Ch_13_Alterations_in_O2_Transport.docx

Chapter 13 – Alterations in O2 Transport PA Pathophysiology Objectives Chapter 13: Alterations in Oxygen Transport What composes the blood and what is the duty of each component? What factors are necessary for normal red blood cell (RBC) production. Describe RBC production. What is erythropoieti...

Chapter 13 – Alterations in O2 Transport PA Pathophysiology Objectives Chapter 13: Alterations in Oxygen Transport What composes the blood and what is the duty of each component? What factors are necessary for normal red blood cell (RBC) production. Describe RBC production. What is erythropoietin, where is it released and why, and where does it act. What is the structure of the RBC and how does that affect its function? What if the structure is altered? What is the structure of hemoglobin (Hb) and how does that affect its function? What if the structure is altered? Describe fetal Hb. How do Red blood cells (RBC) transport oxygen and CO2 in the circulation? What are reticulocytes and how are they used as a diagnostic tool? How are RBC removed from circulation? What is bilirubin, jaundice, and how are they related? How are O2 and CO2 carried in the blood? Which is more important in increasing delivery of oxygen to tissues, dissolved oxygen of hemoglobin content? What causes right and left shifts in the O2 Hb dissociation curve? What is the significance of this curve? How does carbon monoxide affect oxygen delivery to the tissues? What role does bicarbonate ion play in CO2 transport? How are lab tests used to detect and differentiate types of anemia and polycythemia? Describe the different types, causes, lab findings, and treatments of anemia. What are the symptoms? Describe the different types, causes, lab findings, and treatments of polycythemia. What are the symptoms? Describe Sickle Cell anemia – causes, symptoms, treatments, etc. What is a transfusion reaction, what causes it, what are the symptoms? What is the role of the spleen in the lifespan of the RBC and how is the spleen affected in anemic disorders? Composition of Blood (fig 13-1 and suppl fig 1&2 in notes) Plasma = Organic and inorganic Plasma proteins Globulins: large family of proteins– Carry things like Bilirubin , lipid and steroids Iron and copper Example: Albumin – very large, variety of functions (maintain blood volume and pressure) Fibrinogen Precursor to ‘fibrin’ – blood clotting Salts, hormones, metabolic fuels and byproducts (urea, creatinine, etc). Cells (see table 13-2) RBC (red blood cells – erythrocytes) anucleated proteins of the RBC – hemoglobin – oxygen carrying molecule carbonic anhydrase – pH buffering biconcave design allows flexibility to get through tight capillary spaces. Life span 100 days (+ 20) WBC (white blood cells – leukocytes) Numerous types – covered in immunity section Platelets (not really cells) Cytoplasmic fragments of megakaryocytes aid the clotting mechanism life span = 7-10 days Structure and Function of RBC’s Hematopoiesis – maturation of RBC’s (fig 13.3 and 13-5) maturation of RBC from pluripotent stem cells. activated by erythropoietin hormone from kidney Hemoglobin (Hb) synthesis Structure (fig 13-7) Two pairs of protein subunits (α - alpha and β- Beta) Each protein has a heme group (made of an iron cofactor and a 4 porphyrin proteins) attached to it. Fetal Hb (fig 13-10) Made of 2 α (alpha) subunits and 2 gamma subunits Greatly increased oxygen binding (greater affinity for O2)– good for fetus in that it allows oxygen carrying at low oxygen levels. Shortly after birth the beta proteins replace the fetal gamma proteins (fig 13-10) process of Heme synthesis – needs Iron (fig 13-8 – or supplemental fig 3) Iron (Fe) absorbed by gut (proximal jejunum and duodenum) Transferrin molecule carries Fe to RBC Transferrin-Fe complex absorbed into RBC Fe either used to make Hb or stored in RBC. Nutritional requirements of Erythropoiesis Iron – for heme Folate (Vit B9) – cofactors for RBC cell reactions Vitamin B12 (cobalamin) - cofactors for RBC cell reactions B12 absorption requires ‘intrinsic factor’ secretion from parietal cells of stomach. vitamin deficiencies or intrinsic factor hyposecretion can lead to RBC cell malfunctions and anemia. Erythropoietin =EPO Functional stem cells RBC Activation Kidney (fig 13-12) Oxygen “sensor” in kidney stimulates transcription of EPO when cell O2 falls EPO activates the maturation process of pluripotent stem cells in the bone marrow. Increase reticulocyte (RBC with organelles) production. Lab measurement of increased reticulocytes usually indicates increased RBC production. Reticulocytosis Eventually increase RBC production. Kidney produces 85%-90% of EPO Other stimulators of EPO Catecholamines RBC Destruction (fig13-13) Life span of RBC is 80-120 days. Enzymatic activity in RBC decreases with time Iron is oxidized to Fe3+ creating Methemoglobin RBC becomes fragile and less flexible RBC destroyed by M’phages of liver or spleen. Components are either excreted or recycled Porphyrin is reduced to bilirubin which is excreted by the gall bladder. Fe is normally recycled Jaundice – = yellowish tint to skin is caused by excess bilirubin Usually caused by poor breakdown of bilirubin by liver dysfunction (cirrhosis) or by low albumin (bilirubin blood transport) production (newborns). Gas and Acid-Base Transport O2 Transport (fig 13-14) & (table 13-4) Depends on delivery of blood with O2 in it. DO2 = CO x CaO2 Oxygen content (CaO2) = dissolved + bound to Hb Dissolved: PaO2 x 0.003 Bound to Hb: Hb (g/dl) x 1.34 ml O2 per 1gram Hb x Sat Ex: If Hb = 15, PaO2 = 100, SaO2 =1.0 CaO2 = (100 x 0.003) + (15 x 1.34 x 1.0) = 20.4ml O2/dl How does an increase in PaO2 affect oxygen content? If PaO2 increased to 500 mm Hg? (500 x 0.003) + 20.1 = 21.6 ml/dl If PaO2 decreased to 60 mm Hg? (60 x 0.003) + (15 x 1.34 x 0.89) = 18.07 ml/dl How does a change in hemoglobin affect oxygen content? If hemoglobin decreased to 10 g/dl? (100 x 0.003) + (10 x 1.34 x 1.0) = 13.7 ml/dl Alterations in Hb can more drastically affect oxygen carrying capacity of blood than changes in atmospheric oxygen. Cardiac output usually 5000ml/min but can be increased to compensate for a lack of DO2. Oxygen-Hemoglobin Disassociation Curve (fig 13-15) Is an illustration of how oxygen is bound (and freed) from the Hb molecule. Upper part of the curve represents oxygen uptake at the lungs PO2 is high so SaO2 is high (99%) Significant changes in PO2 are needed to alter SaO2 at this part of the curve. Helps to ensure oxygenation of Hb despite minor changes in atmospheric O2 Lower part of the curve represents oxygen release at tissue level. PO2 is lower so SaO2 (or SvenousO2 in this case) is lower (80%). peripheral tissues can extract large amounts of oxygen of hemoglobin for only minute drops in capillary PO2, facilitating diffusion of oxygen into the tissues that need it. Small changes in PO2 here can result in large changes in SvO2 Shifts in O2-Hb curve Certain factors can alter the affinity between O2 and Hb thereby affecting O2 transport. P50 – the PO2 where 50% of the Hb molecule is saturated with O2. This is used as a marker for affinity changes (and therefore shifting) of the O2-Hb curve Right shifts of O2-Hb curve Represents a decreased affinity of O2-Hb. Causes increased P50 More unloading of O2 at tissues. Factors that cause right shift – Think ‘exercising tissues’ Decrease in pH Increases in pCO2 Increase in Temperature Increases in 2,3 DPG (metabolic byproduct) – also increased in anemia and chronic hypoxia Some congenital Hb dysfunctions. Left shift of O2-Hb curve Represents an increased affinity of O2-Hb. Causes decreased P50 Less unloading of O2 at tissues. Factors that cause left shift – Think ‘resting/cold tissues’ Increase in pH Decreases in pCO2 Decrease in Temperature Decreases in 2,3 DPG Some congenital Hb dysfunctions. Carboxyhemoglobin Carbon Monoxide (CO) Poisoning CO can bind Hb with 220X more affinity than Oxygen. Acts as a “competitive inhibitor” of the Hb molecule It causes an increased affinity for O2 - so much so that O2 doesn’t ‘unbind’ very easily. This results in a severe left shift in the O2-Hb curve. Sx Depends on % CO bound to Hb 10% Asymptomatic or may have headaches 20% Dizziness, nausea, and syncope 30% Visual disturbances 40% Confusion and syncope 50% Seizures and coma 60% Cardiopulmonary dysfunction and death Bright red fingernails and skin (= almost dead) Tx – high O2 therapy (overwhelm the concentration gradient) Other O2 delivery measurements (Table 13-4) CaO2 – see above PaO2 – partial pressure of Oxygen in arterial blood. DO2 = Oxygen Delivery DO2 = Cardiac Output x CaO2. Usually 1 L/min VO2 = oxygen consumption (proportional to metabolic rate). Is measured by subtracting venous from arterial blood content and multiplying by CO. = 5000ml/min x (20-15%) = 250ml/min This is the ‘Fick Equation’ - widely used in physiological systems CO2 Transport (fig 13-16) Dissolved CO2 = PCO2 (usually 40mmHg in lungs and 45mmHg in tissue) Very small amounts of CO2 Bound to Hb CO2 can bind directly to Hb molecule Very small amounts of CO2 HCO3- = Bicarbonate anion Primary way CO2 is transferred out of tissue to lungs Steps CO2 generated in tissue diffuses into RBC CO2 combines with H2O to make H2CO3 Carbonic Anhydrase enzyme catalyzes the reaction H2CO3 quickly dissociates into H+ and HCO3- The H+ binds to the deoxygenated Hb while HCO3- diffuses into plasma and Cl- diffuses into RBC to balance the charges. ‘Chloride shift’. HCO3- is transported to the lungs. In the lungs the process is reverses and CO2 is released. Alterations in Oxygen Transport Can be caused by anything that alters Hb formation, RBC formation, oxygen availability to lungs, or cardiac output. Anemia Classifications of Anemia Relative Anemia – when blood is ‘diluted’. RBC mass has not changed but the blood volume has increased Ex – pregnancy – water weight goes up but RBC production can’t always keep up. Absolute Anemia When RBC levels decrease (decline in production or increase in breakdown). General causes Not making enough RBCs Breaking down RBCs too quickly (hemolysis) Blood loss General Effects – based on decreased CaO2 (thereby decreasing DO2) Increased cardiopulmonary function increased heart rate increased respirations (tachypnea, dyspnea) Increased Oxygen extraction from Hb As concentration of tissue Oxygen decreases the gradient for dissociation off of Hb increases – more extraction. Increased EPO secretion. Generalized symptoms Fatigue Decreased activity tolerance Pallor (pale skin) Shunting of blood toward vital organs Increase in 2,3 DPG production – to help right shift the curve (increased O2 dissociation) Generalized lab terminology associated with anemia microcytosis – low volume of fluid in RBC macrocytosis –high volume of fluid in RBC hyperchromia – excess Hb in the cell hypochromia – less Hb in the cell can occur with reticulocytosis – RBCs being made hastily reticulocytosis – excess reticulocytes (immature RBCs) in the blood evidence of rapid production of RBC. hemolysis – breakdown of RBC’s can be due to defective RBC or due to exogenous factor causing breakdown of normal RBC usually associated with bilirubinemia (elevated bilirubin in the blood – by product of Hb breakdown). Anemia due to decreased RBC production aplastic anemia Etiology Stem cell disorder that causes decreased RBC, WBC, and platelet production (pancytopenia). Usually caused by toxic damage to bone marrow (radiation, immune related, etc) see table 13-5 – causes Lab features Low reticulocyte count (not making RBC) No evidence of hemolysis (not breaking down RBC) Low platelets – increased ‘bleeding times’ – Prothrombin time (PT) and Partial Prothromboplastin time (PTT) Symptoms Evidence of infections due to lack of granulocytes bleeding tendencies - Low platelets Other symptoms of anemia – see above Tx Remove causative agent (toxin, etc) Bone marrow transplant RBC and platelet transfusion as needed Infection control Chronic Renal Failure Etiology – Primarily due to decreased erythropoietin production also due to renal failure – poor excretion of fluids can ‘dilute’ the body Sx Similar to other RBC production symptoms If due to renal failure: dilutional decrease in HCT uremia – can lead to hemolysis (uric acid bad for RBC’s) hemolysis can lead to schistocytes. These are fragments of red blood cells produced by hemolysis Tx EPO and Iron (Fe) supplements Monitor HCT Vit B12 or Folate deficiency Etiology – B12 or Folate deficiencies cause poor development of bone marrow progenitor cells. Causes enlarged RBC cell production (macrocytic). Also causes decreased WBC and platelets Pernicious anemia = lack of intrinsic factor secretion causes poor Vit B12 absorption from GI tract. possibly caused by autoimmunity toward gastric parietal cells. Sx Vit B12 deficiency neurologic abnormalities. cognitive dysfunction – paranoia, dementia, delusions, etc. peripheral nerve degeneration or degeneration of posterior columns of spinal cord (dorsal column medial lemiscus pathways). Bilateral proprioception, vibration, light touch paresis. Folate deficiency neurologic abnormalities Depression, sleep deprivation, irritable, other personality changes, etc. Deficits in both neurologic abnormalities Edema in lower limbs, edema may affect pulmonary system (tachycardia, dyspnea), GI effects – Vitiligo - loss of pigment from areas of skin resulting in irregular white patches with normal skin texture Wide variety of others. Tx Supplements *difficult thing is diagnosis of this – not the treatment. Iron deficiency – very common Etiology- Usually due to chronic blood loss poor intake. Increased demand (pregnancy) Poor absorption Renal failure (iron is highly conserved in the body – its normally reabsorbed from kidney) Lab features RBCs are usually microcytic (low volume in the RBC so they look small) decrease in MCV (mean corpuscular volume) hypochromia – especially in chronic bleeding, Hb may be reduced but RBC counts may be normal because RBC are being made/released to replace lost cells faster than Hb can be made to replace lost Hb protein decrease in MCH (mean corpuscular hemoglobin), MCHC (mean corpuscular hemoglobin concentration) Hct can be normal. Serum iron levels are decreased. Sx Generalized symptoms – pallor, weakness, fatigue, other symptoms of anemia. Tx Iron supplements (ferrous sulphate) Anemia due to inherited disorders Sickle Cell anemia (Hemoglobinopathy) (fig 13-20 and fig 13-21) Etiology Genetic substitution of valine for glutamic acid on Hb beta chain causes malformed Hb molecule (called HbS) When pO2 is low the HbS can stick together and cause RBC to assume a sickled shape (fig 13-21) Malaria link Malaria parasite can cause RBCs of people with HbS to form sickled shape and thereby are removed from circulation. This limits the infectiveness of the parasite. Sickle cell anemia is much more common in people of African decent. Symptoms (see box 13-2) Vascular occlusion - Sickled red cells aggregate in the small capillaries (because they can’t squeeze through the small places) and can block blood flow => localized pain – especially in lower extremities. => CVA Thrombosis – due to capillary stasis Sickled cells have decreased survival time (filtered out of blood) => symptoms of anemia (hypererythropoietin, reticulocytosis, etc). Hemolysis – hemoglobinurea, bilirubinemia with jaundice, etc Can undergo periods of exacerbation (crisis) and latency. Can lead to poor development (delayed puberty, poor bone growth, etc). Laboratory features Hemolysis hemoglobinurea, bilirubinemia, etc. RBC cells on slides are sickled (fig 13-21) Tx Stem cell transplantation Fetal hemoglobin activation hydroxyurea can activate fetal Hb synthesis. increase oxygen carrying capacity of blood. Preventative tx stay well hydrated stay well ventilated (hypoxia exacerbates it) infection control (get vaccinated) Polycythemia- increase in RBC’s in the blood. Polycythemia Vera Etiology Over-proliferation of blood cells. Unknown cause Like cancer except no tumor – just unregulated growth of normal RBCs. Perhaps caused by an increased sensitivity to EPO, unregulated growth of a stem cell, constant growth factor secretion on marrow proliferative cells. Lab findings (table 13-14) Increased levels of one or more blood cell types. Normal SaO2 Sx Varied and widespread Increased RBC number so increased blood viscosity Hypertension, vascular occlusions, Mucosal hemorrhage, Hepatomegaly, splenomegaly (likely due to congested venules). Itchy skin Decreased cerebral blood flow => Headache, weakness, visual disturbances, paresthesias, etc. Can go through progressive stages (table 13-15) and eventually lead to anemia due to blood forming cells ‘wearing out’ => acute myeloid leukemia Tx No cure Phlebotomy in early stages to reduce blood volume. Hydroxyurea to decrease blood cell formation. Secondary Polycythemia Etiology Normally caused by hypoxic stimulation of EPO release Symptoms are usually due to whatever is causing the hypoxia (high altitude, heart failure, chronic lung disease, etc) Tx Remove hypoxic stimulus – if possible Phlebotomy can be helpful. Relative Polycythemia Etiology Usually due to dehydration – RBC numbers are constant but percentage increases with lower blood volume. Can be due to stress – hypertension Don’t know mechanism of this pathway. Sx Most due to underlying disease – dehydration (thirst, low blood volume and high viscosity, etc) Similar to hyperviscosity symptoms seen with Polycythemia vera Tx Remove stimulus (dehydration, stress) Supplemental figure 1 Supplemental 2 Supplemental fig 3