NR.120.504 ADVANCED PATHOPHYSIOLOGY COMPLETED STUDY GUIDE 2024, Exams of Pathophysiology

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NR.120.

ADVANCED

PATHOPHYSIOLOGY

COMPLETED

STUDYGUIDE

INTRODUCTION

Advanced pathophysiology is a specialized field within healthcare that focuses on understanding the cellular and molecular mechanisms underlying disease processes. It involves the study of how normal physiological functions are disrupted, leading to the development of various pathological conditions. In nursing education, advanced pathophysiology aims to provide a comprehensive understanding of the complex processes that occur in the human body during disease. This knowledge is crucial for nurses to accurately assess, diagnose, and manage patients with different health conditions. The study of advanced pathophysiology covers a wide range of topics such as alterations in cellular function, inflammation and immune responses, genetic disorders, metabolic dysregulation, cardiovascular and respiratory diseases, neurologic conditions, and cancer, among others. It examines the interplay between genetic, environmental, and lifestyle factors and their impact on the pathogenesis of diseases. By delving into advanced pathophysiology, nursing students can gain a deeper understanding of disease processes at a molecular level, enabling them to provide more specialized and evidence-based care for their patients. This knowledge equips nurses with the ability to anticipate complications, implement appropriate interventions, and educate patients on disease management and prevention strategies. Overall, advanced pathophysiology serves as a foundation for nursing practice, enabling healthcare professionals to provide high-quality, patient-centered care.

Hypersensitivity Reactions o The immune system functions to eliminate pathogens from the body using various mechanisms ▪ Pathogens are bacteria, viruses, and other microorganisms o These mechanisms typically create a localized inflammatory response that effectively eliminates the pathogen with minimal damage to the surrounding tissues o Individuals also come in contact with numerous foreign bodies (plant pollen, food) o Contact with these environmental antigens does not normally elicit an immune response in a majority of individuals o However, in predisposed individuals the immune system can mount a response to environmental antigens, resulting in tissue damage that ranges from mild irritation to life threatening anaphylactic shock o These immune responses are referred to as allergic reactions or hypersensitivity reactions o Hypersensitivity reactions can be divided into 4 categories

• Type I: Allergic Reaction o On initial encounter with an allergen, the individual will produce IgE antibodies o Once the allergen is cleared, the remaining IgE bind to mast cells, basophils, and eosinophils that contain receptors for IgE ▪ This process is referred to as sensitization o When re-exposed to to the allergen the IgE located on the sensitized cells induce immediate degranulation o Degranulation causes the release of inflammatory mediators, such as histamine, leukotrienes, and prostaglandins that result in vasodilation, bronchial smooth muscle contraction, and mucus production o Type I reactions can be local or systemic ▪ Systemic reactions can result in anaphylaxis ▪ Local reactions can produce rash, hives, itching o Allergic asthma is an example of a type I reaction
• Type II Hypersensitivity o Tissue-specific and usually occurs as a result of haptens that cause an IgG or IgM

antibody mediated response o The antibodies are specifically directed to the antigen located on the cell membrane o Haptens are small molecules that can cause an immune responses when it attaches to a protein o Macrophages are the primary effector cells of type II responses

o The type II response begins with the antibody binding to the antigen and may cause the following: ▪ The cell to be destroyed by the antibody ▪ Cell destruction through phagocytosis by macrophages ▪ Damage to the cell by neutrophils triggering phagocytosis ▪ Natural killer cells to release toxic substances that destroy the cell ▪ Malfunction of the cell without destruction o Examples of type II reactions ▪ Drug allergies ▪ Hemolytic anemia ▪ Blood transfusion mismatch with resulting transfusion reaction and Rh hemolytic disease

• Type III Immune-Complex Reaction o The type III hypersensitivity reaction is also an antigen-antibody response o Major difference between type II and type III responses is that in a type II response the antibody binds to the antigen on the cell surface, but in type III responses the antibody binds to the antigen in the blood or body fluids and then circulates to the tissue o Type III reactions are not organ specific and use neutrophils as the primary effector cell o Immune-complex deposition (ICD) causes autoimmune diseases, which is often a complication o As disease progresses more accumulation of immune-complexes occurs and when the body becomes overloaded the complexes are deposited in the tissues and causes inflammation as the mononuclear phagocytes, erythrocytes, and complement system fail to remove immune complexes from the blood o Example of type III reactions: serum sickness
• Type IV cell-mediated, delayed reaction o Type IV hypersensitivity reactions are known as cell-mediated responses and use lymphocytes and macrophages as primary mediators o Unlike the first three type of responses, which are humoral immune functions, type IV responses are mediated by t-lymphocytes and does not use antibodies o A typical reaction from a type IV cell mediated response would be a localized contact dermatitis o When an individual comes in contact with the antigen, t-cells are activated and move to the area of the antigen o The antigen is processed and presented to macrophages, leading to epidermal reactions characterized by erythema, cellular infiltration and vesicles
• Immunodeficiency o Primary vs secondary immunodeficiencies ▪ Primary - Less common - Occur due to a defect of the development of the immune system

• Could involve antibody deficiencies, B and T-cell deficiencies, defects in the phagocytic cells and deficiency of complement ▪ Secondary
• Conditions in which the immune systems become compromised because of something else
• Could be caused by cancer, effect from a drug (chemo that suppresses the immune system), or infections that compromise the immune system in a profound way
• Common secondary immunodeficiency in the US is HIV o HIV is a RNA virus that invades the body through an cell by direct contact with an individual’s blood or body secretions o HIV has a strong affinity for cells of the immune system, especially CD4+ T cells o Once the virus invades, it replicates to cause extensive damage to the immune system o Without a normally functioning immune system the individual becomes susceptible to opportunistic infections, cancer, neurological disease, wasting and death o Biology of cancer ▪ Cancer is another type of secondary immunodeficiency ▪ Tumor is abnormal growth resulting from uncontrolled cellular proliferation (neoplasm) ▪ Any type of cell that is capable of cell division has potential for tumors ▪ Benign or malignant
• Benign o Grow slowly, non invasive, well differentiated cells, grow in a well contained capsule
• Malignant o Grow rapidly, invasive into other tissues, poorly differentiated, not encapsulated, can spread distantly (metastasis) ▪ Carcinoma
• 90% of malignant tumors
• Epithelial cells of organ surfaces and linings ▪ Sarcomas
• Connective tissues (bones and muscle) ▪ Lymphomas
• Involve blood or lymphatic systems ▪ 4 stages
• Stage 1: no evidence of metastases
• Stage 2: evidence of localized invasion
• Stage 3: cancer cells have spread to regional structures
• Stage 4: evidence of distant metastases

▪ TNM

• T refers to primary tumor
• N = the size of the tumor (the larger the number the bigger the tumor)
• M refers to the extent of metastases o Formation of cancer ▪ The formation of cancer begins with cell transformation and other factors ▪ Transformation is the process whereby a normal cell becomes a cancer cell ▪ Controlled (normal) cellular proliferation involves stem cells and the cell cycle ▪ A stem cell is an immature undifferentiated cell that is capable of infinite cellular division when stimulated ▪ The cell cycle is the process whereby the stem cell undergoes the process of cell division ▪ Cell cycle has 2 parts: interphase (23 hours) and mitosis (1 hour cycle)
• Interphase o G0 quiescent phase – resting, nondividing, inactive stem cell capable of growth and proper stimulus o G1 prepatory phase – stimulated, stem cells are starting to become metabolically active o S phase – high rate of DNA replication in stimulated stem cells o G2 – preparation of cell structures for cell division
• Mitosis o M phase – active cell division to form 2 genetically identical daughter cells o Daughter cells can then undergo differentiation to become a mature, end-stage specialized and functional cell with a finite life span o Once a cell has differentiated it can not normally regress
• Apoptosis o Aging, injured, or defective cells are eliminated from the body by a natural cell death process all apoptosis ▪ Cell division, proliferation, differentiation and death (apoptosis) are strictly controlled by a number of regulatory genes to maintain and balance between cell birth rate and cell death rate ▪ Chromosomes of normal cells contain two types of regulatory genes which have necessary function in normal cells
• Proto-oncogenes: code for synthesis of growth factors or GF receptors to promote cell growth = accelerator system
• Tumor suppressor genes: stop further cell growth via triggering cellular differentiation or apoptosis = braking system

▪ How do regulatory genes cause cancer?

• Something can trigger hyperactivation of proto-oncogenes or suppression of tumor suppressor genes
• Proto-oncogene hyperactivation or tumor suppressor gene deactivation can occur as a result of DNA point mutations (damage) or chromosomal amplifications or translocations at those specific gene sites
• In the cell these are caused by a variety of mechanisms: o Radiation exposure o Carcinogenic chemical exposure
• Exposure to radiation or carcinogenic chemicals can directly damage DNA or result in the formation of free radicals that cause DNA changes (point mutations) that alter cellular growth ▪ Amplification of the N-MYC proto-oncogene occurs in many types of cancer ▪ How does gene amplification occur??
• Infection by oncogenic viruses, which contain genetic material identical to human proto-oncogene DNA, can result in amplification of acceleratory systems for growth o Hepatitis B and C liver cancer o Epstein barr (EBV) lymphoma o Kaposi sarcoma herpesvirus sarcoma o Human T-cell leukemia-lymphoma virus (HTLV) o Human papillomavirus (HPV) cervical cancer
• Oncogenic viral infections as well as other mutagenic triggers (chemical and radiation exposure), can also cause chromosomal translocations that place several proto-oncogenes in direct proximity to each other, resulting in dysregulated cell growth ▪ Chronic inflammation triggers release of cytokines that promote cell growth, increased vascular permeability, angiogenesis, and even DNA damage
• Helicobactor pylori cause peptic ulcer disease, if left untreated causes chronic inflammation which can trigger increased risk for stomach cancer ▪ Heredity is another contributing factor to cancer development
• Genetic mutations can occur in germline cells (gametes) that are transmitted to offspring
• BRCA-1: genetic and well established risk factor for breast cancer development o Carcinogenesis: the process of tumor development ▪ Cancer cells have a monoclonal origin – descendants of a single mutant cell ▪ Cancer develops as a result of multiple (3-7) independent DNA mutations

▪ Anaplasia: loss of cell differentiation and function ▪ Cancer cells exhibit autonomy – disregard of cells for normal limitations of growth ▪ Cancer cells become anchorage independent and immortal because they are able to activate genes to synthesize a variety of enzymes, hormones, and other growth promoting substances (ectopic production)

• Autoimmunity o Autoimmunity is an alteration in the ability of the body to tolerate its own self- antigens o Under normal function the immune system does not attack the individuals own antigens o Especially with gaining and even in health individuals across the life span, individuals may produce small quantities of antibodies (autoantibodies) against their own antigens o The presences of a low number of autoantibodies does not automatically indicate the development of a full autoimmune disease o Autoimmune disease may occur when the immune system overreacts against self-antigens to the extent that tissue damage occurs o Damage is caused by the autoantibodies and T-cells o Autoimmune disease include: rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and Sjogren’s syndrome o Presenting clinical manifestations will depend on the area of the body affected o Regardless of the affected body area, autoantibodies and T-cells, and in some cases B-cells react in the associated body system to produce the characteristic signs and symptoms o Types of autoimmune diseases ▪ Systemic lupus erythematosus - Common manifestations: tissue inflammation, vasculitis, rash, tissue inflammation - Immune system changes: autoantibodies and auto-reactive T cells against DNA and nucleoprotein antigens ▪ Rheumatoid arthritis - Common manifestations: joint inflammation, stiffness and pain, loss of range of motion - Immune system changes: autoantibodies and auto-reactive T cells and B cells against joint associated antigens ▪ Multiple sclerosis - Common manifestations: formation of sclerotic plaque in the brain: leads to muscle weakness and ataxia - Immune system changes: autoantibodies and auto-reactive T cells against brain antigens ▪ Sjogren’s syndrome

• Common manifestations: inflammation in salivary and lacrimal glands
• Immune system changes: autoantibodies and auto-reactive T cells against apoptotic cells Week 2: Hematological Disorders
• Anemia o Anemia is a hematological disorder characterized by a reduction in the total number of circulating RBCs and/or a decrease in hemoglobin (Hb) amount or function o Anemia can be caused by: ▪ Impaired RBC production ▪ Excessive blood loss ▪ Increased RBC destruction o In order to recognize and differentiate the type of anemia that is present it is important to understand the components that make up the complete blood count (CBC) o CBC (we will on look at the components that relate to RBCs and their production) ▪ RBCs: the number of erythrocytes in 1 cubic mm of whole blood
• Normal for men: 4.7-6.1 mcL
• Normal for women: 4.5-5.2 mcL ▪ Hemoglobin (Hb): the oxygen carrying pigment of RBCs
• Normal for men is 13.5-17.5 g/dL
• Normal for women is 12.0-15.5 g/dL ▪ Hematocrit: the volume of cells as a percentage of the total volume of cells and plasma in whole blood
• Normal for men is 42 - 45%
• Normal for women is 37 - 48% ▪ Reticulocyte: immature RBCs, used to assess bone marrow function
• Normal in adults is approximately 3% ▪ Mean cell volume (MCV): measures the average size of the RBC
• Normal is 80 - 100 fL ▪ Mean corpuscular hemoglobin (MCH): average weight of hemoglobin per red cell
• Normal is 27 - 33 pg ▪ Mean corpuscular hemoglobin concentration (MCHC): average concentration of hemoglobin per erythrocyte
• Normal is 32 - 36% ▪ Red cell distribution width (RDW): this index is a quantitative estimate of the uniformity of individual cell size
• Normal is 11.5-14.5% o Anemia Classification ▪ Can be classified into 3 categories based on average size of RBCs (MCV)
• Microcytic anemia (MCV <80) describes RBCs that are small
• Macrocytic anemia (MCV >100) describes RBCs that are large

• Normocytic anemia (MCV 80 - 99) describes RBCs that are normal ▪ Microcytic (MCV <80)
• Iron deficiency
• Sideroblastic
• Thalassemia
• Anemia of chronic disease ▪ Normocytic (MCV 80 - 99)
• Anemia of inflammation and chronic disease
• Hereditary spherocytosis
• G6PD deficiency
• Paroxysmal nocturnal hemoglobinuria ▪ Macrocyctic (MCV >100)
• B12 deficiency (pernicious anemia)
• Folate deficiency ▪ Anemias can also be classified according to the color of the RBCs:
• Hypochromic anemia describes RBCs with less hemoglobin than normal and as a result appear paler than normal (MCHC is low)
• Hyperchromic anemia describes RBCs with more hemoglobin than normal and as a result appear darker or more red than normal cells (MCHC is high)
• Normochromic anemia describes RBCs that have a normal amount of hemoglobin (MCHC is normal) ▪ Determining the size and color of RBCs is an important step in identifying the type and source of anemia o Clinical manifestations of anemia ▪ Decreased tissue oxygenation from anemia can manifest as signs and symptoms of the follow
• Severe fatigue
• Pallor
• Weakness
• Dyspnea
• Dizziness ▪ The reduction in RBC level will decrease blood volume which activates the renin-angiotensin, aldosterone (RAA) system, which promotes fluid retention and movement of interstitial fluid into the capillaries
• This will increase plasma volume but will further dilute the plasma
• Dilute blood flows faster, which creates a hyperdynamic state
• This stresses the cardiac system and can result in tachycardia and even heart failure
• Microcytic Anemia o Iron deficiency anemia ▪ Iron deficiency is categorized as a microcytic hypochromic anemia ▪ Iron deficiency anemia (IDA) is the most common type of anemia and affects almost 20% of the world population

▪ The most common problem contributing to this is the insufficient amount of iron availability ▪ Causes of IDA:

• Inadequate dietary intake
• Chronic and or occult bleeding: hemorrhage, colitis, cirrhosis, GI ulcers, esophageal lesions, or menorrhagia (it only takes 2 - 4 mL of blood loss per day to lose 1 - 2mg of iron ▪ Pathophysiology of IDA is simple: insufficient Fe levels or inability for mitochondria to utilize Fe effectively leads to decreased Hb synthesis and the formation of smaller, paler cells ▪ CBC in IDA reveals MCV <80 and low MCHC ▪ Ferritin lab results in IDA reveal low ferritin level which is an indication that the iron stores are depleted
• Due to depletion the mitochondria are unable to utilize iron effectively, which leads to decreased hemoglobin and the production of small (microcytic) and paler (hypochromic) RBS ▪ IDA treatment
• Iron supplements
• Increase dietary intake of iron o Red meat, beans, green leafy veggies, dried fruits, nuts and whole-grain breads/cereals ▪ Vitamin C has an important role in how the body can use Iron
• Macrocytic Anemia o Result from conditions whereby the RBCs are large (MCV>100 dL) o Categorized as megaloblastic and non-megaloblastic ▪ Megaloblastic: folate deficiency and vitamin B12 deficiency ▪ Non-megaloblastic: liver disease, myelodysplastic syndrome, increased reticulocyte count (hemorrhage) o Folate and cobalamin (vitamin B12) are required for red blood cell DNA synthesis ▪ A deficiency in either result in impaired DNA replication of the RBC ▪ Impaired DNA replication of the RBC allows the erythroblast to continue to increase in size (macrocytic) instead of undergoing cell division o Clinical findings of macrocytic anemia ▪ Fatigue ▪ Dyspnea ▪ Loss of appetite or weight ▪ Diarrhea ▪ Pallor o B12 deficiency (pernicious anemia) ▪ Pernicious anemia results from the autoimmune destruction of the gastric parietal cells which decreases the secretion of intrinsic factor

▪ Intrinsic factor binds to B12 in the stomach and travels through the small intestine, when the complex reaches the ileum it is broken and B12 is absorbed into the blood ▪ This is important because B12 is needed for DNA maturation and condensation ▪ B12 deficiency leads to immature RBCs, lack of functional hemoglobin, decreased nerve cell myelination ▪ This genetically induced autoimmune condition is especially prevalent among those of English, Irish or Scandinavian descent ▪ Additional causes of B12 deficiency include insufficient dietary intake, gastritis, H. pylori infections, advanced age, and gastrectomy procedures whereby absorption of B12 is decreased ▪ Without adequate intrinsic factor to help with GI absorption, pernicious anemia is not easily remedied by simple oral B12 supplementation

• For this reason intramuscular injections, sublingual or intranasal formulations are more effective in the treatment of pernicious anemia ▪ Strict vegetarians are at high risk for B12 deficiency which may require B12 supplementation ▪ Those with insufficient intake should be encouraged to eat B12 rich foods:
• Liver
• Beef
• Chicken
• Pork
• Fish
• Whole eggs
• Dairy products (milk, cheese, yogurt) o Folate deficiency ▪ Insufficient folate intake or decreased absorption from diet, due to GI problems (often precipitated by alcohol abuse), leads to abnormal RBC formation and premature death of RBCs ▪ Folic acids is also necessary during fetal development of the brain and spinal cord
• Therefore folic acid deficiency during pregnancy is strongly associated with neural tube defects ▪ Malnutrition, alcoholism, and interactions with medications (especially anticonvulsants) are common causes of folate deficiency ▪ Clinical manifestations of folate deficiencies are the same as those of vitamin B12 deficiency except patients with folate deficiency anemia do not have neurological symptoms ▪ Foods rich in folic acid include: green, leafy veggies, citrus fruits, beans, rice and cereal, and folate fortified foods
• Normocytic anemias o Categorized by normal average red blood cell size (MCV 80 - 99)

o When a patient presents with a normocytic anemia a reticulocyte count should be performed o The number of reticulocytes indicates the number of premature RBCs in the bone marrow o A high reticulocyte count indicates that he bone marrow is producing many immature RBCs in order to compensate for a loss in number o Hemolytic and blood loss anemia are two conditions where RBCs are normal in size, but the reticulocyte counts are high o Aplastic anemia demonstrates RBCs that are normal in size but has a low reticulocyte count o Hemolytic anemia ▪ Means lysis of red blood cells ▪ Caused by the following:

• Infection: this includes parasitic and helminthic organisms and certain hemolytic toxin-producing strains of the bacterium, Escherichia coli, that is found as a common cause of food poisoning outbreaks
• Transfusion reaction: this occurs from an incorrect or incompatible blood product which causes a type II cytotoxic hypersensitivity reaction to occur
• Hemolytic disease of the newborn (Rh incompatibility issues occurring Rh- mothers and their Rh+ fetus): this condition also causes a type II cytotoxic hypersensitivity reaction
• Autoimmune reactions: these can be congenital or idiopathic in nature
• Drug-induced: drugs are chemical and they autoxidize (self- destruct, especially over time and/or with exposure to heat or moisture) to form H2O2 (hydrogen peroxide, a free radial) which causes Fe2+ to oxidize to form Fe3+ (a form of iron that cannot bind O2 as well), additional H2O2 can also attack and oxidize cell membranes to weaken them ▪ In all hemolytic situations there is premature destruction/lysis of RBCs due to enzymes or toxins produced by the infectious agent, chemical release mediated by own immune system or because of certain chemical/drugs ▪ Circulating blood contain vitamin C and RBCs contain glutathione, both of which are natural antioxidants to help protect cells o Blood loss anemia ▪ In situation where the number of RBCs is greater than the number of RBCs produced as the direct result of blood loss is considered blood loss anemia ▪ Can be acute or chronic

▪ Acute blood loss anemia is usually associated with acute GI bleeding, trauma, surgical or labor and delivery complications ▪ Chronic blood loss anemia is usually associated with chronic GI bleeding

• Chronic blood loss will deplete iron store and also produce iron deficiency anemia ▪ A normal healthy young adult can lose 500 - 1000mL (10-20%) of blood with minimal effects ▪ Compensation and recovery begin within 24 hours for losses up to 1500mL ▪ Sudden, severe hemorrhage can induce hypovolemic shock, cardiovascular failure, and death ▪ Diagnosis and management of a blood loss anemia must take into account the reason behind the loss, the rate and amount of blood loss, and the capacity of the patient to compensate for both volume losses and anemia o Aplastic anemia ▪ Reticulocyte levels are low in aplastic anemia ▪ Means without cell growth ▪ Causes of aplastic anemia
• Chemical or radiation exposure (side effect of chemotherapy)
• Viral induced (hepatitis, Epstein Barr virus, cytomegalovirus)
• Tumors (multiple myeloma)
• Antibiotics or other medications (peniciliin, chloramphenicol, phenytoin, diuretics, antidiabetic drugs, sulfa drugs)
• Congenital defects (fanconi’s anemia) ▪ In all cases the “agent” destroys the blood cell producing red bone marrow ▪ These areas of the bone cavity are not replaced by fatty yellow marrow, which does not produce blood cells ▪ Loss of blood-cell producing areas eventually leads to pancytopenia: a decrease in all blood cell types ▪ Since RBCs are the most prevalent of our three types of blood cells the effects of bone marrow suppression are first evident by loss of oxygenation capability with signs and symptoms of hypoxia ▪ This is usually followed by problems with blood-clotting, related to loss of ability to form the second most prevalent blood cell: platelets ▪ Finally increased development of infections indicates that WBC production in the marrow is also now affected
• Hemoglobinopathies o Individuals may inherit a disorder of the erythrocytes called hemglobinopathies o There are 4 genes involved in encoding synthesis of the alpha protein chains for Hb ▪ These genes are located on chromosome number 16

o There are 2 genes involved in encoding synthesis of the beta protein chains for Hb ▪ These genes are located on chromosome number 11 o From these 6 genetic loci, over 300 different Hb gene defects have been documented o The two most common examples include sickle cell anemia and thalassemia o Sickle cell anemia ▪ Inherited autosomal recessive disorder (autosomal recessive disorders develop as the result of inheriting two abnormal genes, one from each parent) ▪ If the individual inherits a normal Hb gene from one parent and an abnormal Hb gene from the other that person would have “sickle cell trait” and be an asymptomatic carrier

• They could pass the abnormal gene to their offspring, but they themselves would experience minimal, if any sign and symptoms of the condition ▪ The pathophysiology of sickle cell anemia involves a single amino acid change on the beta-chain (the amino acid valine replaces glutamic acid)
• the simple change result in the formation of elongated, “sickled” Hb molecules (designated HbS) which does not bind oxygen readily ▪ Oxidative stress (such as occurs with hypoxia), anxiety, fever, cold, and dehydration further decrease oxygen binding to Hb and increases sickling tendencies of Hb ▪ The sickling of millions of hemoglobin molecules causes distortion of RBCs that house those molecules ▪ Sickled Hb weakens the RBCs and they rupture after only 10 - 15 days in circulation ▪ This is a type of hemolytic anemia and presents with the classic anemia signs and symptoms in addition to other serious complications
• The lysis of large amount of RBCs puts the individual at risk for circulatory iron-overload ▪ The abnormal RBCs also occlude cerebral, splenic, and glomerular blood vessels and create a high risk for stroke, splenic and kidney damage
• Damage to the spleen is especially prevalent, therefor many sickle-cell individuals are asplenic by adulthood o Thalassemia ▪ A group of related inherited autosomal recessive genetic disorders and must inherit an abnormal Hb gene from both parents ▪ Unlike sickle cell anemia, thalassemia is characterized by many different possible genetic mutations ▪ These mutations cause single or multiple amino acid changes on alpha- and/or beta-chains resulting in synthesis of Hb with abnormal chains, or even missing alpha- and beta-chains

▪ Depending on the mutation there can be varying degrees of distortion and dysfunction of the RBC ▪ Because of the number of different possible genetic mutations, thalassemia can present in a variety of forms from minor to major and be asymptomatic in the mildest forms and lethal in the most several forms, such as Colley’s thalassemia ▪ Has ineffective erythropoiesis o Collectively sickle cell anemia and the different forms of thalassemia represent the most common genetically inherited disorders o It is estimated that over 300 million people worldwide have one of these conditions and many millions more are carriers of these genetic traits o These conditions are prevalent in individuals from certain geographic regions ▪ Genetic mutations for these conditions are found in people of African, Mediterranean, and southeast Asian descent o The name thalassemia literally translates to the Greek word for sea o The reason the genetic mutations for these hemoglobinopathies persisted in the human gene pool through the centuries is an advantage o It turns out that cells that contain abnormal types of Hb are more resistant to infection by the parasite that causes malaria o Malaria is an endemic disease in the same parts of the world where these types of anemias are prevalent o Not only are the abnormal RBCs more resistant to infection, but their shortened life span in circulation is not long enough to allow the malaria parasite to complete its reproduction cycle ▪ This allowed our ancestors who carried these genetic mutations to be highly resistant to the deadly consequences of a malarial infection and survive long enough to have children to whom they could pass this train, and most importantly, continue the circle of life Week 2: Cardiovascular Disease

• Cardiovascular disorders are prevalent in primary care
• Many of the disorders develop over several years due to risk factors to which individuals have been exposed
• What is coronary artery disease (CAD) o CAD is considered the leading cause of death in the United States o It is the result of longstanding atherosclerosis o Atherosclerosis begins with damage to the endothelium o The endothelium under normal conditions maintains the balance between the vasoconstrictive and vasodilation actions, prevents platelets from aggregating and control production of fibrin o When the endothelium becomes damaged out familiar inflammatory processes occur

▪ Macrophages attach to the endothelium, setting up phagocytosis; plague formation and vasoconstriction also occurs marking the beginning of atherosclerosis ▪ The plague lesion located in the vessels become enlarged which allows the plague to progress within the enlarged vessel lumen ▪ The plague lesion disrupts normal blood floor and cause thrombus formation which can be triggered by cardiac risk factors such as elevated LDL, cholesterol, smoking and diabetes ▪ This is a problem because the plague takes decades to develop in the coronary arteries ▪ With mild disease, blood flow can get through the arteries and the patient is asymptomatic ▪ Overtime the build up can lead to narrowing which results in decreased oxygen supply ▪ When atherosclerosis reaching a clinically significant, the patient will being to experience angina ▪ Further progression of the disease will result in acute coronary syndrome (ACS), formerly known as myocardial infarction o The major risk factor for development of CAD is family history ▪ There is a 50% higher risk for individuals to develop heart disease if they have a first degree relative (especially father) or sibling who has suffered from ACS or premature cardiac death (<55 years old) o Lifestyle also impacts risk ▪ Especially tobacco use and even secondhand smoke exposure ▪ It is always important for healthcare providers to promote smoking cessation with all patients who smoke tobacco, in order to decrease the patient’s risk for CAD ▪ Sedentary lifestyle will also increase one’s risk for developing CAD

• Physical inactivity can lead to overweight (BMI 25.5-29), or obesity (BMI >30) o Males have an increased risk o Hypertension, elevated total cholesterol, elevated low-density lipoprotein (LDL), and/or decrease high-density lipoprotein (HDL), and diabetes are also risk factors
• Heart Failure o Is a very complex disease state that can be the result of structural or functional impairment of the heart, which then leads to the heart’s inability to fill or eject sufficient amount of blood out to the body o Basic concepts related to heart failure: ▪ Cardiac output (CO): the amount of blood that the heart pumps in 1 minute. CO is also known as cardiac contractility ▪ CO formula: CO= heart rate (HR) x stroke volume (SV) ▪ SV: the volume of blood pumped out of the left ventricle during each systolic cardiac contraction

▪ Afterload: the force, or load, which the heart must contract against in order to pump blood. Also known as systemic vascular resistance (SVR) ▪ Preload: the amount of stretch that the cardiac muscle exhibits at the end of ventricular filling o Not all patients present with the same signs and symptoms of heart failure and symptoms are dependent upon which side of the heart is affected o Right sided heart failure ▪ Also called cor pulmonale ▪ Defined as the inability f the right ventricle to provide adequate blood flow into pulmonary circulation ▪ Causes of right heart failure include

• Pulmonary diseases that causes pulmonary hypertension (this is the most common cause)
• Right ventricular myocardial infarction (MI), which weakens the cardiac muscle
• Right ventricular hypertrophy (secondary to cardiac damage)
• Tricuspid valve damage, which causes back flow of blood into the right atrium or right ventricle after ejection
• Secondary failure as a result of left heart failure due to build up of pressure in the damaged left ventricle
• Since pulmonary hypertension is the most common cause of heart failure, it will be used to outline the disease process (keep in mind that regardless of the cause of right heart failure, the overall process will be the same) ▪ How to pulmonary hypertension cause right heart failure?
• High pulmonary vascular pressure (increased afterload) will cause an increased right ventricular contraction force in order to eject the blood into the pulmonary artery
• Overtime this increased workload will reduce the ejection fraction and the right ventricle will be unable to eject the normal amount of blood
• This will increase the amount of blood remaining in the right ventricle and as a result increase right ventricle preload, resulting in the inability for the right atrium to eject the normal amount of blood into the right ventricle
• This will increase the amount of blood remaining in the right atrium and therefore will increase right atrial preload
• Increased atrial preload causes the back-up of blood volume and pressure in the vena cava and systemic veins
• Jugular vein distention is characteristic of right heart failure
• the liver and the spleen can also become engorged due to the large volume of blood flowing through these organs, resulting in hepatosplenomegaly

• increased pressure will force fluid from the systemic capillaries into the peripheral tissues, essentially flooding those areas and resulting in peripheral edema
• unsolved right heart failure will increase pressure on the left sight of the heart, contributing to left heart failure as well, which will result in biventricular failure o Left sided heart failure ▪ high systemic vascular resistance, or increase afterload, will increase the left ventricular contraction force in order to eject blood from the left ventricle ▪ over time this will reduce the patient’s ejection fraction and the left ventricle will be unable to eject a normal amount of blood ▪ this results in an increased amount of blood remaining in the left ventricle ▪ as a result, the left ventricle preload will be increased, impeding the left atrium from ejecting the normal amount of blood in to the left ventricle ▪ this will eventually cause the blood volume in the pulmonary veins to increase and the pressure in the pulmonary veins will increase ▪ this increased pressure will force fluid from the pulmonary capillaries into the pulmonary tissues, which essentially floods those areas ▪ as a result, pulmonary edema and dyspnea develop ▪ if left ventricular heart failure is unresolve, volume and pressure will build until is reached the right side of the heart, contributing to right heart failure as well (in this cause the condition become biventricular heart failure) ▪ disease process that increase left ventricular after load include hypertension and aortic valve disorders o High output heart failure (HOF) ▪ this is the inability of the heart to pump enough amounts of blood to meet circulatory needs of the body, despite normal blood volume and cardiac contractility ▪ in contrast to left and right heart failure, where the heart is unable to effectively increase its output, the heart can in HOF to at least, for a while, increase its output ▪ even with increased cardiac output, the metabolic needs of the body are not met ▪ causes of HOF:
• anemia: regardless of the type impairs oxygen delivery to the tissues
• nutritional deficiencies especially of thiamine, decreases cardiac muscle function and output, which impairs oxygen delivery to the tissues
• hyperthyroidism, fever, and sepsis increase basal metabolic rate, which leads to increased tissue oxygenation demands

• as conditions like these increase oxygen demand, the supply of oxygen is simply not there, which leads to a hypoxic condition
• hypoxia activates the sympathetic response o the catecholamines, epinephrine and norepinephrine, are released, which increases the heart rate and stroke volume to increase cardiac output ▪ in HOF, the heart cannot keep up with the body’s demands for oxygen nor maintain an extended increased heart rate and stroke volume in an attempt to supply the body with the oxygen that is needs ▪ HOF overtime can deplete the cardiac muscle reserve and lead to low- output heart failure o Compensated vs decompensated heart failure ▪ Compensation
• Increases stroke volume and increases heart rate
• Increasing cardiac output
• How does the body compensate? o Activate the sympathetic nervous system (fight or flight) response ▪ When cardiac output goes down the sympathetic nervous systems signals the heart to increase heart rate or contract hard ▪ Downregulation: overuse of sympathetic nervous system receptors (heart will no longer respond to chemicals of sympathetic nervous system) o Increase preload (pressure in the ventricles after filling) ▪ Walls of heart are expanded and stretched ▪ Increased filling = increased pressure ▪ Antidiuretic hormone and aldosterone are released to increase preload (causes retention of water) ▪ How does increasing preload increase stroke volume?
• The more you stretch the more force it will snap back with = more blood ejected ▪ Frank Starling Law = increase pressure = increase stroke volume ▪ Use more energy to contract, which means the need more blood and oxygen, if there is not more blood coming to the heart muscle cells then they can begin to die off o Myocardial hypertrophy (heart muscle gains muscle mass) ▪ Gaining muscle = harder contraction ▪ So to try and make up for this decrease in stroke volume or this death of heart muscle cells, the

surviving heart muscle cells elongate and grow to make up for dead cells ▪ Hypertrophied cells contract harder so they eject more blood = increased stroke volume ▪ More work = need more blood supply (not a sustainable option in heart failure) ▪ More muscle = decreased chamber size = less blood can fill chambers o Compensation is only sustainable for so long, eventually heart failure will get worse because the body is no longer able to compensate decompensated heart failure o Stages of heart failure ▪ When diagnosing heart failure and determining the patient’s treatment plan the NP must consider the stage and classification of heart failure using the American College of Cardiology/American heart Associations (ACC/AHA) current clinical practice guideline on the management of heart failure ▪ Diagnosis and treatment of heart failure always requires identification of its stage and classification ▪ Stage A:

• Patients at risk for heart failure who have not yet developed structural heart changes (ex: those with diabetes or those with CAD without prior infarct) ▪ Stage B:
• Are patients with structural heart disease (ex: reduced ejection fraction, left ventricular hypertrophy, chamber enlargement) who have not yet developed symptoms of heart failure ▪ Stage C:
• Patients who have developed clinical heart failure ▪ Stage D:
• Patients with refractory heart failure that require advanced intervention (ex: the need for biventricular pacemaker, left ventricular assist device, or heart transplant) o The New York Heart Association’s (NYHA) system, included in the 2017 ACC/AHA clinical practice guideline on the management of heart failure, classifies the patient’s heart failure in terms of their overall function and is based on the patient’s symptoms o Classes of heart failure ▪ Class I:
• There is no limitation of physical activity
• Ordinary physical activity does not cause symptoms of heart failure ▪ Class II:
• There is a slight limitation of physical activity

• The patient is comfortable at rest, but ordinary physical activity results in symptoms of heart failure ▪ Class III:
• There is marked limitation of physical activity
• The patient is comfortable at rest, but less than ordinary activity cause symptoms of heart failure ▪ Class IV:
• The patient is unable to carry on any physical activity without symptoms of heart failure, or they have symptoms at rest o Patients with heart failure can progress through the 4 stages of heart failure as their condition worsens o Once a stage has been reached a person can never go back to the prior stage ▪ In other words, the damage to the heart cannot be reversed o This is not the case with the NYHA classification that focuses entirely on the patient’s symptoms ▪ Patients may move between class I and class IV as symptoms can be improved through treatment with medications o While a patient may be in a certain stage of heart failure, they symptoms they exhibit within that stage can be managed and improved
• Heart Valve Disorders o Aortic Stenosis ▪ Aortic valve is tight so not enough blood can get through the valve to systemic circulation ▪ Causes blood to back up into the left ventricle ▪ Causes of aortic stenosis
• Bicuspid aortic valve o Congenital condition that causes only 2 cusps (normal aortic valve has 3 cusps) o More likely to be stenosised because 2 cusps are doing the work of 3 (damaged quicker and become calcified over time)
• Age related calcification o Valve hardens with age and causes the valve to not open o Risk factors for age related calcification ▪ Smoking ▪ HTN ▪ DM ▪ HLD
• Rheumatic Fever ▪ Signs and symptoms
• S: syncope (fainting)
• A: Angina (chest pain) o CAD

o LVH: increased demand for O2 due to muscle enlargement

• D: dyspnea (SOB)
• Pulses Parvus et tardus (small/weak pulse + slow to rise)
• Left ventricular hypertrophy o Can palpate point of maximal impulse (should normally be in the 5 th^ intercostal space at the midclavicular line, in LVH the PMI can move medially towards the sternum)
• Microangiopathic hemolytic anemia (MAHA) o RBCs are sheered as they go through the stenosis valve o Anemia develops as RBCs are lysed
• Systolic Ejection murmur o Best heard at the right upper sternal border o With or without ejection sound o Aortic Regurgitation ▪ Floppy aortic valve ▪ Allows for blood flow back into the left ventricle during diastole ▪ Causes of aortic regurg
• Widening or aneurysmal change of the aortic annulus (ring of fibrous tissue that surrounds the valve) o Tertiary syphilis o Connective tissue disorders (Marfans, ehlers danlas)
• Endocarditis o Vegetation forms and prevents valve from closing properly
• Rheumatic fever ▪ Signs and symptoms of aortic regurg
• Fatigue o All the blood that is being pumped out to the aorta is coming back into the heart
• Syncope
• SOB
• Palpitations
• Wide pulse pressure o Pulse pressure is the difference between SBP and DBP (SBP-DBP)
• Left ventricular dilatation o S3: an extra heart sound which signifies volume overload: heart is getting too much blood back when it is not supposed to o Displaced PMI ▪ Will move laterally and maybe inferiorly from normal location o Early Diastolic Murmur at the left sternal border o Mitral Regurgitation

▪ Mitral valve (between LA and LV) is floppy allowing blood to flow into the LA during systole of the LV ▪ Allows back flow into the LA and then eventually back up occurs in pulmonary circulation ▪ Causes of Mitral Regurg

• Anything that cause LV dilatation o Stretches the heart and does not allow the Mitral valve to come together appropriately o Remodeling post MI o Dilated cardiomyopathy ▪ Ischemic ▪ Nonischemic
• Rheumatic Fever/heart disease o Early presentation
• Endocarditis o Vegetation does not allow valve to close effectively
• Papillary muscle/chordae tendinae dysfunction or rupture o An anchoring system for the valve that ensures they can close effectively o Rupture causes a leaflet of the valve to flail
• Calcification ▪ Signs and symptoms
• Acute o No time to compensate flash pulmonary edema ▪ Medical emergency o Papillary muscle rupture ▪ Can occur after MI
• Chronic o Dilated LV ▪ Dilated ischemic cardiomyopathy o Fatigue, SOB, pulmonary congestion, LV hypertrophy, holosystolic murmur at the apex of the heart o Mitral Valve Prolapse ▪ Valve billows or bulges into the LA ▪ Causes of prolapse
• Idiopathic (unknown cause)
• Occurs secondary to connective tissue disorders o Marfans and ehlers danlos ▪ Signs and symptoms
• Asymptomatic
• MVP syndrome o Atypical chest pain (not anginal in character) o Palpitations