nails)
• * Brittle Nails, Brittle Hair
o Diagnosis:
§ Blood Count & Film (Microcytic, Hypochromic, Poikilocytosis, Anisocytosis, Pencils)
§ Iron Studies (↓Ferritin;↓Iron; ↑TIBC)
o Differentials (for low MCV):
§ Thalassaemia
§ Anaemia of Chronic Disease
§ Sideroblastic Anaemia (Very Rare)
o Treatment:
§ Iron Supplementation
ANAEMIA OF CHRONIC Inflammatory DISEASE (Microcytic/Normocytic):
- Aetiology:
o Chronic Infection (Eg. Tuberculosis)
o Chronic Inflammatory Disease (Eg. Crohn’s/Rh.Arthritis/SLE/Malignancy)
- Pathogenesis:
o Chronic Infection/Inflammation à
§ ↓RBC Survival à RBC Death outpaces RBC production à Anaemia
§ ↓EPO Release à Reduced Stimulus for Erythropoiesis
§ ↓Iron Transfer/Release from Macrophaces in Bone Marrow à Functional iron deficiency à
Anaemia
- Morphology:
o Typically Normocytic (Sometimes Microcytic) [Debatable]
o Hypochromic
o Fewer RBCs

- Clinical Features:
o General Anaemia Symptoms & Signs.
- Investigations:
o Iron Studies:
§ ↓Serum Iron
§ ↓TIBC
§ Normal Serum Ferritin
o B12/Folate
o Blood Film
- Treatment:
o Treat Underlying Chronic Inflammation/Infection
§ Corticosteroids (↓Inflammation)
o Correct Anaemia:
§ Exogenous EPO (↑Erythropoiesis)


THALASSAEMIAS:
- Aetiology:
o Genetic mutation/deletion in the Alpha or Beta Globin genes for Haemoglobin.
o Alpha Thalassaemia:
§ Deletion of 1/more of the 4 Alpha Globin genes.
o Beta Thalassaemia:
§ Mutations in the Beta Globin genes – prevent B-chain formation.
- Pathogenesis:
o ↓ Synthesis of Alpha/Beta Globin chains – Haemoglobin Disorder - Ineffective erythropoiesis
o ↑ Haemolysis – due to aggregation of unmatched globin chains
- Microscopy:
o May exhibit Poikilocytosis (RBCs – weird shapes/sizes)
- Clinical Features:
o May be mild à Minimal symptoms / No treatment required
o May be more severe à Typical anaemia-type symptoms
§ Eg. Fatigue, weakness
§ Eg. Jaundice/Dark urine
- Treatment:
o Severe forms may require regular blood transfusions
- Complications:
o Iron Overload (eg. From frequent blood transfusions) à Damage to heart/liver/endocrine organs.
o Infection (Especially post splenectomy)
o Bone Deformities (Thalassemia can cause physical bone marrow expansion à abnormal bone
structure; especially in face and skull)
o Splenomegaly (May require splenectomy)
o Slowed growth & delayed puberty
o Congestive heart failure

SICKLE CELL ANAEMIA:
- Aetiology:
o Inherited genetically
o Prevalent in Afro-Carribean populations.
- Pathogenesis:
o Abnormal Beta-Haemoglobin Chain à
§ Abnormal Hb – Insoluble – Forms crystals @ low O2 Tension
§ Leads to sickle-shaped RBC à RBCs are rigid, sticky & get stuck in blood vessels
§ RBCs Clog small capillaries à Tissue Necrosis.
§ Episodes of haemolysis à Further anaemia.
- Microscopy:
o sickle-shaped RBCs
- Clinical Features:
o Episodes of Haemolysis
o Anaemia Symptoms
o *Episodes of Pain (‘Pain crises’):
§ Due to microangiopathic blockages due to sickle cells à tissue hypoxia/ischaemia à Pain
§ à Chest/Abdo/Joint/Bone pains
§ ‘Pain crises’ may occur infrequently, or many times a year.
o Swelling of hands and feet
o Frequent infections
o Delayed growth/puberty
- Treatment:
o Currently no cure; But Stem cell transplants have future promise
o Treatment aimed at avoiding pain, relieving symptoms & preventing complications.
o Hydroxyurea – reduces frequency of painful crises.
o L-Glutamine – Reduces frequency & severity of pain crises
o Analgesics
- Complications:
o Retinopathy
o Growth delay
o Renal disease
o Stroke
o Pulmonary hypertension
o Heart disease
o Leg ulcers
o Priapism
o Gallstones
o Increased risk of miscarriage

MACROCYTIC ANAEMIA:
- (2nd most common type of anaemia)
- (“Megaloblasts” = large, Erythroblasts with Immature Nuclei - seen in the Marrow)
- Aetiologies:
o VitB12 Deficiency; Possible causes:
§ **Malnutrition – Lack of VB12 Dietary Intake.
§ Gastric – Deficiency of Intrinsic Factor (Eg. Perncious Anaemia – autoimmune response to
parietal cells of stomach à↓IF à↓VitB12 Absorption)
§ Intestinal – eg. Resected Ileum/Crohn’s Disease
o Folate Deficiency; Possible causes:
§ **Malnutrition – Lack of Folate Dietary Intake
§ Malabsorption – eg. Coeliac Disease/Intestinal Resection.
§ Excess Utilization – eg. Pregnancy/Lactation/Chronic Inflammation/Cancers
§ Excess Urinary Loss – eg. Acute Liver Disease/Congestive Heart Disease.
o Other General Causes:
§ **Alcoholism (or Liver Disease)
§ Cytotoxic Chemo Drugs
§ Old Age

- Pathogenesis:
o VitB12/Folate are Necessary for Nuclear DNA Synthesis
o à defective nuclear maturation of erythroblasts
o à Reduced RBC Production

 - Morphology:
o Marrow Biopsy:
§ Megaloblasts in Bone Marrow (large, Erythroblasts with Immature Nuclei)
o Blood Film:
§ *Normochromic
§ *Oval Macrocytes (Large, Oval RBCs)
§ *Hypersegmented Neutrophils (Some with >6 Lobes in Nucleus)
§ *Pancytopenia (Reduction in Number or ALL Cells – RBCs/WBCs/Platelets)
§ Attempted ↑↑Erythropoiesis:
• ↑Reticulocytes
• Some “Polychromatophils” (Biger, Blueish RBCs)
• Some Nucleated RBCs
§ + An-Isocytosis (variations in size)
§ + Poikilocytosis (Variations in shape)

- Clinical Features:
o General Anaemia Symptoms & Signs
o Signs & Symptoms Specific to Megaloblastic Anaemia:
§ Glossitis (Red Sore Tongue)
§ Angular Stomatitis/Cheilitis
§ Peripheral Neuropathy (Paresthesia, ↓Vibration, ↓Proprioception, Weakness & Ataxia)
- Investigations:
o Blood Film (Oval Macrocytes, Hypersegmented Neutrophils, Pancytopenia)
o FBC (↑MCV, Pancytopenia)
o Bone Marrow Biopsy (Shows Megaloblasts) – Rarely Required
o Serum B12/Folate (↓ if B12/Folate Deficiency)
- Treatment:
o Oral B12
o Oral Folate
o Corticosteroids + B12 Supplements (If Pernicious Anaemia)


 “HA” - HAEMOLYTIC ANAEMIA:
- What is it?
o Anaemia due to Increased/Abnormal/Premature RBC Destruction
- Aetiologies (See Flowchart Below):
o Intravascular Haemolysis: Occurs within the Circulation.
o Extravascular Haemolysis: Occurs in the Reticuloendothelial System (Liver/Spleen/Marrow)

- Pathogenesis:
o Breakdown of RBCs due to any cause à Release of Free Haemoglobin in Plasma.
§ à Heme Molecule à Protoporphyrin & Iron
§ à Protoporphyrin à Excess Bilirubin à↑Bilirubin (Unconjugated)à Jaundice
§ à Bilirubin Conjugated in Liver à Excreted in Bile & Faeces.

 - Clinical Features:
o Symptoms:
§ General Anaemic Symptoms & Signs +
§ Symptoms Specific to Haemolytic Anaemia:
• Jaundice (Mild & Fluctuating)
• Splenomegaly
• Pigment Gall Stones (If Chronic HA)
• Venous Stasis Ankle Ulcers (Sickle Cell)
• Microangiopathy/Infarction/Raynauds
o Laboratory Evaluation:
§ Elevated Free-Hb in Blood (Haemoglobinaemia)
§ Hb in Urine (Haemoglobinuria) à Red-Brown Urine.
§ Haemosiderin (iron from Hb) in Urine (HaemosiderinuriaI)
§ LFTs – (↑Bilirubin, ↓ Haptoglobins)
§ Blood Smear – (Broken RBCs, Reticulocytosis, Congenital RBC Disorders, Anaemia)
§ Coombe’s Test – (?Autoimmune Haemolytic Anaemia)

- A 4Q. Approach to Diagnosing Haemolytic Anaemias:

o 1. Is there ↑ RBC Breakdown? (Anaemia?/Jaundice?/Urinary Urobilinogen?)
o 2. Is there ↑ RBC Production? (Reticulocytes?/↑MCV?/Polychromasia?)
o 3. Is it Extravascular or Intravascular?
§ Extravascular = (Splenomegaly?)
§ Intravascular = (↑Plasma Hb?/↓Plasma Haptoglobin?/Haemoglobinuria?)
o 4. Why is there Haemolysis?
§ Is it Autoimmune (WAHA/CAHA)? à +ve Coomb’s Tests
§ Is it Congenital (Sickle / Thalaaemia / G6PD / Her.Sperocytosis)? à Blood Smear
§ Is it Mechanical (Microangiopathy / March Syndrome / DIC) à Blood Smear
- Treatment:
o Treat Underlying Cause
o Plasmapheresis if Autoimmune
o Splenectomy if Hypersplenism/Heriditary Spherocytosis
o Blood Transfusion if Severe


HAEMOLYTIC DISEASE OF THE NEWBORN:
- What is it?
o Condition that develops in a foetus, when the Mother’s IgG Anti-RhD Antibodies crosses the
placenta àFoetal Circulation.
o àAttacks the red blood cells in the foetal circulation.
o The RBC’s are broken down and the foetus can develop reticulocytosis and anaemia à Death.
- Pathogenesis:
o Mother is usually O-Negative.
§ Will have Anti-A & Anti-B Antibodies
§ BUT..unless she’s been exposed to the RhD-Antigen, she won’t have Anti-D Antibodies.
o During Pregnancy:
§ 1. Sometimes Foetal Blood Mixes with Maternal Blood (eg. Placental Injury/Amniocentesis)
§ 2. If Foetal Blood is Positive, The Mother’s Immune System Sensitizes to the RhD-Antigen.
§ 3. Maternal Immune system produces Anti-D Antibodies.
§ 4. These Maternal Immune Antibodies (‘IgG’-Ab’s) can cross the Placenta à Foetus.
§ 5. Antibodies Attack Foetal RBCs à Haemolysis.
§ 6. Excess Haemolysis may lead to Jaundice (Haem à Bilirubin)

- Lab Findings:
o Cord Blood:
§ Rh-D Antigen Present (Positive)
§ Positive Direct Coomb’s Test (ie. Mother’s Anti-D Antibodies detected on Foetal RBCs)
§ ↑ Bilirubin
o Maternal Blood:
§ Rh-D Antigen Absent (Negative)
§ Positive Indirect Coomb’s Test (ie. High levels of maternal serum Anti-D Antibodies)
- Prophylaxis Against Rh Sensitization:
o Passive administration of Exogenous Rh-D-Antibodies into mother can prevent the Primary Immune
Response from occurring in the first place.
o Ie. The Exogenous Rh-D-Antibodies destroy any foetal Rh-Positive Blood cells (that cross the
placenta) before the immune system has time to become sensitized.

APLASTIC ANAEMIA (Ie. MARROW FAILURE):
- (Aplastic Anaemia = “Pancytopaenia wityh Bone Marrow Hypocellularity (aplasia))
- Aetiology:
o Simple Bone Marrow Failure (NOT Malignant)
§ Primary:
• Congenital
• Idiopathic
§ Secondary:
• Cytotoxic Drugs
• Sensitivity to other drugs (Eg. Chloramphenicol, Chlorpromazine, Phenytoin, NSAIDs)
• Ionizing Radiation
- Pathogenesis:
o Reduction in Pluripotent Stem Cells
o Remaining Stem Cells are FAULTY or IMMUNOGENIC :. Cannot repopulate the Marrow.
o à Pancytpopaenia (Deficiency of all cells)
- Morphology:
o Pancytopaenia with Bone Marrow Hypocellularity (Aplasia)
o There are NO Leukaemic, Cancerous or Abnormal Cells in Marrow OR Peripheral Blood.
- Clinical Features:
o Symptoms & Signs:
§ General Anaemia Symptoms:
• Fatigue, Headaches & Faintness
• Exertional Dyspnoea
• Exertional Angina
• Intermittent Claudication
• (Incl. Exacerbations of CVS/REsp problems in Elderly – Eg. Claudication & Angina)
§ General Anaemia Signs:
• Pallor (Mucosal/Facial/Palmar Crease)
• Tachycardia
• Systolic Flow Murmur (Hyperdynamic Circulation)
• Cardiac Failure
§ Signs Specific to Aplastic Anaemia:
• Anaemia (↓RBCs)
• Bleeding/Bruising/Petechiae/Bleeding Gums (↓Platelets)
• Infection (↓WBCs)
o Investigations:
§ **Bone Marrow Biopsy – For Hypocellularity – Necessary for Diagnosis
§ Reticulocyte Count – Complete Absence of Retics.
§ Blood Count – Pancytopaenia
o Treatment:
§ *Bone Marrow Transplant + Supportive Transfusions



























POLYCYTHAEMIA

POLYCYTHAEMIA/ERYTHROCYTOSIS (EXCESS RBCS):
- Aetiology:
o “True” Polycythaemia:
§ Primary:
• Polycythaemia Vera (Primary Proliferative Polycythaemia)
§ Secondary:
• Tissue Hypoxia – Smoking (Co), High altitude, Pumonary disease, Cyanotic Heart
• Excess EPO – Renal Diseases (Hydronephrosis/Cysts/Carcinoma)
o Relative “Spurious” Polycythaemia:
§ Dehydration - Dehydration
- Pathogenesis:
o Polycythaemia Vera (Primary Proliferative Polycythaemia):
§ (One of the Myeloproliferative Disorders [Leukaemia/Thrombocythaemia/Myelofibrosis])
§ = Malignant Proliferation of an Erythroid Progenitor cell in the Absence of EPO Stimulation.
• à ↑↑RBC Numbers
• (Also à ↑WBCs & Platelets à Thrombotic Complications)
o Excess EPO:
§ Tissue Hypoxia à Renal Hypoxia à Stimulates EPO Secretion à ↑Erythropoiesis.
o Spurious Polycythaemia:
§ Dehydration à ↓Plasma Volume à Relative ↑ in RBC Concentration.
- Morphology:
o Hypercellular Marrow with Erythroid Hyperplasia
- Clinical Features:
o Most common in Elderly (>60yrs)
o May be Asymptomatic
o Vague Symptoms of Hyperviscosity:
§ Headaches
§ Dizziness
§ Tinnitus
§ Visual Disturbances
o Pathogonomic Symptoms:
§ Itch after a Hot Bath
§ Burning sensation in fingers & toes (AKA: Erythermalgia) – Relieved by cold.
o Signs:
§ Facial Plethora
§ Splenomegaly
§ Signs of Art/Ven Thrombosis.
- Treatment:
o Treat Underlying Cause
o Venesection
o Anticoagulation/Antiplatelet



























HAEMOCHROMATOSIS


HAEMOCHROMATOSIS:
- Aetiology:
o (Iron Overload in the Body Due to):
§ Primary – (Heriditary Mutation in HFE Gene à ↑↑Iron Absorption)
§ Secondary – (Repeated Transfusions, Excess Iron Supplements/Dietary Iron)
- Pathogenesis:
o à Iron Deposition in multiple Organs (Skin/Joints/Liver/Pancreas/Pituitary)
§ Liver - Cirrhosis
§ Heart - Cardiomyopathy
§ Endocrine Glands:
• Testicular Failure
• Pituitary Gland
• Tanning of the skin
• Diabetes (Due to Islet Cell Failure)
§ Joints - Arthritis (Iron Deposition in the Joints)
- Clinical Features:
o Symptom Profile:
§ Initially Asymptomatic
§ Early Symptoms:
• Fatigue
• Arthralgia
• Loss of Libido
§ Later Symptoms:
• Skin Bronzing
• Abdo Pain, Hepatomegaly
• Liver Cirrhosis
• Hypogonadism (from Pituitary Dysfunction)
- Diagnosis:
o Iron Studies – (↑Serum Ferritin & Iron Levels, ↑Transferrin Saturation & ↓TIBC)
o +ve HFE Genetic Mutation
o LFTs – (Cirrhosis)
o Echocardiogram – (Cardiomyopathy)
- Treatment:
o Venesection
o Low Iron Diet



























MYELODYSPLASTIC (PRELEUKAEMIC) SYNDROMES


MYELODYSPLASTIC (PRELEUKAEMIC) SYNDROMES:
- Pathology:
o Defective Myeloblast (Myeloid Stem Cell) Differentiation à Marrow Failure à Pancytopaenia à
§ Anaemia
§ Thrombocytopaenia à Bleeding
§ Neutropaenia à Infection
o Preleukaemic - 30% May Transform to Acute Leukaemias
- Morphology:
o Bone Marrow – Hypercellular (Despite Pancytopaenia)
§ + Abnormal Granulocyte Precursors
§ + Abnormal Megakaryocytes
§ + Ring Sideroblasts
§ + ↑Blast Cells in BM
- Clinical Features:
o Most Common in Elderly (60-75)
o Signs & Symptoms:
§ Fatigue, Weakness, Pallor
§ Infections, Fever
§ Bruising
o àOften leads to Acute Myeloid Leukaemia
- Diagnosistic Triad:
o 1. One or More Cytopaenias (Anaemia +/- Thrombocytopaenia +/- Neutropaenia)
o 2. Hypercellular Marrow
o 3. Dysmyelopoiesis in BM Precursors.
- Treatment:
o Supportive Blood Transfusions – RBCs & Platelets
o Gentle Chemotherapy
o Growth Factors – EPO (Erythropoietin) &/or G-CSF (Granulocyte Colony Stimulating Factor)
o Allogeneic Marrow Transplant



























MULTIPLE MYELOMA


MULTIPLE MYELOMA:
- Aetiology:
o Malignancy (Overproduction) of FUNCTIONING Plasma Cells in Bone Marrow
- Pathology:
o Over-Proliferation of Plasma Cells à
§ à Only Produces Monoclonal Igs à Recurrent Infections
§ + à Increased Osteoclastic Activity à Lytic Bone Lesions à Bone Pain.
- Clinical Features:
o Elderly, Males.
o Symptoms:
§ Bone Pain (Typically Back Pain – Vertebral Involvement)
§ BM Failure - Anaemia/Bleeding/Recurrent Infections
o Signs:
§ Pathological Fractures
§ Hypercalcaemia
§ BM Failure à Aaemia/Bleeding/Infection
§ Ig Deposition in Renal Tubules à Renal Impairment
§ Recurrent Infections
o Diagnosis:
§ FBC & Blood Film – (↑↑Plasma Cells (BM & Peripheral Blood))
§ ↑ESR/CRP
§ UEC – (↑Ca)
§ CT/MRI/XR – Lyic Bone Lesions
§ BM Biopsy – Infiltration of BM by Plasma Cells
o Treatment:
§ Supportive Treatment – Transfusions/Antibiotics
§ Allogeneic BM Transplant
§ Bisphosphonates Inhibit Osteoclast Activity
§ Radiotherapy/Chemotherapy



























LEUKAEMIAS

 LEUKAEMIAS

What Are Leukaemias?:
- = Myeloproliferative & Lymphoproliferative Disorders
- =A Type of Cancer Caused by Unregulated Proliferation of Abnormal ‘White Cells’ from a Mutant
Haematopoietic Stem Cell.
o Successive generations of cells from that Mutant Haem. Stem Cell à ‘Clonal Expansion’
o NB: Disease occurs when sufficient excess in Leukocytes.

- Mutation – Genetic Alteration within a Single Myeloid OR Lymphoid Tissue Progeitor.
o Chromosomal Translocations:
§ *Philadelphia Chromosome:
• #1 Cause of: à *CHRONIC MYELOID LEUKAEMIA
o Chromosomal Deletions/Additions:
§ *Monosomy 7:
• #1 Cause of: à *ACUTE MYELOID LEUKAEMIA
o Point Mutations
o Gene Amplification:
§ Changes in Proto/Anti-Oncogenes:
• Oncogenes: Code for proteins involved in cell proliferation/differentiation.
• Abnormal Proto/Anti-Oncogenes à Cancers (ie. Leukaemia)
• Eg. A Hypermorphic Mutation in an Oncogene à Hyperactive Proliferation
• Eg. A Hypomorphic Mutation in a Tumour-Suppressve Gene à Hyperactive
Proliferation

Result:
- Extreme numbers of White Cells in blood à Altered Haematocrit:
o Huge Buffy Coat (of WBCs – generally abnormal)
o Low Proportion of RBCs (Results in Anaemia)

Risk Factors:
- Radiation Exposure – Nuclear/X-Ray/Microwave
- Previous Chemotherapy – Particularly Alkylating Agents
- Genetic – eg. Down’s Syndrome
- Occupational Chemical Exposure – Benzene/Other Aromatic Organic Solvents
- Viral Infection

Classifications of Leukaemia:
- Acute OR Chronic:
o See table below
- Myeloid OR Lymphoid
o See table below
- Other:
o Hairy-Cell Leukaemia
o Prolymphocytic Leukaemia
o T-Cell Leukaemic Lymphoma

Type of Leukaemia Distinguishing Features
ALL – Acute Lymphoblastic Leukaemia Children
Good Prognosis
Small Lymphoblasts, Small Cytoplasm, No Granules/Nucleoli
AML – Acute Myeloid Leukaemia Adults
Poor Prognosis (2mths if untreated)
Gum Hypertrophy
“Auer Rods” in AML Myeloblast Cells
Big Myeloblasts, Big Cytoplasm, Granules, Nucleoli.
CLL – Chronic Lymphocytic Leukaemia Elderly
Commonest Leukaemia
Insidious Onset
Good Survival (9yrs) but NO Cure
“Smear Cells” on blood film
CML – Chronic Myeloid Leukaemia Adults
Philadelphia Chromosome in 80%
Good Prognosis with Glivec (Imatinib)
3 Phases: Chronic, Accelerated, Blast Crisis.
Marked Splenomegaly
(NB: Myeloids are ALWAYS in Adults; Lymphoids are EXTREMES of Age)
(All are ~Good Prognosis EXCEPT AML)
(CML = Philadelphia Chromosome & Tri-Phasic with “Blast Crisis”)


ALL - ACUTE LYMPHOBLASTIC LEUKAEMIA:
- Aetiology:
o Genetic / Environmental
- Pathogenesis:
o Malignancy of Lymphoblasts à Uncontrolled Proliferation à
o à Excess B-Lymphoblasts. (B-Lymphocyte Precursors)
o à Overcrowds the normal cells in the Bone Marrow
o à Bone Marrow Failure
o à Metastases (Bone, Liver, Spleen, Lymph Nodes)
o à à Can be fatal in weeks to months if left untreated.
- Clinical Features:
o Most Common in Young Children (4-5yrs)
o Good Prognosis (70-90% Cure Rate) (Low Mortality)
o Signs & Symptoms:
§ Bone/Joint Pain (Especially sternum)
§ Marrow Failure à
• ↓Hb à Anemia à Pallor, weakness, fatigue, dyspnea.
• ↓Platelets à Thrombocytopenia à Bruising & bleeding
• ↓WCC à Neutropenia à Frequent Fevers & Infections
§ Organomegaly (Liver, Spleen)
§ Lymphadenopathy (Incl. Mediastinal)
§ Weight-Loss/Loss of Appetite
§ Oedema in Lower Limbs
- Diagnosis:
o Physical Examination
o Complete Blood Count:
§ Excess Abnormal Leukocytes (↑WCC)
§ Blast Cells (Big, Immature Cells)
§ Anaemia (↓Hb)
§ Thrombocytopaenia (↓PLTs)
o Blood Film - Characteristic Lymphoblast Cells
o Bone Marrow Biopsy
§ Required for Definitive Diagnosis
§ Characteristic Lymphoblast Cells
o Cytogenetics:
§ Testing for Chromosomal Translocations
§ Particularly for the ‘Philadelphia Chromosome’
o Cytochemistry:
§ Using Cytochemical Stains to Differentiate between AML & ALL
§ Stains = Myeloperoxidase & Sudan Black Stain
• AML – Positive with Both Stains.
• ALL – Negative with Both Stains.
o CXR/CT – Mediastinal/Abdominal Lymphadenopathy
- Treatment:
o Supportive – Transfusions/Fluids
o IV Antibiotics - + Antivirals/Antifungals
o Chemotherapy – Aim for Remission
o Allogeneic Marrow Transplant

AML - ACUTE MYELOID LEUKAEMIA:
- Aetiology:
o Genetic / Environmental
o Or Progression from Myelodysplastic States
- Pathology:
o Malignancy of Myeloblasts àUncontrolled Proliferation à
o à Accumulation in the Bone Marrow à
o à ‘Packs Out’ the boneà interfere with the production of normal blood cells
o à Bone Marrow Failure
o à Metastases
- Clinical Features:
o Poor Prognosis (High Mortality)
o Most Common in ADULTS –↑Incidence with Age
- Signs & Symptoms:
o Bone Pain (Especially sternum)
o Marrow Failure à
§ ↓Hb à Anemia à Pallor, weakness, fatigue, dyspnea.
§ ↓Platelets à Thrombocytopenia à Easy Bruising & bleeding
§ ↓WCC à Neutropenia à Vulnerable to Infections
o Organomegaly (Liver, Spleen)
o Lymphadenopathy (Incl. Mediastinal)
§ Gum Hypertrophy
- Diagnosis:
o Complete Blood Count:
§ Excess Abnormal Leukocytes (↑WCC)
§ Blast Cells (Big, Immature Cells)
§ Anaemia (↓Hb)
§ Thrombocytopaenia (↓Plts)
o Blood Film - Characteristic Myeloblast Cells
o Bone Marrow Biopsy - Characteristic Myeloblast Cells with pathogonomic “Auer Rods”
o CXR/CT – Mediastinal/Abdominal Compression & Infection
o Cytogenetics:
§ Testing for Chromosomal Translocations
o Cytochemistry:
§ Using Cytochemical Stains to Differentiate between AML & ALL
§ Stains = Myeloperoxidase & Sudan Black Stain
• AML – Positive with Both Stains.
• ALL – Negative with Both Stains
- Treatment:
o Supportive – Transfusions/Fluids
o IV Antibiotics - + Antivirals/Antifungals
o Chemotherapy – Aim for Remission
o Allogeneic Marrow (Haematopoietic Stem Cell) Transplant

CLL - CHRONIC LYMPHOCYTIC LEUKAEMIA:
- Aetiology:
o Thought to be acquired Genetic Mutations over time à Malignancy
- Pathology:
o Malignancy of Neoplastic, Mature, Poorly-Functioning B-Cells à
o à Overproliferation of Mutated B-Cells à Can’t Fight Infection.
o à The cells accumulate mainly in the bone marrow and blood.
o Slow Bone Marrow Failureà & Slow Metastasis
- Clinical Features:
o The Commonest Leukaemia, Mainly in Elderly (50-60yrs).
o Good Survival – 9yr Median Survival – But NO CURE (Death due to infection, not mets)
o Symptoms:
§ Typcally Asymptomatic @ Dx – 60%. (Diagnosed on routine blood test)
§ If Bone Marrow Failure – (Anaemia, Recurrent Infection, Bruising)
§ If Severe – Weight Loss, Sweats, Anorexia.
o Signs:
§ Lymphadeopathy (Esp. Cervical) Enlarged, Rubbery, Non-Tender.
§ Organomegaly (Esp. Splenomegaly, Hepatomegaly)
- Diagnosis:
o Blood Count & Film – (↑↑Lymphocytosis, Anaemia, Neutropaenia, Thrombocytopaenia)
- Treatment:
o Early CLL is not treated
o CLL is only Treated when symptoms affect Quality of Life.
o Late CLL treated with:
§ IV-Ig. – For Infections;
§ Chemotherapy/Radiotherapy – Palliative
o (Stem Cell Transplant – Curative)

CML - CHRONIC MYELOID LEUKAEMIA:
- Aetiology:
o Genetic (Philadelphia Chromosome - >80%)
- Pathogenesis:
o Myeloid Proliferation in Bone Marrow & Blood à
§ à High, unregulated growth of myeloid cells
§ à Accumulation of immature granulcytes (neutrophils/eosinophils/basophils)
o 3 Phases:
§ Chronic Phase (Insidious, few/no symptoms)
§ Accelerated Phase (Fever, Increasing BM Failure Symptoms, ↑Splenomegaly)
• ‘Blast Crisis’ is imminent
§ Blast Crisis (Features of Acute Leukaemia à Death from Sepsis/Bleeding):
• Fatal Acute Leukaemic Phase
• Final phase in the evolution of CML
• Behaves like an acute leukaemia
• Rapid Progression + Short survival.
• Requires Immediate Bone Marrow Transplant to Survive.
- Clinical Features:
o Middle-Age (40-60yrs)
o Symptoms:
§ Often Asymptomatic (Usually detected by routine blood tests)
§ BM Failure:
• Anaemia – Low [Hb] (due to ↓RBCs)
• Thrombocytopaenia – (Low Platelets)
• Neutropaenia – (Infection)
§ Malaise (general feeling of being unwell)
§ Fever, Weight Loss, Fatigue
§ Abdo Discomfort (Splenomegaly)
§ Gout (Metabolic Arthritis – Due to ↑[Uric Acid] in blood)
o Signs:
§ Organomegaly in >75%
§ Anaemia/Bruising
- Diagnosis:
o FBC/Blood Smear - ↑↑WCC with ↑All Myeloid Cell Types
o Marrow Biopsy - Hypercellular Marrow
o Molecular Genetics - Philadelphia Chromosome
- Treatment:
o Chronic Phase: Chemotherapy – Glivec (Imatinib) – A Tyrosine Kinase Inhibitor
o **Blast Crisis: Requires Immediate Bone Marrow Transplant to Survive

Results when part of Ch.9 switches places with part of Ch.22. Forms an extra-long Ch.9,
& an extra-short Ch.22 = The Philadelphia Chromosome. – Contains the abnormal gene-fusion.





























LYMPHOMAS

 LYMPHOMAS:

HODGKIN’S LYMPHOMA (15%):
- Aetiology:
o Idiopathic
o Risk Factor = EBV (Infective Mononucleosis)
- Pathology:
o Malignant Lymphocytes à Accumulate in Lymph Nodes, Peripheral Blood & Other Organs
- Clinical Features:
o Bimodal Age Distribution
§ Young Adulthood (15-35)
§ Late Adulthood (55+)
o Good Prognosis – High Cure Rate
o Signs & Symptoms:
§ ***Asymmetrical & Painless Lymphadenopathy – Non-Tender, Rubbery (Neck, Axillary)
§ Systemic “B” Symptoms – (Fever, Night Sweats, Weight Loss, Fatigue)
§ Splenomegaly/Hepatomegaly
§ Pathogonomic Symptoms:
• Pruritis
• Alcohol Induced Lymph Node Pain.
- Diagnosis:
o *Lymph Node Biopsy - Presence of Reed-Sternberg Cells
o *Bone Marrow Biopsy – Presence of Reed-Sternberg Cells
o CT Chest/Abdo/Pelvis (Look for Mets).
- Treatment:
o (Depends on Staging; Curative Intent)
o Radiotherapy +/- Chemotherapy
- Complications:
o SVC obstruction (due to Mediastinal Masses) à ↑JVP, Facial Plethora, Dyspnoea.

NON-HODGKIN’S LYMPHOMAS (85%):
• What Are They?:
o Diverse group of Haematologic Cancers, Encompassing Any Lymphoma other than Hodgkin’s
Lymphoma.
o Complicated Classification.
o Occur At Any Age.
o May be Aggressive/Benign
• Aetiology:
o Post-Viral Infections – HTLV-1, EBV, HHV8, HIV, H.pylori
o Environmental Toxins – Pesticides, Organic Solvents
• Pathology:
o Malignant Lymphocytes à Accumulate in Lymph Nodes, Peripheral Blood & Other Organs
• Clinical Features:
o *POOR Prognosis – 5yrs for treated pts.
o Signs & Symptoms:
§ Initially Painless Lymphadenopathy – Non-Tender, Rubbery (Neck, Axillary)
§ Systemic “B” Symptoms – (Fever, Night Sweats, Weight Loss, Fatigue)
§ Splenomegaly/Hepatomegaly
§ Metastases à GIT, Lungs, Brain, Testes, Thyroid & Skin.
• Diagnosis:
o Bone Marrow Biopsy
o Lymph Node Biopsy
o CXR/CT – for Staging
• Treatment:
o (Depends on Staging)
o Radiotherapy may be Curative if Localised Disease.
o Chemotherapy in Diffuse Disease

























BLEEDING DISORDERS

 BLEEDING DISORDERS

There Are Many Potential Causes Of Bleeding Disorders. Eg:
- Vascular Disorders:
o Abnormalities in Blood Vessel Structure or Perivascular Connective Tissue
o Leads to: Easy Bruising
- Thrombocytopenia:
o Due to deficient number of platelets.
o Results from either:
§ ↓ Platelet Production
§ ↑ Platelet Destruction
§ ↑ Platelet Consumption (in large injuries/burns)
- Defective Platelet Function:
o There are enough platelets, but not working properly.
o May be Inherited (rare)...OR
o Acquired: (eg. From Aspirin/other blood thinners)
- Von Willebrand’s Deficiency:
o Either Not enough vWF....or Dysfunction of vWF.
o vWF is necessary for platelet adhesion. Therefore Deficiency à Poor platelet plug formation
- Coagulopathy = Defective Coagulation:
o Bleeding disorders due to deficiency in 1 or more Coagulation Factors
o Hereditary Coagulopathies:
§ Haemophilia A: Factor VIII Deficiency:
• Most common
• Sex Linked Recessive (Female Carriers; Affected Males)
• Treatment - Recombinant clotting factors
§ Haemophilia B: Factor IX Deficiency:
• AKA. Christmas Disease
• Less common
• Sex Linked Recessive (only affects males)
• Treatment - Recombinant clotting factors
§ Other deficiencies (Factors V, VII, X, XI & XIII) Rare.
• Just know they exist.
o Acquired Coagulopathies:
§ Vitamin K Deficiency (Factors II, VII, IX, X)
• Dietary
• Malabsorption
• Or Long-term warfarin
§ Chronic Liver Disease:
• Eg. Billiary Obstruction:
o Hinders absorption of Fat-Soluble vitamins
o Reduced synthesis of Factors II, VII, IX & X
• Eg. Severe Hepatocellular Damage:
o Reduced synthesis of Factor V & Fibrinogen
§ DIC - Disseminated Intravascular Coagulation:
• AKA. Consumptive Coagulopathy
• Formation of small clots inside blood vessels throughout the body.
• Leads to: ↑Consumption of Platelets & Coagulation Factors.

Evaluation of Bleeding Disorders:
- Platelet Count
o Literally the number of platelets/volume of blood.
o Normal range = 150-400x109/L
o Excessively Low platelet count à Thrombocytopenia (bleeding disorder)

- Platelet Function Tests
o Complete Blood Count (CBC)/Full Blood Evaluation (FBE):
§ Include platelet count & morphology.- eg. Giant platelets
o Bleeding Time
§ Time taken for wound to clot
§ If bleeding time is high à may suggest platelet dysfunction.
§ If bleeding time is high, but normal platelet level à May be due to vWF Deficiency.
o Platelet Aggregometry:
§ Measures platelet aggregation with common haemostatic agonists
• ADP
• Epinephrine
• Collagen
§ Measures the decrease in optical density that occurs in solution as platelets aggregate.

- Tests of Coagulation-Factor Function:
o Prothrombin Time (PT):
§ Time taken for plasma to clot after addition of tissue factor (Factor III)
§ Measures Extrinsic Pathway + part of Common Pathway
§ Measures factors VII, X, V, II (Prothrombin) and I (fibrinogen).
§ Normally 12-15sec.
§ 15sec+ = One/more of above factors are deficient.
§ INR (International Normalized Ratio) is derived from PT à Universal measurement.
o Activated Partial Thromboplastin Time (aPTT):
§ Time taken for plasma to clot after addition of phospholipids
§ Measures Intrinsic Pathway + the Common Pathway
§ Measures factors XII, XI, IX, VIII, X, V, II (Prothrombin) and I (fibrinogen).
§ Normally 25-45sec.
§ 45sec+ = One/more of above factors are deficient.
o Thrombin Time:
§ Measures how quickly Thrombin is being activated.
§ Time taken for a clot to form, following addition of animal Thrombin.
§ Measures:
• The conversion of Fibrinogen à Fibrin.
• Any deficiency of fibrinogen
• Any inhibition of thrombin.

























THROMBOTIC DISORDERS

 THROMBOTIC DISORDERS

Thrombosis = inappropriate formation of Platelet & Fibrin Clots
- Can cause obstruction to flow à Ischaemia à Necrosis
- Can Move Elsewhere = “ThromboEmbolism”:
o Most are asymptomatic
o Fragments move swiftly in large vessels
o Lodge in small vessels – eg. Pulmonary Vessels à Ischaemia/Necrosis of Lung Tissue.
§ 95% of Pulmonary Emboli – due to Thrombosis of Leg/Calf muscles.
- More common with ↑age
- Affects both Arterial & Venous Systems

Arterial Thrombosis:
- 2 Mechanisms:
o 1. Atherosclerotic Plaque Rupture in Arterial walls à Arterial Thrombosis.
§ Ie. Rupture of Atherosclerotic Plaque à
• Exposure of SubEndothelial Collagen
• Exposure of Tissue Factor
• à Thrombosis
o 2. Thromboembolism à Arterial Thrombosis.
§ Eg. Atrial thrombus formation during Atrial Fibrillation à Embolus à CVA/Stroke
- Risk Factors:
o Family Hx
o Males (more common)
o ↑Cholesterol
o Diabetes
o ↑BP
o Smoking
o Obesity
o Age
- Most common cause of:
o CerebroVascular Accidents (CVA’s) – aka. Stroke – Clot in brain à Necrosis of Neurons
o Myocardial Infarction (MI) – Due to Thrombi related to atherosclerosis in Coronary Arteries à
Necrosis of Myocardium
o Peripheral Arterial Disease (PAD)

Venous Thrombosis:
- Occur Mostly in Lower Extremities (due to gravity pooling blood)
o Includes Deep & Superficial Leg Veins
o Patient may present with sore or swollen legs/calves.
- Risk Factors:
o Hereditary Hypercoagulable States:
§ Factor V mutation
§ Prothrombin variant
§ Protein C deficiency
§ Protein S deficiency
§ Antithrombin Deficiency
o Acquired Hypercoagulable States:
§ High-Dose Oestrogen Therapy:
• ↑Plasma levels of Coag. Factors
• ↓ Antithrombin & Tissue-Plasminogen-Activator
§ Major Surgery/Trauma:
• Due to high tissue damage
• Immobility after surgery (Venous Stasis)
• Exposure of Tissue Factor
§ Pregnancy & Post-Partum (↑Levels of Coag. Factors during pregnancy)
§ Sepsis (bacterial infection à widespread damage to endothelium)
§ Heparin-Induced Thrombocytopaenia (some people on heparin develop antibodies to their
own platelets)
§ Blood Stasis:.....from:
• Heart Failure (not pumping adequately)
• Stroke
• Prolonged Immobility
• Nephrotic Syndrome (loss of Coag. Factors through Urine)
• Varicose Veins
- Treatment:
o Anticoagulation (Either oral or parenteral)
o Treat any Haemodynamic Instability of underlying cause.
o Clot may require endovascular retrieval

Evaluation of Thrombotic Disorders:
- Required if:
o Family History of Thrombosis
o Thrombosis at young age/unusual site
o Recurrent DVT
- Complete Blood Count ...&...Erythrocyte Sedimentation Rate:...Detect:
o Change in Haematocrit
o Change in White Cell Count
o Change in Platelet Count
o Change in Fibrinogen
o Red Cell Fragmentation
- Prothrombin Time (PT):
o Time taken for plasma to clot after addition of tissue factor (Factor III)
o See above section for details.
o Detects deficiency of Factor VII
- Activated Partial Thromboplastin Time (aPTT):
o Time taken for plasma to clot after addition of phospholipids
o See above section for details.
o Detects deficiency of Factors VIII, IX, XI or XII.
- If Both PT & aPTT are Abnormal:
o Probably due to:
§ Liver disease
§ Vit. K Deficiency……..or
§ Oral Anticoagulants
- INR – If on Warfarin (Dose too low)

























DRUGS FOR HAEMOSTASIS

 DRUGS FOR HAEMOSTASIS

Factors Involved in Haemostasis – (Those in red are targeted by different Drugs to modulate Haemostasis):
- Platelet Aggregating Agents:
o Sub-Endothelial Collagen (activates Platelets)
o Thromboxane (Stimulates Expression of Glycoprotein Receptor “GP-IIb/IIIa” à Aggregation)
§ (Produced by Cyclo-Oxygenase in Platelets)
o ADP (Stimulates activation of Glycoprotein Receptor “GP-IIb/IIIa” à Platelet-Aggregation)
o Glycoprotein Receptor “GP-IIb/IIIa” – Allow platelets to physically combine with each other.
§ Promoted by ADP Receptor Activation.
- Anti-Platelet-Aggregating Factors:
o ↑cAMPà↑cAMP Inhibits Platelet Aggregation by decreasing Cytosolic Ca+ Levels.
§ ↓Ca+ à Inhibits Ca-Mediated Vesicular Exocytosis of Pro-Aggregation Factors from the
Platelet (Particularly Thromboxane).
- Pro-Coagulating Agents:
o Vitamin K (A Coenzyme in the synthesis of Prothrombin, Factors II, VII, IX & X (TV Channels)
o Coagulation Factors I-XIII
o Activated Factor X (Complex)
o Prothrombin à Thrombin (Factor II)
o Fibrinogen à Fibrin
- Anti-Coagulating Agents (In Non-Damaged Tissue):
o Antithrombin-III (Inactivates Thrombin {Factor II}à Fibrinogen Activation àFibrin)
- Fibrinolysis Factors:
o Tissue Plasminogen Activator à Activates Plasminogen to become Plasmin
o (Plasmin degrades fibrin clots)

Remember, A “Clot” is Different to a “Thrombus”:
- Clot:
o Occurs In-Vitro (Ie. Outside the Body)
o Also structurally different.
- Thrombus:
o Occurs In-Vivo (Ie. Inside the Body – Typically forms in moving blood)
o Also structurally different.

Virchow’s Triad: – Formation of Thrombosis:
- Three Conditions Predispose to Inappropriate Thrombus Formation:
o 1. Endothelial Injury:
§ Eg. Atherosclerosis
§ Eg. Aneurysm
§ Eg. Blood Vessel Disorders (Eg. Heriditary Haemorrhagic Telangiactasia)
o 2. Decreased Bloodflow (Or Stasis):
§ Eg. Atrial Fibrillation
§ Eg. Deep Vein Thrombosis
§ Eg. Incompetent Venous Valves
o 3. Hyper-Coagulability:
§ Eg. During Pregnancy
§ Eg. Drug Side Effects
§ Eg. Hyperproliferative Blood Conditions (eg. Polycythemia Vera)

ANTI-COAGULANTS:
- Heparin (Including Low Molecular-Weight Heparins):
o Mechanism of Action:
§ Binds & Activates Antithrombin-III to form an AT-III:Heparin Complex.
§ The AT-III:Heparin Complex à:
• 1. à Inactivates Thrombin (Factor-II):
o Therefore Inhibits activation of Prothrombin to Thrombin.
• 2. à Inactivates Factor-X:
o Therefore Inhibits activation of Fibrinogen to Fibrin.
• 3. àAlso Inhibits Most Intrinsic Pathway Factors (IX, XI, XII).

o Indications:
§ Any Acute Coronary Syndrome (eg. NSTE-MI/Unstable Angina/Peripheral Arterial Occlusion)
§ Atrial Fibrillation
§ Deep-Vein Thrombosis & Pulmonary Embolism
§ Heart Surgery
o Side Effects:
§ *Haemorrhage – (However Protamine is an antidote)
§ *Thrombocytopaenia – (See Next Page)
§ (Osteoporosis)
§ (Hypoaldosteronism with Hyperkalaemi)
§ (Allergic Reactions/Local Reactions – Skin Necrosis, Irritation, Haematomas)
o Other Info:
§ Rapid (Almost Instant) Onset of Action
§ Heparin is ONLY used in a Clinical Setting (Ie. Pts can’t be sent home on it)
§ Cannot be administered orally (too lipophobic à Poor absorption).
• Therefore Delivered IV à MUST BE MONITORED.
GLS Question: What is Heparin-Induced Thrombocytopaenia?:

 - *Thrombocytopaenia – As a Side-Effect of Heparin:
o What is Thrombocytopaenia?
§ Thrombocytopaenia = Low number of Platelets
o What is Heparin-Induced Thrombocytopaenia?
§ Type-I:
• Occurs during the first 1-2days of Treatment
• Transient & Asymptomatic
• Clinically Insignificant
§ Type-II:
• Occurs around Day 5 of Treatment
• Consequence of an Immune Reaction
• Associated with a Thrombo-embolic Risk.
o Theory behind Heparin-Induced Thrombocytopaenia:
§ Antibodies (IgG & IgM) directed against Complexes of Heparin & Platelet-Factor-4.
§ Binding of Antibodies to Heparin:PF4 forms an Immune Complex (Ab:Hep:PF4) which
Activates Platelets à Thrombus Formation (àThrombocytopaenia).

- Low Molecular-Weight Heparins (LMWH) – Eg. ENOXAPARIN:
o What are they?:
§ = Small Heparin Fragments
o Mechanism of Action:
§ Binds & Activates Antithrombin-III to form an AT-III:Heparin Complex. (Same as Heparin)
• #1. à Inactivates Factor-X:
o Therefore Inhibits activation of Fibrinogen to Fibrin.
§ NB: However, LMWHs are Too Small to inactivate Thrombin :. Only target Factor-X.
o Advantages over Normal Heparin:
§ Longer T1/2
§ Self-Administration (Sub-Cut Injection)
§ Dose-Effects are more predictable
§ NO need for monitoring (Ie. Pt can go home à Frees up a hospital bed)
§ (However, it is quite expensive)

 - Coumarins/Coumadins (Warfarin):
o Mechanism of Action:
§ A Vitamin-K Analogue à Inhibits synthesis of Pro-Coagulation Factors:
• ↓Prothrombin
• ↓Factor-II (Thrombin)
• ↓Factor-VII
• ↓Factor-IX Ie. **All TV Channels**
• ↓Factor-X
§ Explanation:
• Normally: Vit.K is activated by ‘Epoxide Reductase’, allowing it to aid in the synthesis
of the above coagulation factors.
• Warfarin: Warfarin Competes with Vit.K for ‘Epoxide Reductase’, reducing synthesis
of coagulation factors.

o Side Effects:
§ *Bleeding – (However Vitamin-K is an antidote)
§ NB: Many factors influence effectiveness:
• (Diet/Alcohol/Body Mass/Other Meds/Alternative Meds/Comorbidity/genetics)
§ Is TERATOGENIC – CONTRAindicated in Pregnancy.
o Drug Interactions:
§ Warfarin is metabolised by Cytochrome-P-450 Liver Enzymes.
§ Therefore, any drug that Induces CYP-450 enzymes significantly reduces effect of Warfarin.
• Eg. Carbamazepine, Phenytoin, Phenobarbitone – ANTI-EPILEPTICS!!!
o Other Info:
§ Slow Onset – (Takes several days for sufficient competition to occur & for pre-existing
coagulation factors to be used up)
§ Used for Long-Term home-management & doesn’t require monitoring.
§ NB: Vitamin.K can be used as an Antidote for Warfarin Overdose.
• Similarly, a high Vit.K diet can decrease warfarin’s effectiveness.



ANTI-PLATELET DRUGS:
- **Aspirin:
o Mechanism of Action:
§ COX-I Inhibitor – Irreversibly Inhibits Cyclo-Oxygenase-1 (COX-1)à Prevents Thromboxane
formation from Arachidonic Acid.
• (COX-1 (and COX-2) is responsible for Prostanoid synthesis [ie. Prostaglandins,
Thromboxane & Prostacyclin] from Arachidonic Acid, and is expressed by all cells)
o (Cox-2 is only expressed during inflammation & wound healing)
• (NB: Thromboxane is a Platelet-Aggregator – Acts by stimulating the expression of
the Glycoprotein receptor “GP-IIb/IIIa” à Aggregation)
§ NB: Aspirin blocks a Platelet’s Thromboxane-forming abilities for the life of the platelet.
• Why? – Because platelets have NO Nucleus à Can’t Re-synthesize Cyclo-oxygenase.
• Therefore – Aspirin has an ‘apparent’ selectivity for Platelets.

o Indications:
§ Reduce risk of Myocardial Infarction/Angina
§ Acute Stroke
o Side Effects:
§ GI-Bleeding (due to loss of Prostaglandins [which are protective by ↓Acid & ↑Mucus])
§ Toxic dose can cause Respiratory Alkalosis
o Other Info:
§ NB: Antiplatelet effects of Aspirin occur at Low Doses. (≈100-300mg/day)
• Headaches ≈ 600-900mg/day
• Anti-Inflammatory ≈ 5000mg/day (BUT à Now Obsolete due to GI Problems)


 - Dipyridamole:
o 2x Mechanisms of Action:
§ Phosphodiesterase (PDE) Inhibitor:
• (NB: PDE normally inactivates cAMP)
• PDE-Inhibitors Prevent inactivation of cAMP (& cGMP)à ↑cAMP à
§ Adenosine Uptake Blocker:
• à Increased Intracellular Adenosine (the major constituent of cAMP)à ↑cAMP à
• (Adenosine also acts as a Vasodilator)

• à↑cAMPà↑cAMP Inhibits Platelet Aggregation by decreasing Cytosolic Ca+
Levels.
o ↓Ca+ à Inhibits Ca-Mediated Vesicular Exocytosis of Pro-Aggregation
Factors from the Platelet (Particularly Thromboxane).

o Indications:
§ Secondary Prevention of Ischaemic Stroke
§ Secondary Prevention of Transient Ischaemic Attacks (TIAs – ‘Mini strokes’)
o Side Effects:
§ Headache
§ GIT Disturbances
§ Hypotension
§ Allergy


- Clopidogrel:
o Mechanism of Action:
§ ADP-Receptor Antagonists à Prevents Binding of ADP to plateletà
• à Prevents ADP-Mediated activation of Glycoprotein Receptor “GP-IIb/IIIa” à
o à Prevents Platelet-Aggregation
o Indications:
§ (Originally used for Patients Intolerant to Aspirin – now also used in conjunction with Aspirin)
§ Myocardial Infarction (Prevention & Treatment)
o Side Effects:
§ Bleeding
§ GI Discomfort
§ Rashes
o Other Info:
§ Is a ‘Pro-Drug’ à Must be metabolised by Cytochrome-P450 enzymes to be Activated.
• (NB: Active metabolite is unknown)
§ Onset Takes ≈ 8-10 days.
§ Action is augmented by other Antithrombotic Drugs.

- ABCIXIMAB (Yes, that is its actual name):
o Mechanism of Action:
§ GP-IIb/IIIa Antagonist:
§ A Monoclonal Antibody against the Platelet Glycoprotein Receptor “GP-IIb/IIIa”
• (GP-IIb/IIIa Destruction à No Aggregation)
§ Surface-Proteins:
• Vitronectin Receptors (which play a major role in platelet aggregation)
o Indications:
§ Used in Angioplasty (ie. Widening a narrowed/obstructed vessel – Typically Atherosclerotic)
§ Possible use in preventing Thrombus/Embolus complications during Neurovascular Surgery.
o Side Effects:
§ Bleeding
§ Thrombocytopaenia
o Other Information:
§ NB: The name is simply the ‘well number’ + MAB (monoclonal antibody)

THROMBOLYTICS:
- NB: Schematic of Fibrin Formation & Degredation:

- Streptokinase:
o Mechanism of Action:
§ An exogenous Plasminogen Activator (Catalyses conversion of Plasminogen to Plasmin).
• à Plasmin Degrades Fibrin
o Indications:
§ Thrombolysis of Inappropriate Blood Clots:
• Pulmonary Embolism
• Myocardial Infarction
• Stroke
o Side Effects:
§ Risk of Haemorrhage
o Other Info:
§ Derived from Haemolytic-Streptococci Bacteria.
§ *Inhibited by Lipoproteina (an endogenous lipoprotein now considered a risk factor for MI)

 - (Exogenous) Recombinant Tissue Plasminogen Activator (r-tPA):
o NB: Tissue Plasminogen Activator (tPA) is normally a protein expressed on Endothelial Cells lining
Undamaged Blood Vessels:
§ Its role is to prevent inappropriate fibrin-clot formation in Intact Vessels.
§ However, tPA can be Manufactured using Recombinant Biotechnology à r-tPA:
• Ie. “Alteplase/Tenecteplase/Reteplase”.
o Mechanism of Action:
§ Exogenous Plasminogen Activator (Catalyse conversion of Plasminogen to Plasmin).
• à Plasmin Degrades Fibrin à Thrombolysis
o Indications:
§ Thrombolysis of Inappropriate Blood Clots:
• Pulmonary Embolism
• Myocardial Infarction
• Deep Vein Thrombosis
• Stroke
§ Novel use = Frostbite à fewer amputations.
o Side Effects:
§ Risk of Haemorrhage (However, is ‘clot-specific’ à fewer haemorrhages)
• (However, in tPA Overdose, Aminocaproic Acid is an Antidote.)
§ Nausea/Vomiting
§ *Inhibited by Lipoproteina (an endogenous lipoprotein now considered a risk factor for MI)
o Other Info:
§ Very expensive (Sometimes Not Cost-Effective)

 SUMMARY OF HAEMOSTASIS DRUGS & SITES OF ACTION:



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