Chapter 3 Blood Physiology

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Chapter 3 Blood Physiology

• Blood composition and properties
• Blood cells
• Hematopoiesis
• RBC function, anemia.
• WBC
• Platelet function, coagulation and fibrinolysis.
  
• Blood grouping and transfusion

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Introduction

• Blood volume 78 (70-80ml/kg B.W)
• Plasma (60) and cells (40).
• Types of blood cells
• RBC (Erythrocytes), WBC (Leukocytes) and
  Platelets (Thrombocytes)
• Main function
• Maintain homeostasis
• Buffering pH
• Humoral regulation
• Body temperature regulation
• Transportation
• Gases, nutrients, hormones, and so on.
• Host defense
• Immune reaction, coagulation.

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Section 1 Components and Characteristic

• Water 93-95
• Plasma 50-60
• Solutes 5-7
  Proteins
• 
  Nutrients
• 
  Products
• 
  Electrolytes
• 
  Others urea, gases.
• WBC, Platelet 1
• RBC 40-50 (male)
• 37-48 (female)

Whole blood
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Blood Components

• Water
• 9395 (plasma) 6568 (RBC) 8186 (whole
  blood).
• Solvent, humoral balance, osmotic pressure.
• Electrolytes
• Na, K, Mg2, Cl-, HCO3-, etc. Cell shape, pH.
• Proteins
• Albumin 40-48g/L. Colloidal osmotic pressure
  carrier buffer pH.
• Globulin 15-30g/L. Immune reaction antibody
  carrier.
• Fibrinogen 2-4g/L. Blood coagulation.

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• Hemoglobin (Hb)
• 120-160g/L (male), 110-150g/L (female)
• Function carry gases.
• Others
• carbohydrates, lipids, amino acid, pigments,
  hormones, gas (O2, CO2), and others like urea,
  uric acid.

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Physical and chemical properties

• Blood pH
• Normal interval 7.357.45.
• Regulated by lung and kidney.
• Viscosity
• Friction of molecules and cells in blood.
• Relative viscosity
• Whole blood 45 times to water (RBC).
• Plasma 1.62.4 times to water (Proteins).
• Anemia or body fluid loss.

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• Osmotic pressure
• Definition
• An ability of a liquid to attract and retain
  water. It drives osmosis. 300mmol/L
• Composition and roles
• Crystal osmotic pressure 298.7 mmol/L.
• Maintain shape and size of cells.
• Colloid osmotic pressure 1.3 mmol/L.
• Retain blood volume
• Decide distribution of water between blood and
  interstitial fluid.

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Section 2 Blood Cells

• Red blood cell
• White blood cell
• Platelet

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Hemopoiesis

• The process of blood generation.

Cell Lineage Lifespan Daily Production Rate
RBC 120 days 2.5 ? 109/L
Neutrophil 7 hours 0.85 ? 109/L
Platelet 10 days 2. 5 ? 109/L
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• Ontogeny of Hematopoiesis
• Prenatal stages
• First month yolk sac.
• Third month liver
• Fourth month bone marrow
• Postnatal stages
• Bone marrow of almost any bone, predominatantly
  by flat bones and long bones.

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100
100
Hemopoitic activity ()
Bone morrow
Yolk Sac
Liver
Lymph nodes
Spleen
0
2
3
4
5
6
7
8
9
1
Prenatal age (months)
100
100
Vertebrate
Proportion of Red Morrow ()
Tibia
Sternum
Femur
Ribs
birth
20
30
40
50
60
70
80
90
10
Postnatal age (years)
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• Stage 1, hemopoietic stem cells pluripotent
  uncommitted stem cells.
• Stage 2, committed progenitor cell unipotent
  committed stem cells. Includes
• Erythrocytic progenitor cell
• Megakaryocytic progenitor cell
• Granulocytic progenitor cell
• Lymphocytic progenitor cell
• Stage 3, precursors (cell) immature cells,
  differentiate functional cells. Including
• Ery. progenitor?? erythrocytes.
• Mega. progenitor ? platelets.
• Gran. progenitor ? granulocytes and monocytes.
• Lym. progenitor ? T and B lymphocytes.

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• Hematopoietic growth factor and related molecules
• Necessary for proliferation and differentation of
  hematopoietic cells in the marrow.
• Colony-stimulating factors (CSF) see a table in
  next slide.
• Cytokines
• IL-1, stem cell factor (SCF), etc.
• Extracellular matrix proteins
• Sulfated glycosamimoglycans and heparin sulfate,
  may concentrate hematopoitic growth factors in
  local micro environment
• Fibronectin and hemonectin, mediate adhension of
  cells, and may serve a growth promoting function.

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Hematopoietic growth factors
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Red blood cells (erythrocytes)

• Circular, biconcave discs without nuclei. ?78?m,
  thickness 12.5 ?m.

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• Cell count and volume
• Hematocrit Percentage of blood volume occupied
  by packed cell volume.

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• Volume
• 4.55.5?1012/L, average 5.0?1012/L (male).
• 3.84.6?1012/L, average 4.2?1012/L (female).
• Physical properties
• Permeability
• Deformation
• Fragility and hemolysis
• Isosmotic solution and lower osmotic solution
• Suspension stability
• The erythrocytes are very stable in suspension.
• Cause repelling force of same charge and bigger
  surface area.

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• Erythrocytes Sedimentation Rate (ESR)
  Sedimentated distance of RBC after one hour.
• 015 mm/h (male), 020 mm/h (female).
• Ratio of Surface area/Volume of RBC.
• Albumin, globulin, fibrinogen, and cholesterol.
• Rouleaux RBC aggregate.
• Function of RBC
• The main constituent of RBC is hemoglobin.
• To deliver O2 to tissues by hemoglobin.

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Hemoglobin (HB)

• HB is made up of two polypeptide ? chains and ?
  chains.
• Each polypeptide has alpha helical segments
  folded and bent into a globular configuration,
  with a heme ring within a pocket where the iron
  molecule can interact with oxygen.

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• Hb formation materials
• Protein enough intake from food.
• Iron 3-4g/person. Mainly in Hb (70).
• Degrading Hb 95.
• Absorbed from small intestine 1mg/d, 5.
• Microcytic hypochromic anemia Lack of iron.

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• RBC Maturation factors
• Vitamin B12
• Cobalamine, 25?g/d.
• Produced by gut bacteria (esp. in ruminants).
  Good sources include meat, liver, fish, eggs and
  milk.
• Absorbed in terminal ileum with intrinsic factor
  help.
• Function Improve utilization of FA.
• Folic acid
• FA is essential for the synthesis DNA.
• Synthesized by microorganisms and higher plants.
• Good sources are green leafy vegetables, yeast
  and organ meats.
• Absorbed in the proximal jejunum.

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• Lack of folic acid and vitb12 give rise to
  immature cells due to DNA synthesis derangement.
• Megaloblast anemia.

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Regulation of erythropoiesis Hypoxia ? EPO? RBC
Hemopoitic stem cell (uncommitted
progenitor) ? Erythrocytic progenitor (committed
progenitor) ? Pronormblast (precursor) ? Normobla
st, Reticulocyte ? Mature RBC (without nucleus)
EPO
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• Erythropoietin (EPO)
• A glycoprotein, 34kd. Produced in interstitial
  cells in cortical kidney such as fibroblast,
  endothelial cells.
• Roles
• Erythrocytic progenitor proliferate and
  differentiate to precursor.
• Accelerate precursor proliferation and
  differentiation.
• Promote bone marrow release reticulocytes.
• Renal type anemia EPO production decrease
• Other hormones
• Androgen, thyroid hormone, parathyroid
  hormone,etc.
• RBC destruction
• Life span of RBC is about 120 days. Older cells

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White blood cells (leucocyte)

• WBC
• 410?109/L, average is 7?109/L.
• Include
• neutrophil, eosinophil, basophil
• monocyte, lymphocyte.
• Protection, execute specific and non-specific
  immune reaction.
• Physical and chemical properties
• Chemotaxis attracted by chemical substances
  released by bacteria and foreign substances.
• Movement Move to chemotaxic source
• Phagocytosis engulf and digest

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Composition and functions

• Neutrophil
• 1012?m, 2.07.0?109/L, 60-70.
• Function
• Phagocytosis older cells, becteria, dead
  tissues, and other foreign substances.
• To execute non-specific immune activity in first
  front.

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• Monocytes
• 1530?m, 0.12 0.8?109/L, 3 8.
• Monocytes-macrophages system
• Monocytes (in blood) wander into tissues and
  become macrophages (50 80 ?m). Stronger
  phagocytosis.
• Contain many kinds of cytokines such as CSF, ILs,
  TNF?, INF-a,b.
• Roles
• Engulf and clear bacteria, vermins, older,
  necrotic tissues, dead neutrophils, dead cells
  and fragments.
• Activate lymphocytes to execute specific immune
  response.
• Recognize and kill cancer cells.
• Produce CSF, Ils, TNF?, INF-?, ?, regulate growth
  of granulocytes.

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• Lymphocytes
• 0.84.0?109/L, 20 40.
• Development of lymphocyte
• T lymphocyte
• lymphocytic stem cells ? T lymphocytes (thymus
  gland).
• B lymphocyte
• lymphocytic stem cells ? B lymphocytes (lymphoid
  tissue).
• Functions
• T lymphocytes cellular type of immunity
• B lymphocytes humoral immunity

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• Eosinophils
• 0.020.5? 109/L, 0.55.
• Functions
• Inhibit allergic reaction induced by basophils
• Produce PGE to inhibit secretion of basophils
• Engulf substances secreted by basophils
• Secrete matters to hydrolyze histamine and 5-HT.
• Phagocytic action to some worms.

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• Basophils
• 0.01.0 ? 109/L, 01.
• Large cytoplastmic granules contain heparin,
  5-hydroxytryptamine and histamine.
• Function
• Secrete heparin blood to prevent coagulation.
• Wander into tissue and become mast cell.
• Induce allergy.

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Platelet

• Hemostasis
• The process of blood clotting and then the
  subsequent dissolution of the clot.

Platelet ? activation ? adhension ? aggregation ?
clot ? thrombus ? FDP
thrombin
fibrin
plasmin
ADP and TXA2
vWF
fibrinogen
Blood Coagulation
Fibrinolysis
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• Anatomic physiology of platelet
• 24 ?m, thickness 1?m.

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Fibrinogen
GP IIb/III a
Phospholipid
Va
Ca2
Receptor
X
GPI
vWF
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• Membrane
• Receptor For adhension, aggregation and
  coagulation.
• Phospholipid provides the lipid cofactors needed
  for coagulation reactions.
• Granules in platelet
• ?-granules coagulation factors, growth factors
  (e.g. PDGF).
• ?-granules (dense bodies) Ca2, ADP and
  serotonin.
• Volume 100300 ?109/L in adult.
• Thrombocytopenia lt50 ?109/L, ? hemorrhage
• Thrombocytosis gt1000?109/L, ? Thrombosis

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• Physical properties
• Adhesion
• Mediated by von Willebrand factor (vWF).
• vWF is producted and stored in a-granules of
  platelets. Also synthesized by megakaryocytes.
• Function of vWF
• To act as a bridge between glycoprotein on the
  surface of platelets (GPIb/IX) and collagen
  fibrils.
• Serves as a carrier protein for factor VIII.
• von Willebrand Disease (vWD) deficiency in vWF a
  patient with long bleeding time, a low level of
  factor vWF/VIII complex.
• Bernard-Soulier Syndromedeficiency of
  glycoprotein Ib/IX.

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• Aggregation
• Activated platelets aggregate together.
• Activation of platelets induced by thrombin.
• Thrombin receptor ? initiate signal cascade.
• G-protein, and phospholipase C(PLC-g).
• PLC-g ? IP3 and DAG formation.
• IP3 ? Ca2 , and DAG ? PKC.
• Mechanisms
• Ca2 ? phospholipase A2 (PLA2) ?arachidonic acid
  ? thromboxane A2 (TXA2)
• PKC? ADP ? fibrinogen to adhere to two platelet
  surface glycoproteins (GPIIb and GPIIIa) ?
  fibrinogen-induced platelet aggregation.
• Glanzmann-Thrombasthenia, deficiency of
  glycoprotein IIb/IIIa.

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• Contractile function
• PLC-g ? Ca2 ? myosin light chain kinase (MLCK)
• MLCK ? phosphorylation of light chain of myosin
• Myosin interacts with actin
• Platelet morphology, motility, and clot
  retraction.

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• Roles of platelet
• Platelet clot formation at the site of vessel
  injury (primary hemostasis)
• Enhance activation of coagulation factors to
  solidify platelet clot by interlacing with fibrin
  (secondary hemostasis).

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• Platelet function disorders
• Disorders of platelet adhesion
• Bernard-Soulier Syndrome deficiency of
  glycoprotein Ib/IX.
• Disorders of platelet aggregation
• Glanzmann-Thrombasthenia, deficiency of
  glycoprotein IIb/IIIa.
• Disorders of platelet secretion
• Alpha or Dense Granules Deficiency.
• Disorders of platelet procoagulant activity
• Platelets fail to promote activation of the blood
  clotting proteins.
• Acquired platelet function disorders
• Drugs like aspirin, non-steroidal
  anti-inflammatory drugs like indomethacin,
  ibuprofen.

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Blood coagulation

• A process of blood from liquid to colloid. A
  serious of enzymes reactions.
• Coagulation factors
• Factors involved in the blood coagulation
• Attentions
• FIII come from tissue, others from plasma.
• FIV is Ca2, and others are proteins.
• FII, VII, IX, XII exist as proenzymes.

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clotting cascade
Stage 1 Formation of prothrombin activator.
Stage 2 Conversion of prothrombin to thrombin.
Stage 3 conversion of fibrinogen to fibrin
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• Difference of stage 1
• Prothrombin-converting enzyme Xa, Ca2, V, PL.
• Difference of factor Xa
• Intrinsic stage
• Start from XII. The intrinsic pathway requires
  factors VIII, IX, X, XI, and XII. Also required
  are the proteins prekallikrein and
  high-molecular-weight kininogen, as well as Ca2
  and phospholipids secreted from platelets.
• Extrinsic stage
• Start from FIII (TF), is initiated at the site of
  injury in response to the release of TF.
• TF is a cofactor in the factor VIIa
• Factor VIIa, cleaves factor X to factor Xa

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Prevention of coagulation

• Plasma inhibitors
• Fibrinolysis
• Role of the endothelial cells

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Plasma inhibitors
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• Antithrombin III
• Nonspecific protease inhibitors
• Produced in liver and endothelial cells
• Inhibit active sites of FIXa,FXa,FXIa,FXIIa,
  thrombin.
• Protein C
• Vitamin K-dependent protein
• Is activated to activited protein C (aPC) by
  thrombin in presence of endothelial cell-derived
  cofactor thrombomodulin.
• aPC inactivates FV and FVIII in presence of
  another vitamin K-dependent cofactor protein S.
• See next slide.

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Anticoagulation pathway
VIII
VIIIa
VIIIi
PS
aPC
PC
X
X Va
PS
V
Vi
FII
Thrombin
FI
Fibrin
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• Heparin
• A polysaccharide produced in basophilic mast
  cells
• Distributed in the pericapillary tissue.
• Abundant in lung, heart, liver, muscle tissues.
• Inhibit thrombin conversion.
• Promote antithrombin III activity.
• Calcium ions precipitants
• Sodium citrate

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Fibrinolysis

• Fibrinolysis
• Process of liquefaction of fibrin

Activator
plasminogen
plasmin
Inhibitor
fibrin degradation products
fibrin
Activator Tissue plasminogen activator (tPA),
urokinase. Plasmin, a serine protease, is
inhibited by ?2-antiplasma.
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• tPA
• Released from vascular endothelial cells
  following injury
• Binds to fibrin and is consequently activated.
• Urokinase
• Produced as the precursor, prourokinase by
  epithelial cells lining excretory ducts.
• Role to activate the dissolution of fibrin
  clots.
• plasminogen activator-inhibitors
• PAI-1 and PAI-2

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Endothelial cells

• Endothelium produces several inhibitors of
  hemostasis
• Prostaglandin I2
• secreted by endothelial cells and is a potent
  inhibitor of platelet aggregation.
• Thrombomodulin
• Enhances the activiation of protein C by thrombin
  and results in the inactivation of factor V and
  VIII.
• Heparans
• a heparin-like molecule, produced by endothelial
  cells. Increase the anticoagulant effect of
  antithrombin III.
• Plasminogen activator
• necessary for dissolution of fibrin clots, such
  as tPA.

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Coagulation disorders

• Hemophilia A
• Deficiency of FVIII. The disease severity usually
  parallels the factor VIII levels.
• Serve (lt 1 VIII) with spontaneous bleeding
• Moderate (1-5 VIII) with occasional bleeding,
  usually with trauma
• Mild (6-30 VIII) with bleeding only after
  surgery or trauma.
• Therapy administration of FVIII.

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• Hemophilia B (Christmas Disease)
• FIX deficiency.
• Treatment requires IX-rich material fresh frozen
  plasma (FFP) or lyophilized concentrates
  proagulatant proteins.
• Decreased production of coagulation factors
• E.g. Liver disease, vitamin K malabsorption,
  dietary deficiency of vitamin K.
• Inactivation of coagulation factors
• e.g. specific inhibitors, excessive activation of
  coagulation (DIC) and/or enzymatic destruction of
  coagulation factors.

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Blood grouping and transfusion

• The discovery of blood groups
• 1901, Austrian Karl Landsteiner discovered human
  blood groups.
• Blood agglutination was an immunological
  reaction.
• Awarded the Nobel Prize in Physiology or Medicine
  in 1930.

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• Agglutination
• Agglutinogen antigen on membrane of RBC.
• Agglutinin antibody in the plasma.
• RBC grouping
• ABO, Rh, MnSs, lewis
• The differences in human blood are due to the
  presence or absence of certain protein molecules
  called antigens and antibodies.

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ABO grouping
Blood group AA antigens on the surface of RBC,
B antibodies in blood plasma.
Blood group BB antigens on the surface of RBC,
A antibodies in blood plasma.
Blood group ABboth A and B antigens on the
surface of RBC, no A or B antibodies at all in
blood plasma.
Blood group Oneither A or B antigens on the
surface of RBC, but you have both A and B
antibodies in blood plasma
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• Antigens and antibodies
• Antigens
• A, B.
• Carbohydrate
• Antibodies Antibody A and B.
• Ig M congenital,
• Bigger Mr.

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Rh grouping

• Original discovery
• Rhesus monkey Red cells ? injected into rabbits
  ? got serum ? injected back to Rhesus monkey, or
  human ? agglutination happens.
• Rh antigen and antibody
• Antigen D, E, C, c, e.
• 99 Chinese people are Rh
• Minority in China 2-5 is Rh-
• 15 western people are Rh-
• Antibody IgG

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Which blood group do you belong to?
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Blood Transfusion

• Clinical significance
• ABO and Rh blood groups must be compatible
  between the donor blood and the patient blood.
• Agglutinated RBC clog blood vessels or crack to
  becomes toxic when HB outside the cell.
• Cross-match test
• Main lateral donors RBC and recipients serum.
• Co-lateral donors serum and recipients RBC.

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• Principle of blood transfusion
• Agglutination of main lateral absolutely no.
• Both of main and co-lateral do not agglutinate
• Co-lateral agglutinates but Main lateral
• slow and less amount of blood transfusion could
  be recommended.

People with blood group O are called universal
donors. People with blood group AB are called
universal receivers.
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• Clinical importance for Rh group
• Blood transfusion between Rh and Rh- persons.
• A mother who is Rh- woman give birth a baby who
  is Rh.
• Preventive measure given an injection of
  anti-Rh antibodies.

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Donor
Recipient
RBC
RBC (co-lateral)
Serum (main lateral)
Serum
Cross match test
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