NURS 6501 / NRNP 6501N Week 6 Midterm Exam 2024 - PATHO Midterm Review - Pathophysiology II (HLSC2461U)

PATHO Midterm Review - Pathophysiology II (HLSC2461U) NURS 6501 / NRNP 6501N Week 6 Midterm Exam 2024 Review Hematologic Disorders What does our blood contain? Formed elements: cells Regulatory substances: hormones and other substances How are blood cells produced? Hematopoiesis Different blood cells are produced in the bones---bone marrow in the process called hematopoiesis. It is a complex process. Downloaded by Thomas Mboya () lOMoARcPSD| The cells originate from a small number of hematopoiesis stem cells are PLURIPOTENT stem cells (multi potent stem cells), the initial parent cells are undifferentiated cells, when they receive stimulation from different growth factors and cytokine, the progenitor stem cells will then differentiate into different types of cells However, there are different stages of maturation for different cells. Understanding hematopoiesis is essential, because a lot of different blood disorders involve alterations in the production of different blood cells. Multipotent stem cells give rise to two different types (groups) of cells, which we also call as the lineages - The first line is derived from myeloid progenitor cells and the second from lymphoid progenitors From the myeloid progenitor lineage, we have three main groups of cells that are derived. - The first one is megakaryocyte, which give rise to platelets (thrombocytes). Platelets are the fragments of megakaryocytes, they play critical roles in formation of blood clots. Whenever there is bleeding, the platelets will form plug to stop the bleeding. - The second line is the production of RBCs. Erythropoiesis: formation of red blood cells. Characteristics of mature red blood cells is that they lack organelles such as mitochondria and nucleus. When the myeloid progenitors are stimulated, they form committed cells called erythroblasts. Committed means that when they transform into erythroblasts, they will be committed into the production of red blood cells. The cells that develop into red blood cells are called erythroid cells, they include all the immature cells which are basically transforming into red blood cells. Transformation of erythroid precursor cells into red blood cells is stimulated by the hormone called erythropoietin. Erythroblasts cells are immature cells, they have nucleus, during this stage, the red blood cells synthesis proteins, one very important protein is hemoglobin. Once they mature, they lose the nucleus, they develop into the next stage, which is reticulocyte. There are some ribosomes present in reticulocytes. When the reticulocytes are released into circulation, they are present for 1- 2 days, after this period, they lose the ribosomes and transform into mature RBCs Downloaded by Thomas Mboya () lOMoARcPSD| At any given time, we have 1% of reticulocytes in our circulation - The third line is the myeloid lineage, myoblast will mature and transform into four type of white blood cells: monocytes, neutrophils, basophils and eosinophils. Neutrophil, basophil and eosinophil are collectively called granulocytes because in the cytoplasm of these cells, the staining granules are visible. Monocytes are agranulocytes. - Neutrophils: most abundant WBCs in our body, they have characteristic nucleus composed of 3 or 4 lobes, so they are also called as polymorphonuclear cells. Neutrophils are important in innate immunity. They help with the destruction of bacteria by phagocytosis. - Basophil: similar to mast cells, containing histamine, important in allergy reactions. - Eosinophil: Involved in fighting parasitic infection, such as worms. - Monocytes: are agranulocytes, can migrate into tissues, becoming macrophages (swallow or phagocytose bacteria and dead cells). Monocytes can also transform into antigen presenting cells, for example: dendritic cells - Lymphoid progenitor lineage: Lymphocytes are produced from lymphoid progenitor cells. Three different types of lymphocytes. B lymphocyte, T-lymphocyte and Natural killer cells. - T lymphocytes: can fight HIV AIDS. One of the important characteristics is that T cells mature in thymus gland. Three types of T lymphocytes - T-helper cells: activated different immune cells. - T suppressor cells: suppress functions of different immune cells - Cytotoxic T cells: similar to large natural kills cells Downloaded by Thomas Mboya () lOMoARcPSD| - B lymphocytes: produced in the bone marrow and mature in bone marrow. They produce antibodies (immunoglobulin) by transforming into plasma cells. - Natural killer cells: larger in size, destroy virus infected cells and sometime fight cancer cells. Red blood cell physiology RBCs count for 84% of the cells in the human body. -Produced in the bone marrow by erythropoiesis -Help in transport of O2 in the body- -Lacking organelles -Filled with O2 transport protein-hemoglobin, fills the entire space of the RBCs. -Crucial role in acid-base balance -Containing enzyme called: carbonic anhydrase, which catalyze the reaction between carbon dioxide and water to produce hydrogen ions and bicarbonate ions CO2+H2O- H ++HCO3 - , bicarbonate is a very important buffer in the body -Structure of the RBCs -Biconcave discs. Have a depression on either side of the surfaces (darker region under microscope) -The purpose of the biconcave disc structure is to increase the surface area of the RBCs to help efficiently transport O2 -Small diameter (8 micrometers) to squeeze through the capillaries through transport O2 in different tissues. -Cell membrane is made of Phospholipid bilayer, with different membrane proteins, such as Band 3 and glycophorins. Most of membrane proteins of the RBCs are heavily glycosylated, these proteins together with other lipids and glycoproteins help in determining the blood type (blood group) of the person. -Band 3 protein has different functions. One of them is the interaction with cytoskeletal proteins such as Ankyrin and Spectrin. -Ankyrin and Spectrin are important because in some disease, these proteins are mutated, causing structural changes in the RBCs, which cause the RBCs rupture easily. Normal life span of RBCs in the circulation Downloaded by Thomas Mboya () lOMoARcPSD| RBCs are produced and mature in bone marrow through erythropoiesis from erythropoietic stem cells, with an important hormone required: erythropoietin, iron as an important component of hemoglobin molecules is required in the production of normal RBCs, vitamin B12 and folic acid (folate) help in DNA synthesis, which is essential in transformation and maturation of an Erythroblast into a mature RBCs. Once RBCs are generated, they stay in the circulation for 100-120 days-older RBCs-  lots of oxidative damage- biochemical and biophysical changes. Biochemical changes refer to the changes in the enzymes within the RBCs, alteration of different proteins Biophysical changes refer to RBCs will lose the flexibility, they will have reduced deformability. Deformability is an important characteristic of the RBCs, because when RBCs are easily deformed, they are flexible, and easily squeeze into the smaller capillaries. These alteration coincide with the last phase of RBC life span—senescent （衰老的 ), The senescent RBCs are captured in the spleen and removed from the circulation, the components of the RBCs such as hemoglobin and iron are recycled. Polycythemia: excessive red blood cell production Relative e.g. hemoconcentration due to dehydration Absolute: Primary (rare) Secondary: More common In chronic hypoxemia (e.g. high altitude, COPD) Polycythemia: When is increased RBCs count, the blood becomes viscous, increasing the risk of thrombosis. Cause: -Relative cause: person who is severely dehydrated will have lower plasm volume, but the RBCs count stays the same. This is simply because of the plasma volume goes down -Absolute increase of the RBC count: rare Downloaded by Thomas Mboya () lOMoARcPSD| Primary cause is related to the cancer in the bone marrow, leading to excessive production of RBCs, RARE condition Secondary cause: develop as a result of chronic hypoxemia, which means reduced O2 in the blood, can be found in people living in high altitude and people with COPD such as emphysema. In these conditions, the body responds by increasing the production of RBCs. Pinkish tone to the skin, easily visualized in the conjunctiva. Such skin discoloration can be developed in patient with emphysema, they are called pink puffers. Anemia: = decrease of total number of circulating erythrocytes OR decrease in hemoglobin levels According to size: Macrocytic: megaloblastic anemia Normocytic Microcytic According to hemoglobin content: Normochromic Hypochromic According to cause: Decreased RBC production Increased RBC destruction Blood loss (Hemorrhages) Anisocytosis (alterations in size) Poikilocytosis (alterations in shape): Sickle cell anemia Anemia is an important complication of several systemic diseases, such as CKD (chronic kidney disease), liver failure and several inflammatory disease. The underlying mechanisms of the anemia in these disease are diverse, however, the common denominator is that there is reduction of RBCs in the circulation(reduced O2 carrying capacity of the blood)-- tissue hypoxia (reduced O2 transport from the lungs to the tissues) Lab work to detect the size change in the RBCs to look for Mean Corpuscular Volume (MCV), which is always indicated in a complete blood count (CBC) Downloaded by Thomas Mboya () lOMoARcPSD| In Normochromic anemia, the hemoglobin content in the remaining RBCs does NOT change, the blood color stays in the same. While in hypochromic anemia, since the red color is from the iron, there is reduced coloring. Microcytic: reduce RBC volume, cells appear smaller in size Hypochromic: reduced hemoglobin content, show more whitish color Macrocytic: good example is the Vit B12 deficiency Sickle cells： Hemoglobin S is caused from a mutation, causes the replacement of glutamate with valine Anisocytosis: seen in CBC count, RBC RDW (Red blood cell Distribution Width) In Neuroacanthocytosis, we see that the RBCs display Poikilocytosis Clinical Manifestations Of Anemia Mild to moderate anemia: hard to tell Severe anemia： conjunctival pallor, conjunctiva in they eyes appear very pale. Finger nails appear very pale Systemic Effects Of Anemia Increased hemolysis leads to increased destruction Claudication: muscle pain. Pt with anemia have reduce O2 level in the muscle. When exercising such as walking long distance requires more O2 in the muscles. When anemic patients walk long distance, this causes pain in the lower limbs because of reduced O2 level in the legs. Anemic patient have hypoxemia, the way to compensate this is to increase respiration rate as well as depth, which means that the patient is take in more O2 through the lungs. Another classic feature is that anemic patients have lower capacity to moderate exercise, they feel breathless when they do exercise, it is call exertional dyspnea. Fatty changes in the liver is the result of increased lipogenesis and they also have increase fatty acid uptake, they are the consequences of hypoxia. Downloaded by Thomas Mboya () lOMoARcPSD| Brain is not able to receive enough O2, which leads to dizziness. In the kidneys, pt develop hypoxia as well, triggering the compensatory responses, one of them is the activation of RAAS renin-angiotensin-aldosterone system, which will increase Na and water retention (function of aldosterone), so extra cellular fluid volume goes up. Increase ECF will in turn increase blood volume, so the heart become hyperactive, so the heart rate increase, as well as the contractility of the heart(increased stroke volume). The O2 demand of the hyperactive heart in anemic patients increases, which causes chest pain (angina), this is an very important clinical sign of severe anemia, Increase heart rate and blood volume gives the impression that the heart is functioning normally, however, despite of the increase activity of the heart, the patient experience high output cardiac failure, because the heart is not meeting the O2 demand of the body. Very important Adaptation in anemia: increased levels of BPG in cells, BPG is 2, 3 diphosphoglycerate (2,3 DPG), BPG reduces the affinity of hemoglobin to O2, meaning less O2 will bind to HGB when there is 2,3 DPG available. In cells, when there is increased BPG (2,3 DPG) concentration, will cause increased unloading of O2 from HGB. The main purpose of increased BPG levels in anemia is to increase the supply of O2 to different cells in the body Downloaded by Thomas Mboya () lOMoARcPSD| Kidney Response In Anemia Kidney is vital in countering anemia 90% Erythropoietin (EPO) is produced in the peritubular cells of the kidneys, the remaining 10% is produce in the liver. Production of erythropoietin in kidney is stimulated by hypoxemia (hypoxemia is the main characteristics of anemia). When RBC count is normalized, the kidney stops secreting EPO In pt suffering from CKD, there is problem in the secretion of EPO, the pts have reduced EPO, causing anemia, which is a clinical complication of CKD, the treatment to anemia in pt with CKD is to administer recombinant EPO, this basically acts on the bone marrow to increase the production of erythrocytes. Lab investigation of RBC parameters Blood sample is collected in the test tube containing anticoagulant such as EDTA WBC count: leukocytes count as a total, increase can indicate infection and other diseases RBC count: reduced HGB: measure total HGB concentration in the blood, it is lower than normal range From reduced RBC and HGB count, we can conclude that the pt has anemia, but we don’t know what kind of anemia Downloaded by Thomas Mboya () lOMoARcPSD| Hematocrit: packed cell volume, percentage of RBC in the blood content, confirming that the RBC count is reduced. MCV: mean corpuscular volume, in this case, the size of the RBC is within normal range, it is considered as normocytic anemia, because there is no change in cell volume (cell size) MCH: mean corpuscular hemoglobin, within normal range MCHC: mean corpuscular hemoglobin concentration, within normal range MCH and MCHC measure the hemoglobin content in individual RBC , they tell us if the anemia is hypochromic or normochromic. In this case, the pt has normochromic anemia. RDW: Red cell distribution width, telling the variations in cell size within the blood sample. If RDW is high, there is anisocytosis (big variation in cell size) PLT: platelet count, normal range, pt has no problem in blood clotting. Decreased RBC production Altered DNA synthesis by:  Vitamin B12 deficiency (pernicious anemia) caused by chronic atrophic gastritis (auto-immune loss of parietal cells secreting intrinsic factor)  Folic acid deficiency caused by low dietary intake in malnutrition or alcoholism Megaloblastic anemia Altered hemoglobin synthesis by:  Iron deficiency (ferropenic)  HbS (sickle cell anemia) Decreased RBC production in bone marrow, a good example is the megaloblastic anemia. This is macrocytic anemia, cause is related to deficiency of Vit B 12 and folic acid, which are essential to normal synthesis of DNA during erythropoiesis that causes changes in the normal maturation of the erythroid precursor cells in the bone marrow. In the bone marrow, there is increased number of immature RBCs. Mechanism of VB12 deficiency related anemia. Parietal cells in fundus of the stomach secrete hydrochloric acid to help with the digestion and they also secrete intrinsic factor. The main function of the intrinsic factor help the absorption of VB12 in the intestines. In some diseases, the parietal cells functions are damaged, most of these diseases are autoimmune disease, with inflammation in the stomach called gastritis, causing autoimmune damage to parietal cells, leading to decline in the production of intrinsic factor, as the consequence, there Downloaded by Thomas Mboya () lOMoARcPSD| is reduced absorption of VB12, leading to pernicious anemia. Pernicious means causing damage gradually. Anemia caused by folic acid deficiency is caused either by reduced dietary intake of folic acid or malabsorption of folic acid due to alcoholism. Identify megaloblastic anemia in the blood smear: 1 large oval RBCs and 2 hypersegmented neutrophils. Neutrophils are granular cells, called polymorphonuclear cells (PMNs), the nucleus of the neutrophils are made of 3 or 4 lobes. In megaloblastic anemia, because of the changes in the bone marrow, neutrophils will have multiple lobes, more than 6 lobes, thus hypersegmented neutrophils, this is an important feature of megaloblastic anemia. Anemia can also be caused by altered HGB synthesis Iron deficiency: ferropenic anemia Hbs (sickle cell anemia) Aplastic Anemia Replacement of hematopoietic cells by fat cells  Causes pancytopenia: all types of blood cells will have decreases in blood circulation  Caused by radiation  Caused by cancer chemotherapy  Genetic e.g. Fanconi Anemia There is bone marrow failure leading to decrease in hematopoiesis, all types of blood cells will have decreases in blood circulation. Underlying cause is the replacement of normal hematopoietic tissue that is present in the bone marrow by fat cells Anemia due to increased RBC destruction  Hemolysis: RBC rupture  Eryptosis: RBC death (=apoptosis) with no membrane rupture after injury – promotes phagocytosis  ↑ reticulocytes in circulation = Increased compensatory erythropoiesis In health people, there is a fine balance between the production and destruction of RBCs, this basically maintain normal homeostasis, it is a dynamic balance RBCs have life span of 100-120 days, after this period of time, they will be cleaned from the circulation by the spleen. Hemolysis: RBC cell membranes rupture and causes the leakage of HGB Eryptosis: specific in RBCs, not in any other types of cell because it does NOT involve nucleus or mitochondria as in other types of cells Downloaded by Thomas Mboya () lOMoARcPSD| It will be eaten up by macrophages, removing the death cells from the circulation. This type of anemia is basically the RBC destruction outweighs RBC production Compensatory response of the body is to increase the erythropoiesis to normalize the numbers of RBCs in the circulation One of the important features of anemia due to the increased destruction of RBCs is the increased presence of reticulocytes (immature RBCs) in the circulation. This is an important diagnostic tool ID anemia due to RBC destruction. The disease caused due to the increased RBC destruction is called hemolytic anemia. The common denominator of this type of anemia is the RBC destruction and loss of circulating RBCs Pathophysiology of Hemolytic Anemias  Normocytic and normochromic, cell size does not change with normal hemoglobin content  Hyperactive bone marrow meaning there is increased erythropoiesis (reticulocytosis, increased number of immature RBCs)  Haptoglobin binds to intravascular Hb (↓serum haptoglobin), when HGB is outside the RBCs, it causes lots of damage, so body binds the HGB to haptoglobin, so the lab work will find decreased serum level of haptoglobin.)  Conversion of Hb to unconjugated bilirubin (Jaundice, yellow discoloration of skin and eyes) Intravascular hemolytic anemia (complement activation, transfusion mismatch, Type II hypersensitivity) –Hemoglobinemia, hemoglobinuria, jaundice, hemosiderinuria (excretion of iron complexes) Extravascular hemolytic anemia (Spherocytosis – spectrin and ankyrin defects) – Jaundice, hemosiderosis (iron complexes in tissue) Glucose 6 phosphate dehydrogenase deficiency causes hemolytic anemia triggered by different factors e.g. fava bean consumption (favism) Downloaded by Thomas Mboya () lOMoARcPSD| As the RBCs are close to their life span, they undergo process call senescence, Senescent RBCs have important biochemical and physical properties. As RBCs get older, they become stiff, difficult for them to squeeze in to small capillaries. When they enter the spleen, they are captured by the macrophages in the spleen. In some diseases, the RBCs may be defective or injury, they have similar process by macrophages in the spleen. When there are senescent or injured RBCs, they are detected specialized macrophages in the spleen and the liver. It is call reticuloendothelial system, help in the phagocytosis, mainly present in the spleen, also in the liver. For senescence of RBCs, this is normal physiologic process, happens to all RBCs For injury, it is associated with disease. It is Pathophysiological process. What happens when a RBCs is swallowed by macrophages in the reticuloendothelial system When RBCs come into contact with a macrophage, the macrophage will swallow the RBC (the RBC is phagocytosed), the phagocytosed RBC will go under degradation, the hemoglobin will breakdown, dissociate the hemoglobin molecule into two components: protein part (globin) and heme part. Globin part is protein, the amino acid will be recycled (put back into the blood and used up) Heme catabolism is more complicated. The heme is made of iron and porphyrin ring, the iron is taken up by the body, be further used in creating new blood cells. Changes in porphyrin ring are very important in the context of hemolytic anemia. Key features of the transformation of porphyrin ring: Involves many steps. The porphyrin ring will convert into biliverdin,胆 素绿 , which is green pigment, and this will further get reduced to form unconjugated bilirubin, the unconjugated bilirubin 游离胆 素红 is extremely important in hemolytic anemia, because changes in unconjugated bilirubin level in the blood is the key feature of hemolytic anemia. Unconjugated bilirubin will then be removed from the phagocyte and bind to albumin because the unconjugated bilirubin is water insoluble, so it binds to albumin and it then transported into the liver, the unconjugated bilirubin will transform into conjugated bilirubin, which is excreted into the bile and removed through feces and urine after few more steps of transformation. Intravascular hemolytic anemia : happens inside the blood vessels. In this condition, the circulation RBCs may undergo hemolysis by variety of immunological mechanisms Downloaded by Thomas Mboya () lOMoARcPSD| First is complement activation, the second one is transfusion mismatch, third one is type II hypersensitivity, this can be caused by certain medication such as penicillin. The type II hypersensitivity is mediated by antibodies Clinical features: 1 When there is rupture of RBCs, causes increase HGB in the blood, there is presence of HGB outside the RBCs in the plasma, this is hemoglobinemia. 2 When there is HGB in the plasma in the blood, it causes excretion of HGB through the kidneys, thus hemoglobinuria 3 Unconjugated bilirubin leads to the jaundice 4 Increase plasm level of HGB will cause increased hemosiderin， this is stored form of iron, will be excreted through the kidneys, this is hemosiderinuria Extravascular hemolytic anemia happens outside the blood vessels. This is the main difference from the intravascular hemolytic anemia. It happens as the result of increased activity of reticuloendothelial system (macrophages), in the spleen and the liver. In spherocytosis, pt loses the proteins of the RBCs skeleton: spectrin and ankyrin, the RBCs lose the biconcave shape, they become spherical, the spherocytes are very stiff, when they enter the spleen, they will undergo hemolysis, the pt suffers from hemolytic anemia. Clinical features: 1 Because the hemolysis is in the tissue, there is hemosiderosis, deposition of iron complexes in the tissue. 2 Jaundice, which is the common feature of both types of anemia. Glucose 6 phosphate dehydrogenase deficiency is common condition, especially prevalent among people with African or southern European ancestry. The enzyme G6PD is essential in production of a very important reducing agent called NADPH, which ensure that glutathione (antioxidant) is maintained in its reduced state. When RBCs are exposed to any type of oxidant, they will hemolyze. Because of the oxidant in fava bean, when people with G6PD deficiency consume the bean, it will cause RBCs to hemolyze. Favism causes hemolytic anemia. Hemolytic Anemias in Newborn Erythroblastosis fetalis Downloaded by Thomas Mboya () lOMoARcPSD| - Maternal alloantibodies cause hemolysis and jaundice In Rheus (Rh) blood grouping system, based on the presence/absence of Rhesus factor- D antigen, people are either Rh+ or RhWhen a pt with Rh- receives blood transfusion from Rh+ doner, there is transfusion mismatch, antibodies will be produced against the Rh antigen. Sensitization phase: in the first pregnancy, nothing happens to the baby or the mother. Second pregnancy: the mother is sensitized to the Rh factor, having anti-Rh antibodies in the circulation. The anti Rh antibodies will enter the baby’s blood circulation and will bind to the RBCs with Rh antigens, resulting in hemolysis in the baby’s circulation. What happens to the baby: Increased hemolysis because of agglutination, results in the increased bilirubin, thus jaundice and, the bilirubin molecule is toxic, can damage the nervous system, so the baby will have brain damage Increased hemolysis will cause anemia, resulting in the reduced RBCs count in the circulation. Anemia means that the body will have to produce more RBCs, which leads to increased erythropoiesis. In the baby erythropoiesis happens mainly in the liver and the spleen (extra medullary erythropoiesis), it only is seen in the fetus