Blood Chemistry Flashcards
(244 cards)
1
Q
Principal transport medium of body for:
✓ Gases (O2 and CO2)
✓ Absorbed food material from GIT
✓ Intermediate metabolites
✓ Hormones
✓ Serum enzymes
✓Metabolic waste
✓ Drugs
A
Blood
2
Q
Functions of Blood
A
- Regulation
→ Acid Base & Water Electrolyte Balance
→ Body Temperature Regulation - Protective
→ Defense against Infection
→ Homeostasis
3
Q
Physical Properties of Blood
A
Blood Volume: 5 to 7% of body weight
Specific Gravity: 1.060 (whole blood)
Average pH: 7.4 (7.35-7.45)
Viscosity: 1.7 to 2 (water=1)
Freezing Point: -0.56°C
Total Osmotic Pressure: 7 atm
4
Q
Plasma Composition (55%)
A
Non diffusible (Large Molecules)
Diffusible (Small Molecules)
Lipids
5
Q
Not easily diffuse through cell; made up of macromolecules
Examples:
✓ Proteins & Polypeptides
✓ Proteins: Albumin, Globulin, Fibrinogen
✓ Other Macromolecules: Enzymes, Clotting Factors, Peptide Hormones
A
Non diffusible (Large Molecules)
6
Q
Waste products of metabolism; can cross cell wall, simpler unit or monomer
Examples:
✓ Catabolic Products: Urea, Uric Acid
✓ Anabolic Products: Glucose, Amino Acids
✓ Electrolytes: Na, Cl, Ca
✓ Hormones, Vitamins, Metabolites
A
Diffusible (Small Molecules)
7
Q
Example:
Lipoproteins: LDL, HDL, Chylomicrons
A
Lipids
8
Q
Biconcave, anucleate with no organelles but only plasma membrane + hemoglobin
Lifespan: 120 days
Origin:
✓ Formed in red bone marrow
✓ Hemoglobin → most important solid constituent of RBCs
Functions:
✓ O₂ & CO₂ Transport
✓ Acid-Base Regulation (via Histidine in hemoglobin)
A
Red Blood Cells / Erythrocytes (41%)
9
Q
Average RBC Count and Hemoglobin (Male)
A
Male
5.4million/uL
Male
16g/dL (14-18 g/dl)
10
Q
Average RBC Count and Hemoglobin (Female)
A
Female
4.8million/uL
Female
14g/dL (12-16 g/dl)
11
Q
Identify the 2 group membrane proteins
A
Integral Proteins
Peripheral Proteins
12
Q
Embedded in the Membrane
A
Integral Proteins
13
Q
Cytoskeletal or Structural proteins (Cytosolic part of RBC membrane)
A
Peripheral Proteins
14
Q
2 types of Carbohydrates of RBC Membrane
A
Glycoproteins
Glycosphingolipids (5-10%)
15
Q
Made up of Ceramide + Oligosaccharide + Lipid
Example:
✓ Lactosylceramide (a globoside)
Functions:
✓ Blood Typing (A, B, AB, O) – Sugar component acts as an antigen
✓ Recognition Sites on integral proteins
✓ Signaling/Receptor Sites
✓ Component of membrane glycoproteins
A
Glycosphingolipids
16
Q
Type: Multi-pass transmembrane protein
Function:
Facilitates HCO₃/Cl⁻ exchange for CO₂ transport
✓ Peripheral Tissues: CO₂ enters RBC as HCO₃
✓ Lungs: HCO₃ exchanges with Cl⁻ release CO₂ for exhale
Structure:
✓ N-terminal (inside): Binds Ankyrin and other peripheral proteins for stability
✓ C-terminal (outside): Exposed to the external environment
A
Anion Exchange Protein (Band 3)
17
Q
Type: Single-pass transmembrane glycoproteins
Function:
Acts as a receptor for Plasmodium falciparum (malaria) and influenza virus
Subtypes: A, B, C
Type A:
✓ 60% glycosylated (rich in sugar)
✓ Contains 90% of membrane’s sialic acid (important for negative charge)
Structure:
✓ N-terminal (outside): Interacts with peripheral proteins
✓ C-terminal (inside): Binds Protein 4.1 (links to cytoskeleton)
A
Glycophorins
18
Q
Anion Exchange Protein (Band 3) is bounded by
A
Ankyrin and other peripheral proteins
19
Q
Glycophorins is bounded by
A
Protein 4.1
20
Q
2 Integral Proteins of the RBC Membrane
A
Anion Exchange Protein (Band 3)
Glycophorins
21
Q
Function:
✓ Essential for RBC shape and flexibility
✓ Attaches Spectrin (cytoskeletal protein) to Band 3 (Anion Exchange Protein)
✓ Ensures RBC deform, squeeze capillaries
Variants:
2.2, 2.3, 2.6 (proteolysis)
A
Ankyrin (Band 2.1)
22
Q
Function:
✓ Principal cytoskeletal protein (100 nm long)
✓ Provides biconcave shape and flexibility
✓ Contains α- and β-chains
Defect
✓ Hereditary Spherocytosis (rigid, non-deformable RBCs)
A
Spectrin (Band 1)
23
Q
4 Binding Sites of Spectrin
A
- Self-association (Spectrin-to-Spectrin binding)
- Ankyrin
- Actin
- Protein 4.1
24
Q
Binds to
✓ Spectrin tails
✓ Actin
✓ Glycophorins (cytoplasmic side)
Function:
✓ Supports RBC membrane stability and flexibility
A
Protein 4.1
25
Function:
✓ Autosomal dominant
✓ Defect of Spectrin (cytoskeletal protein) — ↓ synthesis or function
✓ Effect: Weak spectrin → Weak membrane → Spherocytes (round RBCs)
Outcome:
↓ Deformability
↑ Osmotic fragility
Hemolysis in spleen
Hereditary Spherocytosis
26
Signs and Symptoms of Hereditary Spherocytosis
✓ Hyponatremia → Water influx → Bursting of RBCs
✓ Splenic hemolysis → narrow passages
✓ Splenectomy may improve RBC survival
27
Diagnosis of Hereditary Spherocytosis: Spherocytes lyse easily in hypotonic solutions due to ↓ surface-to-volume ratio
Osmotic Fragility Test
28
ABO Discovery
1901: Karl Landsteiner → A, B, O
1907: Decastrello & Sturli → AB
29
Location: RBC membrane
Structure: Oligosaccharides linked to:
✓ Lipids → Glycosphingolipids (esp. ceramide)
✓ Proteins → Glycoproteins (in other tissues)
ABO Antigens
30
Base for A & B antigens
Composition: Fructose + Galactose
Converted to:
✓ A antigen: Add N-acetylgalactosamine
✓ B antigen: Add Galactose
H Antigen (Precursor)
31
Formation of H Antigen contains an immuno-dominant sugar at the terminal end
Fucose
32
Enzyme involved in the formation of H Antigen
α-2-L-fucosyltransferase
(adds) L-fucose (from GDP-FUC) to terminal galactose
33
Importance in ABO Typing
H Antigen = Precursor to A & B antigens
Required before A or B antigens form
34
Inheritance & Blood Types
A gene → Add N-acetylgalactosamine → A antigen
B gene → Add Galactose → B antigen
No gene → No modification → O type (H antigen only)
35
Antigen and their Immunodominant sugar
Antigen A
🧬 Sugar: N-acetylgalactosamine
Antigen B
🧬 Sugar: Galactose
Antigen H (Type O)
🧬 Sugar: Fucose
Antigen AB
🧬 Sugars: N-acetylgalactosamine + Galactose
36
Glycolipid Structure: Has both A & B antigens
Key Sugars:
✓ N-acetylgalactosamine → A antigen
✓ Galactose → B antigen
Expression: Both antigens present on RBC membrane
Blood Type AB Oligosaccharides
37
Genetic Basis of ABO Blood Types
Locus: Chromosome 9
A allele: 🧪 GalNAc transferase → A antigen
B allele: 🧪 Gal transferase → B antigen
O allele: ❌ Inactive enzyme → H substance remains
Inheritance: Blood type = Combo of alleles from parents
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RBC Antigen: A
Plasma Antibody: Anti-B
Blood Type A
39
RBC Antigen: B
Plasma Antibody: Anti-A
Blood Type B
40
RBC Antigens: A & B
Plasma Antibodies: None
✓ Universal Recipient
Blood Type AB
41
RBC Antigens: None
Plasma Antibodies: Anti-A & Anti-B
✓ Universal Donor
Blood Type O
42
Discovered: 1940 (Landsteiner & Weiner)
Named after: Rhesus monkeys
Structure: Protein (on RBC membrane)
❗ Not a carbohydrate like ABO antigens
Rh Factor
43
Rh Typing (Rh+ vs Rh-)
Rh+: Agglutination with anti-Rh serum
Rh-: No agglutination with anti-Rh serum
44
Rh Genetics (dominant, recessive)
D allele (dominant) → Rh+
d allele (recessive) → Rh-
Genotypes:
🧬 DD / Dd → Rh+
🧬 dd → Rh-
45
Mother: Rh-, Father: Rh+ → Risk of HDN
Rh+ fetus → Mother may produce anti-Rh antibodies
Antibodies cross placenta → Destroy fetal RBCs
Rh- fetus → No immune reaction
Mother-Fetus Incompatibility
46
A condition in newborns where the mother’s antibodies attack the baby’s red blood cells, causing hemolysis (RBC destruction).
🩸 Commonly due to Rh incompatibility between mother and fetus.
Erythroblastosis Fetalis (Hemolytic Disease of the Newborn)
47
No immediate danger
Fetal Rh+ cells enter mom's blood during delivery
Mom produces anti-Rh antibodies
First Pregnancy (Rh- Mom, Rh+ Baby)
48
Anti-Rh antibodies cross placenta
Destroys fetal RBCs → Hemolytic Disease
Second Pregnancy (Rh+ Baby Again)
49
⚠️ Complications of Erythroblastosis Fetalis (Hemolytic Disease of the Newborn)
✓ Severe anemia
✓ Jaundice, fever, swelling
✓ Hepatosplenomegaly
✓ Life-threatening if untreated
50
Treatment of Erythroblastosis Fetalis (Hemolytic Disease of the Newborn)
Rh- blood transfusion to baby
Exchange transfusion → Removes anti-Rh antibodies
51
This is given at 28 weeks & within 72 hrs post-delivery
Also after miscarriage or abortion
Neutralizes fetal Rh+ cells before mom reacts
RhoGAM (Anti-Rh IgG)
52
RBCs use glucose for ATP production via glycolysis (no mitochondria).
Energy Source in RBCs
53
Intermediate metabolite of glycolysis
Decreases hemoglobin's O₂ affinity → Enhances oxygen delivery to tissues
2,3-Bisphosphoglycerate (2,3-BPG)
54
Auto-oxidation of Hb (Fe²⁺ → Fe³⁺) forms methemoglobin
Methemoglobin can’t bind oxygen
Superoxide Formation
55
Includes: Superoxide, H₂O₂
Oxidize Hb → Impair oxygen transport
Reactive Oxygen Species (ROS)
56
Makes NADPH → Keeps glutathione reduced
Reduced glutathione detoxifies H₂O₂, protects RBCs from oxidative damage
Hexose Monophosphate Shunt (HMP)
57
Important inside RBC to protect against oxidative damage
Glutathione
58
G6PD produces NADPH (via the Hexose Monophosphate Pathway)
NADPH reduces oxidized glutathione (GSSG) → GSH (reduced glutathione)
G6PD Deficiency
58
Glutathione & Antioxidant Defense
GSH + Glutathione Peroxidase neutralizes H₂O₂ (hydrogen peroxide)
Vitamin C, Vitamin E, Selenium support antioxidant defense
59
⚠️ Effects of G6PD Deficiency
No G6PD → No NADPH → No reduced glutathione → Increased H₂O₂
H₂O₂ oxidizes RBCs → Hemolytic Anemia
60
🩺 Clinical Points
Newborn screening includes a G6PD test
Avoid triggers: fava beans, antimalarials, certain drugs/chemicals
61
A complication of the glucose-6-phosphate dehydrogenase deficiency where it results from oxidized hemoglobin globin chains
Heinz Bodies
62
A complication of the glucose-6-phosphate dehydrogenase deficiency formed when macrophages remove Heinz body-laden RBCs
Bite Cells
63
Production Site: Red bone marrow
Process: Erythropoiesis (RBC formation)
Regulating Hormone: Erythropoietin (EPO)
Source of EPO: Kidney (in response to hypoxia)
RBC Synthesis
64
EPO Action
Stimulates progenitors in bone marrow:
✓ BFU-E (Burst-Forming Unit Erythroid)
✓ CFU-E (Colony-Forming Unit Erythroid)
Functions:
✓ Proliferation
✓ Differentiation of RBCs
65
Formation of blood cells from Hematopoietic Stem Cells (HSCs)
Hematopoiesis
66
Multipotent, differentiate into all blood cells, maintain population through continuous division
Hematopoietic Stem Cells
67
Control proliferation, differentiation, and survival of blood cell progenitors
Stimuli Response: Increase specific blood cell types when needed (e.g., RBCs during blood loss)
Cytokines
68
🩺 RBC Production Process
1. Fetal Period: EPO produced by liver
2. Adulthood: EPO produced by kidneys
3. RBC Differentiation:
✓ Cells reduce size, increase number, produce hemoglobin
✓ Cells lose their nucleus
69
EPO Activation Process
Low RBC count → Hypoxemia detected by kidneys → ↑ EPO secretion → ↑ RBC production (3-5 days)
70
RBC Production in High Altitudes & Athletes
Higher RBC count due to:
✓ Low oxygen levels (high altitude)
✓ Increased oxygen demand (athletes)
71
Stimulated by: Colony Stimulating Factors (CSFs)
Source: Lymphocytes, macrophages, or any organ in response to infection
Granulocyte & Macrophage Production
72
Stimulated by: Thrombopoietin (TPO)
Source: Kidneys, liver
Action: Stimulates megakaryocytes → Platelet production via fragmentation
Platelet Production
73
Platelet count regulation/ Feedback Mechanism
↓ Platelet count → ↑ Platelet production
↑ Platelet count → ↓ Platelet production
74
Cause: Inadequate intake or excessive iron loss (e.g., pregnancy)
🩸 Iron Deficiency Anemia
75
Cause: Intake of excess oxidants (e.g., chemicals, drugs, nitrates, quinones)
Treatment: Vitamin C, Methylene blue
🩸 Acquired Methemoglobinemia
76
Cause: Genetic deficiency in NADH-dependent methemoglobin oxidoreductase
Inheritance: HbM gene mutation (MIM 250800)
🩸 Inherited Methemoglobinemia
77
Cause: Codon 6 mutation of β-globin gene (GAG → GTG), valine replaces glutamic acid
🩸 Sickle Cell Anemia
78
Cause: Mutations in α-globin genes (unequal crossing-over, deletions, mutations)
🩸 Alpha Thalassemia
79
Cause: Mutations in β-globin gene (deletions, nonsense mutations, splice site mutations)
🩸 Beta Thalassemia
80
Vitamin B12 Deficiency: Decreased absorption due to intrinsic factor deficiency
Folic Acid Deficiency: Decreased intake or increased demand (e.g., pregnancy)
🩸 Megaloblastic Anemia
81
Cause: Deficiencies in spectrin, ankyrin, band 3, or band 4.1 proteins
🩸 Hereditary Spherocytosis
82
Cause: X-linked mutations in the G6PD gene (point mutations)
🩸 Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
83
Cause: Variety of mutations in the gene for red cell isozyme of PK
🩸 Pyruvate Kinase (PK) Deficiency
84
Cause: Mutations in the PIG-A gene, affecting GPI-anchored protein synthesis
🩸 Paroxysmal Nocturnal Hemoglobinemia
85
Hemolytic Anemias Due to EXTRINSIC Defects
1. Hypersplenism:
Cause: Enlarged spleen → RBCs sequestered → Hemolysis
2. Immunological Incompatibilities:
Causes:
✓ Transfusion reactions
✓ Erythroblastosis fetalis
✓ Autoimmune disorders (warm/cold antibody hemolytic anemias)
3. Infectious and Toxic Agents:
✓ Venoms: Certain reptiles/insects with phospholipases/proteases
✓ Bacteria: Escherichia coli, clostridia (produce hemolysins)
✓ Parasites: Plasmodium species (malaria)
86
Hemolytic Anemias Due to INTRINSIC Defects
1. Pyruvate Kinase Deficiency
✓ Cause: Impaired ATP production → Disrupted membrane integrity → RBC unable to regulate water/ions
2. Hemoglobinopathies
✓ Cause: Defective hemoglobin (e.g., sickle cell anemia, thalassemias)
3. Membrane-Specific Factors:
✓ Hereditary Spherocytosis & Elliptocytosis: Abnormal spectrin affecting RBC shape and osmotic resistance
✓ Paroxysmal Nocturnal Hemoglobinuria (PNH):
Cause: Defect in glycophosphatidylinositol → Impaired anchoring of surface proteins
87
Other Anemia Types
1. Iron Deficiency Anemia:
Cause: Inadequate iron intake, absorption, or excessive loss
2. Megaloblastic Anemia:
Cause: Vitamin B12 deficiency (due to intrinsic factor issues)
3. Inherited Methemoglobinemia:
Cause: Genetic deficiency in NADH-dependent methemoglobin oxidoreductase
88
Function: Defense against infections, inflammation, and immune responses
Leukocytes (White Blood Cells)
89
2 Classification of Leukocytes (White Blood Cells)
Granulocytes
Agranulocytes (Mononuclears)
90
3 Granulocytes
Neutrophil
Eosinophil
Basophil
91
2 Agranulocytes (Mononuclears)
Lymphocyte
Monocyte
92
Nucleus: Multilobed
Function: First responders to bacterial/fungal infections
Neutrophil
93
Nucleus: Bilobed
Function: Defense against parasitic infections; involved in allergic reactions
Eosinophil
94
Nucleus: Bilobed or Trilobed
Function: Releases histamine during allergic responses → Causes vasodilation
Basophil
95
Nucleus: Deep staining; eccentric
Function: Includes B cells, CD4+ T helper cells, and CD8+ T cytotoxic cells; involved in lymphatic system function
Lymphocyte
96
Nucleus: Kidney-shaped
Function: Phagocytosis, antigen presentation; differentiate into macrophages to clear debris and attack pathogens
Monocyte
97
Neutrophil Response to Bacterial Infections
1. Bacterial Signal Release
→ Bacteria release signals alert neutrophils.
→ Infected tissues release chemotactic substances:
✓ Complement factors (e.g., C5a)
✓ Leukotrienes
✓ Eicosanoids
2. Adhesion to Blood Vessel Wall
→ Neutrophils adhere endothelial cells via integrins:
🧬 VLA-1 (Very Late Antigen-1)
🧬 CD49a
🧬 LFA-1
3. Inflammatory Response
→ Damaged tissue releases chemical signals activate endothelial cells.
→ Selectins on endothelial cells slow neutrophils cause rolling.
→ Integrins bind tightly, causing neutrophils to stop rolling (margination).
4. Histamine Release and Vasodilation
→ Mast cells release histamine, causing:
✓ Vasodilation
✓ Open endothelial junctions
✓ Fluid and leukocytes move into infected tissue.
5. Extravasation (Diapedesis)
→ Neutrophils undergo shape change, squeeze via endothelial gaps, enter infected tissues.
6. Chemotaxis and Bacterial Destruction
→ Neutrophils follow chemotactic signals to the infection site.
→ Ingest and destroy bacteria using enzymes like:
🧬 Defensin
🧬 Myeloperoxidase
7. 🩸 Leukocyte Adhesion Deficiency (LAD): Integrin defect → Neutrophils fail to bind → Impaired infection control.
98
Neutrophil Activation and Response to Infection
→ Chemotactic Factor Activation: Factors bind to neutrophil receptors
→ Activate G proteins.
→ Stimulation Phospholipase C
→ Degradation of PIP2 (Phosphatidyl Inositol Biphosphate)
→ Release IP3 (Inositol Triphisohate) and DAG (Diacylglycerol)
→ Increased Intracellular Ca²⁺
→ Activation of Protein kinase C.
→ Phosphorylation of specific proteins (responsible for neutrophil movement e.g actin, myosin, cytoskeletal structures)
→ Affects assembly of microtubules & actin-myosin system
→ Increased neutrophils motility and activity (help neutrophil run after bacteria)
→ Bacteria sought out and destroyed (phagocytosis)
99
Respiratory Burst
A rapid release of reactive oxygen species (ROS) in neutrophils following bacterial engulfment.
100
Respiratory Burst in Neutrophils
→ Bacterial Presence
→ Increased Oxygen
→ ROS Production: NADPH oxidase generates reactive oxygen species (ROS), such as superoxides, hydroxyl radicals, and hypochlorite ions.
→ Bacterial Destruction: ROS effectively kill bacteria by damaging their structure.
Self-Protection Mechanisms:
→ Superoxide dismutase (SOD)
→ Converts superoxide (O₂⁻)
→ into H₂O₂ and O₂.
→ Catalase: Breaks down H₂O₂
→ Into H₂O and O₂
→ Neutralizing ROS.
Disease Association:
Chronic Granulomatous Disease (CGD): NADPH oxidase deficiency → Impaired ROS production → Weakened bacterial defense.
101
Function: Break down proteins & pathogens.
Proteinases in Neutrophils
102
Main Enzymes of Proteinases in Neutrophils
Elastase
Collagenase
Cathepsin G
103
Regulation by Anti-Proteinases in Neutrophils
α1-Antitrypsin (A1AT)
α2-Macroglobulin
α1-Antichymotrypsin
104
Alpha-1 Antitrypsin Deficiency → Uncontrolled elastase
Inflammation Effect:
↑ Chlorinated compounds
→ Promote proteinase formation
→ Inhibit anti-proteinases
→ Enhanced tissue breakdown
Emphysema
105
Cause: ↓ A1AT production in the liver
Less inhibition of elastase, an enzyme that breaks down proteins.
Alpha-1 Antitrypsin Deficiency
105
Pathway to Emphysema
1. ↓ A1AT → ↓ Elastase inhibition
2. ↑ Neutrophils (e.g., during pneumonia)
3. ↑ Elastase release
4. ↑ Elastin digestion in lungs
5. → Early-onset Emphysema
106
Triggering Factors of Alpha-1 Antitrypsin Deficiency
Liver disease → ↓ A1AT synthesis
Lung infections → ↑ Neutrophil-driven elastase
107
Clinical Result of Alpha-1 Antitrypsin Deficiency
🫁 Progressive lung damage, especially emphysema
📌 Common in young non-smokers with unexplained lung disease
108
Oxidative damage to α1-Antitrypsin (A1AT)
🚬 Smoking
109
Mechanism of Smoking & Emphysema
1. Methionine 358 in A1AT binds elastase
2. Smoking → Oxidizes methionine → Methionine sulfoxide
3. A1AT becomes inactive
4. Elastase remains active → Degrades elastin in lungs
➡️ Progressive lung destruction → Emphysema
110
Key Consequences of Smoking & Emphysema
✓ Loss of lung elasticity
✓ Increased air trapping
✓ Early-onset emphysema, especially in smokers with/without A1AT deficiency
111
Regulate gene expression and cell differentiation.
Hematopoietic Growth Factors
112
Key Factors of regulation of WBC production and their Roles
1. G-CSF (Granulocyte Colony-Stimulating Factor): Stimulates granulocyte proliferation.
2. GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor): Induces proliferation of granulocytes, macrophages, and eosinophils.
113
These factors act on WBC precursors to ensure proper cell development and immune response
Progenitors
114
Resemble mast cells.
Contain histamine and heparin.
Essential for immediate-type hypersensitivity reactions.
Basophils
115
Attack parasites.
Produce leukotriene C4 and platelet-activating factor (PAF).
Increased in allergic diseases (e.g., allergic dermatitis, eczema, irritant contact dermatitis).
Eosinophils
116
Stabilizing, stasis, stopping
Refers to the cessation of bleeding from a cut or severed vessel.
Hemostasis
117
Refers to the formation of a blood clot.
Can occur without a visible cut.
Happens when the endothelium lining of blood vessels is damaged or removed.
Example: Rupture of an atherosclerotic plaque
Thrombosis
118
Steps in Hemostasis (Cessation of Bleeding)
1. Vasoconstriction → Constriction vessel to reduce blood flow.
2. Formation of Platelet Plug (White Thrombus) → platelet aggregation forms a plug
3. Formation of Fibrin Clot (Red Thrombus) → stable clot forms via fibrin meshwork, reinforce platelet plug.
4. Dissolution of the Fibrin Clot (Fibrinolysis) → clot dissolves after vessel healed to restore normal
119
🧬 Final Common Pathway
"X → Xa → Thrombin → Fibrin → Stable Clot"
1. Factor X → Xa
2. Xa → Converts Prothrombin → Thrombin
3. Thrombin → Converts Fibrinogen → Fibrin
4. Fibrin → Stabilized by Factor XIIIa → Stable Clot
🩸 Function: Fibrin forms a mesh to seal wounds and stop bleeding.
120
Types of Thrombus
1. White Thrombus
2. Red Thrombus
3. Disseminated Fibrin Clots
121
Mostly platelets, some fibrin, few RBCs
Forms in fast blood flow (e.g., arteries)
White Thrombus
122
Mostly RBCs and fibrin
Forms in slow blood flow/stasis (e.g., veins)
Red Thrombus
123
Found in small vessels/capillaries
Often associated with DIC (Disseminated Intravascular Coagulation)
Disseminated Fibrin Clots
124
Platelet Plug Formation – Steps
1. Injury → Exposed collagen
2. Platelet Activation
✓ Conformational change
✓ Pseudopod formation
3. Granule Release
✓ ATP, clotting factors, enzymes
4. Platelet Aggregation
✓ Platelets stick together → Platelet plug
125
⚙️ Platelet Activation – Key Triggers
Collagen → (initial activator)
Thrombin → (most potent)
ADP → (recruits platelets)
Thromboxane A2 → (enhances aggregation)
vWF → (bridges collagen to platelets)
126
🧬 Activation Pathway
Thrombin
↓
PAR-1, PAR-4 (G-protein receptors)
↓
Phospholipase C → Hydrolyzes PIP2
↓
PIP2 → DAG + IP3
🧩 DAG
→ Activates PKC
→ Phosphorylates Pleckstrin
→ Platelet granule release
🧩 IP3
→ Releases Ca²⁺ from SER
→ Activates Myosin Light Chain Kinase
→ Actin-myosin interaction
→ Platelet shape change
127
🧪 Regulators of Platelet Activation
1. ADPase (endothelial)
2. Prostacyclin
3. Thrombomodulin
4. Protein C + S
5. vWF
128
Breaks down ADP, limits recruitment
ADPase (endothelial)
129
Inhibits aggregation
Prostacyclin
130
Activates Protein C → Degrades Va & VIIIa
Thrombomodulin
131
Anticoagulants (need Gla residues)
Protein C + S
132
Binds collagen to platelet (also promotes adhesion)
vWF
133
2 Platelet Granules
Dense Granules
Alpha Granules
134
🟤 Dense Granules & Their Contents
💡 Think: "A-CAS" (Activator, Calcium, ATP, Serotonin)
🟤 ADP – Platelet activator
🟤 ATP
🟤 Ca²⁺ – Needed for coagulation
🟤 Serotonin – Vasoconstriction
135
⚪ Alpha Granules & Their Contents
💡 Think: "V4P-FBF"
⚪ vWF – Adhesion to collagen
⚪ Platelet factor 4 – Neutralizes heparin
⚪ Platelet-derived growth factor (PDGF) – Healing
⚪ Fibronectin – Wound repair
⚪ Beta-thromboglobulin – Attracts fibroblasts
⚪ Fibrinogen – Platelet cross-linking
⚪ Factors V & VIII – Coagulation cascade
136
🔗 Core Mechanism of Platelet Aggregation
Fibrinogen + vWF
↓
Bind to Gp IIb/IIIa receptor (Ca²⁺-dependent)
↓
Platelets aggregate (stick together)
137
🔄 Supporting Pathways of Platelet Aggregation
LEFT PATHWAY
🔸 Activated platelets
🔸 Gp 1a receptor
🔸 Binds exposed collagen
🔸 ➜ Promotes aggregation
RIGHT PATHWAY
🔸 Activated platelets
🔸 Convert arachidonic acid → thromboxane A2
🔸 Enzyme: Cyclooxygenase (COX)
🔸 ➜ Enhances aggregation
138
Links platelets together
Fibrinogen
139
Anchors to collagen + assists Gp IIb/IIIa binding
vWF
140
Final common receptor for aggregation
Gp IIb/IIIa receptor
141
Potent stimulator of aggregation
Thromboxane A2
142
🔍 Platelets in Circulation
Marginated along vessel walls.
Normal endothelium → Non-adhesive.
Injury → Exposes collagen → triggers adhesion.
143
Step by step Platelet adhesion
1. GP 1a/2a (α2β1) → Initial collagen binding
2. GP6 → Strengthens binding + starts signaling
3. GP 1b-9-5 + vWF → Crucial under high shear (arteries)
📌 vWF bridges GP1b to collagen!
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🌀 Platelet Activation & Shape Change
Circular → Spiky (filopodia) → ↑ surface area
Granule Release:
✓ Dense granules → ADP, Ca²⁺, Serotonin
✓ Alpha granules → vWF, Fibrinogen, Platelet Factor 4
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Platelet Aggregation (Key Activators)
✓ ADP → From dense granules
✓ TXA2 → From arachidonic acid (via COX)
✓ Thrombin (Factor IIa) → From coagulation cascade
➡ All activate Gp IIb/IIIa receptor
➡ Gp IIb/IIIa binds fibrinogen + vWF
➡ Crosslinks platelets → Platelet plug formation
🧠 “Injury → Collagen → GP1a/2a + GP6 → GP1b + vWF → ADP + TXA2 → GP IIb/IIIa → Plug”
146
Mechanism of Action of Aspirin/Acetylsalicylic Acid
🔒 Inhibits COX enzyme (Cyclooxygenase)
⛔ inhibits TXA2 (Thromboxane A2)
⛔ inhibits Platelet aggregation
💉 Prevents clot formation
Clinical Use:
🫀 Cardiovascular prophylaxis (anti-clot therapy)
🧠 Memory Tip:
"Aspirin → COX ↓ → TXA2 ↓ → Platelets ↓ → Clot ↓"
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Autologous blood product rich in platelets
Used for healing, regeneration, and rejuvenation
🧛♀️ PRP (Platelet-Rich Plasma) – "Vampire Treatment"
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Steps of PRP (Platelet-Rich Plasma) – "Vampire Treatment"
1. 🩸 Blood Draw
2. 🌀 Centrifugation:
🔼 PRP → Injected (contains α + dense granules)
🔽 PPP → Often discarded
3. 💉 Injection into target area (skin, scalp, joints)
149
Granule Functions:
Dense Granules → ADP, serotonin, Ca²⁺ (healing triggers)
Alpha Granules → Growth factors (PDGF, TGF-β, VEGF)
150
Common Uses of PRP (Platelet-Rich Plasma) – "Vampire Treatment"
🦴 Orthopedics (joint, tendon repair)
🦷 Dentistry (bone/gum healing)
❤️ Cardiology (tissue repair)
💇♀️ Dermatology (hair & skin rejuvenation)
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Factor I
Fibrinogen
152
Factor II
Prothrombin
153
Factor III
Tissue Factor
154
Factor IV
Calcium (Ca²⁺)
155
Factor V
Proaccelerin
156
Factor VI
(No Factor VI)
157
Factor VII
Proconvertin
158
Factor VIII
Antihemophilic Factor A
159
Factor IX
Antihemophilic Factor B
160
Factor X
Stuart-Prower Factor
161
Factor XI
Plasma Thromboplastin Antecedent
162
Factor XII
Hageman Factor
163
Only non-protein coagulation factor. It's a mineral (not a protein).
Calcium (Factor IV)
164
Intrinsic Pathway:
Triggered by vessel wall damage.
Factors: XII → XIIa → XIa → IXa (with VIIIa) → X.
Key Point: Leads to Factor Xa activation, converging with the extrinsic pathway.
165
Extrinsic Pathway:
Triggered by tissue injury.
Steps: Tissue Factor (III) + Factor VIIa → activates Factor X.
Key Point: Fastest pathway, Factor Xa is the intersection.
166
Common Pathway:
Factor Xa activates Prothrombin → Thrombin.
Thrombin converts Fibrinogen → Fibrin and activates Factor XIII for clot stabilization.
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Thrombin's Roles:
🩸 Activates platelets.
🩸 Amplifies the coagulation cascade by activating Factors XI and VIII.
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Inactive factors needing cleavage (e.g., Factor X → Xa).
Zymogens
169
Vitamin K-dependent Factors
I, VII, IX, X ("1972" mnemonic)
Protein C and S
170
Factor Xa inhibitors
Rivaroxaban, Apixaban
171
T/F: In Intrinsic Pathway, only Factor VIII is NOT activated by a cascade mechanism; it is activated by thrombin.
True
172
T/F: In Extrinsic Pathway, initiated by Factor III (Tissue Factor) released from endothelial cells and monocytes due to tissue injury
True
173
Complex consists of
🩸 VIIIa
🩸 IXa
🩸 X
🩸 Calcium
Tenase Complex
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Complex consists of
🌀 Calcium
🌀 Va
🌀 Xa
🌀 Prothrombin (Factor II)
🌀 Surface of platelets with phosphatidylserine
Prothrombinase Complex
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Serve as high-affinity binding sites for calcium
Include Factors II, VII, IX, X
Referred to as the 1972 Vitamin K-dependent factors
Gamma-carboxyglutamate-containing Factors
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Made up of Factor VIIa and Factor III
Activates Factor IX, linking intrinsic and extrinsic pathways
Tissue Factor Complex
177
Provides an important link between the intrinsic and extrinsic pathways
Arginine-Isoleucine cleavage occurs during the activation of Factor X to Xa in the coagulation cascade
Factor Xa
178
Clotting Factor Sources
Circulating Factors
→ Fibrinogen
Liver-Synthesized Factors
→ Prothrombin
Endothelial Cell-Derived Factors
→ Factor III
Platelet-Derived Factors
→ vWF
→ Factor V
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Structure: Single-chain glycoprotein synthesized in the liver.
N-terminal: Contains 10 gamma-carboxylated glutamic acid residues, important for calcium binding.
C-terminal: Serine-dependent active protease site, where Factor Xa cleaves to convert Prethrombin into Thrombin.
Prothrombin
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Two-chain structure: Linked by disulfide bonds.
Key Role: Amplifies the coagulation cascade by activating further clotting factors.
Thrombin
181
A small number of clotting factors activate Prothrombin to Thrombin.
Thrombin burst rapidly amplifies the cascade, creating more thrombin to accelerate clot formation.
Cascade Effect
182
Structure: Glycoprotein with three non-identical subunit pairs (AαBßγ)₂, linked by disulfide bonds.
Fibrinopeptides A & B: Located at the N-terminal, these peptides have negative charges, preventing fibrin aggregation and maintaining solubility.
Fibrinogen
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Function: Thrombin cleaves the Arg-Gly bonds in fibrinogen, releasing fibrin monomers that form fibrin (αßγ)₂ units.
Activation of Factor XIII: Cross-links fibrin monomers, forming a stable fibrin clot.
Thrombin
184
Regulators of Thrombin:
1. Antithrombin: Inhibits thrombin.
2. Heparin: Enhances antithrombin activity.
3. Factor II: Involved in coagulation.
4. α2-Macroglobulin & α1-Antitrypsin: Protease inhibitors that help regulate thrombin activity.
185
Used in myocardial infarction (MI) to prevent thrombin formation by enhancing antithrombin
Heparin
186
Inhibits the vitamin K-dependent carboxylation of clotting factors II, VII, IX, and X.
Warfarin
187
Prone to venous thrombosis
Inherited Antithrombin Deficiency
188
Stabilizes Factor VIII.
Promotes platelet adhesion at injury sites.
Von Willebrand Factor
189
Inactive zymogen that binds to fibrin during clot formation, converted to plasmin by specific activators.
Plasminogen
190
3 Activators of Plasminogen
1. t-PA (Tissue Plasminogen Activator / Alteplase)
2. Urokinase
3. Streptokinase
191
Type: Serine protease released from the endothelium.
Activation: Inactive unless bound to fibrin (acts within the clot).
Function: Converts plasminogen to plasmin.
Key Role: Initiates fibrinolysis by binding to fibrin and activating plasmin formation.
t-PA (Tissue Plasminogen Activator / Alteplase):
192
Type: Non-specific activator of plasminogen.
Action: Can degrade circulating fibrinogen, making it less selective than t-PA.
Streptokinase
193
Source: Derived from the urinary system and produced by monocytes, macrophages, fibroblasts, and epithelial cells.
Function: Cleaves the same bond in plasminogen as t-PA.
Urokinase
194
Cleavage Sites: Plasminogen
Arginine-Valine.
195
Cleavage Sites: Fibrinogen
Arginine-Glycine
196
Cleavage Sites: Factor Xa
Arginine-Isoleucine
197
2 Therapeutic Fibrinolytic Agents
1. Alteplase (t-PA)
2. Streptokinase
198
Commonly used to restore blood flow in coronary arteries after thrombosis.
Alteplase (t-PA)
199
Serine protease that digests fibrin, producing soluble degradation products.
Regulation: Inactivated by α2-antiplasmin to prevent excessive fibrinolysis.
Plasmin
200
Comprise 6-8% of blood, primarily produced by the liver, except for gamma globulins (produced by lymphocytes).
Plasma Proteins
201
Plasma without fibrinogen and clotting factors
Serum
202
Separated via electrophoresis using agarose gel and an electric current.
Serum Protein Separation
203
Serum Protein Separation divided into 5 classifications based on size and charge
Albumin (60%)
Alpha-1 globulins
Alpha-2 globulins
Beta globulins
Gamma globulins
204
Functions of Plasma Proteins
1. Oncotic Pressure: Maintains water balance inside blood vessels.
2. Buffering Capacity: Contributes 15% of blood’s buffering capacity (pH 7.4).
3. Ionic Environment: Plays a major role in maintaining the plasma’s ionic balance.
4. Specific Functions:
✓ Transport of substances (e.g., hormones, lipids).
✓ Clotting of blood (fibrinogen and other clotting factors).
✓Defense against infection (immunoglobulins, alpha-1-antitrypsin).
205
General Considerations of Plasma Proteins
✓ Synthesis: All plasma proteins are synthesized by the liver except gamma globulin (produced by lymphocytes).
✓ Processing: Synthesized in polyribosomes, processed in RER, SER, and Golgi bodies, then secreted via exocytosis.
✓ Post-Translational Modifications: Include glycosylation and other modifications during protein processing.
✓ Structure: Plasma proteins are glycoproteins with N-linked or O-linked oligosaccharide chains.
206
Functions of Oligosaccharide Chains:
Modulate protein properties.
Aid in membrane insertion and secretion.
Assist in precursor protein processing.
Influence embryonic development.
Protect proteins from protease digestion.
207
Plasma proteins may have isoforms (different forms) due to genetic variations.
Polymorphism
208
Each plasma protein has a unique lifespan.
Example:
Albumin: Half-life of approximately 20 days
Half-Life
209
2 Acute Phase Proteins (increased during inflammation/injury)
1. C-reactive protein (CRP): Marker for tissue injury/inflammation.
2. α1-antitrypsin: Inhibits proteases, protecting tissues from damage.
210
Most abundant plasma protein in the blood.
Gene location: Chromosome 4.
Serum half-life: ~20 days.
Functions:
✓ Maintains oncotic pressure (fluid balance).
✓ Transports thyroid hormones, fatty acids, bilirubin, and drugs.
✓ Binds calcium ions.
✓ Buffers blood pH.
Human Serum Albumin (HSA)
211
Hypo vs Hyper in Albumin
Hypoalbuminemia (↓ Albumin):
Liver disease
Starvation
Malnutrition
Nephrotic syndrome
Protein-losing enteropathy
Hyperalbuminemia (↑ Albumin):
Severe dehydration.
212
Evaluation Considerations in Human Serum Albumin
1. Malnutrition indicator: Takes 2-3 weeks to reflect changes.
2. Hydration status: Decreased plasma volume → falsely high; expanded plasma volume → low albumin.
3. Liver function: Albumin production is liver-dependent.
4. Zinc transport: Affects zinc absorption.
Clinical Monitoring:
Albumin levels reflect long-term protein status and hydration/nutritional health.
213
Alpha-1 Globulin Proteins
Prealbumin
Thyroxine Binding Globulin (TBG)
Retinol Binding Protein (RBP4)
Alpha-1 Antitrypsin (AAT)
Alpha-1 Antichymotrypsin
Serum Amyloid A (SAA)
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Half-life: ~2 days (shorter than albumin).
Function:
Transport protein for
✓ Thyroxine (T4)
✓ Retinol (vitamin A).
Clinical Significance:
✓ TTR Mutation: Leads to amyloid fibril accumulation, causing neurodegeneration (linked to Alzheimer's).
✓ Binds beta-amyloid, preventing plaque formation in Alzheimer's disease.
Indicator:
Monitor nutritional improvement, intervention effectiveness.
Prealbumin
215
Affinity: Binds T4 stronger than T3.
Function:
✓ Serine protease inhibitor but without antiprotease activity.
✓ Deficiency: Does not affect thyroid function (free T4, T3, TSH remain normal).
✓ Nephrotic Syndrome: TBG is lost through the kidneys.
Thyroxine Binding Globulin (TBG)
216
Function: Transports vitamin A from liver to peripheral tissues.
Kidney Protection: Works with transthyretin to prevent retinol loss in urine.
Retinol Binding Protein (RBP4)
217
Function: Inhibits elastase, protecting lungs from tissue damage.
Clinical Significance:
Deficiency: Leads to emphysema and liver disease.
Genotypes:
✓ MM: Normal phenotype.
✓ ZZ: Increased risk for emphysema (5% of cases).
Pathophysiology:
✓ AAT Deficiency: Reduced elastase inhibition → lung tissue damage → emphysema.
✓ Smoking: Oxidizes AAT, worsening elastase activity and accelerating emphysema.
Alpha-1 Antitrypsin (AAT)
218
Function:
Inhibits cathepsin G and chymase
Protecting tissues from proteolytic damage.
Clinical Significance:
✓ Acute Phase Protein → Induced inflammation
✓ Linked to Alzheimer’s disease → amyloid fibril enhancement
Alpha-1 Antichymotrypsin
219
Function: Acute-phase protein that transports cholesterol to the liver and recruits immune cells.
Clinical Significance:
Chronic inflammatory conditions
✓ Amyloidosis
✓ Atherosclerosis
✓ Rheumatoid arthritis.
Serum Amyloid A (SAA)
220
Alpha-2 Globulins
Haptoglobin
Alpha-2 Macroglobulin (A2M)
Ceruloplasmin
221
Function: Binds free hemoglobin in the blood, preventing kidney loss and conserving iron.
Clinical Relevance:
✓ Low levels: hemolytic anemia (due to hemoglobin release).
✓ High levels: acute phase response during inflammation.
Haptoglobin
222
Function: Transports ~10% of plasma zinc and acts as a panproteinase inhibitor (binds various cytokines).
Clinical Relevance: Implicated in Alzheimer’s disease pathogenesis.
Alpha-2 Macroglobulin (A2M)
223
Function: Carries 90% of plasma copper, essential for enzymes like:
✓ Superoxide dismutase
✓ Cytochrome oxidase
✓ Conversion of ferrous (Fe²⁺) to ferric (Fe³⁺) iron.
Clinical Relevance:
✓ Decreased: Wilson’s disease (disorder of copper metabolism).
Ceruloplasmin
224
Beta-1 Globulin
Transferrin
Hemopexin
225
Function: Transports iron to tissues, including bone marrow, by binding 2 ferric ions.
Clinical Relevance:
✓ Alcohol abuse: Glycosylation abnormalities.
✓ Low transferrin: Leads to hemosiderin accumulation.
✓ Immune function: Creates low-iron environment to inhibit bacterial growth.
Transferrin
226
Function: Binds heme, scavenging free heme from hemoglobin turnover and protecting tissues from oxidative damage.
Clinical Relevance: Elevated in hemolytic anemia.
Hemopexin
227
Beta-2 Globulin
Beta-2 Microglobulin
Plasmin
228
Function: Essential for MHC class I stability and CD8 T cell development.
Clinical Relevance: Deficiency impairs CD8 T cell function.
Beta-2 Microglobulin
229
Function: Degrades fibrin clots, activating from plasminogen.
Inactivation: By α2-antiplasmin.
Clinical Relevance: Deficiency can cause thrombosis.
Plasmin
230
Function: Inhibits angiogenesis (new blood vessels).
Clinical Use: Investigated in cancer therapy.
Angiostatin
231
Function: Enhances immune responses and aids in pathogen engulfment.
Clinical Relevance: Located on X chromosome.
Properdin (Factor P)
232
Function: Binds testosterone and estradiol, reducing their bioavailability.
Regulation:
↓ SHBG: Seen in PCOS, diabetes, hypothyroidism.
↑ SHBG: In pregnancy, hyperthyroidism, anorexia nervosa.
Sex Hormone Binding Globulin (SHBG)
235
Mobile phagocytic cells, first responders in acute bacterial infections
Half Life: ~6 hrs circulation
Rich in lysosomes with degradative enzymes
Neutrophils
236
3 Metabolic Pathways in Neutrophils
Active glycolytic pathway
Hexose monophosphate shunt
Moderate oxidative phosphorylation
237
Protective Substances in Neutrophils
Defensin
Lactoferrin
Myeloperoxidase
238
Antibiotic peptide causing bacterial membrane damage
Defensin
239
Inhibits bacterial growth by binding iron
Lactoferrin
240
Ezyme responsible for green pus color that produces hypochlorous acid potent antimicrobial
Myeloperoxidase
241
Small, anuclear cells (2–4 µm); circular at rest, dendritic when activated
Count: 150,000–450,000/µL (↓ in Dengue, esp. Day 3–4)
Origin: From megakaryocytes (5,000–10,000 platelets each)
Regulation: Thrombopoietin (liver & kidneys)
Lifespan: 8–12 days; cleared by spleen & Kupffer cells
Main Role: Blood coagulation
Clinical Notes:
PRP effects last 2–4 weeks
Women respond better to PRP
Platelets (Thrombocytes)
242
Disorders of Platelets (Thrombocytes)
Thrombocytopathy: Platelet dysfunction
Thrombocytopenia: Low count → bleeding risk
Thrombocytosis: High count → clot risk
Thrombasthenia: Weak platelet function
PENIA = Low
OSIS = High
PATHY = Abnormal
ASTHENIA = Weak
243
Growth Factors Released in Platelets (Thrombocytes)
PDGF: Cell recruitment to injury
TGF-β: ECM deposition (tissue repair)
FGF: Fibroblast proliferation (wound healing)
IGF-1: Cell growth & repair
EGF: Skin/epithelial regeneration
VEGF: Angiogenesis ("Vessel growth")
244
Prostacyclin (PGI₂) & Platelet Aggregation
PGI₂ = Prostaglandin that inhibits platelet aggregation
Pathway:
Arachidonic acid → (via COX) → PGI₂ → ↑ cAMP → ↓ Ca²⁺ → ↓ Aggregation
Mechanism:
PGI₂ → Activates adenyl cyclase → ATP → cAMP → Lowers intracellular Ca²⁺ → Prevents platelet clumping
Clinical Tip:
❗ Avoid COX inhibitors (e.g., Ibuprofen) in Dengue → Bleeding risk ↑
Memory Aid:
🧠 “PGI₂ → cAMP ↑ → Ca²⁺ ↓ → Aggregation ↓”
🧠 “Dengue + Ibuprofen = ❌”
