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					             Biology 221
        Anatomy & Physiology II


         TOPIC 1
Circulatory System – Blood

               Chapter 18
               pp. 651-677


    E. Lathrop-Davis / E. Gorski / S. Kabrhel
                                                1
             Major Components of the
               Circulatory System
  • Blood - does most functions
  • Heart - provides pressure for movement of blood
  • Blood vessels - conduits for movement of blood
    (more efficient that open circulatory system seen
    in many invertebrates)


 Fig. 20.2, p. 720

Good websites: http://www.fpnotebook.com/HEM.htm

                                                        2
          Major Functions of the
           Circulatory System
• Transportation - blood carries many substances
  through the body (e.g., hormones, respiratory gases,
  wastes, nutrients)
• Protection - the circulatory system protects the body
  againt:
   – disease and toxins - white blood cells (leukocytes)
     remove bacteria, viruses and toxins; antibodies aid
     removal (see Topic 6 - Immune System)
   – blood loss - platelets, clotting, vascular spasm all
     contribute to control of blood loss (see hemostasis
     later in this Topic)
                                                            3
           Major Functions of the
            Circulatory System
• Regulation
  – blood pressure (see Topic 4) - heart output and vessel
    diameter play major roles in controlling blood
    pressure
  – blood volume (the circulatory system plays a less
    important role in controlling blood volume than does
    the urinary system; control of blood volume will be
    discussed in Topics 4, 10 and 11)
  – body temperature - hypothalamus controls blood
    vessel diameter to regulate where warm blood goes
* Most functions are most directly accomplished by blood
                                                         4
 Physical Characteristics of Blood
• Specific gravity = 1.045-1.065
• Viscosity (relative to water) = 4.5-5.5
   – i.e., blood really is thicker than water (about
     4.5-5.5 times as thick)
• pH = 7.35 – 7.45
   – normally slightly alkaline
   – acidemia (lower than normal pH) and alkalemia
     (higher than normal pH) will be determined
     based on normal blood pH


                                                       5
 Physical Characteristics of Blood
• Volume = 7-9% of body weight
   – 5-6 L in adult males
   – 4-5 L in adult females
• Temperature ~ 100.4 oF (38 oC)




                                     6
             Composition of Blood
Connective tissue (all connective tissues are compoesd of
  cells in a matrix, which consists of ground substance and
  protein “fibers” - review A&P I, Unit 4 - Tissues)
• cells & cell fragments = “formed elements”
   – erythrocytes or red blood cells (RBCs) account for
     approximately 99.9% of the cells; their function is to
     carry respiratory gases (O2 and CO2)
   – leukocytes or white blood cells (WBCs) – fight
     disease
   – thrombocytes or platelets are cell fragments involved
     inhemostasis
• matrix (plasma)                               Fig. 18.1, p. 651

   – serum (analogous to ground substance)
   – plasma proteins (analogous to “fibers”)
                                                                    7
Plasma: Definition and Composition
• Plasma = whole blood minus cells
• Serum = plasma without protein clotting factors
   – straw-colored liquid in which proteins and cells
     are suspended
• Constituents
   – 92% water
   – 7% plasma proteins
   – 1% other solutes including inorganic ions [also
     called electrolytes], organic nutrients and
     wastes, respiratory gases
                                                        8
              Plasma Proteins
• Most made by liver
• Albumins (account for ~ 60% of plasma proteins)
  – important to osmotic force
  – buffer pH
• Globulins (account for ~ 35%)
  – immunoglobulins (antibodies) protect against
    disease
  – transport proteins
      ° bind ions (e.g., transferrin binds iron) and
        small molecules that would otherwise be lost
      ° transport fatty acids, thyroid and steroid
        hormones
                                                       9
        Plasma Proteins (con’t)
• Fibrinogen – soluble protein essential to clotting
• Other plasma proteins:
   – hormones (e.g., insulin, glucagon; review A&P
     I, Unit XI, Endocrine System)
   – clotting factors (e.g., prothrombin and other
     proenzymes; see Hemostasis, this Topic)
   – enzymes (e.g., renin)
   – antibacterial proteins (e.g., complement; see
     Topic 6)


                                                       10
                  Blood Cells
• Red blood cells or erythrocytes (erythro = red; -
  cyte = cell) transport respiratory gases
• White blood cells or leukocytes (leuko = white)
  fight disease
• Platelets or thrombocytes (thromb = clot) are cell
  fragments important to hemostasis




                                                       11
           Functions of Erythrocytes
Main function: transport of respiratory gases
• transports about 98.5% of O2 (as oxyhemoglobin,
  which refers to hemoglobin with oxygen bound to it)
• transports about 23% of CO2 (as
  carbaminohemoglobin, which refers to hemoglobin
  with carbon dioxide bound to it)
• aids conversion of CO2 to bicarbonate (HCO3- ;
  covered with respiratory system)
http://www.usc.edu/hsc/dental/ghisto/bld/d_5.html




                                                        12
  Characteristics of Erythrocytes
• Small, biconcave disk
• Anucleate, no ribosomes
   – Can mature RBCs make new proteins?
• No mitochondria
   – What type of ATP synthesis would you expect -
     aerobic or anaerobic?




 Fig. 18.3, p. 654
 http://www.vh.org/Providers/CME/CLIA/Hematology/14RedCell.html
                                                                  13
    Characteristics of Erythrocytes
• Diameter = 7-8 micrometers (μm)
• Mean corpuscular volume (MCV)
   – is the average volume of individual RBCs in
     sample
   – microcytic means the cells are abnormally small
     (micro = small)
   – macrocytic means the cells are abnormally large
     (macro = large)
• Life span ~ 120 days (or less)


Fig. 18.3, p. 654

                                                       14
       Measuring RBC Abundance
• Normally, RBCs account for 99.9% of all formed
  elements
• Red blood cell count is an estimate of the number of
  RBCs in 1 microliter of blood
   – males: 4.5-6.3 x 106 / mm3 (microliter)
   – females: 4.2-5.5 x 106 / mm3
   – polycythemia = excess of RBCs (8-11 x 106 / mm3)
      ° renal hypoxia (low oxygen levels in kidney, which
        may be due to high altitude [less O2 at higher
        altitudes] among other causes) results in release of
        hormone from kidney that stimulates RBC
        production
                                                           15
                Hematocrit (PCV)
• Also called packed cell volume
• measured by centrifuging tiny sample of blood in a
  capillary tube
• separates formed elements from plasma         Fig. 18.1, p. 651
   – most formed elements are RBCs
   – “buffy coat” between packed RBCs and plasma;
     consists of white blood cells and platelets
• Ratio of formed elements to whole sample is
  expressed as percentage
   – males: average 45% (range: 40-54%)
   – females: average 42% (range 37-47%)
   – minimum hematocrit to donate blood = 38%
                                                                    16
                    Hematocrit (PCV)
• Blood doping is when an athlete reinfuses packed
  RBCs to increase hematocrit
  – What advantage would this give an athlete?
Fig. 18.1, p. 651




                                                     17
                Hemoglobin (Hb)
• Accounts for > 95% of protein in RBC
• Functions
   – transportation of respiratory gases
      ° carries ~ 98.5% of all O2
      ° carries ~ 20-30% of all CO2
   – aids local blood pressure regulation by carrying
     NO and super nitric oxide (SNO), which affect
     local vasomotor tone




                                                        18
         Hemoglobin (Hb): Structure
• Hb is a protein with quaternary structure (review
  Chapter 2, pp. 51-53) consisting of:
  – 4 protein chains: 2 alpha chains & 2 beta chains
  – 4 non-protein, lipid-like molecules called heme
     ° each heme is a porphyrin ring with an iron
       atom at its center (each iron binds 1 molecule
       of oxygen)
     ° having 4 chains/heme allows for cooperative
       binding of O2 (see Topic 7, Respiration)
  – At 4 heme per hemoglobin (one per protein
    chain), how many oxygen can one molecule of
    hemoglobin bind?                        Fig. 18.4, p. 655
                                                                19
   Hemoglobin (Hb) Content of Blood
• measured as g/dl (grams per deciliter, or per 100 ml)
  using hemoglobinometer
• average values:
   – male: 14-18 g/dl (g/100 ml)
   – female: 12-16 g/dl
   – infants: 14-20 g/dl




                                                          20
  Hemoglobin (Hb) Content of Blood
• mean corpuscular Hb = average mass of Hb in one RBC
• measured as hemoglobin concentration/ number of
  RBCs
  – normochromic = normal amount of hemoglobin (cells
    are normal colored - light red)
  – hypochromic = abnormally low hemoglobin per cell
    (cells appear more pale than normal)
  – hyperchromic = abnormally high hemoglobin per cell
    (cells appear darker than normal)
• What is the significance of the blood Hb content?


                                                         21
        Location of Erythrocyte
       Formation (Erythropoiesis)
• During the 1st 8 weeks of fetal development RBCs are
  formed in the yolk sac outside the embryo
• During 2nd to 5th months of fetal development, RBCs
  are formed in liver (main supplier), spleen, thymus
  (WBCs), bone marrow (begins in bone marrow during
  5th month)
• Post-natal development and in adults, RBCs are
  formed in red bone marrow (myeloid tissue)
   – especially portions of the vertebrae, ribs, scapula,
     skull, pelvis, proximal heads of femur and humerus
   – yellow marrow of medullary cavities (see A&P I,
     Unit XII, Skeletal System) can be converted back
     into red marrow, if needed                             22
            Stages of Erythropoiesis
Formed from hemocytoblasts (undifferentiated blood stem
  cells) in the following order:
 proerythroblasts, which are differentiated RBC
  precursors
 erythroblasts, which begin to synthesize Hb
 normoblasts (formed after about 4 days), which lose
  nucleus, some mitochondria
 reticulocytes, which
   – contains ribosomes & mitochondria (but no nucleus);
      Hb synthesis continues
   – leaves bone marrow after ~ 2 days
   – reticulocyte count: normally ~ 0.8% (0.8-2.0%) of
      RBC population
 mature erythrocyte                          Fig. 18.5, p. 656
                                                              23
        Control of Erythropoiesis
Production is controlled by erythropoietin
• which is secreted by kidney under hypoxic (hyp- =
  low; -oxic = oxygen) conditions like:
   – anemia (decrease in blood’s ability to carry O2 due
     to low hematocrit, low hemoglobin, or both)
   – decreased blood flow to kidney
   – decreased environmental oxygen availability (e.g.,
     from increased elevation)
• and which stimulates:
   – increased cell division of stem cells and
     erythroblasts
   – increased rate of Hb synthesis

                                                           24
              Control of Erythropoiesis
Control is under negative feedback:
renal hypoxia stimulates kidney cells to secrete
erythropoietin, which stimulates development and
differentiation of hemocytoblasts leading to production
of more RBCs, which carry more O2 thus alleviating the
hypoxia

Fig. 18.6, p. 657




                                                          25
          Other Factors Influencing
           Rate of Erythropoiesis
• Indirectly stimulated by thyroxine, androgens
  (testosterone), growth hormone
• Adequate diet (Why does each influence erythropoiesis?)
   – amino acids
   – vitamins (B12, B6, folic acid)
       ° pernicious anemia – lack of Vit. B12 due to
         deficiency of intrinsic factor produced by gastric
         mucosa and needed for uptake of B12
   – iron (Fe)
       ° iron-deficiency anemia – lack of sufficient iron in
         diet, inability to absorb iron; secondary to
         hemorrhagic anemia                                26
           Erythrocyte Recycling
• 10% of RBCs are hemolyzed before component are
  degraded
   – hemolysis is breaking of RBCs (literally, “blood
     breaking”)
• 90% of RBCs are phagocytized by macrophages in
  spleen, liver, bone marrow
   – macrophages are white blood cells that engulf
     (phagocytize) other things (in this case, red blood
     cells)



                                                           27
           Erythrocyte Recycling
Products of breakdown include:
• amino acids, which are released into blood and can
  be used by any tissue
• heme, which is broken into Fe and porphyrin ring
   – Fe transported by attachment to a plasma protein
     as transferrin to red bone marrow for
     reincorporation into Hb, or to the liver or spleen
     for storage as ferritin or hemosiderin (both of
     which are storage proteins)



                                                          28
  Erythrocyte Recycling (con’t)
– porphyrin ring of heme converted by the liver into
  biliverdin, which is converted to bilirubin (or
  other molecules), which is excreted in
   ° bile and released in feces, or
   ° urine
– jaundice is a disorder resulting from failure to
  remove bilirubin and results in deposition of
  bilirubin in skin due to excess in blood; caused by:
   ° liver dysfunction
   ° excessive rupture of RBCs
   ° obstruction of bile passageways
                                                         29
                 Blood Typing
• Is accomplished based on surface antigens
   – antigens are integral glycoproteins
      ° glycoproteins consist of protein with attached
        carbohydrate
   – antigens on RBCs arecalled agglutinogens because
     they cause agglutination (clumping) of RBCs when
     mixed with antibodies (called agglutinens) against
     the protein
• At least 50 kinds of proteins may be used for typing
   – most commonly used for typing are ABO blood
     group and Rh factor because incorrect matching
     between blood types causes transfusion reactions
                                                          30
             ABO Blood Typing
ABO blood group (See table, p. 8 of Notes)
• two types of proteins (agglutinogens) are involved - A
  and B
• typing is based on which protein(s) is(are) present:
   – a person whose cells have the A protein has Type A
     blood
   – a person whose cells have the B protein has Type B
     blood
   – a person whose cells have neither protein has Type
     O blood
   – a person whose cells have both proteins has Type
     AB blood
                                                           31
             ABO Blood Typing
• A and B result from IA and IB alleles (gene variants),
  respectively; they are codominant and both dominant
  to i, which is the allele for type O.
   – What are the possible genotypes of persons with
     Type A blood? Type B blood? Type O blood? Type
     AB blood
   – Can a mother with Type A blood and a father with
     Type B blood have a child with Type O blood?
     Explain.



                                                           32
               ABO Blood Typing
• Typing is accomplished by mixing blood of unknown type with
  anti-serum of known type:
   – if a person’s blood agglutinates with serum containing anti-
     A, his/her cells have the A protein and he/she has Type A
     blood
   – if a person’s blood agglutinates with serum containing anti-
     B, his/her cells have the B protein and he/she has Type B
     blood
   – if a person’s blood agglutinates with serum containing anti-
     A and with serum containing anti-B, his/her cells have both
     the A and the B protein and he/she has Type AB blood
   – if a person’s blood agglutinates with neither type of anti-
     serum, he/she has neither agglutinogen and Type O blood

                                                                    33
     ABO Blood Typing - Antibodies
• With regard to ABO blood types, each person makes
  antibodies (agglutinens) against factors
  (agglutinogens) he/she does NOT have on his/her cells
• Person with:
   – Type A blood makes anti-B antibodies
   – Type B blood makes anti-A antibodies
   – Type O blood makes both types of antibodies
   – Type AB makes neither

  Table 18.4, p. 673


                                                          34
              ABO Transfusions
• Recipient will reject transfused blood if he/she makes
  antibodies against that type
   – e.g., person with Type A blood make anti-B
     antibodies and, therefore, rejects Type B blood
• Refer to the chart on page 8 of the Notes and
  Objectives to see who can receive blood from whom
  and who can donate to whom
   – Make sure you understand the reasoning!
   – AB is the universal recipient; O is the universal
     donor - Make sure you understand why!

                                                           35
               Rh Blood Typing
• Rh (Rhesus) factor is based on the “D” protein
• Person’s cells either have the protein or not
   – person with the D protein is called Rh positive
     (Rh+)
   – person without the D protein is called Rh negative
     (Rh-)
• Rh+ person does not make the antibodies against D
  protein
• Rh- person only makes the antibodies if he/she is
  exposed to Rh+ blood by transfusion or during
  childbirth (or both other exposure)
                                                          36
              Rh Blood Typing
• making the protein (being Rh+) is dominant to not
  making the protein (Rh-)
   – Rh- person is homozygous recessive; Rh+ person
     may be homozygous dominant or heterozygous
• See Table page 9 of Notes and Objectives




                                                      37
     Blood Typing Cross Reactions
• Cross reactions are caused by giving blood type to
  which recipient has antibodies (See Fig. 18.15, p. 675)
   – reactions cause agglutination (clumping)
• Erythroblastosis fetalis – occurs when an Rh- mother
  who has been exposed to Rh+ blood is carrying Rh+
  fetus
   – because she’s been exposed, she makes antibodies,
     which cross the placenta and attack fetal blood cells
   – RhoGAM® may be given to mother to tie up the
     anti-Rh antibodies, thus preventing them from
     crossing placenta and destroying RBCs of fetus
   – What was the blood type of the father?
                                                             38
 Check These Blood Typing Links
• http://sln.fi.edu/biosci/blood/types.html
• http://www.biology.arizona.edu/human_bio/proble
  m_sets/blood_types/Intro.html




                                                    39
        RBC & Associated Disorders
• Thalassemia – genetic inability to produce adequate
  amounts of alpha or beta chains; results in limited
  production of fragile, short-lived RBCs
• Sickle-cell anemia – results from a genetic mutation in
  which 7th amino acid in the beta chain is changed, which
  causes Hb molecules (called S hemoglobin) to stick when
  oxygen is not bound leading to characteristic sickle shape
  of RBCs when oxygen levels decrease
   – people with both S hemoglobin alleles have the
     disease
   – people who are heterozygous also have the normal
     allele, are carriers, and are said to have sickle cell trait
                                                               40
      RBC & Associated Disorders
• Hemolytic anemia results when RBCs rupture
  prematurely, thus decreasing the number of circulating
  RBCs; causes include sickle-cell disorder, transfusion
  cross-reactions, certain bacterial or parasitic infections
• Hemoglobinuria refers to Hb in urine; caused by a
  variety of problems that increase the breakdown of
  RBCs, including transfusion reactions, other hemolytic
  anemias, severe burns




                                                               41
      RBC & Associated Disorders
Other Anemias
• iron-deficiency anemia results from a lack of iron in
  diet, which may be secondary to hemorrhagic
  anemia; RBCs are microcytic and hypochromic
• pernicious anemia results from lack of Vit. B12
  (which is necessary for RBC formation) due to lack
  of intrinsic factor (which is essential for absorption
  of Vit. B12); RBCs are macrocytic
• hemorrhagic anemia results from heavy bleeding;
  RBCs are normal but fewer than normal in number

                                                           42
          Leukocytes: Functions
• Fight pathogens
   – pathogens are disease-causing organisms and
     viruses
      ° “microbes” = bacteria
      ° parasites = eukaryotic pathogens
      ° viruses
   – provide both innate and adaptive immunity
     (covered in Topic 6)
• Clear debris from damaged areas
• Fight cancer
                                                   43
                 Leukocyte Abundance
• Normal range: 4,800-10,800 cells / mm3
  – leukopenia – less than normal number of cells
  – leukocytosis – excessive abundance
     ° normal with disease
     ° > 100,000 WBCs / mm3 not uncommon with
       leukemia
• Measured by (see Lab Manual):
  – White blood cell count
  – Differential WBC Count
     ° relative abundance of different kinds of WBCs
     ° accomplished by counting number of each
       different type in a total of 100 cells
   Fig. 18.9, p. 661
                                                       44
    Major Groups of Leukocytes
Leukocytes can be classified into two major groups:
• Granulocytes
  – contain stainable granules in cytoplasm
  – specific types are neutrophils, eosinophils, and
    basophils
• Agranulocytes
  – lack stainable granules
  – specific types are monocytes and lymphocytes



                                                       45
            Granulocytes: Neutrophils
• Normally account for 40-70% of circulating WBCs,
  based on differential WBC count (according to
  Marieb, 5th Ed.)
• Phagocytic, especially against bacteria
• Contain a large number of lysosomes (see Chapter 3)
  in cytoplasm
• Highly mobile
• 10-14 µm in diameter
• Short life spans (~ 10 hrs; less if highly active)
• Neutrophilia refers to an increase in relative
  abundance of neutrophils; associated with acute
  bacterial infections
http://www.usc.edu/hsc/dental/ghisto/bld/d_1.html
                                                        46
            Granulocytes: Eosinophils
  • Normally account for 1-4% of circulating WBCs,
    based on differential WBC count (according to
    Marieb, 5th Ed.)
  • 10-14 µm in diameter
  • Phagocytize antibody-covered objects (bacteria,
    cellular debris, parasitic worms and protozoa); also
    respond during allergic reactions; release nitric
    oxide and cytotoxic enzymes onto target particles
  • Eosinophilia refers to an increase in relative
    abundance of eosinophils; associated with parasitic
    worm infections

http://www.usc.edu/hsc/dental/ghisto/bld/d_3.html
                                                           47
            Granulocytes: Basophils
• Normally account for < 1% of circulating WBCs,
  based on differential WBC count (according to
  Marieb, 5th Ed.)
• 10-12 µm in diameter
• Accumulate in damaged tissues where they release
  histamine and heparin
• Associated with chronic inflammatory diseases
• Basophilia – increase in number of basophils
  associated with allergic reactions
http://www.usc.edu/hsc/dental/ghisto/bld/d_4.html




                                                     48
       Agranulocytes: Lymphocytes
• Normally account for 20-30% of circulating WBCs,
  based on differential WBC count (Marieb, 5th Ed.)
• 5-17 µm in diameter
• Most remain in lymphatic tissue
• 3 classes of circulating lymphocytes
   – T cells are involved in cell-mediated immunity
   – B cells differentiate into plasma cells that produce
     antibodies; humoral immunity
   – Natural killer (NK) cells detect and destroy abnormal
     tissue cells (fight potential cancers) and cellular
     foreign invaders
• Increase associated with a number of infections,
  especially viral
                       http://www.usc.edu/hsc/dental/ghisto/bld/d_5.html
                                                                           49
        Agranulocytes: Monocytes
• Normally account for 2-8% of circulating WBCs,
  based on differential WBC count (according to
  Marieb, 5th Ed.)
• largest cells, > 15 µm in diameter
• Some become fixed macrophages within tissues
• Phagocytize viruses, debris, bacteria; enhance scar
  tissue formation

http://www.usc.edu/hsc/dental/ghisto/bld/d_6.html




                                                        50
       Agranulocytes: Mononucleosis
  • Highly contagious viral disease
  • Symptoms include large numbers of atypical
    agranulocytes (enlarged lymphocytes that
    resemble monocytes), fatigue, soreness, chronic
    sore throat, low-grade fever

http://image.bloodline.net/stories/storyReader$680

http://www.gopbi.com/shared/health/adam/ency/imagepage/1456.000591.html




                                                                          51
                  Leukocyte Production
Arise from hemocytoblasts (stem cells) which give rise to:
• lymphoid stem cells, which develop into lymphoblasts,
   which develop into prolymphocytes, which develop
   into lymphocytes
• myeloid stem cells, which develop into:
    – monoblasts, which develop into promonocyte,
       which develop into monocytes
    – myeloblast, which develop into differentiated
       myelocytes, which develop into various
       granulocytes

  Fig. 18.11, p. 655
                                                             52
  Regulation of Leukocyte Production
• Thymic hormones promote differentiation and
  maintenance of T cells
• Presence of antigens stimulates lymphocyte production
• Cytokines (molecules released by one cell that affects
  the growth or activity of another)
   – Colony stimulating factors (CSFs)
      ° stimulate production and development of WBCs
      ° named according to what type(s) of cells they
        stimulate
   – Interleukins are released by WBCs to affect activity
     of other WBCs; most important to lymphocyte
     production
                                                            53
                  Leukemias
• Cancer of WBC producing cells
• Acute leukemia are rapidly developing forms
  – comes from “-blast” cells (i.e., myeloblasts,
    monoblasts, lymphoblasts)
  – occurs more often in children
• Chronic leukemia are slowly developing forms
  – comes from later stages (e.g., myelocytes,
    promonocytes, prolymphocytes)
  – more common in elderly


                                                    54
                      Platelets
• Small (2-4 µm in diameter), anucleate cell fragments
• Short-lived (5-10 days)
• normal abundance is 250,000 –500,000 platelets /
  mm3 of plasma
   – thrombocytopenia – abnormally low amount (<
     80,000/mm3)
      ° due to excess platelet destruction or inadequate
        production
      ° symptoms include bleeding in digestive tract,
        skin, CNS
   – thrombocytosis – abnormally high count due to
     infection, inflammation, or cancer

                                                           55
            Platelet Functions
• Hemostasis (stoppage of bleeding)
  – platelet plug formation
  – enhance clotting
  – clot retraction




                                      56
  Platelet Formation and Regulation
• Formation:
   – hemocytoblasts (stem cells) give rise to
     megakaryocytes which break apart to form
     platelets
• Regulation - production of platelets is stimulated by
  several factors including:
   – thrombopoietin (TPO or thrombocyte-stimulating
     factor), which is produced in the kidneys
   – interleukin-6 (IL-6), which is produced by active
     T cells
   – multi-CSF, which promotes growth of
     megakaryocytes
Fig. 18.12, p. 667                                        57
                      Hemostasis
• Is stoppage of bleeding
• Occurs in 3 phases (by 3 mechanisms):
   – Vascular phase (vascular spasm)
   – Platelet phase (platelet plug formation)
   – Coagulation (clotting )
 Fig. 18.13, p. 668




                                                58
               Vascular Phase
• Is primarily due to vascular spasm, which is
  contraction of smooth muscle of vessel wall
• Endothelial cells are also involved. They help by:
   – contracting to pull vessel walls closer together
   – releasing chemical factors and local hormones
     that stimulate vascular spasm & division of
     endothelial cells, smooth muscle cells and
     fibroblasts to aid healing
   – becoming sticky and adhering to each other to
     close capillaries


                                                        59
             Platelet Phase –
         Platelet Plug Formation
Has two stages:
• First is Platelet adhesion wherein platelets stick to
  exposed collagen fibers in broken vessel
• Next is Platelet aggregation wherein activated
  platelets change shape & develop processes to
  reach out to other platelets, thus trapping them and
  adding to the plug




                                                          60
                   Platelet Phase
    Activated platelets release chemicals that enhance
    hemostasis:
•   ADP stimulates platelet activation
•   thromboxane A2 & serotonin stimulate vascular spasm
•   protein clotting factors are proteins involved in
    clotting
•   platelet-derived growth factor stimulates vessel repair
•   calcium ions are a non-protein clotting factor (aid
    reactions catalyzed by several clotting factors)


                                                              61
            Natural Limits to
         Platelet Plug Formation
Several chemicals work to limit platelet plug formation
• Prostacyclin (a local prostaglandin) is released by
  endothelial cells and inhibits platelet aggregation
• WBCs secrete several compounds that inhibit platelet
  aggregation
• Certain circulating enzymes degrade ADP (see
  previous slide)
• Serotonin blocks action of ADP




                                                          62
              Natural Limits to
           Platelet Plug Formation
• Clotting also limits platelet plut by isolating the
  platelet plug from circulation, thus limiting the
  number of platelets affected and release of
  stimulatory compounds




                                                        63
      Coagulation (Clotting) Phase
• Clotting is a series of reactions resulting in formation
  of insoluble fibrin fibers
• Clotting reactions occur as cascades resulting in a
  large amount of fibrin formed from a small amount of
  initial reactants
• Clotting occurs by positive feedback in which
  thrombin (produced near end of reaction sequence)
  stimulates formation of tissue factor and release of
  PF-3 from platelets (both used early in sequence)
• Clottting includes 2 initial pathways that share a
  common pathway at the end; differ in starting point
  and stimulus                                               64
        Coagulation Requirements
Clotting requires many chemicals including:
• clotting factors (proteins also called procoagulants)
  that catalyze the reactions
   – most are produced by liver or released by platelets
   – synthesis of 4 factors by liver requires vitamin K
• fibrinogen the soluble plasma protein produced by
  liver that will become the insoluble fibrin fibers of the
  clot
• Ca2+ ions, which act as an important cofactor to
  enzymes in several reactions (Review Marieb Chapter
  2, pp. 55-56, Enzymes and Enzyme Activity)
                                                              65
        Measuring Coagulation
Clotting can be measured as:
• Coagulation time, which is the time for blood in a
  test tube (refered to as in vitro) to clot
   – coagulation time is normally in the range of 8
     to 18 minutes
• Bleeding time, which is the time for a small
  puncture wound to stop bleeding (within the living
  individual and referred to as in vivo)
   – Bleeding time is normally between 1 and 4
     minutes (that is, most small wounds stop
     bleeding within 4 minutes)
                                                       66
         Pathways of Coagulation
• Clotting proceeds through one of two pathways
  (which may occur simultaneously) to a single
  common pathway
• The two pathways to the common pathway differ in
  origin and are called the extrinsic pathway and the
  intrinsic pathway




                                          Fig. 18.13a, p. 668
                                                                67
    Initial Pathways of Coagulation
• The extrinsic pathway starts with tissue factor (factor
  III) and has fewer steps. The extrinsic pathway is
  initiated by damage to tissue
• The intrinsic pathway starts with activation of
  proenzymes in blood and may be activated in an
  unbroken blood vessel
• Which of these pathways may lead to formation of a
  thrombus?
• Which of these pathways would wall off a damaged
  area of tissue?


                                            Fig. 18.13a, p. 668
                                                                  68
  Common Pathways of Coagulation
• The common pathway involves the final reactions for
  both initial pathways
• It starts from activated factor X, which leads to
  prothrombin activator formation
• Prothrombin activator activates prothrombin to
  thrombin
• Thrombin catalyzes the conversion of fibrinogen,
  which is soluble, to fibrin, which is insoluble, and the
  formation of cross-connections between fibrin
  molecules to stabilize the clot


                                            Fig. 18.13a, p. 668
                                                                  69
                 Clot Retraction
• is accomplished by platelets that adhere to fibrin fibers
• these platelets pull the torn edges of the vessel together
  thus reducing the size of damaged area




                                                               70
                   Fibrinolysis
• Fibrinolysis is the breakdown of fibrin fibers by the
  enzyme plasmin
• Plasmin is formed from inactive precursor called
  plasminogen (inactive precursors are also called
  zymogens)
• Plasminogen is activated by:
   – thrombin produced by common pathway of
     clotting
   – tissue plasminogen activator (t-PA) produced by
     damaged tissues

                                                          71
        Natural Control of Clotting
Clotting is naturally restricted by a number of
  compounds including:
• plasma anticoagulants (such as antithrombin III
  produced by platelets)
• heparin (which is released by basophils and mast cells,
  and accelerates the activity of antithrombin III)
• thrombomodulin (released by endothelial cells;
  converts thrombin into different enzyme that activates
  protein C, which inactivates a number of clotting
  factor enzymes and stimulates production of plasmin)
• prostacyclin (which inhibits platelet aggregation; and
  opposes the action of thrombin, ADP and several other
  factors)                                                  72
     Clinical Control of Clotting
• Heparin, which is a synthetic version of naturally
  occurring compound; interferes with conversion of
  prothrombin to thrombin; enhances action of
  antithrombin III
• Warfarin (Coumadin), which interferes with
  production of clotting factors that require vitamin
  K for synthesis
• Aspirin – interferes with platelet aggregation
• Which - heparin or warfarin - would be more
  useful for short-term control? for long-term
  control?
                                                        73
      Genetic Bleeding Disorders
• Hemophilia is a recessive, x-linked genetic disease
  in which clotting factors (most often factor VIII,
  but several others as well) are not made in adequate
  amounts
   – Would you expect most people with hemophilia
     to be male? or female?
• von Willebrand disease is the most common
  genetic bleeding disorder; failure to make adequate
  amounts of von Willebrand’s factor, which
  stabilizes factor VIII in the extrinsic pathway

                                                         74
              Bleeding Disorders
• Thrombus is a clot formed in intact vessel wall; often
  occurs where cholesterol plaques are present; may
  break free or completely block vessel
• Embolus is an abnormal mass (especially a clot) that is
  carried by the blood
   – When the embolus is a clot, it may start out as
     thrombus or may form spontaneously in pooled
     blood
   – An embolus may result in an embolism (blockage of
     vessel) and cause an infarct (tissue damage)
      ° An infarct in the CNS is called a stroke.
      ° An infarct in the heart is called a myocardial
        infarct
                                                            75
Return to Rh Blood Typing

               Table, p. 9 - Rh Blood Types
                  Blood Type                                 Rh+                        Rh-
          Agglutinogen D (antigen
                 proteins)                                Present                    Absent
            Present or Absent
      Makes Agglutinins (antibodies)
                                                             No                       Yes[1]
          Against Agglutinogen

         May Receive Blood From:                        Rh+ or Rh-                     Rh-[2]

        May Give Blood To Without
                                                             Rh+                    Rh+ or Rh-
               Reaction[2]:

                    Genotype                             DD or Dd                       dd


 [1] Only makes antibodies (agglutinens) after exposure to Rh+ blood cells (via transfusion or during
 birth process)
 [2] Transfusion of Rh- individual with Rh+ blood results in production of anti-D agglutinens; sensitizes
 person to Rh factor and may result in anaphylaxis if exposed a second time. Erythroblastosis fetalis
 arises when Rh- mother has been exposed to Rh+ blood and is carrying Rh+ child.                        78

				
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