DPAS 5200a25 Day 2 Hematology PDF

Cynthia C. Bennett, MD revised January 2025 DPAS 5200a25 day 2 Hematology and the bloodstream  Today’s PA Instructional Objectives: Describe the composition of blood- its water content, cells, and proteins. Define eryth...

Cynthia C. Bennett, MD revised January 2025 DPAS 5200a25 day 2 Hematology and the bloodstream  Today’s PA Instructional Objectives: Describe the composition of blood- its water content, cells, and proteins. Define erythropoietin, understand its production, and describe its role in red blood cell formation Describe the characteristics and affecters of hemoglobin function Describe normal hematopoiesis--- understand the origin, characteristics and function of all blood cell lines Define anemia and polycythemia and briefly state their relevance Describe the normal function of both the anticoagulant and the pro-coagulant factors in the blood (we will go into more detail in Pathophysiology I)  Blood = Plasma + Cells Plasma = organic + inorganic substances (including proteins) dissolved in water. Cells = white cells, red cells, platelets  Plasma Vocab! Plasma is about 90% water Dissolved proteins make up most of the solute weight of plasma. Albumins, globulins, fibrinogen, clotting factors They exert osmotic pressure that keeps fluid in the bloodstream. Each protein also has a role as a carrier or a clot- former One way to think about it: Serum: the watery portion of plasma with all Hydrostatic pressure = the force clotting factor proteins (and some other proteins) of water pushing outward removed Osmotic pressure = the quality of solutes (especially proteins!!) that “pulls water inward” 4  Plasma is a transporter its role is to move things from one spot to another. NOTE: plasma proteins are part of “the river” and don’t jump in/jump out like the carried molecules do. Where do Baby Blood Cells Come From? Hematopoiesis  Hematopoiesis occurs in the bone marrow. It begins with a Pluripotential Stem Cell which can create many cell lines by dividing over and over. As it differentiates, its new cells “decide” which type of cell to become. First “decision” of the pluripotent cell’s descendants: Lymphoid or Myeloid? Future lymphocytes = lymphoid Future erythrocytes, platelets and white cells = myeloid 8  A complex bunch of growth factors exist to signal for the growth of a “colony” of blood cells from the bone marrow. Once a myeloid stem cell is created, it’s “committed” to its path– it will only make that particular kind of progeny. Blood cancers are the uncontrolled and/or abnormal cell division of one of these precursors. Growth Factors in Blood Cell Production These Growth Factors are produced… ….then travel (via the bloodstream)… …..to the bone marrow where they play a role in differentiation of precursor cells and rate of cell division. 10 Erythrocytes “erythro” = “red” 11 Erythrocytes Here’s what you see if you’re looking in a light microscope: What if red cells were stuck in a round shape, or couldn’t flex and bend? 12  Quick 2 minutes: Erythrocytes (Red Blood Cells) 1. Main function…? 2. Why are they shaped like a tire with a double trampoline in the middle…..? (2 reasons) 3. What things are they missing that almost all other cells have??? 4. What can they NOT do that other cells can do? 5. Why are they red? 6. How do they contribute to pH control? 13 Quick 2 minutes: Erythrocytes (Red Blood Cells) 1. function in oxygen and carbon dioxide transport. 2. Biconcave disk shape gives a large surface area which favors diffusion, and makes the tiny cells flexible enough to fit through teeny capillaries. 3. No nucleus, few organelles. No mitochondria– they use fermentation to get energy (they have enzymes to do so). 4. Can’t do mitosis or aerobic respiration 5. Hemoglobin (binds oxygen and carbon dioxide) has iron, which is red when reversibly bound to oxygen. 6. They carry carbonic anhydrase: 14  Requirements for Erythrocyte Production: Iron – Component of hemoglobin – Normal hemoglobin content of blood: Men: 13–18 gram / dL Women: 12–16 gram / dL Folic acid and Vitamin B12 Erythropoetin (EPO) 15  HEMOGLOBIN (Hb): Iron is here A 4-piece molecule with Fe++ incorporated into its structure at 4 different sites. Each blood cell has 280 million molecules of it. FUN FACT: Octopi use hemocyanin rather than hemoglobin as their oxygen carrier. Their blood is blue because it contains copper instead of iron.  Here’s a fact that will help you with this: CO2 causes a low pH. When more CO2 is present, will hemoglobin hold on tighter, or looser? pH also tends to be low when tissue is dying or infection is present. Quick 2 minutes: Hb holds oxygen TIGHTLY at higher blood pH’es. Hb holds oxygen LOOSELY at lower blood pH’es. How does this affect oxygen delivery to tissues?  QUICK 2 MINUTES: Oxyhemoglobin looks redder than deoxyhemoglobin because of the shape change in the heme area of the molecule. EXPLAIN: 1. Which drop above is venous, and which is arterial? 2. Clinical correlation: Carbon Monoxide binds to hemoglobin at the same site as oxygen, but over 100X tighter than oxygen does. What would blood loaded with Carbon Monoxide look like: the arterial sample, the venous sample, or something different? why do people die of Carbon Monoxide Poisoning? QUICK 2 MINUTES: EPO. You and a partner identify the following: Where is it from? What does it do? Name a way you could increase your own EPO. Name a disease processes that would increase EPO. Name a disease process that would decrease EPO. Name a therapeutic scenario for using EPO. The Negative Feedback Loop for EPO: 21  Clinical Issues Kidney Failure Patients: too little erythropoietin! Solution: synthetic EPO injections. Athlete abuse of synthetic EPO (to increase stamina)= risk of death! Why? blood becomes much more viscous, increasing risk of clotting, stroke and heart failure. Testosterone increases EPO production (hence men have higher hematocrit than women) Be very careful when dosing testosterone; risks above also apply to steroid abuse. 22  RBCs have a 120 day lifespan. Some pathological conditions lead to breakage of erythrocytes into fragments called schistocytes. Occasionally, slightly immature forms of erythrocytes make their way into the bloodstream– like reticulocytes and nucleated RBC’s. What conditions might cause the bone marrow to push those slightly immature forms of RBC’s out early? NRBC 23  What happens to old/broken Erythrocytes? The spleen filters and removes old/ broken erythrocytes, and sends their byproducts to the liver for recycling/reuse. Iron is transported in the blood (bound to transferrin) to the bone marrow to use in new red cells. When not needed immediately by the bone marrow, iron is stored bound to ferritin in the Please know the roles of the spleen, liver, bone marrow, liver, spleen and small intestines. ferritin, and transferrin in this process. 24 TOO MANY RED CELLS: TOO FEW RED CELLS/ TOO LITTLE HEMOGLOBIN: polycythemia anemia  Next up: Coagulation Break Time!  Clotting Clot Dissolution In the human body, microscopic bleeding and clotting are happening all the time. Clot formation is always in balance with clot dissolution. Both are happening all the time, and they need to occur in balance. Decreased (or overly increased) function of either of these processes can lead to bleeding/ clotting disorders. First: let’s discuss Hemostasis  Platelet Aggregation (create a “stopper” for the hole in the blood vessel) Clot Vasoconstriction (make the hole in the blood Formation glue the stopper vessel smaller) together and hold it in place) Hemostasis The Trifecta of Hemostasis:  Platelets: cytoplasmic fragments which bud off of a parent call called a megakaryocyte. Because they are cell fragments they have no nucleus or organelles, but they do contain: pre-formed granules full of chemical products important for clotting and pre-made enzymes that activate chemical reactions. Platelet activation causes the granules to be released and enzymes to activate, kicking off the coag cascade and amplifying the platelet activation process. 30  Vessel lining Damage VASOCONSTRICTION AND PLATELET AGGREGATION: positive- This damage exposes positive- feedback subendothelial collagen and feedback loop! “tissue factor”, which activates loop! platelets. ACTIVATED PLATELETS: Release enzymes Release more that produce inflammatory Thromboxane. mediation chemicals, Activates more THROMBOXANE: which… platelets. Makes the blood vessel Makes platelets clump constrict, so… together, creating a “platelet plug.” The Activate the clotting cascade, platelet plug… which serves as “glue” for the platelet plug Hole that needs fixing is Fills the hole in smaller; blood the blood vessel loss is less. 31  Thromboxane is localized to the site of injury. ILLUSTRATION NOTE: “TXA2” = thromboxane, which is: An inflammatory mediator/molecule A potent vasoconstrictor A platelet activator “PGI2” = prostacyclin, which is: an anti-inflammation mediator/molecule A potent vasodilator a platelet anti-activator Activated platelets produce THROMBOXANE, a potent platelet aggregator and vasoconstrictor. It’s made from arachidonic acid. Meanwhile, endothelial cells around the rapidly-enlarging clot produce PROSTACYCLIN, which has the opposite effects. It’s also made from arachidonic acid. This is a “check and balance” against the positive feedback loop on the prior slide. Q: HOW CAN BOTH A CONSTRICTOR AND A DILATOR COME FROM THE SAME SUBSTANCE? 32  A: Different enzymes! “Which app (enzyme) does each cell have?” Platelets have the app called COX-1. Vessel lining cells it converts PGH2 have the app into Gets called COX-2. It thromboxane. converted to converts PGH2 PGH2. into prostacyclin. This is a “check and balance” against the positive feedback loop of clotting.  Aspirin for Coronary Artery Disease… Aspirin Aspirin helps prevent clotting in the heart’s arteries by inhibiting (blocking) the enzyme COX-1 (the thromboxane-producing enzyme that platelets have). Without COX-1, platelets can’t make thromboxane. Less thromboxane means decreased vasoconstriction and decreased platelet aggregation. Less of these processes means less likelihood of a small clot growing and blocking an already-narrowed coronary artery. COAGULATION: Coagulation= conversion of dissolved (liquid) blood proteins into a solid gelatin-like substance Blood converted into solid gel is called a clot or thrombus This process usually occurs around platelet plug (though can happen at other solid surfaces) This is our dominant hemostatic defense mechanism when bleeding happens. 35 Two pathways exist for activating the clotting cascade: Intrinsic Extrinsic Slower The major pathway utilized Activated by stasis against a surface, Faster including the surface of a platelet plug Activated by tissue factor and platelet granules The two pathways both end in a Common pathway involves “common” part of the coag Factor 10, prothrombin, cascade that creates fibrin- the fibrinogen, and factors 8 gelatinous “glue” for coagulation and 13. Please know these! You will learn the others later.  Vessel damage happens The Extrinsic Pathway: “falling domino” series of enzyme activations (from a “pro” version to an “activated” version) When Factor 10 (X) is activated, it is converted to Factor 10a (Xa). Factor 10a activates prothrombin to become thrombin Thrombin activates fibrinogen, converting it to fibrin Fibrin is the “clot glue”, made of lots of microscopic strands of protein like a web of tiny ropes. **The extrinsic pathway requires exposure to something outside of the bloodstream. 37  Clotting factors are left sitting still beside a surface for a period of time. The Intrinsic Pathway: “falling domino” series of enzyme activations (from a “pro” version to an “activated” version) When Factor 10 (X) is activated, it is converted to Factor 10a (Xa). Factor 10a activates prothrombin to become thrombin Thrombin activates fibrinogen, converting it to fibrin Fibrin is the “clot glue”, made of lots of microscopic strands of protein like a web of tiny ropes. **The intrinsic pathway requires prolonged exposure to a surface. 38  In both pathways: Factors 5 and 8 (V and VIII), when activated, amplify the clotting process by making particular steps go significantly faster. Factor 13 (XIII), when activated, strengthens the fibrin in the clot. 39  That’s all the detail you need to know for now. You’ll memorize the clotting cascade later in Pathophys.  Facts about the Factors: Clotting factors are made by the liver and secreted (released) into blood in inactive forms which are activated “heme” = blood, or bleeding during the clotting cascade (e.g., XII → XIIa, V → Va) “philia” = ‘love of’ or ‘affection for’ Plasma can be used to treat patients with clotting Hemophilia= disorders. A disease process that creates a lot of bleeding Lask of factor 5, 8 or 13 causes hereditary bleeding that’s difficult to stop. disorders. Parahemophilia Hemophilia B (rare) Hemophilia A How did this disorder get its name? 41  Facts about the Factors: Most clotting factors are produced by the liver. Vitamin K is required for synthesis of many coag factors Vitamin K deficiency can cause severe bleeding Vitamin K is stored in the liver  What conditions can increase clotting? Things that damage the endothelium. Examples: inflammation, altherosclerosis, diabetes, and increased blood pressure (traumatic to the endothelium). Slow-moving blood. Examples: elevated hematocrit, bed- ridden patients, long flight with no movement of the lower limbs, all allow clotting factors to accumulate and become static Aspirin, heparin and warfarin are all (non-moving)- which can activate the intrinsic pathway. used clinically to prevent clots. Processes that increase the action of the coag cascade. Examples: pregnancy and elevated estrogen levels (increase production of coag factors), diseases that limit the ability to prevent or reverse clot formation. 43  Clots and your Bloodstream (thrombus vs. embolus) A thrombus is a clot that forms within an unbroken blood vessel. It can block the vessel if it gets large enough. leads to ischemia and tissue death downstream from the clot. cause of fatal heart attacks. An embolus is a clot that has broken off from somewhere and is now free-floating in the blood stream. Can get wedged in a vessel downstream from it– especially if that vessel is already narrowed by a thrombus!! Examples: Pulmonary emboli block blood flow to the lungs cerebral emboli block blood flow to the brain (embolic stroke) 44  Physiologic Clot Control To prevent a clot from becoming unnecessarily large, there is swift removal of clotting factors by the moving bloodstream and rapid deactivation of active clotting factors (in other words, they have a limited time of activity before they are deactivated) Unbound thrombin is inactivated by Antithrombin III and Protein C to keep the clotting process in check. Heparin is an anticoagulant contained in mast cells, some white blood cells, and endothelial cells. Heparin inhibits the intrinsic pathway and It enhances antithrombin III, making it work even faster. 45 Antithrombin III and Protein C: Clotting these work to “tilt the pendulum” away from clotting, and toward clot dissolution. Clot Dissolution Antithrombin III (ATIII) Protein C -deactivates loose thrombin, so it won’t convert When activated, it turns off the amplification power fibrinogen to fibrin. of factors V and VIII (5 and 8)– Needs heparin to work. much like unplugging the sound system at a rock concert– this is a big effect! It’s activated by thrombin– so the more thrombin there is, the more protein C gets activated (negative feedback)  Real-life logic problems: Think for 2 minutes! Q: What if a person had a deficiency of Protein C? More likely to clot, or less likely? Answers right after that… Q: What if a person had plenty of More likely to clot, or less likely? Protein C, but could not *activate* it? Q: What if a person made no ATIII? More likely47to clot, or less likely? Q: What if a person made no Factor 8? More likely to clot, or less likely?  Real-life logic problems: Q: What if a person had a More likely to clot, or less likely? more deficiency of Protein C? Q: What if a person had plenty of more More likely to clot, or less likely? Protein C, but could not *activate* it? Q: What if a person made no ATIII? More likely48to clot, or less likely? more Q: What if a person made no Factor 8? More likely to clot, or less likely? less TRUE Physiologic Clot Dissolution (dissolving) While other processes can slow down clotting, only plasmin can actually dissolve an established clot. Dissolved Clot 49  Plasminogen Activators Plasminogen activators convert plasminogen to plasmin. We can use recombinant tissue plasminogen activator (TPA) to dissolve clots– not just slow down the clot formation process. TPA is often used to treat stroke patients if they arrive soon enough to the hospital. Q: any risks to giving a patient TPA?? 50 We’ll cover the WBC’s when we discuss the Immune System. The End of Today!