The Cardiovascular System (Blood)

I. Overview

A. Components Diagram

B. Physical Characteristics:

• 8% of body weight
• Blood is more dense than water and five times more viscous
• Slightly alkaline --> pH 7.35-7.45
• Slightly higher than body temperature (100 degrees F)
• Males = 5-6 liters, females 4-5 liters

C. Functions

II. Formed Elements

A. Blood Cell Formation (Hemopoiesis)

• Occurs in red bone marrow (myeloid tissue of axial skeleton and, esp. proximal epiphyses of humerus and femur)
• controlled by feedback mechanisms
• All formed elements derived from stem cells called hematocytoblast in red bone marrow
• Maturation pathways differ (cells are committed to a specific blood cell pathway)
• Commitment is signaled by specific hormones binding to surface receptors on the cell membrane

B. Erythrocytes (RBCs) Diagram

i. Characteristics

• Small biconcave, anucleate disks
• Contain the oxygen-binding protein, hemoglobin
• Hemoglobin has a quaternary structure (four polypeptide chains, each with a ring-like heme group)
• Forms of hemoglobin --> oxy, deoxy, and carbamino
• RBCs are thin in center and thick around rim (increases surface to volume ration) thereby maximizing diffusion of gases
• RBCs contain a protein (spectrin) which forms a net and is deformable, enabling RBCs to change shapes
• RBC count (per mm cubed) males = 4.8 - 6.2 million, females 4.2 - 5.4 million
• RBC production (erythropoiesis) occurs in three stages: 1) production of ribosomes, 2) synthesis of hemoglobin, and 3) ejection of erythrocyte's nucleus and organelles

1. Hemocytoblast
2. Proerythroblast - Committed cell
3. Early (basophillic) erythroblast - produce large quantities of ribosome
4. Late (polychromatophillic) erythroblast - blue color (ribosomes) of cytoplasm turns to a pink color (hemoglobin)
5. Normoblast - organelles are ejected
6. Reticulosite - nucleus is ejected, contains small number of ribosomes, 1-2% are found in circulation
7. Erythrocyte - matured reticulocutes (2 days), most if not all ribosomes degraded

NOTE: cell division takes place during the first two phases of development

ii. Regulation of Erythropoiesis via a homeostatic mechanism:

1. Oxygen blood levels constantly monitored (e.g. chemorecetpors: carotid body? oxygen sensors in kidney?)
   
2. Drop in oxygen levels as a result of:
   • reduced number of erythrocytes
   • reduced oxygen availability
   • increased tissue demands
3. Declining oxygen levels in blood (hypoxia) signal kidney to release the hormone erythropoietin (EPO)

Note: A synthetic EPO is used by kidney dialysis patients and athletes - why?

iii. Dietary Requirements for Erythropoeisis:

• B vitamins → needed for DNA synthesis (Folate) and new cell production (Riboflavin)
  
• iron → needed for heme production; iron toxic in body and needs transport protein (transferin) and storage proteins (hemosiderin and ferritin)

iv. Destruction of RBCs

• RBC life span is 100-120 days
• RBCs may become trapped and fragment in the smaller circulatory channels (capillaries) and are then phagocytized by macrophages.
• RBCs are broken down into globin and heme which is further broken down into iron and the greenish pigment biliverdin (then converted into bilirubin).

v. Life Cycle of RBCs: Diagram

• Raw materials (iron & B vitamins absorbed by intestine) and erythropoeitin promote eryhtropoeisis in marrow
• Erythrocytes enter blood stream and circulate 120 days
• Aged/damaged RBCs engulfed by macrophages of liver and spleen, hemoglobin sequestered by liver
• Low RBC count or low oxygen levels stimulate secretion of erythropoeitin

vi. Issues in red blood cell production

Anemia = condition of decreased number of RBC or decreased concentration of hemoglobin

1. Insufficient number of RBCs

• hemorrhagic = results from blood loss
• hemolytic = erythrocytes are ruptured (due to hemoglobin abnormalities, transfusions, and bacterial/parasitic infections)
• aplastic = results from destruction or inhibition of red marrow (by bacterial toxins, drugs, and ionizing radiation)

2. Decreased in hemoglobin content

• iron-deficiency = deficient intake, poor absorption, and excessive loss of iron; produce microcytes (small pale RBCs)
• pernicious = intrinsic factor deficiency causes inability to absorb adequate amounts of vitamin B-12; produces large RBCs called macrocytes (developing RBCS grow but dont divide)

3. Abnormal hemoglobin

• thalassemia = genetic defect, absence of one of the polypeptide chains (RBCs are thin and fragile)
• sickle-cell = genetic defect, change in one amino acid causes hemoglobin to be crescent-shaped
• Polycethemia = abnormal excess of RBCs
  • Primary polycethemia (erythemia) - excess RBCs as a result of tumorous abnormalities of bone marrow
  • Secondary (physiologic) polycethemia - results when decreased oxygen availability occurs or erythropoeitin production increases

C. Leukocytes (WBCs)

i. Characteristics

• Nucleated polymorhic cells with normal counts ranging from 4,000 -11,000 per mm cubed
  • < 4,000 = leukopenia and >11,000 = leukocytosis).
• WBCs are able to slip out of capillary blood vessels (diapedesis) to areas of body where they are needed for an immune response. Once out of the cappilary, WBCs move through tissue spaces by amoeboid motion (forming cytoplasmic extensions that propells the cell along).
• WBCs can locate areas of tissue damage and infection by responding to chemicals released by damaged cells or other leukocytes. This process is called positive chemotaxis.
• Leukocytes are grouped into two major subdivisions: granulocytes and agranulocytes.

ii. DIFFERENTIAL WBC COUNT - measure the percentage of WBC in blood

iii. White Blood Cells 

Granulocytes Diagram

• Neutrophils (40-70% of WBC count)
  • Chemically attracted to sites of inflammation
  • Phagocytizes bacteria (and some fungi)
  • Bacteria killing via respiratory burst (oxidants and defensins used to cause lysis)
• Eosinophils (1-4% of WBC count) -
  • Contains digestive enzymes - yet eosinophils don't contain enzymes to digest bacteria
  • Kills parasitic worms, destroys Ag-Ab complexes, and inactivates inflammatory chemicals
• Basophils (0-1% of WBC count) - releases histamine and other inflammation mediators

Agranulocytes Diagram

• Lymphocytes (20-40% of WBC count) - immune response by direct cell attack or via antibodies
• Monocytes (4-8% of WBC count) - phagocytosis/macrophages

iv. Leukopoiesis

• Occurs in red bone marrow
• Initiated by cytokines (interleukins, IL and colony stimulating factors, CSFs)
• Hemocytoblasts are transformed into myeloid stem cells and lymphoid stem cells: Diagram

v. Leukocyte disorders

1. Leukemias
   • named according to abnormal cell type (egs. myelocytic and lymphocytic)
   • classified as acute (quickly advancing and derived from blasts) or chronic (slowly advancing and derived from cytes)
2. Mononucleosis
   • caused by Epstein-Barr virus
   • causes excessive production of atypical agranulocytes

D. Platelets (thrombocytes)

• Cytoplasmic fragments; 250,000 - 400,00 per mm cubed of blood
• A hemocytoblast is converted into a megakaryoblast which undergoes repeated mitosis but cytokinesis never occurs, forming a multi-lobed nucleus and a large cytoplasmic mass.
• The megakaryoblast differentiates into a megakaryocyte that invaginates its cell membrane to compartmentalize the cytoplasm. Once compartmentalization is complete, the megakaryocyte ruptures into fragments (thrombocytes).
• The production of thrombocytes is regulated by thrombopoietin.
• Platelets produce proteins (fibrin) which aid in the clotting of blood vessels.
• Thrombocytopenia - number of circulating platelets are deficient

II. Hemtology Results

III. Hemostasis, rapid and localized stoppage of blood flow.

i. Three phases:

A. Vascular spasms - immediate response to blood vessel injury is vasoconstriction. Factors that help to initiate the spasm response include direct injury to smooth muscle, compression of the vessel by escaping blood, chemicals released by endothelial cells and platelets, and reflexes triggered by activation of local pain receptors

B. Platelet plug formation - endothelium lining blood vessels rupture and underlying collagen fibers are exposed. Platelets change shape, forming sticky spiky processes that adhere to exposed areas. Once attached, Thromboxane A-2 is generated from lipids in the platelet membrane. Thromboxane A-2 causes degranulation. Platelet granules breakdown and release serotonin (increases vascular spasms) and ADP (attracts more platelets to the area).

C. Clotting (coagulation) - clot formation is the result of converting the soluble protein fibrinogen into relatively insoluble threads of the protein fibrin. Damage to tissue causes the production of prothrombin activator which in the presence of calcium converts prothrombin into thrombin. Thrombin, in turn, acts as an enzyme and causes fibrinogen molecules to join and form fibrin threads that stick to exposed areas/forms clot.

ii. Clot Retraction, vessel repair, and fibrinolysis:

• Platelets contain contractile proteins (actin and myosin) and contract much like muscle cells. Contraction causes clot to becomed compacted.
• Platelet-derived growth factor (PDGF) stimulates smooth muscle and fibroblasts to divide and rebuild the vessel walls
• When vessels are repaired fibrinolysis removes clots
• In fibrinolysis, fibrin can be degraded by the enzyme plasmin.
• Plasminogen is the inactive form of plasmin and can be activated by activating factors such as tPA (tissue plasminogen activator)
• Other clot regulators include prostacyclin (opposes thomboxane 2) and anticoagulents (such as Heparin and Coumadin)

iii. Thromboembolytic disorders

• Thrombus - clot deveopling in an unbroken blood vessel
• Embolus - clot that breaks away from a blood vessel wall

IV. Blood Plasma - clear, straw-colored, liquid portion of the blood in which the cells and platelets are suspended. Plasma is composed of water and various solutes (proteins, nonprotein nitrogenous compounds, nutrients, electrolytes, gases).

V. Blood Groups and Transfusions

A. Human Blood Groups - RBC membranes have highly specific glycoproteins (antigens). One person's RBC proteins may be recognized as foreign if transfused into another person with a different RBC type, and the transfused cells may be agglutinated (clumped) and destroyed. There are 30-100 types of RBC antigens (agglutinogens) but A,B,O and Rh cause most vigorous transfusion reactions. Preformed antibodies called agglutinins act against RBC carrying ABO antigens that are not present on a person's own red blood cells.

B. ABO Groups:

C. Rh Blood Group - individuals may have Rh antigens on their RBC membranes and are considered Rh+. If one lacks these antigens on the membranes then they are considered Rh-. If an Rh- mother is carrying a Rh+ fetus then hemolytic disease of the newborn (HDN) may occur. Rh+ leaks through the placenta causing the mother to produce Rh antibodies. Rh antibodies may then cause hemolysis to occur. Anti-Rh gamma globulin (RhoGAM) is administered to prevent HDN in subsequent pregnancies

V. Clinical Terms

• Hemophilia - blood disorder characterized by a deficiency in particular clotting proteins
• Septicemia - excessive and harmful levels of bacteria or their toxins in the blood
• Methemoglobinemia - condition in which the iron in the hemoglobin molecule (the red blood pigment) is defective, making it unable to carry oxygen effectively to the tissues
• Nuetropenia - decreased number of neutrophils