The Cardiovascular System, Blood

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  1. PLASMA AND THE CELLULAR ELEMENTS OF BLOOD
    1. Plasma is Extracellular Martix
      1. Plasma
      2. Plasma Proteins. Albumin. 
        1. Plasma is identical to the interstitial fluid except for the presence of Plasma Proteins. Albumin makes up 60% of plasma proteins. Albumin, with globulins, and clotting protein fibrinogen, and the iron transporting protein transferrin make up more than 90% of all plasma proteins.
        2. Liver makes most proteins
        3. Immunoglobulins are not made in the liver
        4. Protein makes the osmotic pressure in the blood higher than the interstitial fluid
        5. Functions:
          1. Albumin - osmotic pressure of plasma, carrier protein.
          2. Globulins - Clotting factors, enzymes, antibodies, carrier protein
          3. Fibrinogen - Fibrin threads essential for clotting
          4. Transferrin - Iron transport
    2. Cellular Elements Including RBCs, WBCs, and Platelets
  2. BLOOD CELL PRODUCTION
      1. All blood descend from a pluripotent hematopoietic stem cell. This cell is found primarily in the bone merrow. 
      2. Become uncommitted stem cells, then progenitor cells that are committed to develop into one or perhaps two cell types. 
      3. Pluripotent stem cells maybe useful to replace lost stem cells for patients on chemotherapy - cord blood is a rich source of pluipotent hematopoietic stem cells. 
    1. Blood Cells are Produced in the Bone Marrow
      1. Hematopoiesis
        1. In about the third week of fetal development, specialised yolk cells from the embryo form clusters. These cell clusters become endothelial lining of blood vessels, while others become blood cells. The common embryonic origin of the endothelium and blood cells perhaps explains why many of the cytokines that control hematopoiesis are released by the vascular endothelium. 
        2. As the embryo develop the blood cell production spreads from the yolk sac to the liver, spleen and the bone marrow. 
          1. Hematopoiesis stops in the spleen at birth
          2. continues in the all bone marrow till age 5
          3. continues in adult bone marrow of the pelvis, spine, ribs, cranium, and proximal ends of long bones.
      2. hemoglobin
        1. Active bone marrow is red - with hemaglobin. Inactive bone marrow is yellow with adipocytes
        2. 75% makes WBC's with short half lives, 25% makes RBC with half lives of 120 days
    2. Hematopoiesis is Controlled by Cytokines
        1. Cytokines are peptides or proteins released from one cell that affect the growth or activity of another cell. All nucleated cells synthesize and secrete cytokines in response to stimuli. Cytokines control development, cell differentiation, and immune response. 
          1. Cytokines are not produced by specialised cells, and are made on demand. This is unlike a hormone - cytokines also use different signal pathways to hormones.
        2. Cytokines - referred to as factors
          1. growth factor, differentiation factor, trophic factor. 
          2. Colony-Stimulating Factors - molecules made by Endothelial cells and WBC's
          3. interleukins - important role in the immune system
          4. Erythropoietin - called a hormone but fits the definition of a cytokine. 
    3. Colony-Stimulating Factors regulate Leukopoiesis
      1. Made by the endothelial cells, morrow fibroblasts, and white blood cells
      2. Regulate leukocyte production and development, or leukopoiesis.
      3. CSFs induce both cell division (mitosis) and cell maturation in stem cells.
      4. The production of new WBCs is regulated by existing white blood cells - making the production of new WBCs very specific to the current environment
      5. Leukemias - are a group of diseases characterised by the abnormal growth and development of white blood cells.
      6. Neutropenias - patients have too few white blood cells.
      7. Clinically available CSFs for WBC stimulation - sargramostatin, and filgrastim 
    4. Thrombopoietin Regulates Platelet Production
      1. Thrombopoetin (TPO) - is a glycoprotein that regulates the growth and maturation of megacaryocytes, the parent cells of platelets
      2. Produced in the Liver and the kidney
      3. TPO is Manufactured for research using recombinant DNA techniques
    5. Erythropoitin Regulates RBC production
      1.  erythropoiesis is controlled by a glycoprotein Erythropoietin (EPO), assisted by several cytokines. 
      2. Erythropoietin is made primarily in the kidneys of adults.
      3. Stimulus for EPO synthesis and release is hypoxia
        1. Hypoxia stimulates a transcription factor hypoxia inducible factor 1 (HIF-1) which turns on the EPO gene to produce EPO synthesis. 
      4. EPO is manufactured for clinical use using recombinant DNA techniques, 
  3. RED BLOOD CELLS
      1. hematocrit - ratio of RBC to Plasma, expressed as a percentage of total blood volume. 40 to 54% males, 37 to 47% females. Thin "buffy layer" of WBC and platelets (<1%) in the middle and plasma on top.
    1. Mature RBCs lack a Neucleus
      1. Committed progenitor cells - nucleated erythroblasts that mature and condense nucleus and the cell shrinks in diameter. The nucleus in pinched off and phagocytosed by bone marrow macrophages. Other membranous organelles like mitochondria breakdown and disappear.  
      2. The final immature cell form - reticulocyte - leaves the bone marrow and enters the circulation where it matures into a RBC in 24 hours. 
      3. Glycolysis for ATP - cant use anaerobic metabolism as no mitochondria. This inability leads to an increasing loss of membrane flexibility, making older cells more fragile and likely to rupture.
      4. Biconcave shape - held in place by a complex cytoskeleton - flexible
        1.  respond to osmotic changes in blood
        2. hypotonic media - swell, 
        3. Crenated: hypertonic media - shrink, the rigid cytoskeleton remains intact, creating a spiky surface
    2. Hemaglobin synthesis requires Iron
      1. transferin
        1. Iron is absorbed in the small intestine by active transport
        2. transported by carrier protein transferrin
        3. used to make the heme group of hemoglobin
        4. Excess iron is stored in the liver as ferritin
      2. Excess Iron - GI pain, cramping, and internal bleeding - which occurs as iron corrodes the digestive epithelium. Subsequent problems are liver failure 
    3. RBCs live About Four Months
      1. Fragile older RBCs rapture as the squeeze through he narrow capillaries - engulfed by scavenging macrophages as they pass through the spleen.  
      2. Components are recycled, 
      3. waste is converted to bilirubin - Bilirubin carried by albumin to the liver where it is converted to bile. 
      4. Bile is secreted in the digestive tract - excreted in feces, a small amount makes urine yellow
      5. Jaundice - elevated bilirubin levels
    4. RBC Disorders Decrease Oxygen Transport
      1. Anaemia causes: 
        1. Accelerated RBC loss
          1. Blood Loss
          2. Hemolytic Anaemias
            1. Hereditary
              1. Membrane defects - spherocytosis
              2. Enzyme defects
              3. Abnormal Hemoglobin - sickle cell anaemia - HbS 
                1. HbS is a genetic defect in which glutimate is replaced by valine in the hemaglobin chain. 
                2. Damage and pain from hypoxia
                3. Rx: hydroxyuria - stimulates the formation of fetal hemaglobin instead of adult hemaglobin. HbF -
                  1. Also hydroxyuria is metabolised to NO that gives vasodilatation before the HbF is formed - this gives relief to the patients with Sickle cell anaemia. 
                  2. Inhaled NO is also used as treatment for sickle cell anaemia
            2. Acquired
              1. Parasitic infections - malaria
              2. Drugs
              3. Autoimmune reactions
        2. Decreased RBC Production
          1. Defective RBC or Hemoglobin synthesis in the Bone Marrow
            1. Aplastic anaemia - drugs or radiation
            2. Inadequate intake of dietary nutrients
              1. Iron deficiency anaemia - iron required for heme production
                1. Microcytic hypochromic anaemia
              2. Folic Acid deficiency - folic acid is required for DNA synthesis
              3. Vitamin B12 deficiency - B12 is required for DNA synthesis - maybe due to a lack of intrinsic factor for B12 absorption
          2. Inadequate Production of erythropoietin
      2. Too much RBC
        1. Polycythemia vera
          1. Hematocrits of 60 to 70% (37-54%)
          2. Viscous blood and more resistant to flow
        2. relative polycythemia
          1. Normal RBC but low plasma - Hct is elevated
            1. Dehydration. Overhydration may also lower the Hct
  4. PLATELETS AND COAGULATION
    1. Platelets are Small Fragments of Cells
      1. Magakaryocytes are massive cells - polipoid cell with a lobulated nucleus. They extend through the endothelim - sticking into the lumen of the marrow blood sinuses - where the cytoplasmic extension fragment into disc like platelets. 
      2. Platelets contain mitochondira, smooth Endoplasmic Reticulum, and many grannules filled with clotting proteins and cytokines. 
      3. Lifespan 10 days.   
    2. Hemostasis Prevents Blood Loss from Damaged Vessels
      1. Hemostasis - keeping blood within the damaged blood vessel. Three steps:
        1. Vasoconstriction
          1. vasoconstrictive paracrines are released by the endothelium
          2. vasoconstriction temporarily decreases the blood pressure and blood flow within the vessel. 
        2. temporary blockage by a platelet plug, and
          1. Mechanical blockage with a Platelet plug. The plug forms as platelets stick to the exposed collagen - Platelet adhesion and become activated - releasing cytokines to the area surrounding the injury.
          2. Platelet factors reinforce local vasoconstriction and activate more platelets, which stick to one another - platelet aggregation to form a new platelet plug.
        3. Blood Coagulation, or formation of a clot that seals the hole until the tissue is repaired.
          1. Simultaneous exposure to exposed Collagen and tissue factor - a protein phospholipid mixture - initiate the coagulation cascade. The cascade ends in the formation of a fibrin protein fiber mesh that stabilises the platelet plug. The reinforced platelet plug is a clot. 
          2. Eventually the damaged vessel repairs itself and the clot is dissolved by plasmin. 
      2. Platelet activation Begins the Clotting Process
        1. Platelets adhere to the exposed collagen with integrins - membrane receptor proteins that are linked to the cytoskeleton. Binding of the integrins release the platelet intracellular granules, including:
          1. serotonin, ADP, and platelet activating factor (PAF). PAF sets up a positive feedback loop by activating more platelets. It also initiates pathways that convert membrane phospholipids into Troboxane A2
          2. Serotonin and tromboxane A2 are vasoconstrictors. Also contribute to platelet aggregation, with ADP and PAF.  
          3. The net result is a growing platelet plug that seals the damaged vessel wall.
        1. Platelets do not adhere to normal endothelium - 
        2. Prostacycline
        3. Coagulation Converts a Platelet Plug into a Clot
        4. Anticoagulants prevent Coagulation

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