1. Chapter 19
The Blood

2. The Blood The cardiovascular system consists of three components:
Heart
Blood vessels

3. Functions of Blood Blood transports:
oxygen & CO2 between lungs & tissues
nutrients from the digestive tract
metabolic wastes- from body to kidneys for elimination
hormones from endocrine glands to target organs
Blood regulates:
body temperature
pH using buffer systems
Blood protects
against blood loss by initiating hemostasis & coagulation
against infection – antibodies, complement proteins, WBCs

4. Physical Characteristics of Blood
It is viscous (thick) and more dense than water
temperature slightly warmer than core body temperature (T = 38o C)
slightly alkaline pH ( )
oxygenated blood bright red,
poorly oxygenated blood dark red
makes up 8% of body mass
Blood volume: 5–6 L for males, and 4–5 L for females

5. Constituents of Blood
Blood is 5 liters of a specialized fluid connective tissue composed of formed elements (45%) suspended in a solution called plasma (55%)
If a sample of blood is centrifuged cellular portion will precipitate out of solution and form a heavier sediment below the straw colored liquid plasma
The normal RBC mass is almost
45% by volume – this is called the
hematocrit (Hct)

6. Constituents of Blood

7. Blood Plasma Plasma is 92% water, with dissolved solutes:
Plasma proteins – produced by the liver
albumin, globulins, fibrinogen
Nitrogenous wastes
urea, uric acid, creatinine
Nutrients –
glucose, fatty acids, amino acids
Electrolytes
sodium, potassium, calcium, chloride, bicarbonate
Respiratory gases
oxygen and carbon dioxide
Hormones
Clotting factors
If plasma is allowed to coagulate it is called serum - serum is just plasma without the clotting factors- used or blood testing

8. Plasma Proteins Albumin
contributes significantly to colloidal osmotic pressure of blood
It also plays an important role as a carrier molecule for lipid soluble substances e.g. hormones
globulins, of which there are several types:
α-globulins and β- globulins are carrier proteins
δ-globulins are immunoglobulins (antibodies) made by activated B lymphocytes called plasma cells
Fibrinogen- clotting factor –forms the blood clot

9. Formed Elements The formed elements of blood include:
Erythrocytes ( RBCs)- highest count
Leukocytes( WBCs)
Platelets
Are continuously formed in the bone marrow
1mm3 = 1uL = mL
The Hct = % females, 40-54% for males; Hemoglobin (Hgb) = g/dl

10. Hematopoiesis
The process by which the formed elements of blood develop is called hemopoiesis (hematopoiesis).
blood cells are formed in red bone marrow from pluripotent stem cells.
Red bone marrow:
In adults : bones of axial skeleton, pectoral & pelvic girdles, heads of humerus & femur
In newborns- all bone marrow is red
Lymphoid tissues includes the thymus, spleen, tonsils, or lymph nodes.

11. Hematopoiesis

12. Hematopoiesis Blood cells are formed from pluripotent stem cells.
The pluripotent stem cells (hemopoietic stem cells) produce the myeloid stem cell and lymphoid stem cell
myeloid stem cell gives rise to: RBCs, platelets, monocytes, neutrophils, eosinophils, and basophils
lymphoid stem cell gives rise to: T lymphocytes, B lymphocytes, NK cells
Regulation of hematopoiesis:
Erythropoietin (EPO) regulates RBC formation
Thrombopoietin regulates platelet formation
Colony stimulating factors & interleukins stimulate WBC formation

13. Clinical connection
Bone marrow examination by bone marrow aspiration or bone marrow biopsy
For diagnosis of leukemias, anemias
Site: usually iliac crest of hip bone, sternum

14. Red Blood Cells to the tissues of the body-
About 5 million RBCs/mm3 of blood
Red blood cells are bi-concave discs-
increases the cell surface area- gives them a high oxygen carrying capacity
Mature RBCs don't have a nucleus or any protein making machinery -die in about 120 days.
specific purpose – to carry O2
to the tissues of the body-
also carry 23 % CO2
Their shape also allows them to
deform and fit in small capillary beds

15. RBCs and Hemoglobin Each RBC contains 280 million molecules of Hb
Hemoglobin (Hb) is a protein molecule adapted to carry O2 (and CO2 as well)
A Hgb molecule consists of globin protein (2 alpha and 2 beta polypeptide chains), each embedding an iron-containing heme group
Oxygen binds to the heme group ( one Hb binds 4 oxygen molecules)
CO2 binds to globin
proteins
Red cells contain hemoglobin. A heme is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic subunit; these are known as hemoproteins.

16. RBCs
RBCs and CO2:
Red blood cells contain the enzyme carbonic anhydrase
Carbon dioxide diffuses fron tissues into RBCs
It combines with water to form carbonic acid- H2CO3 which quickly dissociates into hydrogen ions and bicarbonate ions
70 % of CO2 is transported in blood as bicarbonate ions which is an important blood buffer

17. RBCs Life Cycle
Erythropoiesis is the part of hematopoiesis that deals with the production of RBCs.
Control is by negative feedback
Erythropoiesis increases when states of hypoxia (O2 deficiency)- stimulates the kidneys to release the hormone erythropoietin (EPO)
EPO circulates to the red
marrow and speeds up the
maturation and release of
immature red cells
Thrombopoietin shows great promise for preventing the depletion of platelets, which are needed to help blood clot, during chemotherapy. CSFs and thrombopoietin also improve the outcome of patients who receive bone marrow transplants. Hemopoietic growth factors are also used to
treat thrombocytopenia in neonates, other clotting disorders, and various types of anemia. Research on these medications is ongoing and shows a great deal of promise.

18. Negative feedback regulation of Erythropoiesis
Some stimulus disrupts homeostasis by
Decreasing
Oxygen delivery to kid-neys (and other tissues)
Receptors
Kidney cells
detect low
oxygen level
Input
Increased erythropoietin
secreted into blood
Control center
Return to homeostasis
when oxygen delivery
to kidneys increases to
normal
Proerythroblasts in
red bone marrow
mature more quickly
into reticulocytes
Output
Increased erythropoietin
secreted into blood
Effectors
Larger number
of RBCs in
circulation
Increased oxygen
delivery to tissues

19. RBCs Life Cycle As cells mature in the bone marrow, they
become smaller
the nucleus is lost
Most organelles lost
the amount of Hb increases
At reticulocyte stage RBCs are sent out into the blood stream

20. Reticulocytes Reticulocytes:
At this stage the RBCs are sent out into the
blood stream
Normally 1-2% of the RBCs in the peripheral circulation are reticulocytes
The rate of erythropoiesis is measured by the number of immature RBCs (called reticulocytes or “retics”) in the peripheral circulation
A low retic count (<.5%) indicates a low rate of erythropoiesis while an elevated rate (>2%) indicates a high rate of erythropoiesis

21. RBC Life Cycle
RBCs live only about 120 days- are destroyed mainly in spleen
To maintain normal numbers, new cells must enter the circulation at 2 million/s to balance high rate of RBC destruction
Ruptured RBCs are destroyed by macrophages in the spleen and liver
Heme and globin are separated
Globin is metabolized into amino acids- released into the circulation
Iron of the heme is salvaged for re-use
Heme is degraded to bilirubin

22. RBC Life Cycle Key: 10 9 8 7 6 5 4 3 2 1 Key: 9 8 7 6 5 4 3 2 1 Key:
Amino
acids
Reused for
protein synthesis
Globin
Circulation for about
120 days
Bilirubin
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver +
Vitamin B12
Erythopoietin
Key:
in blood
in bile
Erythropoiesis in
red bone marrow
Macrophage in
spleen, liver, or
Ferritin
Heme
Biliverdin 10 9 8 7 6 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Circulation for about
120 days
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver +
Vitamin B12
Erythopoietin
Key:
in blood
in bile
Erythropoiesis in
red bone marrow
Macrophage in
spleen, liver, or
Ferritin
Heme
Biliverdin
Bilirubin 9 8 7 6 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Stercobilin
Bilirubin
Urobilinogen
Feces
Small
intestine
Circulation for about
120 days
Bacteria
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver +
Vitamin B12
Erythopoietin
Key:
in blood
in bile
Erythropoiesis in
red bone marrow
Macrophage in
spleen, liver, or
Ferritin
Heme
Biliverdin 12 11 10 9 8 7 6 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Urine
Stercobilin
Bilirubin
Urobilinogen
Feces
Small
intestine
Circulation for about
120 days
Bacteria
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver +
Vitamin B12
Erythopoietin
Key:
in blood
in bile
Erythropoiesis in
red bone marrow
Kidney
Macrophage in
spleen, liver, or
Ferritin
Urobilin
Heme
Biliverdin 13 12 11 10 9 8 7 6 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Urine
Stercobilin
Bilirubin
Urobilinogen
Feces
Large
intestine
Small
Circulation for about
120 days
Bacteria
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver +
Vitamin B12
Erythopoietin
Key:
in blood
in bile
Erythropoiesis in
red bone marrow
Kidney
Macrophage in
spleen, liver, or
Ferritin
Urobilin
Heme
Biliverdin 14 13 12 11 10 9 8 7 6 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Circulation for about
120 days
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver +
Vitamin B12
Erythopoietin
Key:
in blood
in bile
Erythropoiesis in
red bone marrow
Macrophage in
spleen, liver, or
Ferritin
Heme 8 7 6 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver +
Vitamin B12
Erythopoietin
Key:
in blood
in bile
Macrophage in
spleen, liver, or
red bone marrow
Ferritin
Heme 7 6 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Red blood cell
death and
phagocytosis
Key:
in blood
in bile
Macrophage in
spleen, liver, or
red bone marrow
Heme 3 2 1
Globin
Red blood cell
death and
phagocytosis
Key:
in blood
in bile
Macrophage in
spleen, liver, or
red bone marrow
Heme 2 1
Amino
acids
Reused for
protein synthesis
Globin
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Key:
in blood
in bile
Macrophage in
spleen, liver, or
red bone marrow
Heme 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver
Key:
in blood
in bile
Macrophage in
spleen, liver, or
red bone marrow
Ferritin
Heme 5 4 3 2 1
Amino
acids
Reused for
protein synthesis
Globin
Red blood cell
death and
phagocytosis
Transferrin
Fe3+
Liver
Key:
in blood
in bile
Macrophage in
spleen, liver, or
red bone marrow
Ferritin
Heme 6 5 4 3 2 1
Red blood cell
death and
phagocytosis
Key:
in blood
in bile
Macrophage in
spleen, liver, or
red bone marrow 1

23. Clinical connections
Anemia is a condition of insufficient RBC’s or hemoglobin (quality or quantity)
It is most often the result of low iron intake, hemolysis, blood loss, or lack of production in the bone marrow
Polycythemia is a condition of excess number of RBCs
It occurs in response to hypoxia, shots of EPO (illegal “doping”), COPD

24. Anemias
Iron deficiency anemia is the most common anemia in the U.S., and affects primarily menstruating women
Chronic blood loss is a cause
Hemorrhagic anemia is the result of precipitous blood loss, and results in an equal decrease in Hct, Hb content, and RBC count

25. Anemias
Sickle-cell disease (SCD), also called sickle-cell anemia, is an autosomal recessive disorder. A genetic defect in the primary DNA sequence leads to production of a faulty Hb β chain, and RBCs that take on a rigid, sickle-shape
Sickling decreases the cells' flexibility and results in a variety of complications; life expectancy is shortened

26. White Blood Cells WBCs number- between 5000-10,000 cells/mm3
There are 5 different types of WBCs
(WBCs) or leukocytes have nuclei and other organelles
1mm3 = 1uL = mL

27. Leukocytes
Leukocytes are divided into two groups depending on whether they contain conspicuous cytoplasmic granules (when stained)
Granulocytes include the neutrophils, eosinophils, and basophils
Agranulocytes are the monocytes and lymphocytes

28. Neutrophils
The most numerous WBC in normal blood (60-70% )is the neutrophil, or polymorphonucleocyte (PMN)
PMNs are granulocytes lilac granules and nuclei have 2-5 lobes
They are phagocytes - their principal role is to fight bacterial infections
PMN phagocytizing
a microbe

29. Eosinophils
Eosinophils are characterized by their large red granules and bilobed nuclei
They are (2-4% of circulating WBCs), but their numbers increase slightly with allergic reactions & parasitic infections
they have also been associated with
the development of allergies

30. Basophils
Basophils are the granulocytes that contain large, dark blue, histamine containing granules
Normally, they are the lowest number of circulating WBCs (only 0-1%),
May have a role to play in the
inflammatory responses

31. Monocytes
While monocytes are not granulocytes, they come from the same immediate precursor cell as the 3 granulocytes (the myeloid stem cell)
3-8% of the circulating WBCs
Along with neutrophils, monocytes are the other major group of phagocytic cells.
they are more numerous in
the peripheral, tissues where they
act as “fixed” phagocytes
The dead cells of PMNs and monocytes make up the debris found in pus.

32. Lymphocytes Approximately 20-30% of circulating WBCs are lymphocytes
increase in number in acute viral infections
Most lymphocytes continually move between lymphoid tissues, lymph, and blood, spending
only a few hours in blood
Lymphocytes are the cornerstone of the specific immune response
There are two types of lymphocytes: T cells and B cells
T cells control immune responses
B cells give rise to plasma cells, which produce antibodies

33. Functions of Leukocytes
To get rid of pathogens the WBCs have to leave the blood stream and collect at sites of infection or injury
WBCs leave the bllod vessels by the process called emigration :
Rolling along the endothelium & then sticking- by complementary adhesion molecules on endothelium (selectins) and on leucocytes (integrins )
Squeeze out between endothelial cells -diapedesis
Chemicals released by microbes and inflamed tissues attract phagocytes, a phenomenon called chemotaxis

34. Functions of Leukocytes
Neutrophils are the first to emigrate in bacterial infections
Reach by chemotaxis & engulf pathogen by phagocytosis
Release strong oxidants & defensins to destroy engulfed bacteria
Neutrophils are followed by monocytes- which get transformed into phagocytic tissue macrophages
Lymphocytes take part in immune responses
B cells- antobody mediated humoral immunity
T cells – immune regulation & destruction of viral infected and cancer cells

35. Emigration of neutrophils
Interstitial fluid
Blood flow
Emigration
of neutrophils
Neutrophil
Endothelial cell
Rolling
Sticking
Squeezing between
endothelial cells
Key:
Selectins on
endothelial cells
Integrins on
neutrophil

36. Chemotaxis & phagocytosis
Diapedesis
Chemotaxis & phagocytosis
From Wikimedia Commons

37. WBC Indices
For diagnostic purposes, physicians measure the total leucocyte count
A leukocytosis is any WBC count > 10,000/mm3, and usually indicate an infectious process or inflammation
A leukopenia is any WBC count < 5,000/mm3, and usually indicates a severe disease (AIDS, bone marrow failure, severe malnutrition, or chemotherapy)
Differential leucocyte count : percentages of each of the 5 types of WBCs

38. WBC Indices
Shifts in the normal percentages of circulating WBCs will often point towards a bacterial infection (elevated neutrophils) or a viral infection (elevated lymphocytes)
In this peripheral blood smear
a patient with lymphocytic
leukemia has a WBC >150,000
and 90% of the WBCs are
cancerous lymphocytes!
Lymphocytic leukemia.

39. Platelets
Platelets (thrombocytes) are about 150, ,000 cells/mm3 , they have a short life span (5 to 9 days)
Their granules contain chemicals
(serotonin, Ca2+, ADP) that,
once released, promote
blood clotting
Also release PDGF-
promotes growth & healing
of damaged vessels
1mm3 = 1uL = mL

40. Platelets
Megakaryocytes (immediate precursors of platelets) are huge cells that splinter into 2000 to 3000 fragments while still in the red bone marrow
Each disc shaped fragment is a platelet
Platelets leave the red bone marrow
and enter the circulation

41. Hemostasis
Hemostasis is a sequence of responses that stops bleeding when blood vessels are damaged or ruptured
Three mechanisms reduce blood loss
Vascular spasm
Formation of a platelet plug
Blood clotting (coagulation)

42. Hemostasis Platelets adhere to damaged endothelium to form a
Vascular spasm occurs as damaged blood vessels constrict- (by neural & chemical stimuli)
Platelets adhere to damaged
endothelium to form a
platelet plug

43. 2.Platelet Plug Formation1 2 3
Red blood cell
Platelet
Collagen fibers
and damaged
endothelium
Liberated ADP,
serotonin, and
thromboxane A2
Platelet plug
Platelet adhesion
Platelet release reaction
Platelet aggregation 1 2
Red blood cell
Platelet
Collagen fibers
and damaged
endothelium
Liberated ADP,
serotonin, and
thromboxane A2
Platelet adhesion
Platelet release reaction 1
Red blood cell
Platelet
Collagen fibers
and damaged
endothelium
Platelet adhesion
2.Platelet Plug Formation

44. Hemostasis
Clotting (coagulation) is possible because of the presence of several clotting proteins normally dissolved in the blood in inactive state
Coagulation occurs in a cascade whereby one activated clotting protein triggers the next step in the process, which triggers the next
There are 2 pathways to
activate the clotting cascade:
extrinsic & intrinsic

45. Blood clotting cascade
Tissue trauma
Tissue
factor
(TF)
Blood trauma
Damaged
endothelial cells
expose collagen
fibers
(a) Extrinsic pathway
(b) Intrinsic pathway
Activated XII
Ca2+
platelets
Platelet
phospholipids
Activated X
Activated
PROTHROMBINASE V
Prothrombin
(II)
THROMBIN
Loose fibrin
threads
STRENGTHENED
FIBRIN THREADS
Activated XIII
Fibrinogen
(I)
XIII
(c) Common
pathway 1 2 3 +
Tissue trauma
Tissue
factor
(TF)
Blood trauma
Damaged
endothelial cells
expose collagen
fibers
(a) Extrinsic pathway
(b) Intrinsic pathway
Activated XII
Ca2+
platelets
Platelet
phospholipids
Activated X
Activated
PROTHROMBINASE V
Prothrombin
(II)
THROMBIN
(c) Common
pathway 1 2 +
Tissue trauma
Tissue
factor
(TF)
Blood trauma
Damaged
endothelial cells
expose collagen
fibers
(a) Extrinsic pathway
(b) Intrinsic pathway
Activated XII
Ca2+
platelets
Platelet
phospholipids
Activated X
Activated
PROTHROMBINASE V 1
Blood clotting cascade

46. Hemostasis
The extrinsic pathway has few steps, occurs within seconds, once the protein “tissue factor” (TF) or tissue thromboplastin leaks into the blood from cells
The intrinsic pathway is more complex, & slower in response blood contact with collagen under endothelial cells- activates factor XII

47. Hemostasis
Both the extrinsic and intrinsic clotting pathways converge at a common point (pathway) where factor X becomes activated (Xa), combines with factor V to form:
Prothrombin activator(prothombokinase)
Prothrombin is converted into thrombin
Thrombin converts soluble fibrinogen
into insoluble fibrin threads,

48. Hemostasis Ca2+ plays an important role throughout the clotting system
Clot retraction is the consolidation of the fibrin clot.
Fibrin threads contract as platelets pull on them
As the clot retracts, it pulls the edges of
the damaged vessel closer together,
decreasing the risk of further
damage – new endothelial cells can
then repair the vessel lining

49. Fibrinolysis
Because blood clotting involves positive feedback cycles, a clot has a tendency to enlarge, this is checked by:
The fibrinolytic system - dissolves clots
Vessel endothelial cells release tissue plasminogen activator ( tPA) that can activate plasminogen an inactive plasma enzyme to become plasmin, (the enzyme that actively dissolves clots)

50. Intravascular Clotting
Inappropriate clotting in an unbroken blood vessel is called thrombosis; the clot itself, called a thrombus
Such clots may be initiated by:
endothelial injury resulting from atherosclerosis, trauma, or infection
Stasis of blood- allowing clotting factors to accumulate locally and initiate the coagulation cascade

51. Intravascular Clotting
A thrombus may become dislodged and be swept away in the blood
blood clot transported
by the bloodstream is
called an embolus
emboli can obstruct a
blood vessel and cause ischemia to
the tissue beds e.g. pulmonary embolism,
stroke

52. Blood Groups Red cells have antigens or agglutinogens on their surface
These antigens are:
Unique to the individual
Recognized as foreign if transfused into another individual
Presence or absence of these antigens is used to classify blood groups
Major blood group antigens are A and B antigens & Rh antigen
The major blood groups are ABO & Rh blood groups

53. Blood Groups In transfusion medicine the presence or absence of the
A and B red cell antigens forms the basis of the ABO blood group system
Another major red cell antigen is the Rh antigen, which 85% of the population have, and comprises the other important blood grouping

54. Blood Groups
For reason that are not totally clear, serum contains anti-ABO antibodies of a type opposite to the ABO antigen on the red cell surface
For instance, those with A antigens on their red cells have anti-B antibodies in their serum

55. Blood Groups
By knowing the status of the A antigen, B antigen, and Rh antigen, most of the major blood incompatibility issues can be avoided
Type AB individuals are “universal recipients” because they has neither anti-A nor anti-B antibodies in their serum that would destroy transfused RBCs
Type O individuals are “universal donors” because their RBCs have no antigens on the cell surface that can potentially react with the recipients serum

56. Rh Incompatibility
Individuals whose RBCs have the Rh antigen are said to be Rh+ while those who lack the Rh antigen are Rh-
Unlike ABO blood groups, anti-Rh antibodies are not spontaneously formed in Rh– individuals
If an Rh– individual is exposed to Rh+ blood, anti-Rh antibodies form( e.g. receiving Rh+ transfusion)
A second exposure to Rh+ blood will result in a transfusion reaction

57. Hemolytic Disease of the Newborn
Rh– mother carries a Rh+ fetus
At the time of birth she gets exposed to Rh+ blood- anti RH antibodies are formed
In a subsequent pregnancy, these Rh+ antibodies cross the placenta and attack the RBCs of a Rh+ baby
Results in hemolyis of babys RBCs- baby is born with severe anemia
Prevention- RhoGAM given to Rh– mother ( during pregnancy & at birth)
RhoGAM destroys any Rh+ cells before the mother’s immune system can produce
anti-Rh antibody

58. Blood Typing & Cross Matching
Blood typing for ABO status is done using single drops of blood mixed with different antisera:
Anti-A serum contains anti-A antibodies
Anti-B serum contains anti-B antibodies
Agglutination with an antisera indicates the presence of that antigen on the RBC
Rh typing: a drop of blood mixed with antiserum containing anti- Rh antibodies
Cross matching: RBCs of donors blood of same type mixed with recipients serum- checked for agglutination

59. Transfusion Reactions
Mismatched transfusions cause transfusion reactions
Donor’s cells are attacked by the recipient’s plasma antibodies causing agglutination & hemolysis :
Clumped cells block small blood vessels & hemolyse
Ruptured RBCs release free hemoglobin into the bloodstream
Free hemoglobin can block kidneys tubules and cause acute renal failure
Person can go into shock