CHAPTER 33

Red Blood Cells, Anemia, and

Polycythemia

BLOOD

Blood cells (45%) Plasma (55%)

RBC WBC PLATELET Liquid (90%) Solid (10%)

Water Proteins Nutrients Gases Ions Wastes

Functions: Coagulation factors
• Nutritive Function Antibody
• Respiratory Function Proteins
• Excretory Function Albumin
• Transport of hormones / Enzymes Fibrinogen
• Regulation of Water balance
• Regulation of Acid-base balance
• Regulation of body temperature *Serum = Plasma - Fibrinogen
• Storage function
• Defensive function

242
 7.8um
RED BLOOD CELLS
Biconcave 2.5um
Males: 52 lac/mm² 1um
Females: 47 lac/mm ↑ membrane
↓ material inside Squeeze
Functions

Oxygen Transport CO₂ transport Acid-Base buffer

↓ ↓ ↓
100ml blood → 45ml RBCs Carbonic Anhydrase Hemoglobin
100ml RBC → 34gm hemoglobin ↓ (protein)
l00ml blood → 15gm hemoglobin(males) H₂O+ CO₂ → H₂C0₃ (tissues)
1gm hemoglobin → 1.34ml Oxygen H₂CO₃ → H₂O+ CO₂ (lungs)
100ml blood → 20ml Oxygen (males)

Hemoglobin
↓
Oxygen binding protein present in RBCs

Production of Red Blood Cells

Early weeks of gestation Yolk sac

Middle trimester Liver, Spleen, Lymph node

Last month of gestation

Bone Marrow of all bones
+ After birth up till 5 years
Membranous bones +
5 years - 20 years
Proximal portion of humeri & tibiae
Only Membranous bones
> 20years
(Vertebrae, Sternum, Ribs)

243
 Pluripotent Haematopoietic Stem Cells"
(PHSC) *Growth Inducers
(Interleukin-3)
*Differentiation Inducers

Lymphoid Stem Cell Colony Forming Unit-Spleen

(LSC) (CFU-S)
CFU
Blast
CFU CFU CFU
Megakaryocytes Granulocytes Erythrocytes
Monocytes

Lymphocytes Platelets WBCS RBC

Stages of Erythropoiesis
Haemoglobin Mitochondria , Ribososomes
Stage Size Nucleus Nucleoli
(Hb) & other points

Pro-Erythroblast- Nucleus Nucleoli Haemoglobin

14-19um
present present absent
Basophil- Nucleus Nucleoli Haemoglobin
12-17 um
Erythroblast present Absent absent

Haemoglobin
Poly Chromatophil- Nucleus Nucleoli
12-15 um synthesis
Erythroblast present Absent
starts

Ortho Chromatic- Pyknotic degeneration (shrinkage & condensation)

Nucleus Nucleoli Haemoglobin
Erythroblast 10-15 um Karyolysis (swelling)
is lost Absent present
Karyorrhesis (degeneration of chromatin)
Bone marrow Mitochondria , Ribososomes
Nucleus Nucleoli Haemoglobin 2-3 days Present
Reticulocyte 7-10 um
absent Absent present Circulation Mitochondria , Ribososomes
24 hours Lost
Erythrocyte Nucleus Nucleoli Haemoglobin Mitochondria , Ribososomes
6-7.5 um
(MATURE RBC) absent absent present Absent

244
 "ERYTHROPOEITIN and RBC production"
Low blood volume
Anemia
↓ Hemoglobin Hypoxia Renal tissue hypoxia
↓ Blood flow ↓
Lung disease Hypoxia Inducible factor
↓
Hypoxia Response Element
(Erythropoietin gene)
Epinephrine
Norepinephrine Erythropoietin
Prostaglandins
Fibroblast like peritubular interstitial cells
Renal epithelial cells – 90%
Liver – 10%
↓
Bone Marrow
↓
↑Proerythroblast ↑Proerythroblast ↑Release of
production ↓ Mature Erythrocytes
Mature RBC conversion (5 days)

Factors Necessary for

Erythropoiesis
↓
General factors Maturation factors Factors for Hemoglobin synthesis
↓ ↓ ↓
• Erythropoietin • Vitamin B-12 • Proteins
• Thyroid hormone • Folic acid • Aminoacids
• Growth factors • Intrinsic factor • Iron
IL-3, IL-6, IL-11 • Copper
• Vitamins • Cobalt
Vitamin B, C, D, E • Nickel
• Vitamins
Vitamin C, B2, B3, B6

245
“Vitamin B-12, Folic Acid & RBC maturation"
“Vit B-12 Absorption” "Pernicious Anemia“ “Folic Acid”
"Folic Acid"
Beef, Liver, chicken Atrophy in gastric mucosa ↓
↓ Green vegetable
↓
B-12 ↓gastric secretions Fruits
↓
↓ Meat (Liver)
Stomach ↓Intrinsic factor
↓
deficiency
↓ ↓
Intrinsic factor ↓B-12 absorption * Dietary Deficiency
↓ Malabsorption Maturation failure
produced by parietal cells ↓Thymidine triphosphate
↓
↓
Intrinsic factor B-12 Prevents Digestion ↓DNA maturation
Assists Absorption
↓
Intrinsic factor B-12 but normal RNA synthesis
Intrinsic factor B-12 Mucosal cell
Intrinsic factor B-12 ↓
Nucleo-
↓ (Ileum) Nucleus not maturing
cytoplasmic
Pinocytosis Cytoplasm maturing normally asynchrony
↓ ↓
Blood Cell grows large before nucleus
↓ matures & replicates
Stored in LIVER
Liver -B-12
B-12 ↓
↓ Flimsy Membrane (↑fragility)
Maturation of RBC ↓
Bone Marrow B-12 Short life of RBC

246
 Heme globin
HEMOGLOBIN FORMATION
2 Succinyl-CoA + 2 glycine Pyrrole
4 Pyrrole Protoporphyrin IX
Protoporphyrin IX + Fett Heme
Hemoglobin A
Heme + Polypeptide Hemoglobin chain
(α, β, δ, Y, ζ, ε)

HEMOGLOBIN TYPES
97% Hemoglobin A : 2 alpha chains + 2 beta chains alpha: α
Adult 2% Hemoglobin A2 : 2 alpha chains + 2 delta chains beta: β
21% Hemoglobin F : 2 alpha chains + 2 gamma chains delta: δ
Embryo Gower 1 : 2 zeta chains + 2 epsilon chains gamma: Y
0-7 weeks
Gower 2 : 2 alpha chains + 2 epsilon chains zeta: ζ
Fetal life
8 weeks-onwards Hemoglobin F : 2 alpha chains + 2 gamma chains epsilon: ε

Hemoglobin Abnormalities
Sickle Cell Anemia a-Thalasemia
HemoglobinSS: 2 alpha + 2 beta(s)
Hemoglobin
Hemoglobin H : 4 beta chains
In beta chain [beta(s)]
aminoacid glutamic acid Hemoglobin Barts : 4 gamma chains
is replaced by aminoacid Valine. Sickle cell
↓ Low oxygen Crisis
Elongated crystals
Block blood
Sickle shaped inside RBCs supply to cells
RBC ↓
Cells stuck in small capillaries
↓
Rupture
↓
Anemia
(Sickle Cell Anemia)

247
 Transport and Storage of IRON
Food
(Iron)
↓
LIVER (Apotransferrin) Bile Intestine
(Transferrin)
↓
Feces O.6mg (Daily loss) Blood
Menstrual loss (Transferrin) LIVER + Reticuloendothelial cells
0.7mg ↓ (Iron + Apoferritin) of bone marrow
Bone Marrow ↓
(Erythroblasts) Ferritin (Soluble, small storage form)
↓ ↓
Myoglobin Hemoglobin Hemosiderin (Insoluble, Large clusters)
cytochrome formation
cytochrome oxidase (120day)
Peroxidase RBC destroyed
Catalase (Monocyte-Macrophage) system

Life span of Red blood cells

120 days
Still RBC
No nucleus can produce
No mitochondria
ATP
Cytoplasmic enzymes
No Endoplasmic Reticulum

Maintain cell Maintain membrane Maintain Prevent

membrane pliability transport ferrous form oxidation

(with time enzymes becomes less active)

↓
Membrane become fragile
↓
84um RBC is destroyed passing 3 um Splenic red pulp trabecular spaces
↓
Macrophages (Liver + spleen) phagocytize hemoglobin

Iron Porphyrin
↓
Stored as used by
Bilirubin Bile
Ferritin new RBCS

248
 ANEMIAS

↓ in Red Cell Mass / ↓ in Hemoglobin

Microcytic Anemia Normocytic Anemia Macrocytic Anemia

MCV<80fl MCV-80-100fl MCV>100fl

↓ Production Hemolysis ↓
↓ ↓
Iron deficiency anemia Aplastic anemia Hereditary Spherocytosis Vit. B-12 deficiency
Anemia of chronic disease Renal disease Sickle cell anemia Folic acid deficiency
Thalassemia Malignancy Erythroblastosis Fetalis Liver Disease
Sideroblastic anemia G6PD deficiency Drugs
Paroxysmal Nocturnal hemoglobinuria
Auto-immune hemolytic anemia

Blood loss
loss Anemia Hereditary
Hereditary Spherocytosis
Spherocytosis
Blood Anemia
Rapid hemorrhage RBCs lack normal loos bag-like membrane
↓ ↓
Body replaces fluids (1-3 days) Shape becomes spherical instead of Biconcave
↓ ↓
Hemodilution RBCs cannot squeeze thru splenic red pulp
↓
↓
Anemia ruptured
↓
↓
Returns to normal (3-weeks) anemia
APLASTIC Anemia
APLASTIC Anemia
Chronic
Chronic blood
bloodloss
loss
↓
SLE Radiations Chemotherapy Insecticides Benzene
Iron not absorbed rapidly
↓
↓
Body tries to ↑ RBC production Damage Stem cells
↓ ↓
Smaller than normal RBC Treat with Blood Transfusion
è less hemoglobin are produced
cause unknown: IDIOPATHIC APLASTIC Anemia

249
 Effects of Anemia on Circulatory System

Anemia
↓
Anemia
↓
↓ number of RBC
↓ ↓ number of RBC
↓ Oxygen supply to tissues of flowing blood ↓
↓ ↓ internal friction of flowing blood
Peripheral blood vessels dilate (↓Viscosity) (1.5 times of H₂O)
↓ ↓
↑ blood flow to tissues ↑ in ease of blood flow to tissues
↓ ↓
↑ Cardiac Output ↑ Cardiac Output

It balances ↓oxygen carrying effect of anemia

↓
until the person exercises
(cardiac failure)

"POLYCYTHEMIA"
(↑number of RBCs)
SECONDARY POLYCYTHEMIA POLYCYTHEMIA VERA

High altitude Cardiac Failure Genetic defect in Hemocytoblastic cells

↓
physiological ↓ oxygenation of tissues Blasts keep on producing RBC, WBC + platelets
polycythemia ↓
Normal-BP ↓

↑ RBC production Vessels become engorged è RBCs

↓
↑viscosity ↓

↓venous return ↑ed viscosity &

↑ Viscosity ↑ed blood volume
↓ ↑blood volume
↑ blood volume ↑Venous return

↓
Cardiac Output-Normal

↑ Viscosity → Sluggish blood flow (skin subpapillary venous plexus)

↓
↑ De-oxygenation
↓
Bluish discoloration of skin (cyanosis)

250
 CHAPTER 34
Resistance of the Body to Infection: I.
Leukocytes, Granulocytes, the Monocyte-
Macrophage System, and Inflammation

White Blood Cells (WBC)

Granulocytes
Granulocytes Agranulocytes
Agranulocytes

Neutrophils Eosinophils Basophils Monocytes Lymphocytes

62% 2.3% 0.4% 5.3% 30%
Bone Marrow Bone Marrow Bone Marrow Bone Marrow Lymphogenous tissues
↓ ↓ ↓ ↓ ↓
Blood Blood Blood Blood Lymph
(4-8 hrs) (4-8 hrs) (4-8 hrs) (10-20 hrs) ↓
↓ ↓ ↓ ↓ Blood
Tissues Tissues Tissues Tissues ↓
(4-5 days) (4-5 days) (4-5 days) (months) Tissues
↓ ↓ ↓ (week-months)
↓ ↓ ↓ Tissue Macrophages B-cells T-cells
↓ ↓ ↓
↓ ↓
Provide defense ↓
↓ ↓ Plasma cells
mainly by • Allergic Reaction ↓ ↓
↓
↓ • Anti-parasitic • Allergic
Reactions •Phagocytosis • Antibodies • Kills by
• Phagocytosis • Modulation of • Release Histamine (Tissues) production cytotoxins
(Blood + tissues) inflammatory response

251
 Chemotaxis
(the movement of an organism or a cell in response to a chemical stimulus)
Caused by: Toxins, Inflamed degenerated tissue & complement complex
(Released by: Bacteria, Virus, Parasite)
↓
Margination
(process where WBCs move to the periphery, or margins, of blood vessels)
Selectin
Integrin
ICAM
Neutrophils Endothelial cells
↓
Diapedesis
(squeezing thru pores)
↓
Ameboid
Ameboid Movement
Movement
in
in tissues,
tissues, towards
towards chemotactic
chemotactic source
source
↓
Chemotactic
Phagocytosis
Source
Cellular ingestion

Phagocytosis
Loss of smooth surface
NEUTROPHILS:
Loss of protective layer
• Can phagocytize both Interaction of (foreign body-antiboaly-C3-phagocytic membrane)
in blood & tissues “OPSONIZATION”
• Can phagocytize
3-20 bacteria
Pseudopodia formation
Fusion of psendopods around foreign body
MACROPHAGES: Phagosome formation
• Can phagocytize only
in tissue.
• Can phagocytize Lysosome attaches Phagosome
- 100 Bacteria Digestive vesicle
- RBCS Digestion by PROTEOLYTIC Enzymes & LIPASES)
- Malarial Parasite
• Survive for months
Peroxisome attaches Phagosome
(kills, FOREIGN ORDANISM by OXIDATION)
(Superoxide, hydrogen peroxide, hydroxyl ions, hypochlorite)

252
 MONOCYTE-MACROPHAGE SYSTEM
(RETICULO-ENDOTHELIAL SYSTEM)

• Monocytes
• Mobile Tissue Macrophages
• Fixed Tissue Macrophages
• Specialized endothelial cells
(lymph node, bone marrow, Spleen)

Skin
Skin Lungs
Lungs GI
GI tract
tract Lymph
Lymph Blood
Blood

Lung Lymph node Macrophages in

Histiocytes Kupffer cells Spleen & Bone
Macrophages (in LIVER) Macrophages
Marrow
Digestible Indigestible
Intestine Afferent lymphatic
↓ ↓ Afferent artery
↓ ↓
Digest "Giant cell capsule“ ↓
Portal circulation Nodal Medullary Sinuses
↓ Trabeculae of
-Tuberculosis (Tb) ↓
LIVER Efferent Lymphatics Splenic red pulp
-Silica Dust ↓
Carbon particles Venous sinus

Inflammation
Injury
↓
Substances released by injured tissues
↓

• Histamine • Lymphokines
• Bradykinin • Complements reaction products
• Prostaglandins • Blood system clotting system
• Serotonin • Clotting reaction products
↓
• Vasodilation
• ↑Permeability
• Swelling of tissue
• WBC migration
• Clotting of fluid in
interstitial spaces

253
 Lines of Defence
(during Inflammation) Walling-Off effect of Inflammation
1st line of Defence
→(Tissue Macrophages) vasodilation
↓
1st hour ↑permeabilty
-↑ in size ↓
-Sessile -> Mobile fibrinogen mores in interstitial spore
↓
2nd line of Defence tissue spaces & lymphatics
→(Neutrophils from blood) are blocked by fibrinogen clots
↓
Several hours
Stops spread
-↑ in number (NEUTROPHILIA)
• Staphylococci - ↑toxicity - ↑walling off effect
3rd line of Defence • Streptococci - ↓toxicity - ↓walling off effect

→(Monocytes from blood enter tissues)

Days to weeks
Pus formation
↑in size - ↑lysosomes
-converted to macrophages
Dead foreign organisms,
4th line of defence Dead neutrophils & macrophages,
Dead Necrotic tissue,
(↑ed Granulocyte + Monocyte Tissue fluids
production from bone marrow) (post-infection)
Months to years

254
 EOSINOPHILS 2%

Parasitic Infections
Allergic Reactions
↓
Attached to parasite and kill them by
Mast cells + Basophills
release
Hydrolytic enzymes Highly reactive Major Basic "Eosinophillic chemotactic factor"
(lysosomes) oxygen species Protein ↓
Eosinophil accumulate at allergic site

Detoxification of Phagocytosis of
Inflammatory mediators Allergen-Antibody
complex

Prevents spread
of
local inflammatory process

Allergin (First Exposure)

B-cell
BASOPHIL Antibodies
& Plasma cell
Y Y
MAST CELLS Y
Y Y
Mast Cells Basophils

(2nd Exposure)
Y Y

Slow Reacting
Release of chemical mediators Substances of
Anaphylaxis
Histamine Bradykin Heparin Serotonin (Leukotrienes)
↓ ↓ ↓
Vasodilation Vasolilation Anti-inflammatory Vasodilation
Broncho- constriction Broncho- constriction effect Broncho-Constriction
chemotaxis

255
 LEUKOPENIA
X-rays, Gamma rays, Benzene, Anthracene nuclei,
Chloramphenicol, Thiouracil, Barbiturates
↓
Damage Bone Marrow
↓
↓ in production of White Blood Cells
↓
↓ Immunity
↓
Normal bacterial flora cause opportunistic infections
(2 days)
↓
Death results
(less than a week)
↓
Stop the triggering factor / Bone Marrow transplant

LEUKEMIAS
Cancerous mutation in
myelogenous or lymphogenous cells
↑ in abnormal WBCS ↓
↓ in RBCS ↑ In WBC production
↓ in Platelets ↓
Bone become weak
Cancerous cell invade ↓
normal bone marrow Fractures
↓
Myelogenous leukemia ↓ in RBC and Platelets production
↓
Bone Marrow
Lethargy, bleeding infections
↓
lymph node, spleen, liver Lymphogenous Lenkemia
↓ ↓
Nentrophilc lenkonia Partially differentiated Band T lymphocytes
Eosinophilic lenkemia Leukemias ↓
Basophilic leukemia (good prognosis) Lymphoid cells

256
 CHAPTER 35
Resistance of the Body to Infection:
II. Immunity and Allergy

IMMUNITY
Ability of the body to
resist harmful Acquired Immunity
organisms/toxins
Innate Immunity Active Immunity Passive Immunity

• Anatomic barriers (Skin) Artificial

Natural
Natural Artificial
Artificial Natural
Natural Artificial
• Phagocytosis (WBCS) Infection Vaccination Antibodies from antibodies
↓ ↓ mother directly injected
antibodies antibodies ↓ to blood
• Acidic secretions (Stomach)
antibodies
•Chemicals
-Lysozymes (Tear, Saliva, Milk) Acquired Immunity

-Basic Polypeptides (Skin, eye, Humoral Immunity Cell-mediated Immunity

mouth, gut- Mucous layers)
B-lymphocytes T-lymphocytes
-Complement Complex (Proteins) ↓ ↓
Antibodies Activated
-Natural killer Lymphocytes T-lymphocytes

257
 Antigen Foreign body
Molecule/Molecular structure
present on the outside of any foreign body
and has ability to generate immune response.
(High Molecular Weight Protein/Polypeptide) Antigen

Epitope Antigen
It is basically the part of antigen Epitope
which has ability to generate antigenic response
Also antibody binds antigen at epitope.
Epitope Y Antibody

(Regularly Recurring Molecular Groups

Bone Marrow

B-lymphocyte T-lymphocyte

Pre-Processing: Pre-Processing Pre-Processing

-Self reacting are done in done in
destroyed
-Specific reactivity
Bone Marrow Thymus
Spleen
lymph node Thymus
lymph node
Bone Marrow
Antigen Antigen Resp. GI tract

Activated
Antibodies T-lymphocytes

Directly killing Killing by Killing by

Foreign invaders Complement system Cytotoxic T-cells

258
 Acquired Immunity
gene segments Spleen
Thymus
gene Cell mediated immunity Bone marrow
Respiratory tract (adenoids)
GI tract
Different
T-cell clones

Activated T
lymphocytes
Pre-processing Antigen
Before birth
till few weeks Antibodies
after birth
Y Y Y
Different Lympho- Plasma-
B-cell clones blast blast
Foreign body
Antigen
Mid-fetal life Macrophage
Liver Pre-processing
Humoural immunity (Antigen Presenting Cell)
i) Develop specific reactivity against 1 antigen.
ii) Self-antigen reacting lymphocytes are destroyed. Antibody on cell Surface receptor
membrane of B-cells protein on T-cells

259
 B-cell clones

Lympho-
bast

Plasma-
bast
Divides 10 hourly
x 9 times
‘500’ in 4 days
Plasma-
cell
2000
molecules/second
Y
Y
Y

1st Antigen 1st Antigen

Exposure Exposure MEMORY CELLS
Primary & Secondary Immune Response

B-cell B-cell
Antibody Concentration

i) Added Response
Lympho- ii) Less time for activation
bast iii) Prolonged response

Antibodies

Plasma- YYY
bast 1st 2nd

Time

Plasma-
cell

Antibodies YYY

260
 Antigen-Antibody bond/forces:
ANTIBODY
i) Hydrophobic bonding
ii) Hydrogen bonding Classes:
Classes: (GAME-D)
iii) Ionic attractions Ig G: 80% of all. Raised in chronic infection
iv) Van der Waals forces Ig A: Present in body secretions (Saliva mucus)
Ig M Largest structure. Anti A & Anti B (Blood)
Ig E: Attaches to Basophils + Mast cells (Allergy)
Ig D: Part of B-cell receptor
Variable
Variable portion
portion
Unique amino acid organization
Attaches to antigens
Light
Chain Constant
Constant portion
portion
Antibody diffusion
Heavy Adherence to tissue
Chain Attachment to complement complex
Ease of passing through membrane

"Affinity Constant” = "Ka” = Conc. of bound Antigen-Antibody

2 heavy chains 10 heavy chains (Measure of how tightly Conc. of antibody x Conc. antigen
2 light chains 10 light chains antibody binds antigen)

“CLASSICAL PATHWAY” Lytic

Of Complement System Complex

261
 Mechanism of Action of ANTIBODIES

Direct Action Activation of complement system

20 proteins (Enzyme precursors)
Activated by: Classical Pathway

• Agglutination • Agglutination
Antigens are bound Complement products make invading organism stick each other
together in a CLUMP
• Neutralization
complement enzymes attack toxic structures of invaders
• Precipitation
Antigen-Antibody complex • Lysis (Lytic complex - C5b6789)
becomes insoluble Rupture of membrane of invader

• Neutralization • Opsonization C3b

Antibodies cover toxic C3b tags foreign invaders to get them phagocytosed by phagocytes
sites of antigenic agent • Chemotaxis CSa
C5a attracts neutrophils & macrophages.
• Lysis
Antibodies directly • Mast cell & Basophil activation C3a, C4a, C5a
rupture foreign bodies Release of histamine, heparin → Inflammation.
• Inflammation
↑ Blood flow, ↑ Permeability, Walling off etc.

Antigen Presenting Cells, MHC, T-cells

Cytotoxic Helper
T-cell T-cell

(antigen) (antigen)
MHC - I MHC - II
Protein Protein

All nucleated cells Professional Antigen Presenting cells

MHC Dendritic cells

(Major Histocompatibility Complex) Macrophages
B-cells
MHC proteins are encoded by
MHC gene

262
 Types of T-cells

i) T-helper cells
Helps T cells, B cells, Macrophages (by Lymphokines)
↓ in AIDS
Interleukin-1
ii) Cytotoxic T cell
Kills invaders by:
-Secreting Perforins (hole forming proteins)
-Secreting cytotoxic substances
-Destroying cancer cells & transplanted organs
-Being leathel to invaded tissue IL-2
IL-2

iii) Suppressor T cells

Suppresses helper & cytotoxic T cells
IL4 IL-2
IL5
IL6

Immune Tolerance
It is the state of unresponsiveness of the
immune system to body's own antigens.

Before birth
self-antigens are exposed to Lymphocytes
↓
lymphocytes which react with
Self antigens are destroyed
Auto-immune diseases

Immune Tolerance is lost

↓
lymphocytes react self-antigens

Rheumatic fever Glomerulonephritis Systemic Lupus Erythematosis Myasthenia Gravis

263
 Vaccination
Dead organisms, Live attenuated organisms, Toxins
are injected into the body
↓
unable to produce disease but able to generate
immune response

Dead organisms Live attenuated organisms Toxins

↓ ↓ ↓
Typhoid Smallpox Tetanus
Whooping caugh Yellow Fever Botulism
Diphtheria Poliomyelitis
Bacterial disease Measles
Viral Diseases
2nd dose
1st dose
Secondary Immune Response
Primary Immune Response
(Memory Cells)

Anaphylaxis
Antigen in circulation Allergy & Hypersensitivity Asthma
↓
Histamine SRA antigen in
↓ ↓ ATOPIC Allergies bronchioles
Permeability Bronchoconstriction (↑IgE Antibodies) ↓
Vasodilator ↓ SRA
↓ Asthma like attack ↓
Allergen
↓Bp Bronchoconstriction
(Antigen that reacts & IgE Antibodies)
↓ ↓
Urticaria IgE Antibody production Suffocation
Antigen in Skin ↓
↓
IgE Antibody attached è Mast cell + Basophils
Histamine ↓
↓ Delayed Reaction Allergy
Permeability & Vasodilation 2ndAllergen exposure Poison Ivy
↓ ↓ ↓
Hives Mast cells + Basophils icells
attached è IgE Antibodies are ruptured ↓
Hay Fever ↓ 2nd exposure
Histamine, ↓
Antigen in nose
↓ Slow reacting substance of anaphylaxis (SRA), Tcells enter tissues
Histamine Protease, Eosinophil chemotactic substance, ↓
↓ Heparin, Neutrophil chemotactic substance Tissue Damage
local Intranasal dilation Platelet activating factor
Runny Nose, Sneezing

264
 CHAPTER 36
Blood Types;
Transfusion;
Tissue and Organ Transplantation

RBCs have antigens on their surfaces

(Total = Hundred antigen types)
(Commonly occurring = 30 antigen types)
(strong antigenic response = 2 antigen types)

ABO ABO Rh
Rh
blood grouping
bloodsystem
grouping system blood
blood grouping system
grouping system

Blood Groups = A, B, AB, O Blood Groups = Rhtive & Rh-ive

ABO gene has 3 types of Alleles
IA = A AA AO AB (co-dominance)
IB = B BB BO
IO = O OO

IO is recessive

265
 “ABO Blood Group System”
Antibodies in
Antigen on RBC Can donate Can receive
Red blood cell Percentage Genotype plasma
(Agglutinogen) blood to blood from
(Agglutinin)

A 41% OA or AA A Anti –B A, AB A, O

B 9% OB or BB B Anti –A B, AB B, O

AB 3% AB A+B None AB A, B, O, AB

Anti –A
O 47% OO None + O, A, B, AB O
Anti –B

*A & B antigens are also present on food & bacteria 2-8 months after birth antibodies (IgM & IgG) are produced

Rh blood types

6 common types of Rh antigens

C c
D d
E e

'D' and 'd' are the most prevalent

and most antigenic.
If 'D‘ is present If 'D' is absent
then 'd' is absent then 'd' is present
When 'D' is present - Rh tive When 'D' is absent – Rh -ive

*Rh -ive person produce Rh antibodies (2-4 months)

on exposure to Rh tive blood

266
 Blood typing & Cross-Matching

Blood Typing ↑
RBCs are separated from plasma & diluted
RBCs are mixed è Anti-A antibodies & Anti-B antibodies
Blood group A - shows coagulation with Anti-A antibody
Blood group B- shows coagulation with Anti-Bantibody
Blood group AB- shows coagulation with both AntiA &, AntiB antibody
Blood group O - does not show coagulation

Cross-Matching ↑
Donor's and recipients blood samples are
mixed with each other to observe any coagulation.
Basically mixing recipients plasma with donor's red cells

TRANSFUSION REACTIONS

Mismatched Blood Transfusion

↓
Antibodies attached to Antigens on RBC,
↓
Clumping of cells
↓
Blood vessels are blocked

WBC, attacking RBCs Antigen-Antibody reaction

Physical distortion of calls ↓
↓ Toxic substance released
Hemolysis
Anemia Hemoglobinemia Circulatory Shock Renal
↓ ↓ ↓ vasoconstriction
Tissue Ischemia Hemoglobinuria Renal failure
↓
Renal Tubular blockage
(Acute Ronal failure)

267
 ERYTHROBLASTOSIS FETALIS

Father Rhtive, Mother Rh-ive Rh

Baby Rhtive
↓
At the time of delivery baby's Rhtive enters mother's body
↓
Production of Rh-antibodies in mother
↓
On 2nd pregnancy with Rhtive baby
Rh antibodies from mother enter baby
↓
RBC agglutination

Jaundice Anemia Hepato-spleenomegaly Kernicterus Blasts

Hemoglobin →Bilirubin Hemolysis ↑ production of RBCs from Bilirubin precipitation ↑ new RBC
LIVER & Spleen in brain production
↓
Replace baby's Rhtive blood with Rh-ive blood
(transfuse 400ml blood in 1.5 hours & repeat)
Rh-immunoglobulin (Anti-D antibodies) injection at 28-30 weeks % can be after birth

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 CHAPTER 37
Hemostasis and Blood Coagulation

Platelets
- 1-4 um diameter
Blood cells which form clots and prevent blood loss
- 150,000 – 300,000
Large hematopoietic stem cells - 8-12 days half life
(Megakaryocytes)
↓
Platelets

Cell membrane Endoplasmic Golgi Apparatus Mitochondria Contractile proteins

Glycoprotein
Reticulum ↓ ↓ Actin Myosin
Phospholipids ↓
↓ Enzymes ATP
↓ Ca++
Thrombosthenin
Adherence to Activation of ↓
injured endothelial blood clotting Platelets cont.
cells process

Prostaglandins Fibrin stabilizing Growth factors

↓ factor Growth of:
Inflammation Factor XIII Vascular endothelial cells
Blood flow It crosslinks Vascular smooth muscles
Clot formation fibrin fibers fibroblast

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 HEMOSTASIS
DEFINITION
• Hemostasis is defined as arrest or stoppage of bleeding.

STAGES OF HEMOSTASIS
• When a blood is injured, the injury initiates a series of
reactions, resulting in hemostasis.
It occurs in three stages :-
1. Vasoconstriction

2. Platelet plug formation

3. Coagulation of blood.

Severed vessel

Platelets agglutinate

Fibrin appears

Fibrin clot forms

Clot retraction occurs

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 HEMOSTASIS
• Hemostasis is defined as arrest or stoppage of bleeding.
STAGES OF HEMOSTASIS: It occurs in three stages :-
1. Vasoconstriction 2. Platelet plug formation 3. Coagulation of blood.

1. VASOCONSTRICTION
• Immediately after injury, the blood vessel constricts and decreases the loss of blood from damaged portion.
Usually, arterioles and small arteries constrict.
• Vasoconstriction is purely a local phenomenon.
• When the blood vessels are cut, the endothelium is damaged and the collagen is exposed.
• Platelets adhere to this collagen and get activated.
• The activated platelets secrete serotonin and other vasoconstrictor substances which cause constriction of the blood vessels.
• Adherence of platelets to the collagen is accelerated by von Willebrand factor.
This factor acts as a bridge between a specific glycoprotein present on the surface of platelet and collagen fibrils.

2. PLATELET PLUG FORMATION

• Platelets get adhered to the collagen of ruptured blood vessel and secrete adenosine diphosphate (ADP) and Thromboxane A2.
• These two substances attract more and more platelets and activate them.
• All these platelets aggregate together and form a loose temporary platelet plug or temporary hemostatic plug, which closes the
ruptured vessel and prevents further blood loss. Platelet aggregation is accelerated by platelet activating factor (PAF)

3. COAGULATION OF BLOOD
• During this process, the fibrinogen is converted into fibrin.
• Fibrin threads get attached to the loose platelet plug, which blocks the ruptured part of blood vessels and prevents further
blood loss completely.

1. Vasoconstriction
Blood vessels are cut
The endothelium is damaged
Collagen is exposed
Platelets adhere to this collagen
(von-willebrand factor acts as a bridge between a
specific glycoprotein present on the surface of
platelet and collagen fibrils)
Platelets get activated
Activated platelets secrete serotonin and other
vasoconstrictors
Vasoconstriction blood vessels
(Local arterioles and small arteries)
Decreases the loss of blood from damaged portion
* Local myogenic spasm & nervous reflex also helps vascular smooth muscle contraction

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2. PLATELET Platelets swell & pseudopodia forms
PLUG Platelets becomes sticky get adhered to the collagen of ruptured blood vessel
FORMATION Secrete adenosine diphosphate (ADP) and thromboxane A2
More and more platelets are attracted and then activated
Platelets aggregate together forming a loose temporary platelet plug or hemostatic plug
Ruptured vessel is closed
Prevents further blood loss
*Platelet aggregation is accelerated by platelet activating factor (PAF)

adhesion serotonin +
vasoconstrictor
shape change substances
Platelet

1. Vasoconstriction 2. PLATELET PLUG FORMATION

adhesion serotonin +
vasoconstrictor
shape change substances
Platelet

Collagen

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3. COAGULATION OF BLOOD ENZYME CASCADE THEORY
Stages of Blood Clotting:-
STAGE 1: FORMATION OF PROTHROMBIN ACTIVATOR:-
• Blood clotting commences with the formation of a substance called prothrombin activator, which converts
prothrombin into thrombin.
• Thus, formation of prothrombin activator occurs through two pathways:
i. Intrinsic pathway ii. Extrinsic pathway.

STAGE 2: CONVERSION OF PROTHROMBIN INTO THROMBIN

Blood clotting is all about thrombin formation.
• Once thrombin is formed, it definitely leads to clot formation.

STAGE 3: CONVERSION OF FIBRINOGEN INTO FIBRIN

•The final stage of blood clotting involves the conversion of fibrinogen into fibrin by thrombin.

PROTHROMBIN
ACTIVATOR

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Schema for conversion of prothrombin to thrombin and polymerization of fibrinogen to form fibrin fibers.

274
 Extrinsic pathway for initiating blood clotting.

Intrinsic pathway for initiating blood clotting.

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Clotting Factors

Factor I Fibrinogen
Factor II Prothrombin
Factor III Tissue factor; tissue thromboplastin
Factor IV Calcium
Factor V Proaccelerin; labile factor; Ac-globulin (Ac-G)
Factor VII Serum prothrombin conversion accelerator (SPCA); proconvertin; stable factor
Factor VIII Antihemophilic factor (AHF); antihemophilic globulin (AHG); antihemophilic factor A
Factor IX Plasma thromboplastin component (PTC); Christmas factor; antihemophilic factor B
Factor X Stuart factor; Stuart-Prower factor
Factor XI Plasma thromboplastin antecedent (PTA); antihemophilic factor C
Factor XII Hageman factor
Factor XIII Fibrin-stabilizing factor
Prekallikrein Fletcher factor
High-molecular-weight kininogen - Fitzgerald factor; HMWK (high-molecular-weight kininogen)
Platelets

COAGULATION OF BLOOD

DEFINITION
Coagulation or clotting is defined as the process in which blood
loses its fluidity and becomes a jelly-like mass few minutes
after it is shed out or collected in a container.

FACTORS INVOLVED IN BLOOD CLOTTING

Coagulation of blood occurs through a series of reactions due
to the activation of a group of substances.
Substances necessary for clotting are called clotting factors.

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 CLOT RETRACTION
(Contraction of the blood clot after being formed)

Blood clot formed

after 30-45 minutes Contraction of blood clot

(Actin, Myosin & Thrombosthenin - contractile proteins in platelets)

Straw-colored serum oozes out of the clot

FIBRINOLYSIS
(Lysis of blood clot inside the blood vessel is called fibrinolysis)

It helps to remove the clot from lumen of the blood vessel.

This process requires a substance called plasmin or fibrinolysin.

ANTICLOTTING MECHANISM IN THE BODY

Under physiological conditions, intravascular clotting does not occur. It is
because of the presence of some physicochemical factors in the body.

1. Physical Factors
Continuous circulation of blood Smooth endothelial lining of the blood vessels.

2. Chemical Factors - Natural Anticoagulants

Presence of natural Production of thrombomodulin by endothelium of the blood All the clotting factors
anticoagulant called vessels (except in brain capillaries). are in inactive state.
heparin that is Thrombomodulin
produced by the liver thrombin-binding protein
endothelium of the blood vessels (except in brain capillaries).
Thrombomodulin binds thrombin
protein C activated
protein C + its cofactor protein S inactivates
Factor V and Factor VIII.
Inactivation of these two clotting factors prevents clot formation

3. Commercially available anticoagulants & anti-platelet drugs:

Heparin, warfarin, clopidogrel

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 BLEEDING DISORDERS

Bleeding disorders are the conditions characterized by prolonged bleeding time

or clotting time.
Bleeding disorders are of three types:

1. Hemophilia.
2. Purpura.
3. von Willebrand disease.

Hemophilia
Hemophilia is a group of sex-linked inherited blood disorders, characterized by prolonged clotting time.
Hemophilia occurs due to lack of formation of prothrombin activator.
That is why the coagulation time is prolonged.
The formation of prothrombin activator is affected due to the deficiency of factor VIII, IX or XI.

TYPES OF HEMOPHILIA
Hemophilia A Hemophilia B Hemophilia C
(classic hemophilia) (Christmas disease) (factor XI deficiency)
Due to the deficiency of factor Due to the deficiency of factor IX. Due to the deficiency of factor XI.
VIII. 85% hemophilia 15% of hemophilia It is a very rare bleeding disorder.

Symptoms of hemophilia
Spontaneous bleeding.
Prolonged bleeding due to cuts, tooth extraction and surgery.
Hemorrhage in gastrointestinal and urinary tracts.
Bleeding in joints followed by swelling and pain
Appearance of blood in urine.

Treatment for hemophilia

Effective therapy for classical hemophilia involves replacement of missing clotting factor.

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 PURPURA
Purpura is a disorder characterized by prolonged bleeding time.
However, the clotting time is normal.
Characteristic feature of this disease is spontaneous bleeding under the skin from ruptured capillaries.
It causes small tiny hemorrhagic spots in many areas of the body.
The hemorrhagic spots under the skin are called purpuric spots (purple colored patch like appearance).
That is why this disease is called purpura.

TYPES AND CAUSES OF PURPURA

Purpura is classified into three types depending upon the causes:

Thrombocytopenic purpura
Thrombocytopenic purpura is due to the deficiency of platelets (thrombocytopenia).
In bone marrow disease, platelet production is affected leading to the deficiency of platelets.

Idiopathic thrombocytopenic purpura

Purpura due to some unknown cause is called idiopathic thrombocytopenic purpura.

Thrombasthenic purpura
Thrombasthenic purpura is due to structural or functional abnormality of platelets.

VON WILLEBRAND DISEASE

Von Willebrand disease is a bleeding disorder, characterized by excess

bleeding even with a mild injury.

It is due to deficiency of von Willebrand factor, which is a protein

secreted by endothelium of damaged blood vessels and platelets.

THROMBOSIS

Thrombosis or intravascular blood clotting refers to coagulation of

blood inside the blood vessels.

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