Nu Patho Unit 4 Study Guide

25b. DEFECTS DECREASING PULMONARY BLOOD FLOW, OBSTRUCTIVE DEFECTS (pg. 1207-1214)

DEFECTS DECREASING PULMONARY BLOOD FLOW: Tetralogy of Fallot (TOF): The most common cyanotic congenital heart defect. It accounts for 10% of all defects. It includes four defects: a large VSD high in the septum, an overriding aorta that straddles the VSD, pulmonary stenosis (PD), and RV (right ventricle) hypertrophy. Clinical manifestations from chronic hypoxemia include clubbing of toes and fingers. (A rare symptom of TOF is known as hypercyanotic spell or tet spell, which is manifested by sudden dyspnea, cyanosis, and restlessness with crying and exertion. If these spell are often or do not stop spontaneously, they are considered a medical-surgical emergency.) Squatting in a spontaneous compensatory mechanism used by older children with unrepaired TOF to alleviate hypoxic spells. The typical murmur of TOF patients is a pulmonary systolic ejection murmur caused by obstruction in outflow tract, which creates turbulence during systole. Pages 1207-1209. Tricuspid Atresia: consists of an imperforate (lacking normal opening) tricuspid valve, resulting in no communication between the RA and RV- the 3rd most common cyanotic heart defect. Clinical manifestations show some degree of central cyanosis, as well as growth failure, exertional dyspnea, tachypnea, and hypoxemia. Murmur noted includes several components. The VSD results in a systolic regurgitant murmur, which grows softer and shorter as the VSD enlarges. A narrowly split second heart sound caused by decreased pulmonary blood flow may present, or the second heart sound may be single if there is pulmonary atresia. Pages 1209-1210. OBSTRUCTIVE DEFECTS: Coarctation of the Aorta (COA): consists of a narrowing of the lumen of the aorta that impedes blood flow. About 50% of patients with COA have a bicuspid aortic valve. CHF symptoms occur if the coarctation is severe enough. In infants, once the ductus closes, their condition may deteriorate quickly from hypotension, acidosis, and shock. A systolic ejection murmur is best heard at the left interscapular area. Pages 1210-1212. Aortic stenosis (AS): narrowing of aortic outflow tract. Usually children with mild to moderate AS are asymptomatic. In more severe cases, fainting, epigastric pain, and exertional chest pain may occur. A systolic ejection murmur is noted at the right upper sternal border that transmits to the neck and left lower sternal border. An ejection click may be noted with valvular AS. Pages 1212-1213. Pulmonary Stenosis (PS): narrowing of the pulmonary outflow tract. Pulmonary atresia is the most severe form. Clinical manifestations depend upon the severity of the defect. A systolic ejection murmur at the left upper sternal border is noted. In some, a variable systolic ejection click is present with valvular stenosis at the upper left sternal border. Pages 1213- 1214. Hypoplastic Left Heart Syndrome (HLHS): is the abnormal development of the left sided cardiac structures, resulting in obstruction to blood flow from the LV outflow tract. Newborns with HLHS appear normal. Yet, once the ductus closes, perfusion is decreased, causing hypoxemia, acidosis, and shock. Generally, no heart murmur is detected. The second heart sound is loud and single due to aortic atresia. Page 1214.

37b. PCV and HH - DIAGNOSTICS, TREATMENT, COMPLICATIONS (PG. 1002-1005)

DIAGNOSTICS Polycythemia Vera- Unique feature of development of intense, painful itching that is intensified by heat or exposure to water. Diagnosis is usually based on clinical features such as thrombotic event, splenomegaly and aquagenic pruritis. An absolute increase in the # of RBCs in total blood volume as well as presence of JAK2 mutation confirms diagnosis. Major diagnostic criteria in BOX 28-2 pg. 1004. HH-Many are diagnosed as a result of serum iron studies. Lab findings show elevated serum iron levels, transferrin saturation, and ferritin levels. TREATMENT Relative Polycythemia-fluid administration or tx. Of underlying cause Polycythemia Vera-Minimizing risk of thrombosis and preventing progression to myelofibrosis and acute leukemia. In low-risk younger individuals, recommended tx. Is phlebotomy (300- 500ml at a time) to decrease then maintain safe Hct, & low dose aspirin. Hydroxyurea, an antimetabolite that blocks DNA synthesis and reduces vascular cellularity is drug of choice for myelosuppression. Interpheron alpha has been used when other tx. Fail and is considered in individuals who are intolerant to hydroxyurea, younger individuals, and individuals who are pregnant. Hct is the optimal target that defines successful tx. HH- Aimed at preventing Cirrhosis. Tx. Consists of phlebotomy of 550ml of whole blood (equivalent to 200-250mg of iron). Pts. Should be instructed to refrain from takin iron and vit. C supplements and consuming raw shellfish, and limited alcohol. Family screening is recommended. COMPLICATIONS PV-Thrombosis, leukemia HH-cirrhosis

31. Know the mechanisms of hemostasis: function of the blood vessels, platelets and clotting factors. Know what regulates hemostasis. What vitamins are needed for normal clotting factor synthesis? (Pg. 965 - 969)

(Pg 965) (1) vascular injury leads to a transient arteriolar vasoconstriction to limit blood flow to affected site. (2) damage to the endothelial cell lining of the vessel exposes prothrombogenic subendothelial connective tissue matrix, leading to platelet adherence and activation and formation of a hemostatic plug to prevent further bleeding (primary hemostasis); (3) Tissue factor, produced endothelium, collaborates with secreted platelet factors and activated platelets to activate the clotting system to form fibrin clots and further prevent bleeding (secondary hemostasis) (4) The fibrin/platelet clot contracts to form a more permanent plug, and regulatory pathways are activated (fibrinolysis) to limit the size of the plus and begin the healing process Blood vessels (Pg 966)—Endothelial cells produce nitric oxide from L-arginine and synthesize prostacyclin from arachidonic acid both which (1) are vasodilators that work in concert with endothelin (vasoconstrictor) to maintain blood flow and pressure (2) inhibit platelet adhesion and aggregation. Endothelial cell surfaces contains antithrombotic molecules, such as glycosaminoglycans (e.g. heparin sulfate) thrombomodulin, and plasminogen activators which limit platelet activation and fibrin deposition. Platelets (Pg 967)—The role of platelets is to (1) contribute to regulation of blood flow into a damaged site by induction of vasoconstriction, (2) initiate platelet-platelet interactions resulting in formation of a platelet plug to stop further bleeding, (3) activate the coagulation cascade to stabilize the platelet plug, (4) initiate repair processes including clot retraction and clot dissolution (fibrinolysis). The process of platelet activation is (1) increased platelet adhesion to the damaged vascular wall, (2) activation leading to secretion of chemicals form platelet granules which stimulate changes in platelet shape and biochemistry, and (3) aggregation as platelet-vascular wall and platelet-platelet adherence increases. Clotting Factors (Pg 969)—two pathways intrinsic and extrinsic that join a common pathway. Intrinsic- activated when Hageman factor (factor XII) in plasma contacts negatively charged subendothelial substances exposed by vascular injury. Activated factor XII (XIIa) is an active enzyme with factor XI as a substrate. Extrinsic is activated when tissue factor (also called tissue thromboplastin) reacts with a high affinity with circulating activated factor VII (TF/VIIa); approx. 1% of circulating activated factor VII has been spontaneously activated to VII. TF is a transmembrane protein that exists in an inactive form on the endothelial membrane but is activated into an active enzyme with factors IX and X as substrates. (Pg 966) Under normal conditions, the endothelium actively regulates blood flow and prevents spontaneous activation of platelets and the clotting system. ?? Pg # Vitamin K is needed for normal clotting

11. What is kernicterus? (Pg 1060, 1501)

- A complication of HDN. - Occurs when the maternal antibodies remain in the neonatal circulation after birth, leading to erythrocyte destruction. - Without transfusing the child with Rh negative erythrocytes, the bilirubin is deposited in the brain, causing Kernicterus. - Kernicterus produces cerebral damage and usually results in death (icterus gravis neonatorum) - Infants who do not die may have significant developmental delay, cerebral palsy, and high-frequency deafness.

40. How do varicose veins develop? Patho? (PG. 1129 - 1130)

A superficial vein in which blood has pooled caused by (1) trauma to the saphenous veins that damages one or more valves, or (2) gradual venous distension caused by the action of gravity on blood in the legs. Standing for long periods, wearing constricting garments, or crossing the legs at the knees causes distention that damages venous valves, rendering the valve incompetent. Damaged valves can't maintain normal venous pressure, which causes hydrostatic pressure in the vein to increase. Evidence has ben emerging that varicose veins are not just the result of mechanical pressures. Altered connective tissue proteins, increased proteolytic enzyme activity, and decreased transforming growth factor-beta (TGF-B) in vein walls probably precede the development of valvular damage and the development of veriscoties. Inflammatory changes that affect autonomic innervation of veins has also been implicated.

17f. NORMAL INTRACARDIAC PRESSURES (PG. 1089)

Atrial pressure curves are composed of the a wave, which is generated by atrial contraction, and the v wave, which is an early diastolic peak caused by filling of the atrium from the peripheral veins. A smaller pressure increase, the c wave, occurs after the a wave in early systole and may represent bulging of the mitral valve into the LA during early systole. Two aspects of falling atrial pressure have also been named. The x descent follows the a wave and is produced by the descent of the tricuspid valve ring and by the ejection of blood from both ventricles. The y descent that follows the v wave reflects the rapid flow of blood from the great veins and RA into the RV. LV pressures are illustrated by a peak systolic pressure and an end diastolic pressure, which is the ventricular pressure immediately before the onset of systole. The minimal LV pressure occurs in early diastole.

9. Know normal/abnormal hematology values in infants. (Pg.978, Table 27-11 or Table 30-1, Pg. 1057 for ranges)

Blood cell counts tend to rise above adults levels at birth and then decline gradually throughout childhood. The immediate rise in values is the result of accelerated hematopoiesis during fetal life, increased numbers of cells that result from the trauma of birth and cutting of the umbilical cord. Age Hgb Hct reticulocytes leukocytes neutrophils lymphocytes eosinophils monocytes platelets Cord blood 16.8 55 5.0 18,000 61 31 2 6 290 2 wks 16.5 50 1.0 12,000 40 48 3 9 252 3 mos 12.0 36 1.0 12,000 30 63 2 5 140-340 6 mos-6 yrs 12.0 37 1.0 10,000 45 48 2 5 140-340

29. Know hematopoiesis-the process and where does it occur in the fetus, neonate, child and adult. (PG. 954)

Blood cell production, hematopoiesis, is constanslty ongoing, occuring in the liver and spleen of the fetus and only the bone marrow after birth. Prenatally, hematopoiesis occurs in the yolk sack, then in the liver, and lastly in the bone marrow. In the normal situation, hematopoiesis in adults occurs in the bone marrow and lymphatic tissues.

17c. CHAMBERS OF THE HEART (PG. 1086)

CHAMBERS OF THE HEART (PG. 1086) - The heart has four chambers: the right atrium (RA), left atrium (LA), right ventricle (RV), and left ventricle (LV). These chambers form two pumps in series: the right heart, which is a low pressure system pumping blood through the lungs; and the left heart, which is a high pressure system pumping blood through the rest of the body. The RA and LA are smaller than the ventricles and have thinner walls (2 mm thick). The ventricles have a thicker myocardial layer and make up much of the bulk of the heart. The wall of the RV is about 5 mm thick, and that of the LV (the most muscular chamber) is about 15 mm. The ventricles are formed by a continuum of muscle fibers that originate from the fibrous skeleton at the base of the heart (chiefly around the aortic orifice). The wall thickness of each cardiac chamber depends on the amount of pressure or resistance it must overcome to eject blood. The two atria have the thinnest walls because they are low pressure chambers that serve as storage units and conduits for blood that is emptied into the ventricles. Normally, there is little resistance to from the atria to the ventricles. The ventricles, on the other hand, must propel blood all the way through the pulmonary or systemic circulation. The ventricular myocardium must be strong enough to pump against pressures in the pulmonary or systemic vessels. The mean pulmonary capillary pressure, the force the RV must overcome, is only about 15 mmHg whereas the mean arterial pressure, the force the LV must overcome, is about 92 mmHg. Because the pressure is markedly higher in the systemic circulation, the LV's myocardial wall is several times thicker than that of the RV. The RV is shaped like a crescent, or triangle, enabling it to function like a bellows and efficiently eject large volumes of blood through the pulmonary semilunar valve into the low pressure pulmonary system. The LV is larger and bullet shaped, helping it eject blood through the larger aortic semilunar valve into the high pressure systemic circulation. The ventricles are structurally more complex than the atria. Each ventricle contains muscle fibers that divide it roughly into an inflow tract, which receives blood from the atrium, and an outflow tract, which sends blood to the circulation. Normally blood does not flow between the chambers of the right side of the heart and the chambers of the left side of the heart except in the fetus before delivery. The adult right and left sides of the heart are separated by intact septal membranes. The atria are separated by the interatrial septum and the ventricles by the interventricular septum. There is an opening between the RA and LA before birth called the foramen ovale; however, this opening closes shortly after birth in most individuals. The interventricular septum is an extension of the fibrous skeleton of the heart. Indentations of the endocardium form valves that separate the atria from the ventricles & the ventricles from the aorta and pulmonary arteries. FIBROUS SKELETON OF THE HEART - Four rings of dense fibrous connective tissue provide a firm anchorage for the attachments of the atrial and ventricular musculature, as well as the valvular tissue. The fibrous rings are adjacent and form a central, fibrous supporting structure collectively termed the annuli fibrosis cordis.

17a. Know the heart: circulation (oxygenated and deoxygenated blood), chambers, valves, cardiac cycle, pressures. (Pg. 1083 - 1090)

CIRCULATORY SYSTEM (PG. 1083) - The functions of the circulatory system include delivery of oxygen, nutrients, hormones, cells of the immune system, and other substances to body tissues and removal of the waste products of cellular metabolism. Delivery and removal are achieved by a complex array of tubing (the blood and lymphatic tissues) connected to a pump (the heart). The heart continuously pumps blood through the blood vessels in collaboration with other systems, particularly the nervous and endocrine system, which are intrinsic regulators of the heart and blood vessels. Immune system cells, nutrients and oxygen are supplied by the immune, digestive, and respiratory systems; gaseous wastes of cellular metabolism are blown off by the lungs; and other wastes are removed by the kidneys and digestive tract. A critical component of the circulatory system is the vascular endothelium, which is a multifunctional tissue whose health is essential to normal vascular and hemostatic physiology and whose dysfunction is an important factor in the pathogenesis of vascular and other disease. The heart is comprised of two conjoined pumps that power the movement of blood through two separate circulatory systems, one to the lungs and one to all other parts of the body. Structures on the right side of the heart (right heart) pump blood through the lungs (pulmonary circulation). The left side of the heart (left heart) sends blood through systemic circulation, which supplies all of the body except the lungs. These two systems are serially connected so that the output of one pump becomes the input of the other. Arteries carry blood from the heart to all parts of the body, where they branch into arterioles and even smaller vessels until they become a fine meshwork of capillaries. Capillaries allow the closest contact and exchange between the blood and the interstitial space, or interstitium - the environment in which cells live. Veins then carry blood from capillaries back to the heart. Some of the plasma (liquid component of blood) passes through the walls of the capillaries into the interstitial space. This fluid, called lymph, is returned to the cardiovascular system by vessels of the lymphatic system. The lymphatic system is also a critical component of the immune system. (PG. 1084, Figure 31-1) Diagram showing serially connected pulmonary and systemic circulatory systems and how to trace the blood flow. A - Right heart chambers propel unoxygenated blood through the pulmonary circulation, and the left heart propels oxygenated blood throughout the systemic circulation. B - The direction of blood flow begins at the left ventricle of the heart; flows to the arteries, arterioles, capillaries of each body organ, venules, veins, right atrium, right ventricle, pulmonary artery, lung capillaries, pulmonary veins, and left atrium; and then returns to the left ventricle.

22b. Rheumatic Fever ~ CLINICAL MANIFESTATIONS, DIAGNOSTICS, TREATMENT, COMPLICATIONS (1171-1173)

CLINICAL MANIFESTATIONS Common Sx's of acute RF are fever, lymphadenopathy, arthralgia, nausea, vomiting, epistaxis (nose bleed), abdominal pain, and tachycardia. The major clinical manifestations of acute rheumatic fever (carditis, acute migratory polyarthritis, chorea, & erythema marginatum) usually occur singly or in combination 1-5 wks after strep throat infxn. • Carditis—Occurrs a few wks after initial infxn in 50% of pts w/ acute RF. Earliest Sx's are previously undetected murmur caused by mitral or aortic semilunar valve dysfunction. CP is caused by pericardial inflammation. Pericardial effusion produces audible friction rub. Extra heart sounds, heart block, a-fib, & prolonged PR interval are often associated w/ chronic RHD. Endocardial inflammation may be seen yrs later w/ serious valvular diseases (stenosis & regurgitation) and recurrent infective endocarditis. • Polyarthritis—Acute migratory polyarthritis (inflammation of >1 joint occurs in 60- 80% of those w/ RF (usu. affecting large joints of extremities). 2 or > joints are usually involved simultaneously or in succession, w/ ea. Joint being symptomatic for approx. 2- 3 wks while overall polyarthritis continues for up to 3 wks. Causes heat, redness, swelling, severe pain, & tenderness, but no perm. disability. Palpable subQ nodes often dvp over bony prominences & along extensor tendons, but don't interfere w/ joint fxn & often go unnoticed. • Chorea (AKA: Sydenham chorea or St. Vitus dance)—D/o of CNS characterized by sudden, aimless, irreg., involuntary movements. It is the most common acquired chorea in children and is more common in girls. Self-limiting, usu. resolves in 1-6 months, w/ no perm. neural sequelae. Erythema Marginatum—A distinctive truncal rash that often accompanies acute RF. Consists of nonpruritic, pink, erythematous macules that never occur on face or hands. Rash is transitory and may change in appearance w/I minutes or hours. Heat darkens it and the macules may fade in the center and be mistaken for ringworm. DIAGNOSTICS Throat Cx positive for group A beta-hemolytic strep can be important finding when assoc'd w/ certain physical Sx's. Cx's may be negative when rheumatic attac begins. A high or rising antistreptolysin-O sntibody titer is an accurate means of diagnosing presence of strep infxn. Elevated WBC, erythrocyte sed rate, & CRP indicate inflammation. All 3 are usu. increased at time cardiac or joint Sx's begin to appear. They are > useful in identifying acute inflammatory process & suggesting prognosis thatn in Dx'ing acute RF. TREATMENT Therapy for acute RF is aimed at eradicating strep infxn using 10-day regimen of abx. NSAIDS are used as anti-inflam agents for rheumatic carditis & arthritis and help relieve Sx's, but don't prevent complications. Serious carditis may require cardiac glycosides, diuretics, & bed rest as well. Surgical repair of damaged valves may be neces. for chronic, recurrent RF or carditis. Continuous prophylactic abx for as long as 5 yrs is necessary to prevent recurrence of acute RF. COMPLICATIONS Possible recurrence, Rheumatic heart Disease from scarring and deformity of cardiac structures.

21b. CLINICAL MANIFESTATIONS and DIAGNOSTICS of HTN (1138-1139)

CLINICAL MANIFESTATIONS- The early stages of hypertension have no clinical manifestations other than elevated blood pressure. Most important, the lack of signs and symptoms means the individual is unlikely to seek health care; thus hypertension is called a lanthanic (silent) disease. The likelihood of developing primary hypertension increases with age, over and above the natural rise in blood pressure associated with aging. Although hypertension usually is thought to be an adult health problem, it is important to remember that hypertension does occur in children and is being diagnosed with increasing frequency. If elevated blood pressure is not detected and treated, it becomes established and may begin to accelerate its effect on tissues when the individual is 30 to 50 years of age. This sets the stage for the complications of hypertension that begin to appear during the fourth, fifth, and sixth decades of life. The clinical manifestations of chronic hypertension tend to be specific for the organs or tissues affected. Evidence of heart disease, renal insufficiency, central nervous system dysfunction, impaired vision, impaired mobility, vascular occlusion, or edema can be caused by sustained hypertension DIAGNOSTICS-A single elevated blood pressure reading does not mean that a person has hypertension. Diagnosis requires the measurement of blood pressure on at least two separate occasions averaging two readings at least 2 minutes apart, with the individual seated, the arm supported at heart level, after 5 minutes rest, with no smoking or caffeine intake in the past 30 minutes. Some individuals benefit from 24-hour ambulatory blood pressure monitoring because of better correlation with end-organ damage and the ability to screen out "white coat hypertension" (elevated blood pressure that occurs only in a clinic setting) and "masked hypertension" (normal blood pressure in the clinic setting but elevated elsewhere). Ambulatory measurement also detects those who fail to have a nocturnal decrease in blood pressure and who may be at higher cardiovascular risk. It is especially recommended for individuals with drug resistance, hypotensive symptoms with medications, episodic hypertension, and autonomic dysfunction. Evaluation of the hypertensive individual should include a complete medical history and assessment of lifestyle and other risk factors for hypertension and cardiovascular disease, as well as evidence of possible secondary causes of hypertension. Physical examination should include examination of the optic fundi; calculation of body mass index; auscultation for carotid, abdominal, and femoral bruits; examination of the heart and lungs; palpation of the abdomen; assessment of lower extremity pulses and edema; and neurologic examination. Further routine diagnostic tests for the evaluation of hypertension include hematocrit, urinalysis, biochemical blood profile (fasting glucose, sodium, potassium, calcium, creatinine, total cholesterol, high- density cholesterol, triglycerides), and an electrocardiogram (ECG). Optional tests include urinary albumin excretion or albumin/creatinine ratio. Individuals who have elevated blood pressure are assumed to have primary hypertension unless their history, physical examination, or initial diagnostic screening indicates secondary hypertension.

34e. Microcytic-Hypochromic Anemias: Sideroblastic Anemia (SA) Chapter 28 page 991-993

Characterized by abnormally small erythrocytes that contain abnormally small amounts of hemoglobin. Hypochromia even occurs in cells of normal size. Also, this type of anemia can result from disorders of iron metabolism, disorders of porphyrin and heme synthesis, disorder of globin synthesis. Ch. 28 989-993 Sideroblastic Anemia (SA) Chapter 28 page 991-993 PATHO SA results from altered heme synthesis in the erythroid cells in bone marrow. SAs are either acquired or hereditary. Acquired SA (ASA) is most common and occurs as a primary disorder with no known cause (idiopathic) or is associated with other myeloproliferative or myeloplastic disorders.Myelodysplastic syndrome (MDS) is the leading cause of primary ASA It is a group of disorders of hematopoietic stem cells, with all three stem lines demonstrating dysplastic characteristics. Two different subsets of myelodysplastic ringed sideroblast were identified based on cell lines that were affected. Pts with pure SA require transfussions that can produce iron overload. Can convert to leukemia. Second subset of MDS is characterized by abnormalities of multiple cell lineages along with neutrophil and platelet alterations. Of those who survive, 40% develop acute myeloblastic leukemia. Reversible SA is associated with alcoholism (impairs heme synthesis by reducing activity of specific enzymes) and results from folate or nutritional deficiency. Also copper deficiency and specific drugs can cause reversible SA. Hereditary SA rare and occurs almost exclusively in males suggesting recessive x-linked transmission. Has been linked to missense mutations in the erythroid-specific ALAS-E gene Xp11.21. ETIOLOGY Heterogeneous group of disorder characterized by anemia of varying severity caused by a defect in mitochondrial heme synthesis. SA characterized by presence of ringed sideroblast (erythroblast that contain iron-laden mitochondria arranged in a perinuclear collar around 1/3 or more of nucleus) within bone marrow. Pts with SA have increased levels of iron in their tissue. Blood contains hypochromic erythrocytes, either microcytic or macrocytic depending on form of disease. CLINICAL MANIFESTATIONS Hemoglobin levels varying from 4 to 10 g/dl. In addition to cardiovascular/respiratory CM of all anemias, these pts show signs of iron overload (hemochromatosis), mild to moderate spleen enlargement (splenomegaly), and liver enlargement (hepatomegaly). Liver function remains normal or only slightly impaired. Occasional skin pigmentation (bronze-tinted) is seen. No neuro or epithelial alterations. DIAGNOSTICS Bone marrow examination: Diagnostic Dimorphism: Normocytic and normochromic cells concomitantly observed with microcytic- hypochromic cells TREATMENT Identify causative agents (drugs or toxins) Transfusion Iron-depletion therapy Phlebotomy Prolonged administration of erythropoietin Hereditary: Pyridoxine therapy; life-long maintenance therapy at a lowered dose Congenital: Stem cell transplantation Myelodysplastic syndrome: Recombinant human erythropoietin COMPLICATIONS Hemosiderosis of cardiac tissue resulting in heart rhythm disturbances or CHF related to iron overload.

2b. Leukemia- Etiology, Clinical Manifestations, Treatment (pg 1013-1023)

ETIOLOGY *Risk factors include lg. doses of ionizing radiation, cigarette smoke, and benzene. Risk factors for childhood ALL includes prenatal exposure to x-rays and postnatal exposure to high dose radiation. HTLV-1, Epstein-Barr, and Down Syndrome also linked. AML- radiation, benzene, and chemotherapy. *AML is the most frequently reported secondary cancer after high doses of chemotherapy Acute Leukemia *Mortality= 7 per 100,000, 1/3 in children <15 yrs. Old from cancer. Chronic Leukemia *Have longer life expectancy *Accounts for majority of cases in adults (ages 60-80) CLINICAL MANIFESTATIONS Acute Leukemia (Pg. 1020, Table 29-4) has complete list of manifestations and patho for each. .Signs and symptoms r/t bone marrow suppression include fatigue caused by anemia, bleeding from thrombocytopenia (i.e. petechiae, ecchymosis, discoloration of skin, gum bleeding, hematuria, and heavy menstrual cycle), and fever caused by infection. Common organisms that cause infection include E. coli, Psuedomonas aeruginosa, and Klebsiella pneumonia. Anorexia, diminished sensitivity to sweet and sour, muscle atrophy, difficulty swallowing, splenomegaly and hepatomegaly (usually go together), pain in bones and joints (results from infiltration and stretching of periosteum). CNS symptoms include headache, vomiting, papilledema, facial palsy, blurred vision, auditory disturbances, and meningeal irritation. Without prophylaxis 1/3 will develop CNS involvement Chronic Leukemia CLL-Most common initial symptom is lymphadenopathy. Most significant effect is suppression of humoral immunity and increased infection with encapsulated bacteria. Neutrophils suppressed. Individuals with diffuse lg. B cell lymphoma present w/ extreme fatigue, weight loss, night sweats, low-grade fever, elevated levels of lactic dehydrogenase, hypercalcemia, anemia, and thrombocytopenia. CML includes 3 phases: chronic (lasts 2-5yrs.), accelerated phase (lasts 6-18mths; symptoms develop), and terminal blast phase "blast crisis" (survivial only 3-6 mths.). Splenomegaly most common in accelerated phase. Hyperuricemia also common and produces gouty arthritis. In blast phase, blast cells or promyelocytes predominate and blast crisis occurs. Splenomegaly more prominent and painful than acute leukemia. DIAGNOSTICS Acute Leukemia Made by examining blood cells and bone marrow using a stained peripheral smear. Smear will exhibit low blood cells & platelet count along with leukemic blast cells. Bone marrow exhibits hypercellularity w/ 60-100% blast cells. Chronic Leukemia lab analysis of peripheral blood and bone marrow samples. Based on detection of a monoclonal B-cell lymphocytosis in the blood. TREATMENT Acute Leukemia Chemotherapy and supportive measures (blood transfusions, abx, antifungals, and antivirals). Allopurinol is used for preventing production of uric acid. Stem cell transplantation considered standard therapy for selected individuals. Bone marrow transplant has been increasing. All- trans-Retinoic acid is made from Vit. A and helps cells grow and develop into functioning cells. Chronic Leukemia Based on prognostic indiators. Usually on observed until progression bc it is slow and usually occurs in older individuals. CLL- Chlorambucil, w/ or without corticosteroids, is most common tx. For those with the most aggressive disease. Combination therapy (CHOP)includes cyclophosphamide, hydroxydaunomycin (Adriamycin), vincristine (Oncovin), and prednisone. CML- tx does not cure, prevent blastic transformation, or prolong survival. Standard tx. Consists of combined chemo, biologic response modifiers, and allogenic stem cell transplant. Transplantation is potentially curative, but limited by donor availability and high toxicity in older adults.

30. Know erythropoiesis and the iron cycle. What are the nutritional requirements? (Pg 959-963)

Erythropoiesis - in bone marrow, erythroid progenitor cells proliferate and differentiate into large, nucleated proerythroblasts which are committed into producing cells of the erythroid series and contained in a compartment known as the erythron. The proerhtyhroblasts, which has ribosomes and can produce protein differentiates through several intermediate forms of erythroblast while synthesizing hemoglobin and progressively eliminating most intracellular structures, including the nucleus. Thus the maturing erythroblast becomes more compact and progressively assumes shape and characteristics of an erythrocyte. Hemoglobin is readily apparent and increases in quantity as nuclear size shrinks throughout the basophilic and polychromatophilic stages. The orthochromatic erythroblast (normoblast) is the smallest of the nucleated erythrocyte precursors. The last immature form of erythroblast is the reticulocyte, which is anucleate and contains a meshlike (reticular) network of rRNA. The reticulocyte contains polyribosomes (for globin synthesis) and mitochondria (for oxidative metabolism and heme synthesis). The reticulocyte matures into an erythrocyte with 24-48 hours. Mitochondria and ribosomes disappear and become disklike and erythrocyte loses it capacity for hemoglobin synthesis and oxidative metabolism. They remain in the bone marrow for one more day and then are released into the venous sinuses where they continue to mature in the bloodstream and travel to spleen for several days of additional maturation. Approx. 1% of body's circulatory erythrocyte mass is normally generated every 24 hours. The body responds to reduced oxygenation of blood in two ways: (1) stimulation of chemoreceptors of the carotid body and aortic arch that signal the brain to increase respiration and (2) stimulation of receptors on the kidney peritubular cells to increase erythropoietin synthesis and release. Nutritional Requirements- (Pg 962) See table for more info; Protein, Cobalamin(vit B12), Folate(folic acid), Pyrioxine(Vit B6), Riboflavin(Vit B2), Ascorbic acid(Vit C), Pantothenic acid, Niacin, Vitamin E, Iron, Copper. Iron Cycle- (Pg 963) 1. The transferrin iron complex binds to a transferrin receptor on the erythroblast's plasma membrane 2. The complex moves into the cell by receptor-mediated endocytosis 3. Iron is released (dissociated) from transferrin 4. The dissociation transferrin is returned to the bloodstream for reuse

34c. Macrocytic-Normochromic Anemias: Folate Deficiency Anemia Ch. 28 pg 989

Folate Deficiency Anemia Ch. 28 pg 989 PATHO Impaired DNA synthesis secondary to a folate deficiency results in megaoblastic cells w/ clumped nuclear chromatin. Anemia may result from apoptosis of erythroblast in the late stages of erythropoiesis. Folate deficiency in pregnant women is associated with neural tube defects of the fetus. Folate necessary for reduction of circulating levels of homocysteine (atherosclerosis risk factor). Folate deficiency can result in colorectal cancer. ETIOLOGY 10% of North Americans have folate deficiency but it is now on the decline due to increased use of folate supplements. Folate deficiency more common than vitamin B12 deficiency, particularly alcoholics and individuals with chronic malnourishment. Alcohol interferes with folate metabolism in the liver, causing a profound depletion in folate stores. Fad diets and diets low in vegetables can cause folate deficiency bc of absence of plant folate sources. CLINICAL MANIFESTATIONS Cachectic, malnourished appearance, severe cheilosis (scales and fissures of lips and corners of mouth), stomatitis (inflammation of mouth), painful ulcers of buccal mucosa and tongue, burning mouth syndrome, GI s/s, dysphagia, flatulence, and watery diarrhea. Also, histologic and roentgenographic changes of the GI tract (chronic malabsorption syndrome. DIAGNOSTICS Measurement of serum folate levels and symptoms TREATMENT Daily oral administration of folate preparations until adequate blood levels are obtained and clinical symptoms are reduced or eliminated. One milligram per day is sufficient, unless an alcoholic and they can require 5mgs. Prophylactic doses may be administered during pregnancy. After folate deficiency corrected, long-term treatment is not needed if appropriate dietary adjustments have been made.400 mcg/day is recommended to prevent heart disease. COMPLICATIONS

28. Know function of all granulocytes and agranulocytes. (PG. 948 - 949)

Granulocytes have many membrane bound granules in their cytoplasm. These granules contain enzymes capable of killing microorganisms and catabolizing debris ingested phagocytosis include neutrophils, basophils, and eosinophils Neutrophils- They are formed from stem cells in the bone marrow. They are short-lived and highly motile. Constitute about 55% of the total leukocyte count in adults. Neutrophils may be subdivided into segmented neutrophils (or segs) and banded neutrophils (or bands). They form part of the polymorphonuclear cell family (PMNs) together with basophils and eosinophils. Basophils-are the least common of the granulocytes, contain cytoplasmic granules that have an abundant mixture of biochemical mediators, including histamine, chemotactic factors, proteolytic enzymes, and an anticoagulant. Stimulation of basophils induces synthesis of vasoactive lipid molecules and cytokines Eosinophils-are large coarse granules and constitue noly 1%-4% of the normal leukocyte count in adults. Phagocytosis response to parasites, control of allergic reactions. Agranulocytes- monocytes, macrophages, and lymphocytes Monocytes are a type of white blood cells (leukocytes). They are the largest of all leukocytes. They are part of the innate immune system. They are amoeboid in shape, having clear cytoplasm. Monocytes have bean-shaped nuclei that are unilobar, which makes them one of the types of mononuclear leukocytes (agranulocytes). Monocytes constitute 2% to 10% of all leukocytes in the human body. They play multiple roles in immune function. Such roles include: (1) replenishing resident macrophages under normal states, and (2) in response to inflammation signals, monocytes can move quickly (approx. 8-12 hours) to sites of infection in the tissues and divide/differentiate into macrophages and dendritic cells to elicit an immune response. Half of them are stored in the spleen (except in people who have undergone splenectomy). Monocytes are usually identified in stained smears by their large kidney shaped or notched nucleus. These change into macrophages after entering into the tissue spaces. Macrophages are a type of white blood cell that engulf and digest cellular debris, foreign substances, microbes, and cancer cells in a process called phagocytosis. They play a critical role in non-specific defense (innate immunity), and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes. Lymphocytes constitute approximately 36% of the total leukocyte count and are the promary cells of the immune response.

25a. Know heart defects in children. What kind of murmur will you hear and where? How do children compensate for heart defects? (PG. 1200 - 1218)

Heart failure: otherwise known as congestive heart failure (CHF), occurs when the heart cannot sufficiently pump enough blood to the body to meet the metabolic demands. Causes include cardiomyopathy or poor ventricular functioning. Table 33-5 (page 1201) gives a list of congenital defects which cause heart failure. Myocardial hypertrophy results from compensatory measures, as the body attempts to maintain cardiac output. Symptoms in infants include failure to thrive. Other symptoms are those which accompany difficulty breathing, as well as poor skin color. Peripheral edema and weight gain are not usually found in infants, like adult CHF patients. Box 33-2 (page 1202) gives a complete list of symptoms. A complete evaluation includes and ECG, growth plotting, and chest x-ray. Treatment is designed to lessen cardiac workload and improve heat functioning. Management included diuretics, at first. Other measures may include ACE inhibitors and beta blockers. It is also important to supplement caloric intake, if necessary. Pages 1200-1202. DEFECTS INCREASING PULMONARY BLOOD FLOW: Patent Ductus Arteriosus (PDA): Occurs in 5-10% of all congenital cardiac defects. Due to incomplete closure, blood is able to shunt left to right, from aorta to the PA. This causes increased pulmonary blood flow, resulting in increased pulmonary venous return to the left atrium and left ventricle. This makes more work for the left side of the heart. The clinical manifestation will include a continuous-machinery type murmur that will be best detected at the left upper sternal border during systole and diastole. Significant PDA will also present with bounding pulses, active precordium, thrill upon palpation, and other signs of pulmonary congestion. Pages 1202-1204. Atrial Septal Defect (ASD): Occurs in 5-10% of all congenital cardiac defects. This is due to an abnormal opening between the atria. Blood is shunted left to right, causing right atria and ventricle enlargement. Children with ASD are usually asymptomatic. Clinical manifestations include auscultation of a crescendo-decrescendo systolic ejection murmur noted between the second and third intercostal spaces along the left sternal border. A wide fixed splitting of the second heart sound is also common in ASD. Pages 1204-1205. Ventricular Septal Defect (VSD): Most common type of congenital heart lesion, accounting for 25-33% of all congenital heart defects. This is a condition that reflects an abnormal opening between the ventricles. Newborns with small VSDs are asymptomatic. Larger VSDs have CHF symptoms and poor weight gain. Auscultation of the left lower sternal border reveal a loud, harsh, holosystolic (relating to entire systole) murmur and systolic thrill. An apical diastolic rumble may be present also. Pages 1205-1206. Atrioventricular Canal Defect (AVC): This defect includes abnormalities in both the atrial and ventricular septa and the AV valves. The three types are: 1. Complete AVC (CAVC) defects: consist of an inlet VSD, a primum type of ASD, and defects in both mitral and tricuspid valves 2. Partial AVC (PAVC) defects consist of a primum type of ASD and a cleft in the septal or anterior leaflet of the mitral valve. 3. Transitional AVC (TAVC) defects involve partial fusion of the endocardial cushions. Shunting is minimal at first, but eventually leads to CHF. Children with PAVC are usually asymptomatic. Heart auscultation is similar to those with secundum ASD, with the addition of a holosystolic, regurgitant murmur of mitral regurgitation at the apex. Children at 4-12 weeks of age, with CAVC, start to show signs of CHF. Auscultation is similar to those with VSD with the addition of a holosystolic murmur radiating to the back and apex. Pages 1206-1207.

27. Know the process of hemoglobin synthesis. What is methemoglobin? (Pg. 961)

Heme is a large, flat, iron-protoporphyrin disk that is synthesized in the mitochondria and carry one molecule to oxygen (02). Thus an individual hemoglobin molecule with its four hemes can carry four oxygen molecules. If all four oxygen binding sites are occupied by oxygen, the molecule is said to be saturate. Through a series of complex biochemical reactions, protoporphyrin, a complex four-ringed molecule, is produced and bound with ferrous iron, It is crucial that the iron be correctly charged; reduced ferrous iron (Fe²+) can bind oxygen in the lungs and release it in the tissues, where oxygen concentration is less, whereas ferric iron (Fe³+) cannot. Binding of oxygen to ferrous iron (oxyhemoglobin) temporally oxidizes Fe²+ to Fe³+, but after the release of oxygen the body reduces the iron to Fe²+ (deoxyhemoglobin [reduced hemoglobin]) and reactivates the hemoglobin's capacity to bind oxygen. Without reactivation by methemoglobin reductase, the Fe³+ - containing hemoglobin (methemoglobin) cannot bind oxygen. What is methemoglobin? Page 961 A form of the oxygen-carrying metalloprotein hemoglobin, in which the iron in the heme group is in the Fe3+ (ferric) state, not the Fe2+ (ferrous) of normal hemoglobin. Methemoglobin cannot bind oxygen, unlike oxyhemoglobin. (Although the Page 961 states this it is not in-depth. I had to search elsewhere)

23. Cardiac complications in patients with HIV/AIDS (Ch. 32, p. 1175)

Individuals w/ HIV & AIDS are at risk for numerous cardiac complications. Pericardial effusion & left heart failure are the most common complications of HIV. Other conditions include cardiomyopathy, myocarditis, tuberculosis pericarditis, infective and nonbacterial endocarditis, heart block, pulmonary HTN, & non-antiretroviral drug-related cardiotoxicology. Malignancies, such as lymphoma & Kaposi sarcoma, are often seen in individuals w/ AIDS and can affect the heart. Also, Tx w/ combination antiretroviral therapay (cART) can cause hyperlipidemia & atherosclerotic disease. Infection has been linked to increased risk for CAD. One hypothesis is that systemic infection results in increased inflammation of vessels and therefore contributes to vascular disease. (Pg. 1153)

4a. Know lymphomas: patho, clinical manifestations, diagnostics, treatment and complications. (Pg. 1023 - 1035)

Lymphomas consist of a diverse group of neoplasms that develop from proliferation of malignant lymphocytes in the lymphoid system. Lymphomas are the result of genetic mutations or viral infection. Malignant transformation produces a cell with uncontrolled and excessive growth that accumulates in the lymph nodes and other sites, producing tumor masses. Lymphomas usually start in the lymph nodes or lymphoid tissues of stomach or intestines. Types discussed: Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Burkitt Lymphoma, Lymphoblastic lymphoma, Waldenstrom macroglobulinemia or lymphoplasmacytic lymphoma.

25c. MIXING DEFECTS, COMPENSATION (pg. 1214-1218)

MIXING DEFECTS: Transposition of the Great Arteries: Here the aorta arises from the RV and the PA from the LV. This results in 2 separate, parallel circuits in which unoxygenated blood circulates continuously through the systemic circulation and oxygenated blood circulates continuously through the pulmonary circulation. This condition would not support life outside of the uterus unless a mixing of the two occurred by way of a PDA, ASD, or VSD. This defect is the most common cyanotic congenital heart defect, representing 10% of all congenital heart defects. The first heart sound is normal, and the second sound may be heard as a single sound, even though both aortic and pulmonic valves are working. The loud single S2 may occur because transposition places the aortic valve closer to the chest wall. No murmur is noted with TGA with an intact ventricular septum. Pages 1214-1216. Total Anomalous Pulmonary Venous Connection (TAPVC): Pulmonary veins abnormally connect to the right side of the heart either directly or through one or more systemic veins that drain into the RA- extremely rare. Main clinical manifestation is cyanosis. Auscultation reveals a systolic murmur at the left upper sternal border and a mid-diastolic murmur at the left lower sternal border. A murmur may not occur is obstructed TAPVC. A characteristic quadruple rhythm, consisting of a S1, widely split S2, and S3 or S4, or gallop rhythm also is present. Pages 1216-1217. Truncus Arteriosus: failure of the large embryonic artery, the Truncus arteriosus, to divide into the PA and aorta. This results in one vessel arising from both ventricles. A harsh systolic regurgitant murmur is usually present along the left sternal border as a result of VSD, and a systolic click at the apex and left upper sternal border may be present. An apical rumble with or without a gallop rhythm also may be present. If truncal valve insufficiency exists, an early diastolic, high pitched decrescendo murmur may be present. Pages 1217-1218. COMPENSATION: Any condition that stimulates an increase in the right-sided pressures or causes dilation of the RA can reopen the foramen ovale. Conditions that would induce a patent foramen ovale include pulmonary hypertension, RV failure and tricuspid atresia. Conditions that involve low arterial oxygen saturations, such as cyanotic heart disease, decreased medial muscle layer within the ductus, or increased levels of circulating vasodilating substances in the blood may delay or prevent ductal closure. These types of responses are means for compensating for the effects of a heart defect by providing an alternative way to shunt blood for oxygenation, or to provide a mixing of oxygenated/deoxygenated blood in order to oxygenate tissues. Squatting is a spontaneous compensatory mechanism used by older children with unrepaired TOF to alleviate hypoxic spells. Squatting and its variants increase systemic resistance while decreasing venous return to the heart from the inferior vena cava. (PG. 1209)

34b. Macrocytic-Normochromic Anemias: Pernicious Anemia

Macrocytic-Normochromic Anemias: Chapter 28 987-989 Macrocytic (megaloblastic) anemias are characterized by unusually large stem cells (megaloblast) in the marrow that mature into erythrocytes that are usually large in size (macrocytes), thickness, and volume. The hemoglobin content is normal (normochromic). This anemia is a result of defective erythrocyte DNA synthesis such as B12 deficiency (cobalamin) or folate (folic acids) coenzymes that are required for nuclear maturation and DNA synthesis. The defective erythrocytes die prematurely and cause anemia. Eryptosis (premature death of damaged erythrocytes) is a common mechanism of cellular loss in individuals with anemias secondary to deficiencies of iron, infections, chronic diseases, genetic diseases, and myelodysplastic syndrome. Pernicious Anemia-most common megaloblastic anemia PATHO Caused by a vitamin B12 deficiency (often associated with end stage of type A chronic atrophic gastritis-gastiric atrophy results from destruction of parietal and zymogenic cells) Pernicious means highly injurious or destructive and reflects the fact this condition was once fatal. The principal disorder in PA is absence of Intrinsic Factor (IF), a transporter required for absorption of dietary vitamin B12. IF is secreted by gastric parietal cells and complexes w/ dietary B12 in the small intestine. B12-IF complex binds to cell surface receptors in the ileum and is transported across the intestinal mucosa. Normally an autoimmune process directed against gastric parietal cells. Individuals w/ PA have autoantibodies against gastric H+-K+ ATPase (major protein constituent of parietal cells. ETIOLOGY Affects individuals >30 of North European decent, primarily those of Scandinavian, English, and Irish descent. PA is less common in individuals of Greek or Italian origin. Recently, PA has been reported in blacks and Hispanics. Females are more prone to develop PA with black females having an earlier onset. CLINICAL MANIFESTATIONS Develops slowly over 20-30 years; 60 yrs median age at diagnosis. Early symptoms normally ignored bc they are nonspecific and vague (infections, mood swings, GI, cardiac, and kidney ailments). Hemoglobin decreased and people experience normal anemia s/s (weakness, fatigue, paresthesias feet/fingers, difficulty walking, loss of appetite, abd pain, weight loss, sore tongue) Nero s/s-loss of position and vibration, ataxia, spasticity due to posterior & lateral columns being affected (pose serious threats bc not reversible even with tx). Increased presence in Alzheimer disease. DIAGNOSTICS Dx Pa is based on variety of test which include bone test, bone marrow aspiration, serologic studies, gastric biopsy, and CM. Schilling test no longer done and serologic test have replaced them-Measuring methylmalonic acid and homo-cysteine levels which are elevated early in PA. Also, presence of circulating antibodies against parietal cells and intrinsic factor. TREATMENT Replacement of vitamin B12 is treatment of choice. Initial B12 injections administered weekly until deficiency is corrected, followed by monthly injections for the remainder of individual's life. Effectiveness measured by rising reticulocyte count. 5-6 weeks and blood counts return to normal. COMPLICATIONS Cannot be cured. Untreated PA leads to heart failure. Death is rare.

26. Know function and life span of RBCs and platelets. (PG. 947 - 951)

RBCs or erythrocytes: provide the body tissues with oxygen. It contains the hemoglobin, which carries the gases, and electrolytes, which regulates diffusion through a cell's plasma membrane. It has a life span of about 100-120 days, cannot undergo mitotic division, ages, and is removed from circulation. Pages 947-948. Platelets or thrombocytes: are used for blood coagulation and to control bleeding. A platelet circulates for about 10 days, ages, and is removed by macrophages. Pages 950-951

35. How do deficiencies in folate and B12 cause anemia? (Pg. 987 - 989)

Megaloblastic anemias are a result of defective erythrocyte DNA synthesis, commonly caused by deficiencies of vitamin B12 and folate, coenzymes that are required for nuclear maturation & DNA synthesis. These defective erythrocytes die prematurely, which decreases their numbers in the circulation, causing anemia. (p.987) Deficiencies in folate (p.989) Essential vitamin for RNA & DNA synthesis within maturing erythrocyte Anemia may result from apoptosis of erythroblasts in late stages of erythropoiesis. It is required for synthesis of thymine & purines (adenine & guanine) and conversion of homocysteine to methionine Stored in liver, absorbed in small intestine More common deficiency than B12 deficiency Deficiencies in B12 (p. 987) Also known as Pernicious Anemia, Most common type of megaloblastic anemia Associated with end stage of type A chronic atrophic gastritis Most common in: age > 30 & Northern European Patho: absence of Intrinsic Factor (IF) à required for B12 absorption à B12 is essential for nuclear maturation & DNA synthesis in erythrocytes

8. Genetic abnormalities leading to thrombus formation. . (Pg.1049, Box 29-10)

Most are autosomal dominant, thus individuals who are homozygous for the mutation are at greatest risk for thrombosis. These include mutations in coagulation proteins, fibrinolytic proteins, platelet receptors, and other factors. The particular mutations that have been most strongly linked as risk factors for venous thrombosis or for arterial thrombosis leading to coronary artery disease or stroke include those that affect fibrinogen, prothrombin, factor V, PAI-1 of fibrinolytic system, the platelet receptor GPIIIa, and methylenetetrahydrofolate reductase (MTHFR) as well as mutations that result in excessive levels of homocysteine. Other inherited thrombophilias include deficiencies in protein C, protein S, and AT III.

41. Know consequences of low albumin. (PG. 946)

Most essential role is regulation of the passage of water and solutes through the capillaries. In the case of decreased production (cirrhosis, liver disease, and malnutrition) or excessive loss of albumin (certain kidney diseases, extensive burns), the reduced oncotic pressure leads to excessive movement of fluid and solutes into the tissue and decreased blood volume.

34g. Normocytic-Normochromic Anemias (NNAs): Posthemorrhagic Anemia (acute blood loss) Chapter 28 page 996

PATHO Normocytic-normochromic anemia caused by acute blood loss. CLINICAL MANIFESTATIONS Initial CM depend on amount of blood loss. If blood loss severe then CM are related to loss of blood volume rather than loss of hemoglobin. Normal, healthy young adult can tolerate 500-1000 ml blood loss (10-20% volume) without s/s. Additional losses up to 1500ml do produce s/s in recumbent position and only appear when pt is in an upright position. Blood loss > 1500 ml produces s/s in recumbent position. Volume loss results in decreased venous return (increased sympathetic nerve activation, reduced BP/CO/CVP). >2000 ml blood loss equal severe shock, lactic acidosis, and death. DIAGNOSTICS Low hematocrit from hemodilution and rapid elevation in neutrophils and platelets. TREATMENT Intravenous administration of saline, dextran, albumin, or plasma Large volume losses: Fresh whole blood. Successful therapy happens when RBCs return to normal shape and size. Increase in RBCs equal and increase in reticulocytes. RBC return to normal in 4-6 weeks, but hg may take 6-8 weeks.

21c. TREATMENT of HTN (1139-1140)

TREATMENT- Treatment of primary hypertension depends on its severity. Treatment begins with reducing or eliminating risk factors. Lifestyle modification can prevent hypertension from developing in those individuals who fall into the prehypertension category, may control the blood pressure in stage I hypertension, and can enhance the effects of drug treatment for those with more significant blood pressure elevation. The usual dietary recommendations are to restrict sodium intake to 2.4 g/day, to increase potassium intake, to restrict saturated fat intake, and to adjust calorie intake as required to maintain optimum weight. The Dietary Approaches to Stop Hypertension (DASH) diet is recommended. Although it has been widely recommended since 1998, the DASH diet continues to be studied with beneficial effects extending to reduce coronary risks, increased insulin sensitivity, and improved lipid profiles; especially in those with diabetes. An exercise program that promotes endurance and relaxation usually is recommended. Physical training increases stroke volume, which has the effect of lowering heart rate and hence systolic blood pressure, and should consist of regular aerobic physical activity. Relaxation is expected to reduce levels of circulating catecholamines, which has the effect of reducing vascular tone and blood pressure. Individuals are counseled to stop smoking to eliminate vasoconstrictor effects of nicotine. Pharmacologic treatment of hypertension reduces the risk of end-organ damage and prevents major diseases, such as myocardial ischemia and stroke. Thiazide diuretics and beta-blockers have been shown to be safe and effective medications for lowering blood pressure and preventing the cardiovascular complications of hypertension for many individuals. However, these medications are associated with lipid disorders and glucose intolerance. Many individuals will have "compelling indications" for choosing a particular antihypertensive as a first-line medication. For example, individuals with heart failure or those who have chronic kidney disease, are post myocardial infarction, or have had recurrent stroke should begin antihypertensive treatment with an ACE inhibitor, ARB, or aldosterone antagonist. It is widely anticipated that the new report from the National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC8) will have a greater emphasis on managing the RAAS in hypertension as a first- line intervention; however, diuretics and beta-blockers will continue to be effective choices for many individuals. If a person requires two drugs for blood pressure control, the recommendation is combinations of thiazide diuretics and other antihypertensive, such as beta-blockers and ACE inhibitors. As described on page 1133, "What's New", a new development is the use of renal denervation, which is being investigated for the treatment of selected individuals with severe or refractory hypertension. COMPLICATIONS See Table 32-4 on page 1138

34f. Normocytic-Normochromic Anemias (NNAs): Aplastic Anemia (AA)-Critical conditon Chapter 28 page 993-996

NNAs are characterized by erythrocytes that are relatively normal in size and hemoglobin content but insufficient in number. These are not common etiology, pathologic mechanisms, or morphologic characteristics. Occur less frequent than macrocytic-normochromic and microcytic-hypochromic anemias. NNAs include five distinct groups. Aplastic Anemia (AA)-Critical conditon Chapter 28 page 993-996 PATHO Hypocellular bone marrow that has been replaced with fat. Most aplastic anemias are autoimmune disorders against hematopoietic stem cells; some are due to chemical exposure (benzene, arsenic, chemotherapy drugs). ETIOLOGY Pancytopenia-(Reduction or absence of all three types of blood cells) This incidence of AA is relatively rare. Higher in developing countries and possibly related to exposure to certain chemicals known to cause AA. Bimodal peaks. 1st peaks at age 15-25 years of age and 2nd peak in ptss >60. Equally distributed between genders. Another condition with AA is Pure RBC aplasia (Only RBCs are affected-Very rare and can occur as complication with allogeneic bone marrow transplantation related to donor-recipient ABO mismatch. Small % of AA linked to Fanconi anemia (Rare genetic anemia from defects in DNA repair) CLINICAL MANIFESTATIONS Onset of CM insidious and related to rapidity w/ which bone marrow is destroyed and replaced: Hypoxemia, pallor (occasionally with a brownish pigmentation of the skin), Weakness along with fever and dyspnea with rapidly developing signs of hemorrhaging if platelets are affected (unexplained bruising, nosebleeds, gum bleeds, GI bleed, prolonged bleeding at minor injury sites) Late CM: ulcerations of mouth and pharynx, cellulitis in neck, paresthesis DIAGNOSTICS Blood test and Bone marrow biopsy (contains yellow/white material mostly fat, fibrous tissue, and lymphocytes). Suspected with low levels of circulating erythrocytes, leukocytes, and platelets; granulocyte less than 500; platelets less than 20,000, &low absolute reticulocyte count TREATMENT Bone marrow transplantation Peripheral blood stem cell transplantation (May receive radiation or chemotherapy before procedure) Immunosuppression-(Antithymocyte globulin with cyclosporine; Corticosteroidal medications) Identification of high-risk individuals If not treated or identified, death occurs COMPLICATIONS At risk for treatment failure or late clonal/malignant conditions, or both.

2a. Know the leukemias: patho, clinical manifestations, diagnostics, treatment & complications (pg 1013-1023)

PATHO *Common feature of all forms is an uncontrolled proliferation of malignant leukocytes, causing an overcrowding of bone marrow and decreased production and function of normal hematopoietic cells *Primary disruption of the bone marrow *Genetic translociations (mitotic errors) are observed in leukemic cells. Most common is the reciprocal translocation b/w chromosomes 9 and 22, the Philadelphia chromosome. Results in the novel fusion of the BCR1 gene region from chromosome 22 and the proto-oncogene ABL1 from chromosome 9. *Considered clonal disorders in that a single progenitor cell undergoes malignant transformation. *Leukemia cells divide more slowly and take longer to synthesize DNA causing accumulation and overcrowding of the marrow. Then they are ejected to the blood where they accumulate and infiltrate other organs Acute Leukemia- *Characterized by undifferentiated or immature cells, usually a blast cell, and the onset of disease is abrupt and rapid with a short survival time. 2 types: Acute lymphocytic leukemia (ALL) and Acute myelogenous leukemia (AML). ALL= greater than 30% lymphoblasts. Most cases occur in children. Immunotyping of leukemic blast cells allows for the identification of subtypes of ALL. Cases of ALL in children originate from B cells, whereas adult's is a mixture of B-cell or T-cell. Null cell originate from neither B nor T cells. Phenotype of B-cell ALL express CD19 and human leukocyte antigen DR (HLA-DR). The most immature form (pro-B-cell ALL) is characterized by lack of expression of CD10 (a cell surface metalloprotease). Cytoplasmic CD3 is the most common T-cell lineage marker. Hyperdiploid have better prognosis than those with less than 46 chromosomes. Genetic translocations b/w MYC locus on chromosome 8 and one of the loci for the immunoglobulin heavy-or light chain genes. Philadelphia chromosome + ALL carries worst prognosis of all types of ALL. Infants and adults w/ translocation of the MLL gene on chromosome 11 develop very aggressive form of leukemia w/ poor prognosis. ALL develops at different rates at different geographical locations. AML is most common adult leukemia. Poor survival rates. Results from an abnormal proliferation of myeloid precursor cells, decreased rate of aptosis, and an arrest in cellular differentiation. Characterized by blast cells and leukocytosis. Most common genetic abnormality are balanced translocations or inversions that disrupt genes critical to hematopoiesis of myeloid cells (most common b/w chromosome 8 and 21) Chronic Leukemia- *2 types- chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) *Chronic cells are well differentiated and can be readily identified *CML is a group of disease called myeloproliferative disorders, which include polycythemia vera, primary thrombocytosis, and idiopathic myelofibrosis CLL involves transformation and accumulation of monochonal B lymphocytes, rarely of T-cell origin. Characteristic immunophenotype is expression of CD5, CD19, & CD23 molecules, and low Ig and CD20 molecules. CLL derived from a transformation of partially mature B cell that has not encountered antigen. CLL cells don't interfere w/ normal blood cell production like acute leukemias. Major deficit in CLL is the failure of B cells to mature into plasma cells that synthesize immunoglobulins, which results in hypogammagobulins. CML is clonal and thought to arise from a hematopoietic stem cell. Cells are heterogeneous. During the chronic phase the predominant cell is hematopoietic stem cell. Philadelphia chromosome is present in 95% of cases, and BCR-ABL1 protein is responsible for initiation.

3. Know multiple myeloma: patho, clinical manifestations, diagnostics, treatment, complications, electrolyte imbalances (Pg. 1030)

PATHO A clonal plasma cell cancer characterized by slow proliferation of malignant cells as tumor cell masses in the bone marrow that usually results in destruction of the bone. Neoplastic cells of MM reside in the bone marrow and are usually not found in peripheral blood. Many myelomas are aneuploidy. Primary translocation involves the immunoglobulin heavy chain on chromosome 14 that relocates to sites containing genes that cell cycle on chromosome 11, 12, and 6; oncogenes on chromosome 16, 18, and 20; and fibroblast growth factor receptor on chromosome 4. Secondary genetic alterations cause aggressive MM. Molecular pathogens involves proto-oncogene mutations, and more rarely, inactivation of tumor suppressor genes. Malignant plasma cells arise from one clone of B cells that produce abnormally lg amts. Of one class of immunoglobulin (usually IgG). Malignant transformations usually occur early in B- cell development before encountering antigens in the secondary lymphoid organs, then the myeloma cells return to bone marrow or other tissue sites. Return is aided by cell adhesion molecules. Myeloma cells secrete hepatocyte growth factor and parathyroid hormone-related peptide and adhere to stromal cells, inducing production of cytokines. Factor IL-6 (cytokine) stimulates osteoclasts to reabsorb bone, which results in bone lesions and hypercalcemia. Paraprotein-abnormal protein in blood. Bc of the lg #'s of malignant plasma cells, the abnormal antibody, called the M protein, becomes the most prominent protein in the blood. The myeloma may produce free immunoglobulin light chain (Bence Jones protein), which contributed to damage to renal tubular cells. It is abundant in pts. w/ MM. ETIOLOGY *Poor prognosis (median 3 yrs.) CLINICAL MANIFESTATIONS Common presentation of MM is characterized by hypercalcemia, renal failure, anemia, and bone lesions. Hypercalcemia leads to "lytic lesions" (round, punched out regions of bone). Pain is most common presenting symptom. Pain is initially aching, intermittent, and aggravated by weight bearing. Progression leads to more severe, prolonged pain. Proteinuria and renal failure are usually caused by hypercalcemia. Bence Jones protein may lead to damage of the proximal tubules. Hyperviscosity syndrome is caused by high concentration of paraprotein. Suppression of humoral response leads to repeated infections, particularly pneumonia and pyelonephritis (streptococcus pneumonia, Staphylococcus aureus, E. coli, and Klebsiella pneumonia are most common gram neg. organism). Infection is most common cause of death. Monoclonal gammopathy of undetermined significance (MGUS)- dx by presence of M protein. Smoldering myeloma-Asymptomatic MM usually characterized by the presence of M protein and clonal bone marrow plasma cells w/ no end organ damage. Solitary plasmacytoma-characterized by a solitary tumor of malignant plasma cells that may result in lytic lesions or may be in the tissues (commonly the upper respiratory tract) DIAGNOSTICS Radiographic and lab studies, bone marrow biopsy, and quantitative measurements of immunoglobulins. One class of immunoglobulins (the M protein) is greatly increased while the others are suppressed. Serum electrophoretic analysis reveals increased levels of M protein. Bence Jones protein is also observed via immunoelectrophoresis or using ELISA tests. The amount of M protein may be used as a measure to determine extent of disease and response to therapy. Serum levels of free b2-microglobulin is indicator of prognosis or effectiveness of therapy. Individual must have all 3 major criteria for diagnosis: (1) + biopsy results (2) >30% plasma cells in bone marrow sample (3) monoclonal antibody in blood/urine. TREATMENT Chemo, radiation, plasmapheresis (exchange), and marrow transplantation. The drug thalidomide disrupts the stromal marrow. In combination w/dexamethasone, lenalidomide (r/t thalidomide) is now approved for second line tx. High dose chemo followed by blood forming stem cell transplantation is tx. Choice for younger individuals. Survival may be prolonged with a second autologous transplant, called a tandem transplant, within 6-12mths from 1st transplant. COMPLICATIONS Proteinuria, renal failure d/t hypercalcemia, pain, hyperviscosity syndrome, pneumonia and pyelonephritis r/t immunocompromised ELECTROLYTE IMBALANCES HYPERcalcemia

22a. Know Rheumatic Fever: patho, etiology, clinical manifestations, dx, tx and complications. (Pg. 1171 - 1173)

PATHO Acute rheumatic fever (RF) can develop ONLY as a sequel to pharyngeal infection by group A beta-hemolytic streptococci. It affects the heart, joints, CNS, and skin through an abnormal humoral and cell-mediated immune response to M proteins on microorganisms that cross-react w/ normal tissues. Antibodies against a streptococci bacterial wall antigen (GlcNAc) display cross-reactivity against laminin, a protein present in extracellular tissues around heart cells and in valves. Antibodies also cross-react w/i neuronal cells triggering dopamine release. These antibodies also affect skin, muscles, and synovial joints. Auto immunity and associated intense inflammation result in diffuse, proliferative, & exudative lesions in connective tissues, esp. in heart, joints, & skin. Inflammation may subside before Tx, leaving behind damage to heart valves and increasing the individual's susceptibility to recurrent acute RF after any subsequent strep infxns. Repeated attacks of acute RF cause chronic proliferative changes in the above organs as a result of scarring, granulomas, & thromboses. Approx. 10% of cases of RF develop RHD. RHD begins as carditis, or inflam. of the heart. Although RF can cause carditis in all 3 layers of the heart wall, the primary lesion usu. involves the endocardium, which includes heart valves. Endocardial inflam. causes swelling of valve leaflets, w/ secondary erosion along the lines of the leaflet contact. The valves lose their elasticity, and leaflets may adhere to each other. Scarring & shortening of involved structures occur over time. If inflammation penetrates myocardium, localized fibrin deposits develop that are surrounded by areas of necrosis and are called Aschoff bodies. ETIOLOGY Rheumatic fever (RF) is a systemic, inflammatory disease caused by delayed immune response to infection by group A beta-hemolytic streptococci. In acute form, RF is a febrile illness characterized by inflame. Of joints, skin, nervous system, & heart. If untreated, RF can cause scarring & deformity of cardiac structures, resulting in rheumatic heart disease (RHD). RF continues to be a major cause of death & disability for underprivileged populations due to crowding & poor hygiene. Acute RF occurs most often in children betw. 5-15 yoa. Abx given w/i first 9 days of infxn usu. prevents RF. Initiation of abx 2 wks after start of strep infxn does not prevent RF in susceptible individuals. RF tends to run in families and those who've experienced 1 attack of acute RF are more susceptible than general population to recurrent attacks.

14. Know the thallasemias: patho, inherited pattern, clinical manifestations, diagnostics, treatment and complications (PG. 1069 - 1070)

PATHO Alpha and beta thallasemias are inherited autosomal recessive disorders that cause an impaired rate of synthesis of a or B of Hb-A. Thalassemia (greek for sea) (Common in Greeks, Italians, some Arabs and Sephardic Jews). Both types common in blacks. Anemia associated with this illness is microcytic-hypochromic hemolytic anemia. ETIOLOGY Normally 2 genes control B-chain synthesis and 4 genes control a synthesis. The number of genetic defects determines severity of disease. Just like with SCD, hemoglobin usually consists of substituting an amino acid for another amino acid. Beta thalassemia is uncoupling of a and B-chain synthesis. B chain production is depressed moderately in heterozygous form, beta-thalassemia minor, severely in homozygous form, beta- thalassemia major a.k.a. cooley anemia. Some precipitate carrying cells mature and enter bloodstream results in anemia. 4 forms of alpha: 1. Alpha trait: carrier state, single gene defective 2. Alpha-thalassemia minor, 2 genes defective 3. Hemoglobin H disease- 3 genes defective 4. Alpha-thalassemia major - fatal condition where all 4 genes are defective. Death inevitable, b/c oxygen cant get to tissues. Beta-thalasemia is more common than alpha. CLINICAL MANIFESTATIONS Beta- thalassemia minor causes mild to moderate microcytic hypochromic hemolytic anemia, mild splenomegaly, bronze skin. Patient is usually asymptomatic. Beta Major: severe anemia with cardiovascular burden, CHF. *Mildest form-alpha-thalassemia , alpha trait, symptom free and at most have mild microcytosis. Alpha-thalassemia major are similar to symptoms of beta- thalassemia major, but milder; moderate mircro-cytic -hypochromic anemia, enlargement of liver and spleen, and bone marrow hyperplasia. Alpha-thalassemia major causes hydrops fetalis and fulminant intrauterine CHF. Alpha thalassemia major and beta-thalassemia major are life threatening. DIAGNOSTICS Diagnosis based on familial disease history, clinical man., and blood tests. Peripheral smears show microcytosis. Hemoglobin electrophoresis demonstrates diminished amounts of alpha or beta chains. Analysis of DNA from amniotic fluid diagnosis hydrops fetalis. TREATMENT Thalassemia minor requires no specific treatment. Thalassemia major treatment aimed at prolonging life and include; blood transfusions, iron chelation therapy, splenectomy (prolongs erythrocyte survival). Cures include bone marrow, cord blood, and stem cell transplantation.

1. Know Infectious mononucleosis: patho, clinical manifestations, diagnostics, treatment & complications (pg. 1011)

PATHO An acute, self-limiting, neoplastic lymphoproliferative syndrome characterized by acute viral infection of B lymphocytes (B cells). Transmission of EBV usually through saliva via personal contact (kissing). Disease begins with widespread infection of B lymphocytes which possess receptors for EBV. Initially infects the oropharynx, nasopharynx, and salivary epithelial cells, then later spread to lymphoid tissue and B cells (permits the virus to enter bloodstream). There is a massive proliferation of cytotoxic T cells (CD8) directed against EBV infected cells. The immune response against EBV-infected cell cause proliferation of lymphoid tissues ETIOLOGY Most common etiologic agent is EBV (a ubiquitous, lymphotrophic, gamma-group herpesvirus) CLINICAL MANIFESTATIONS Sore throat and fever are earliest manifestations. Classic triad of symptoms include fever, pharyngitis, and lymphadenopathy of cervical lymph nodes. Pharyngitis causes whitish or grayish green, thick exudate and is painful. Fatigue may last 1-2 mths after resolution of infection. Splenomegaly may occur. Splenic rupture is most common cause of death related to IM DIAGNOSTICS Commonly based on Hoagland's criteria (50% lymphocytes and at least 10% atypical lymphocytes) in presence of typical manifestations. Serologic tests are used to determine a heterophile antibody response. TREATMENT Medical intervention rarely required. Supportive measures include use of analgesics and antipyretics. Ampicillin is contraindicated b/c it causes rash. If splenectomy is needed, vaccinations for streptococcus pneumonia, Haemophilus influenza, and Meningococcus are essential. COMPLICATIONS *Duncan disease is a rare disorder characterized by severe dysregulation of the immune system, often in response to EBV. Underlying cause leading to death is the absence of a functional SAP protein that allows for the unregulated proliferation of cytotoxic T cells and the production and release of cytokines.

34a. Know all the anemias: patho, etiology, clinical manifestations, diagnostics, treatment, compensation of the body and complications. (PG. 982 - 987)

PATHO Anemia is a reduction in the total number of erythrocyte in the circulating blood or a decrease in the quality of or quantity of hemoglobin. Anemia result from impaired erythrocyte production, acute or chronic blood loss, increased erythrocyte destruction, or a combination of the three factors. Anemias are classified by their causes or by changes that affect the size, shape or hemoglobin content of the erythrocyte. Terms that end in cystic refer to cell size and chromic refers to hemoglobin content. Additionally, anisocytosis (assuming various sizes) or poikilocytosis (assuming various shapes). CLINICAL MANIFESTATIONS The fundamental physiological manifestation of anemia is reduced oxygen-carrying capacity of the blood resulting in tissue hypoxia. Symptoms vary depending on the body's ability to compensate for the reduced oxygen carrying capacity. Mild anemia may only cause CM during physical exertion. As the reduction of red blood cells continues, the symptoms become more pronounced. A reduction in the number of blood cells in the blood causes a reduction in the consistency and volume of blood. Reduced blood volume compensation causes interstitial fluid to move into intravascular space, expanding plasma. This causes decreased blood viscosity. Because the blood is diluted, it flows faster and more turbulently causing a hyper dynamic state can cause cardiovascular changes. Increased stroke volume and heart rate which can lead cardiac dilation and heart valve insufficiency if not corrected. Hypoxemia-reduced oxygen levels in the blood. (can cause dilation of arterioles, capillaries, and venules, leading to decreased vascular resistance and increased flow) Increased peripheral blood flow and venous return further contribute to an increase in heart rate and stroke volume in order to meet normal oxygen demands and prevent cardiopulmonary congestion-may lead to heart failure. Rate and depth of breathing increase in an attempt to increase available oxygen. Hemoglobin releases extra 02- cause dyspnea, palpitations, dizziness, and fatigue. Pale Skin, mucous membranes, lips, nail beds, and conjunctiva (result of reduced hemoglobin concentration) Hemolysis of RBC can cause yellow skin due to lysis products accumulating. Skin tissue hypoxia results loss of elasticity and impaired healing, thinning/graying of hair, fever (tissue ischemia produces leukocyte pyrogens) Nervous system CM occur B12 deficiency anemia. Myelin degeneration causing loss of nerve fibers and producing paresthesias(numbness), gait disturbances, extreme weakness, spasticity, and reflex abnormalities. GI-Abd pain, N/V, anorexia. Severe/acute onset anemia causes peripheral blood vessel constriction-diverting blood flow to vital organs resulting in renin-angiotensin response (Na and H20 retention)

24. Know infective endocarditis: patho, etiology, clinical manifestations, diagnostics, treatment and complications. (Pg. 1173 - 1175)

PATHO At least 3 elements are required to cause IE: 1. Endocardial damage: Trauma, congenital heart disease, valvular heart disease, & presence of prosthetic valves are the most common risk factors for endocardial damage that leads to IE. Endocardial damage exposes endothelial basement membrane, which contains collagen that attracts platelets & thus stimulates sterile thrombus formation on the membrane, causing an inflammatory reaction (nonbacterial thrombotic endocarditis). 2. Blood-borne microorganism adherence to damaged endocardial surface: Bacteria may enter the bloodstream during IV drug use, trauma, dental procedures involving manipulation of gingiva, cardiac surgery, GU procedures & indwelling catheters in the presence of infxn, or GI instrumentation, or they may spread from uncomplicated URI's or skin infxns. 3. Formation of infective endocardial vegetations: Bacteria infiltrate the sterile thrombi & accelerate fibrin formation by activating the clotting cascade. These vegetative lesions usu. occur on heart valves & surrounding structures. These bacterial colonies are protected from host defenses (antibodies) because they are embedded in protective fibrin clots. Embolization from these vegetations can lead to abscesses & characteristic skin changes (i.e., petechiae, splinter hemorrhages, Osler nodes, & Janeway lesions). ETIOLOGY Infective endocarditis (IE) is a general term used to describe infxns & inflammation of endocardium, esp. heart valves. Approx. 15,000 new cases per yr in U.S. Bacteria are the most common cause of IE, esp. streptococci, staphylococci, and enterococci. Other causes include viruses, fungi, rickettsia, & parasites. Morbidity & mortality diminished significantly w/ advent of abx & improved diagnostic techniques. CLINICAL MANIFESTATIONS IE may be acute, subacute, or chronic. It causes varying degrees of valvular dysfunction & may be associated w/ manifestations involving several organ systems (lungs, eyes, kidneys, bones, joints, CNS). Signs & Sx's of IE are caused by infxn & inflame., systemic spread of microemboli, & immune complex deposition. Classic findings are fever, new/changed cardiac murmur, & petechial lesions of the skin, conjunctiva, & oral mucosa. Characteristic physical findings include Osler nodes (painful red nodules on pads of fingers & toes) & Janeway lesions (painless hemorrhagic lesions on palms & soles). Other manifestations include weight loss, back pain, night sweats, & heart failure. CNS, splenic, renal, pulmonary peripheral arterial, coronary, & ocular emboli may lead to a wide variety of signs & Sx's. DIAGNOSTICS Diagnostic criteria include persistent bacteremia, new heart murmurs, vascular complications, & appropriate EKG & echocardiogram findings. If emboli are suggested, organ scans can be performed to confirm their presence. TREATMENT Antimicrobial therapy is usu. given for 4-6 wks, starting w/ IV abx & ending w/ oral abx. Sometimes 2 abx are given simultaneously to prevent abx resistance. Other drugs may be neces. to treat L heart failure secondary to valvular dysfunction, & surgical intervention to repair or replace the valve may be required. Individuals w/ valvular heart disease are no longer recommended to get prophylactic abx for procedures. Now, only high-risk individuals (Hx of IE, prosthetic valves, cyanotic congenital heart disease, heart transplant w/ valvular defect) receive abx prophylaxis, and only during gingival procedures or in the presence of documented acute GI or GU infection. COMPLICATIONS Death probably

4b. Hodgkin Lymphoma (1023-1027

PATHO Characterized by its progression from one group of lymph nodes to another, the development of systemic symptoms, and presence of Reed-Sternberg cells (RS). Widely accepted that the RS cell represent the malignant transformed lymphocyte; RS cells are often large and binucleate with occasional mononuclear variants. RS cells are hallmark sign of HL and are necessary for diagnosis. However, they are not specific to HL. Classic HL appears to be derived from a B cell in the germinal center that has not undergone successful immunoglobulin gene rearrangement and would normally be induced to undergo apoptosis. RS cells secrete and release cytokines that result in accumulation of inflammatory cells that produces the local and systemic effects. 2 main types: classic Hodgkin and nodular lymphocyte-predominant Hodgkin. There are 4 types of classic Hodgkins based on the morphology of RS cells and the characteristics of the inflammatory cell infiltrate in the tumor. Lymphocyte-predominant disease presents with earlier-stage disease, longer survival, and fewer tx failures than classic HL. ETIOLOGY Malignant lymphoma. CLINICAL MANIFESTATIONS Physical findings - adenopathy, mediastinal mass, splenomegaly, abdominal mass; symptoms - fever, wt loss, night sweats, pruritis; lab findings - thrombocytosis, leukocytosis, eosinophilia, elevated ESR, elevated alkaline phosphatase, paraneoplastic syndromes. These can be explained by complex action of cytokines and other growth factors that are secreted by malignant cells. These substances induce infiltration and proliferation of inflammatory cells, resulting in enlarged, painless lymph node in neck (often 1st sign of HL). Anemia is found in individuals with HL, accompanied by low serum iron level and decreased iron-binding capacity. DIAGNOSTICS Early detection may be difficult. Median age for dx is 64; peaks at 2 different ages: early in life in the 2nd and 3rd decades and later in life during 6th and 7th decades. Careful eval, including CXR, lymphangiography, and biopsy should be carried out for pts with fever of unknown origin and peripheral lymphadenopathy. Lymph node biopsy with scattered RS cells and cellular infiltrate is highly indicative of HL. TREATMENT Approx 75% of pt's dx with HL are cured because of successful combined tx with radiation and chemo. More recent tx include high dose chemo with bone marrow or stem cell transplantation. Poorer survival is related to high WBC and low Hb level, low lymphocycte count, male gender.

15. Know hemophilias/bleeding disorders: patho, inherited pattern, clinical manifestations, dx, tx & complications (pg 1070-1072)

PATHO Congential defeciencies of these three plasma proteins include, clotting factor VIII, IX, and XI account for 90-95% of hemophilia. Hemophillia A (classic hemophilia) Factor VIII defenciey, occurs in 1 in 5000 males. Most common at 80-85 % of hemophilias. Inherited as an X-linked recessive disorder that affects men and is transmitted by women. Hemophilia B (Christmas disease) caused by factor IX defencicy and also is x-linked recessive disorder. The severity of the disease depends on the concentration of clotting factors in blood. Hemophilia C (factor XI deficiency)- autosomal recessive and occurs in men and women equally. Bleeding less severe. Von Willebrand disease- Autosomal dominant trait that can be factor VIII deficient. The most important difference between this one and hemophilia A is the response of infusion of plasma; which in this case infusion of plasma causes more activity of factor VIII. ETIOLOGY Gene deletions and point mutations are the two hereditary defects. Both types are associated with severe types of hemophilia A, where no factor VIII circulates. Point mutation where a single base in DNA is mutated to another base represents second type of hemophilia. CLINICAL MANIFESTATIONS Children with hemophilia bleed at different ages. During the first year of life, spontaneous bleeding minimal. Many children are diagnosed when they are mobile. By 3-4 years, 90% of children with hemophilia have had bleeding episode. DIAGNOSTICS Phase I - complex part of coagulation is elevated by several tests. Activated partial thromboplastin time (aPTT) time required for clotting of plasma that has been activated by kaolin. aPTT assesses the adequacy of factors XII, XI, IX, and VII. Prothrombin consumption is standard prothrombin test of serum instead of plasma. Phase II- Prothrombin time (PT)- time required for plasma to clot after thromboplastin and calcium. Prolonged prothrombin time indicates II, V, VII, or X Phase III- Thrombin time- the addition of bovine thrombin for plasma to clot. TREATMENT Cryoprecipiate (quick frozen precipitate) rich in factor VIII. Recombinant antihemolytic factor plasma/albumin-free method (rAHF-PFM), Advate- prevention and control of hemophilia A.

4c. NON - Hodgkin Lymphoma (1027-1029)

PATHO Progressive clonal expansion of B cells, T cells, NK cells. Most common type of chromosomal alteration in NHL is translocation, which disrupts the genes encoded at the breakpoints. NHL is disease of middle age, found usually in individuals more than 50 yrs old. B cells account for 80- 90% of NHLs, with T cells and NK cells accounting for remaining percentage. NHL tumors are categorized by level of differentiation, cell of origin, and rate of cellular proliferation. Tumors with characteristic nodular pattern, vaguely resembling lymphoid follicular structures, are generally less aggressive than lymphomas with diffuse pattern of proliferation. ETIOLOGY Reclassified into B-cell neoplasms, which include variety of lymphomas including myelomas that originate from B cells at various stages of differentiation, and T-cell and NK-cell neoplasms, which include lymphomas that originate from either T or NK cells. These cancers lack RS cells. CLINICAL MANIFESTATIONS Usually begin as localized or generalized lymphadenopathy; cervical, axillary, inguinal, and femoral chains are common affected sites. Swelling is painless. Some pts have retroperitoneal and abd masses with symptoms of abd fullness, back pain, ascites, and leg swelling. Classified as low, intermediate, or high grade. Low grade (indolent) has slow progression with painless, peripheral adenopathy. Night sweats with elevated temp and wt loss are more common in advanced or end stages of disease. DIAGNOSTICS Biopsy is primary means for dx NHL. CT neck, chest, abd and pelvis, as well as bilateral bone marrow aspirate exams are performed. Common finding in NHL is noncontiguous lymph node involvement. TREATMENT Tx depends on type, tumor stage, histologic status, symptoms, age, and comorbities. Tx with chemo alone may be adequate, although radiation freq included. Rituximab has been proven effective; it depletes most B cells and allows replenishment of normal B cells from lymphoid stem cell pool. Radioimmunotherapy combines radiation therapy with monoclonal antibody therapy and used to improve rates of complete remission both in indolent forms of lymphoma and in aggressive forms.

34h. Normocytic-Normochromic Anemias (NNAs): Anemia of Chronic Disease Chapter 28 page 1001-1002

PATHO Decreased erythrocyte lifespan (result of eryptosis) Suppressed production of erythropoietin Ineffective bone marrow response to erythropoietin Altered iron metabolism (result of iron sequestration) During chronic inflammation a large variety of cytokines are released by lymphocytes, macrophages, and the affected tissue. ETIOLOGY Mild-to-moderate anemia from decreased erythropoiesis (Acquired immunodeficiency syndrome (AIDS), malaria, rheumatoid arthritis, lupus erythematosus, hepatitis, renal failure, and malignancies). Competitive iron binding from increased lactoferrin and apoferritin • During inflammation, neutrophils release lactoferrin to bind iron and to reduce its availability for bacteria • Apoferritin: Higher affinity for iron results, and available iron is affected in a similar manner. RBC defect in ACD is a failure to increase erythropoiesis in response to decreased numbers of erythrocytes Kidney damage, affecting erythropoietin production in kidneys (hormone for production of erythrocytes) CLINICAL MANIFESTATIONS Same as iron-deficiency anemia if hgb levels drop. Most significant finding of ACD is very high total body iron storage, although inadequate iron is released from bone marrow for erythropoiesis. First indication is failure to respond to conventional iron replacement therapy, low to normal TIBC, normal or high serum ferritin levels, and low levels of soluble transferrin receptor. DIAGNOSTICS Very high total body iron storage, Failure to respond to conventional iron replacement therapy *Morphologically, ACD is initially normocytic-normochromic, but as it persist it becomes hypochromic and microcytic. TREATMENT Alleviation of underlying disease COMPLICATIONS

4e. Lymphoblastic Lymphoma (LL) (pg. 1030)

PATHO E Disease arises from clone of relatively immature T cells that becomes malignant in the thymus. LL freq assoc with translocations, primarily of the chromosomes that encode for the T- cell receptor (chromosomes 7 and 14). ETIOLOGY Relatively rare variant of NHL but accounts for almost 1/3 of cases of NHL in children and adolescents, with male predominance. Majority (85%) of LL is of T-cell origin and remainder arises from B cells. Similar to ALL CLINICAL MANIFESTATIONS First sign of LL is usually a painless lymphadenopathy in the neck. Peripheral lymph nodes in the chest become involved in about 70% pts, mostly above the diaphragm. LL is very aggressive tumor that presents as stage IV in most people. T-cell LL is assoc with unique mediastinal mass because of apparent origin of tumor in the thymus. Mass results in chest pain, suppression of bone marrow leads to increased susceptibility to infection. DIAGNOSTICS TREATMENT Most common chemo with multiple drugs. Although LL is easily tx, high relapse rate.

4d. Burkitt Lymphoma (1029-1030)

PATHO EBV assoc with almost all cases. B cell undergoes chromosomal translocation that result in overexpression of C-MYC proto-oncogene and loss of control of cell growth. Most common translocation is between chromosome 8 and 14. ETIOLOGY B cell tumor that accounts for 30% of childhood lymphomas worldwide. Highly aggressive B- cell non-Hodgkin that is fastest growing human tumor. Occurs in east central Africa and New Guinea and rapidly growing tumor primarily in jaw and facial bones. In US, rare and usually involves abdomen. EBV is assoc with Burkitt lymphoma in African children. CLINICAL MANIFESTATIONS Non-African BL, common presentation is abd swelling. More advanced disease may involve eye, ovaries, kidneys, grandular tissue, and present with type B symptoms (night sweats, fever, wt loss). DIAGNOSTICS Distribution of tumors and biopsies of enlarged lymph nodes or bone marrow containing malignant B cells are usually indicate BL. One of most aggressive and quickly growing malignancies. TREATMENT African variety in children have successfully been tx with radiotherapy and cyclophosphamide. American type is more resistant to tx. Adjuvant monoclonal antibody therapy with rituximab appears to be promising agent for improving outcomes with minimal toxic effects.

12. Know G-6-PD: patho, inherited pattern, clinical manifestations, dx, treatment & complications (Pg 1062, 1501)

PATHO G6PD is an enzyme that normally enables erythrocytes to maintain metabolic processes despite injury, such as certain drugs; indigestion of fava beans; hypoxemia; infection; fever; or acidosis. In absence of G6PD, oxidative stressors damage hemoglobin and the plasma membranes of erythrocytes and possible interfere with the activities of other enzymes within the cell. Hemoglobin is oxidized progressively to methemoglobin, sulfmethemoglobin, and denatured globin-glutathione complexes. Eventually, exposure to odixating substancesresutls in the precipitation of insoluble hemoglobin inclusions, called Heinz bodies within the cell. Plasma damage and the presence of Heinz bodies cause hemolysis, primarily in the spleen. The deficiency is usually asymptomatic unless one of those events occurs Erythrocyte damage in affected children begins after intense or prolonged exposure to one of these substances or conditions, and it will cease when they are removed In black males, the G6PD defect becomes more pronounced as the erythrocyte ages and in other populations the defect is profound even in young erythrocytes By ingesting a substance with oxidant properties (aspirin), a pregnant wombn may cause an episode of hemolysis in a fetus with G6PD deficiency. ETIOLOGY an inherited, X-linked recessive disorder, most fully expressed in heterozygous males. Partial expression and a carrier state are possible in heterozygous females Present in 10& of blacks, and tends to occur in Sephardic Jews, Greeks, Iranians, Chinese, FIlipinos, and Indonesions CLINICAL MANIFESTATIONS In Asian and Mediterranean infants, G6PD deficiency is likely associated w/ icterus neonatorum Most common manifestation: acute hemolytic anemia, usually after infections or the ingestion of certain of certain oxidative drugs. Fava bean produces severe hemoltyic reaction in infants with G6PD deficiency S/sx of hemolytic episodes: pallor, icterus, dark urine, back pain Severe s/sx: shock, cardiovascular collapse, and death. **Child does NOT have hemolytic episodes and erythrocytes are normal between episodes** DIAGNOSTICS reduced G6PD activity in erythrocytes is required for diagnosis Laboratory evaluation should be performed shortly after a crisis so that low level of enzyme activity can be demonstrated. Can also be detected by electrophoretic analysis. G6PD low normal range in presence of high reticulocyte count suggests G6PD TREATMENT Prevention of hemolysis is the most important therapeutic measure

16. Know Heparin Induced Thrombocytopenia (HIT): patho, etiology, clinical manifestations, diagnostics, treatment and complications. (P. 1038)

PATHO HIT is an immune-mediated, adverse drug reaction caused by IgG antibodies against the heparin-platelet factor 4 complex leading to platelet activation through platelet FcyIIa receptors (Figure 29-19). The release of additional platelet factor 4 from activated platelets and activation of thrombin lead to increased platelet consumption and a decrease in platelet counts beginning 5 to 10 days after administration of heparin. ETIOLOGY Heparin is a common cause of drug-induced thrombocytopenia. Approximately 4% of individuals treated with unfractionated heparin develop HIT. The incidence is lower (about 0.1%) with the use of low molecular-weight heparin. CLINICAL MANIFESTATIONS The hallmark of HIT is thrombocytopenia. A decrease of approximately 50% in the platelet count is seen in more than 95% of individuals. However, 30% or more of those with thrombocytopenia are also at risk for venous or arterial thrombosis. Venous thrombosis is most common and results in deep venous thrombosis and pulmonary emboli. Arterial thrombosis affect the large arteries of the lower extremities, causing acute limb ischemia. Arterial thrombosis also may lead to cerebrovascular accidents and myocardial infarctions. Other major arteries (renal, mesenteric, upper limb) also may be affected. Bleeding is uncommon in HIT, even with low platelet counts. DIAGNOSTICS Diagnosis is primarily based on clinical observations. The individual presents with dropping platelet counts after 5 days or longer of heparin treatment. On average, platelet counts may reach 60,000/mm^3. Because most individuals develop this condition after surgery, and the onset of symptoms, including thrombosis, may be delayed until after release from the hospital, other possible causes of thrombocytopenia (e.g. infection, other drug reactions) must be considered. Tests are available to measure antibodies against heparin-platelet factor 4. The test sensitivity is extremely high (more than 90%), but the specificity is less because of false- positive reactions (e.g., persons receiving dialysis). HIT antibody titers may be measured, but the titers must be evaluated in the context of the clinical presentation. TREATMENT Treatment is the withdrawal of heparin and use of alternative anticoagulants. A switch to low- molecular-weight heparin is not indicated, and warfarin should not be used until the symptoms of HIT have resolved because of an increased risk of initiating skin necrosis. The thrombocytopenia should progressively resolve. The chance of spontaneous blood clots can be diminished using thrombin inhibitors (e.g., lepirudin, argatroban). COMPLICATIONS If HIT is not recognized and treated, intravascular aggregation of platelets causes rapid development of arterial and venous thrombosis. Although rare, heparin antibodies have caused anaphylactic shock.

21a. Know hypertension: patho, etiology, RAAS system effects, clinical manifestations, diagnostics, treatment and complications/effects on other organs. (PG. 1132 - 1140)

PATHO Hypertension is caused by increases in cardiac output or total peripheral resistance, or both. Cardiac output is increased by any condition that increases heart rate or stroke volume, whereas peripheral resistance is increased by any factor that increases blood viscosity or reduces vessel diameter (vasoconstriction). ETIOLOGY A combination of genetic and environmental factors is thought to be responsible for the development of primary hypertension. Genetic predisposition to hypertension is thought to be polygenic. The inherited defects are associated with renal sodium excretion; insulin and insulin sensitivity, activity of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS), and cell membrane sodium or calcium transport. In blacks, variants of the apolipoprotein L1 (APOL1) gene are associated with hypertension and renal disease. Risk factors associated with primary hypertension include: (1) family history of hypertension; (2) advancing age; (3) gender (men younger than 55 and women older than 70 years); (4) black race; (5) high dietary sodium intake; (6) glucose intolerance (diabetes mellitus); (7) cigarette smoking; (8) obesity; (9) heavy alcohol consumption; and (10) low dietary intake of potassium, calcium, and magnesium. Many of these factors are also risk factors for other cardiovascular disorders. In fact, hypertension, dyslipidemia, and glucose intolerance often are found together in a condition called metabolic syndrome. Although populations with high dietary sodium intake have long been shown to have an increased incidence of hypertension, recent studies indicate that low dietary potassium, calcium, and magnesium intakes are also risk factors because without their intake, sodium is retained. The nicotine in cigarette smoke is a vasoconstrictor that can elevate systolic and diastolic blood pressure acutely. In habitual smokers an individual cigarette may not raise blood pressure; yet habitual smoking is associated with a high incidence of severe hypertension, myocardial hypertrophy, and death resulting from coronary artery disease (CAD). The incidence of hypertension is higher among heavy drinkers of alcohol (more than three drinks per day) than among abstainers, but moderate drinkers (two to four drinks per week) appear to have the lowest average blood pressures and cardiovascular mortality. Obesity is recognized as an important risk factor for hypertension, even in children and adolescents. ***RAAS system effects (1133-1136)- In the healthy individual the RAAS provides an important homeostatic mechanism for maintaining adequate blood pressure and therefore tissue perfusion. In hypertensive individuals, over activity of the RAAS contributes to salt and water retention and increased vascular resistance. High levels of angiotensin II contribute to endothelial dysfunction, insulin resistance, dyslipidemia, and platelet aggregation and play an important role in the complications associated with the metabolic syndrome. Further, angiotensin II mediates arteriolar remodeling, which is structural change in the vessel wall that results in permanent increases in peripheral resistance. Angiotensin II is associated with end-organ effects of hypertension, including atherosclerosis, renal disease, and cardiac hypertrophy. Finally, aldosterone not only contributes to sodium retention by the kidney but also has other deleterious effects on the cardiovascular system. Medications, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), oppose the activity of the RAAS and are effective in reducing blood pressure and protecting against target organ damage. A second RAAS has also been described. This system uses ACE 2 to create Ang 1-7, which has cardiovascular protective effects. Its discovery may lead to new and more effective medications.

34d. Macrocytic-Normochromic Anemias: Iron deficiency Anemia (IDA)

PATHO IDA can arise from one or two different etiologies or a combo of both- inadequate dietary intake or excessive blood loss. There is not an intrinsic dysfunction in iron metabolism. Both result in a depletion of iron stores or reduce hemoglobin synthesis. Second category develops from metabolic or functional IDA (various metabolic disorders lead to insufficient iron delivery to bone marrow or impaired iron use within the marrow. Iron stores may be sufficient, but delivery inadequate to maintain heme synthesis. Also, can result from erosive esophagitis, gastric and duodenal ulcers, colon adenomas, or cancers. H. pylori infections can cause IDA. In females, menorrhagia is a common cause of primary IDA. Others include meds that cause GI bleeds, surgical procedures that decrease gastric secretions, insufficient dietary intake of iron, eating disorders such as PICA (craving/eating nonnutritional substances. 3 main IDA stages: I- body's iron stores depleted (erythropoiesis proceeds normally and Hg remains normal). II-iron transportation to bone marrow diminished, resulting in ID-erythropoiesis. III- begins when small hemoglobin-deficient cells enter the circulation to replace normal aged erythrocytes that have been removed from circulation. Manifestations of IDA appear in this stage due to depleted iron stores and diminished Hg production. ETIOLOGY Most common type of anemia worldwide, occurring in developing and developed countries. Affects 1/5 of world population. Populations at higher risk include women living in poverty, women of childbearing age, and children. IDA in children in associated with numerous adverse health-related manifestations, especially cognitive impairment (may be irreversible). Children in developing countries often are affected by chronic parasite infestations that result in intestinal blood and iron loss that outpaces dietary intake. IDA can occur in individuals with lead poisoning. Females affected more than males. Those at highest risk are black females living in urban poverty. Increased prevalence of IDA in overweight children. Most common cause of IDA in developed countries is pregnancy and chronic blood loss (1-2mg of iron day) CLINICAL MANIFESTATIONS Begin gradually and pts usually do not seek medical attention until Hg is about 7-8g/dL. Early symptoms- non-specific and include fatigue, weakness, SOB, and pale earlobes/palms/conjunctivae. Progressed S/S-Epithelial tissue changes, course/rigid/brittle/thin/spoon shaped or concave (koilonychias) from impaired capillary circulation, burning mouth syndrome, tongue papillae atrophy, sore/red/burning gums (glossitis), dryness/soreness of epithelium corners of mouth (angular stomatitis) DIAGNOSTICS Clinical s/s and decreased H/H levels. Iron stores measured directly by bone marrow biopsy and iron staining or indirectly by lab test of serum ferritin, transferrin saturation, or total iron binding capacity. Serum ferritin widely accepted and available measurement of iron status. 1 mcg/L serum corresponds to 8-10 mg or 120 mcg of storage iron/kg body weight. Ferritin levels may be elevated independently of iron status during acute or chronic inflammation, malignancy, liver disease, and alcoholism. Sensitive indicator of heme synthesis is the amount of free erythrocyte protoporphyrin (FEP) within erythrocytes. A test that determines the concentration of soluble fragment transferrin receptor differentiates primary IDA from IDA chronic disease. Indicator of iron levels is the level of serum transferrin receptor. The ratio of serum levels of transferrin receptor to ferritin (R/F) estimates body iron stores. TREATMENT Identify and eliminate source of blood loss. Within ongoing bleeding, any replacement therapy is likely ineffective. Iron replacement therapy is required and very effective with initial dose being 150- 200 mg/day. Hematocrit levels should improve within 1-2 months of therapy. Serum ferritin more precise measurement of iron stores (once reaches 50 mcg/L, adequate replacement of iron has occurred). Fatigue, lethargy, and other s/s rapidly improve. Replacement therapy continues for 6-12 months after bleeding stopped but may continue for 24 months. Menstruating females may need 325 mg/day until menopause. Parental iron replacement (IM, and IV) injections also used if oral not tolerated. IV preferred route but IM recommended.

13. Know sickle cell disease: patho, inherited pattern, clinical manifestations, dx, treatment & complications

PATHO Inherited Pattern: SCD is inherited autosomal recessive disorder that is expressed as sickle cell anemia, sickle cell-thalassemia disease, or sickle cell Hb-C disease, depending on mode of inheritance. Sickle cell anemia is a homozygous form and most severe. Sickle cell-thalassemia disease and sickle cell Hb C disease are heterozygous form where child simultaneously inherits another type of abnormal hemoglobin from one parent. Sickle cell trait is where child inherits Hb S from one parent and normal hemoglobin from another. Tends to occur in people from central Africa, Near East, Mediterranean, and parts of India. 1:12 blacks carry the trait and 1:500 blacks have the disease. CLINICAL MANIFESTATIONS 2 characteristics determine presentation: chronic disease with acute exacerbations, can affect any part of the body. First seen in infants 6-12 months. Like hemolytic anemia: pallor, fatigue, jaundice, and irritability, sometimes called a crisis. 4 types of crisis: 1. Vaso-occulsive crisis (thrombotic crisis) sickling in microcirculation. Thrombosis and infarction of local tissue follow. Very painful, usually lasts 4-6 days. 2. plastic Crisis: transient cessation in red cell production resulting in acute anemia. Occurs after infection with parvovirus B19 (fifth disease). Causes temporary shutdown of red blood cell production. 3. Sequestrian crisis: lg. amount of blood is pooled in liver and spleen. Only in young children. Removal of spleen is treatment. Death in 50% 4. Hyperhemolytic crisis: accelerated rate of RBC destruction. Anemia, jaundice, and reticulocytosis. DIAGNOSTICS Sickle solubility test necessary for diagnosis, confirms prescense of Hb S. Hemoglobin electrophoresis provides amount of Hb S in erythrocytes. Prental diagnosis made by chorionic villus sampling at 8-10 weeks, and 15 weeks amniotic fluid sampling. TREATMENT Aggressive management of fever, early diagnosis of acute chest syndrome, red blood cell transfusions, and pain management improve quality of life. Prevent consequences of anemia and avoid crisis. Annual vaccinations, aggressive antibiotic treatment for infections. Pain with SCD is very complex, usually need PCAs. COMPLICATIONS Acute Chest syndrome: new pulmonary infiltrate involving one segment of a lung and chest pain. Temp > 101, wheezing, and cough. Sickled RBCs attach to endothelium of lung, causing infarction. Poor Prognosis, 25% SCD deaths. Glomerular disease: damage to glomeruli, sickling RBCs in the kidney, leads to kidney failure. Earliest clinical man: hyposthenuria (inability to concentrate urine). Proteinuria. Cholecystitis: inflamed gallbladder, from gallstone blocking duct. Can be caused from hemolysis causing gallstones to accumulate. *Sickle Cell-thalassemia has mildest clinical manifestations. *Sickle cell trait does not affect life expectancy, however, hypoxia, anesthesia, exercising at high elevation can cause vaso-occulsive episode, causing ivy shape instead of sickle shape.

7. Know Disseminated Intravascular Coagulation (DIC): patho, clinical manifestations, diagnostics, treatment & complications. (Pg. 1043 - 1048)

PATHO Results from abnormally widespread and ongoing activation of clotting. The common pathway for DIC appears to be excessive and widespread exposure of tissue factor (TF). Widespread damage to the vascular endothelium results in exposure of subendothelial TF. Endotoxin triggers the release of multiple cytokines that play a significant role in the development and maintenance of DIC. Proinflammatory cytokines and platelet activating factor are responsible for the clinical signs and symptoms associated with sepsis. TF binds clotting factor VII which leads to conversion of prothrombin to thrombin and formation of fibrin clots. Predominant Natural anticoagulants are diminished. The rate of fibrinolysis is also diminished in DIC. ETIOLOGY Box 29-6, p 1044. Is an acquired clinical syndrome characterized by widespread activation of coagulation, resulting in the formation of fibrin clots in medium and small vessels throughout the body. The magnitude of clotting may result in consumption of platelets and clotting factors leading to severe bleeding. Diagnostic criteria include systemic thrombohemorrhagic disorder with clotting activation, fibrinolytic activation, coagulation inhibitor consumption, and biochemical evidence of end organ damage/failure. Gram negative endotoxins are the primary cause of endothelial damage, DIC may occur in up to 50 % of individuals with gram negative sepsis. Sepsis is most common condition associated with DIC. DIC occurs in 10-20% of individuals with metastatic cancer or acute leukemia. Direct tissue damage, blood transfusions, severe trauma (esp to the brain), and some complications of pregnancy are associated with DIC. CLINICAL MANIFESTATION Most symptoms are the result of either hemorrhage or thrombosis. Acute DIC presents with rapid development of hemorrhaging or development of ecchymotic lesions (purpura, petechiae) and hematomas. Other sites include eyes, nose, and gums. Usually will have bleeding at 3 or more sites, development of shock, may lead to multisystem organ dysfunction or failure. Indicators- Level of consciousness changes, behavior, mentation, confusion, seizure activity, oliguria, hematuria, hypoxia, hypotension, hemoptysis, chest pain, & tachycardia. Symmetric cyanosis of fingers and toes, and occasional nose & breasts. May progress to gangrene, jaundice. Individuals with chronic or low grade DIC present with subacute bleeding & diffuse thrombosis. DIAGNOSTICS Table 29-8. No single lab test can be used to effectively diagnose DIC. Diagnosis is based on primarily on clinical symptoms & confirmed by combination of lab tests. The most commonly used combination of laboratory tests usually confirms thrombocytopenia or a rapidly decreasing platelet count on repeated testing, prolongation of clotting times, the presence of fibrin degradation products, and decreased levels of coagulation inhibitors. D-dimer used for detection of various fibrin degradation products and ELISA's for markers of thrombin activity are sometimes used. TREATMENT Directed toward eliminating underlying pathology, controlling ongoing thrombosis and maintaining organ function. Heparin has been used for control of thrombosis however its use is controversial bc its mechanism of action is binding to and activating AT III which is deficient in many types of DIC. Replacement therapy (interventions based on restoring the balance of coagulation factors, deficient coagulation factors, platelets, and other coagulation elements) is also effective treatment modality. Components include platelets, fresh frozen plasma, and cryoprecipitate. Antifibrinolytic drugs are used in treatment but are limited to instances of life threatening bleeding. Maintenance of organ function is achieved by fluid replacement to sustain adequate circulating blood volume and to maintain optimal tissue and organ perfusion. Complications: Hemorrhage. Activation of clotting also leads to activation of other inflammatory pathways including the kallikrein-kinin and complement systems. Activation of these systems contributes to increased vascular permeability, hypotension, shock and induce platelet destruction. The deposition of fibrin clots in the circulation interferes with blood flow causing widespread organ hypoperfusion. This may lead to ischemia, infarction, and necrosis. Multisystem organ dysfunction and failure ultimately result.

37a. Know myeloproliferative RBC disorders: patho, etiology, clinical manifestations, diagnostics, treatment and complications. (PG. 1002-1005)

PATHO Results from an overproduction of cells as well as a deficiency. Can be overproduced in marrow in response to exogenous (radiation, drugs) or endogenous (compensatory responses, immune disorders) signals. Polycythemia-excessive RBC production. 2 types: relative and absolute Relative Polycythemia- Results from hemoconcentration of blood ass. w/ dehydration (decreased water intake, vomiting, diuretic use. Absolute Polycythemia-Primary or secondary (most common). Secondary results from increased erythropoietin secretion in response to chronic hypoxia (i.e. living @ high altitudes, smokers w/ high carbon monoxide, COPD, and CHF), or abnormal types of hemoglobin that have greater affinity for O2, and certain tumors (renal cell carcinoma, hepatoma, and cerebral hemiangioblastoma). Polycythemia Vera- Overproduction of RBCs, increased levels of WBCs (leukocytosis), and platelets (thrombocytosis), and spenomegaly. Erthrocytosis is essential component. 95% possess an acquired mutation in Janus kinase 2 (JAK2), whose activity usually diminishes over time, however PV negates the self-regulatory activity so that the erthryropoietin receptor is always active. Hereditary hemochromatosis (HH)-A common, hereditary autosomal recessive disorder of iron metabolism characterized by GI iron absorption w/ subsequent tissue iron deposition. Excess iron is deposited in liver, pancreas, heart, joints, and endocrine glands causing tissue damage that lead to cirrhosis, diabetes, heart failure, athropathies, and impotence. ETIOLOGY Polycythemia Vera- One of several disorders collectively known as chronic myeloproliferative disorders. Results from abnormal regulation of hematopoietic stem cells. Major characteristics: 1. Involvement of multipotent hematopoietic progenitor cell 2. Overproduction of the formed elements of the blood in the absence of a stimulus 3. Dominance of a transformed progenitor cell 4. Narrow hypercellularity or fibrosis 5. Cytogenic abnormalities 6. Predisposition to thrombus formation and hemorrhage 7. And transformation to acute leukemia Rare, peaks b/w ages 60-80. Can survive 10-15 yrs, but only 50% survive past 18mths w/o proper tx. HH-Primary hereditary- Caused by 2 genetic base-pair alterations, C282Y & H63D, in the HFE gene on chromosome 6. Homozygosity of C282Y is the most common genotype and accts. For 82-90% of cases. Mutant HFE protein loses its functional ability and causes a relative iron deficiency in duodenal crypt cells. Deficiency results in an increase in expression of divalent metal ion transporter 1, which is responsible for iron absorption in the villus cells of the sm. Intestine. CLINICAL MANIFESTATIONS Polycythemia Vera- Splenomegaly, increased viscosity leads to a hypercoagulable state w/ formation of venous/arterial thrombosis and vessel occlusion. Extreme thrombocytopenia increases the risk for excessive bleeding rather than thrombosis. Viscosity leads to plethora (ruddy,red color of face, hands, feet, ears and mucous membranes), and engorgement of retinal and cerebral veins. Death is increased five-fold d/t cerebral thrombosis. Cardiac workload and output are unchanged, although increased volume may lead to increased bp. Evidence of cardiac involvement include Raynaud phenomenon, thromboangitiitis obliterans, and angina. GI and duodenal thrombosis may result in hemorrhage. Mesenteric thrombosis requires immediate intervention. Intense itching r/t the concentration of mast cells in the skin and is not usually responsive to antihistamines or topical lotions. HH-fatigue, malaise, abd. Pain, arthralgias, impotence, and clinical findings of hepatomegaly, abnormal liver enzymes, bronzed skin, diabetes, and cardiomegaly.

17d. VALVES OF THE HEART - (PG. 1086 - 1088)

VALVES OF THE HEART - (PG. 1086 - 1088) One way blood flow through the heart is ensured by the four heart valves as well as the pressure gradients that they maintain. During ventricular relaxation the two atrioventricular valves open and blood flows from the relatively higher pressure in the atria to the lower pressure in the relaxed ventricles. With increasing ventricular pressure these valves close and prevent backflow into the atria as the ventricles contract. The semilunar valves of the heart open when intraventricular pressure exceeds aortic and pulmonary pressures and blood flows out of the ventricles and into the systemic and pulmonary circulations, respectively. After ventricular contraction and ejection, intraventricular pressure falls and the pulmonic and aortic semilunar valves close when the pressure in the vessels is greater than the pressure in the ventricles, respectively. The atrioventricular (AV) (tricuspid and mitral) valve openings are composed of flaps of tissue called leaflets or cusps that are attached at the upper end to one of the rings in the fibrous skeleton of the heart and at the lower end to the papillary muscles by the chordae tendineae. The papillary muscles are extensions of the myocardium that help hold the cusps together and downward at the onset of ventricular contraction, thus preventing their backward expulsion, or prolapse, into the atria. The right AV valve is called the tricuspid valve because it has three cusps. The tricuspid opening (orifice) has the largest diameter of all the heart valves. The left AV valve is a bicuspid (two cusps) valve called the mitral valve. The mitral valve resembles a cone shaped funnel that extends into the cusps, which are connected by a fibrous tissue called the commissure. The anterior cusp of the mitral valve is continuous with supporting tissues of the aortic semilunar valve cusps. Thus damage to this continuous tissue can alter function of the aortic as well as the mitral valves. The tricuspid and mitral valves function as a unit because the atrium, fibrous rings, valvular tissue, chordae tendineae, papillary muscles, and ventricular walls are all connected. Collectively, these six structures are known as the mitral and tricuspid complex. Damage to anyone of the complex's six components can alter function significantly. Blood leaves the LV through the pulmonic semilunar valve, and it leaves the LV through the aortic semilunar valve. The pulmonic and aortic semilunar valves have three cup shaped cusps that arise from the fibrous skeleton. The pulmonic cusps are slightly thinner than the aortic cusps. The lower edges of each cusp are suspended from the root of the pulmonary artery or aorta, with the upper valve edges freely projecting into the vessel lumen. When the ventricles contract, the cusps behave like one way swinging doors. The force of the blood propels the cusps outward against the vessel wall. When the ventricles relax, blood fills the cusps and causes their free edges to meet in the middle of the vessel, closing the valve and preventing any backflow. GREAT VESSELS (PG. 1088) - Blood moves in and out of the heart through several large vessels. The right heart receives venous deoxygenated blood from systemic circulation through the superior vena cava and the inferior vena cava, which enter the right atrium. Blood leaves the RV and enters the pulmonary circulation through the pulmonary artery. The pulmonary artery divides the right and left pulmonary arteries to transport unoxygenated blood from the right heart to the right and left lungs. The pulmonary arteries branch further into the pulmonary capillary bed, where oxygen enters the blood and carbon dioxide leaves it as each gas moves from its higher to lower concentration gradient. Four pulmonary veins, two from the right lung and two from the left lung, carry oxygenated blood from the lungs to the left side of the heart. The oxygenated blood moves through the LA and LV and out into the aorta, which delivers it to systemic vessels that supply the body.

4f. Waldenstrom Macroglobulinemia (WM) - AKA lymphoplasmacytic lymphoma (pg. 1035)

PATHO WM arises from plasma cells that have undergone genetic rearrangement of variable region genes (V, D, J), but have not undergone class-switch. WM may originate from aberrant B-cell maturation and class-switch. Most of patho is assoc with production of large amounts of IgM, a high-molecular-wt protein. Excessive production leads to thickening of the blood and abnormally high blood viscosity. Increased viscosity interferes with circulation to various sites. ETIOLOGY R rare type of slow-growing plasma cell tumor that secretes a monoclonal IgM molecule. The overproduction of macromolecule IgM leads to certain unique clinical characteristics. CLINICAL MANIFESTATIONS M any clients with WM are asymptomatic. Most common symptoms include weakness and fatigue, bleeding from gums and nose, wt loss, and bruising. If hyperviscosity syndrome occurs, pt may develop neurologic problems such as blurred vision, loss of vision, headaches, dizziness, vertigo. Macromolecules may also precipitate in colder regions of body leading to Raynauds. DIAGNOSTICS Diagnosis is made on basis of high levels of monoclonal IgM in the blood and identification of malignant cells in bone marrow aspirates. Other hematologic abnormalities may be observed, esp anemia but also thrombocytopenia and leukopenia. Bence Jones protein may be observed in almost half of individual with WM. TREATMENT Tx similar to multiple myeloma. First line therapy includes combined chemo with nucleoside analogs, alkylating agents, and monoclonal antibody. Bone marrow stem cell transplantation has also proven effective in some pts. Current recommendations include combination of dexamethasone, rituximab, and cyclophosphamide, with use of other drugs in individuals with very high levels of M protein.

10. Know hemolytic disease of the newborn: patho, clinical manifestations, diagnostics, treatment and complications. (Pg. 1059-1062)

PATHO mother and fetus have antigenically incompatible erythrocytes. HDN results from: 1mother's blood continuing to perform antibodies against fetal erythrocytes or produce them on exposure to fetal erythrocytes; 2 sufficient amounts of IgG cross the placenta and enter fetal blood; 3 IgG binds with sufficient fetal erythrocytes to cause widespread antibody-mediated hemolysis or splenic removal. IgM antibodies formed against ABO antigen that a person does not express. IgM do NOT cross placenta or cause HDN. Anti-Rh antibodies are formed ONLY in response to presence of incompatible (Rh-positive) erythrocytes in the blood of Rh-negative mother. Large amounts of fetal erythrocytes enter mothers blood stream when placenta detaches at birth — leading to mother producing Rh antibodies Antibodies against Rh antigen D are of the IgG class, and cross placenta easily. IgG coated fetal erythrocytes destroyed through extravascular hemolysis (*primarily by mononuclear phagocytes in the spleen*) —>fetus becoming anemic Erythropoesis accelerates (liver& spleen)—>erythroblasts released into bloodstream (erythroblastosis fetalis) Unconjugated bilirubin (indirect) formed from breakdown of Hgb which is transported across placental barrier to maternal circulation then excreted by mother Hyperbilirubinemia: occurs in neonate secondary to excretion of lipid-soluble unconjugated bilirubin via placenta is NOT possible. Rh incompatibility MORE likely to cause severe or life-threatening anemia, death in utero, damage to CNS. Hydrops fetalis: still born fetuses due to anemia in utero that exhibit gross edema throughout entire body. Can occur as early as 17 weeks. ETIOLOGY Occurs only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes. Most all cases are due to ABO incompatibility (not Rh) Types: A, B, or O; and Rh antigen D (positive if D present, negative if D absent). Incompatibility occurs when: mother and fetus differ in ABO blood, or if fetus Rh- positive and mother Rh- negative. Prevalence: 1/10 cases of ABO incompatibility. Usually affects subsequent fetuses other than the first (antibody produced with first). CLINICAL MANIFESTATIONS Mild: slightly pale; slight spleen and liver enlargement Severe: pronounced pallor, splenomegaly, hepatomegaly Severe predisposes neonate to cardiovascular failure and shock. DIAGNOSTICS Coombs test. Indirect: measures antibodies in mothers circulation. Direct: measures antibodies already bound to fetal erythrocytes, mostly used to confirm dx Diagnostic measures: maternal antibody titers, fetal blood sampling, anmiotic fluid spectrophotometry, ultrasound fetal assessment. TREATMENT Prevention (ummunoprophylaxis) RhoGAM:preparation of antibody against Rh antigen D. Administered within 72 hours of exposure to Rh- positive erythrocytes. Ensures mother does NOT produce antibody, next baby protected. Avoid transfusions with Rh-positive blood. Tx with HDN baby: exchange transfusions which neonates blood replaced with new Rh-positive blood NOT contaminated with anti-Rh antibodies. Instituted within 24 hours. Phototherapy: reduce toxic effects of unconjugated bilirubin. (420-470 nm) COMPLICATIONS Icterus Neonatorum (neonatal jaundice): continued neonatal erythrocyte destruction after birth —> hyperbilirubinemia Kernicterus: bilirubin deposits in the brain. Caused by lack of replacement transfusions. This leads to cerebral damage and usually causes death (icterus gravis neonatorum). If infant does not die, can lead to: cerebral palsy, significant developmental delay, and high-frequency deafness.

39. What is Raynaud phenomenon and disease? Patho? (PG. 1144 - 1145)

Raynaud phenomenon and Raynaud disease are characterized by attacks of vasospasms in the small arteries and arterioles of the fingers, and less commonly, the toes. Clinical manifestations of the phenomenon and disease are the same (changes in skin color and sensation caused by ischemia), the causes differ. In severe cases ulceration and gangrene can occur. Raynaud phenomenon is secondary to systemic diseas3es, such as collagen vascular disease. Chemo, cocaine use, hypothyroidism, pulmonary hypertension, thoracic outlet syndrome, serum sickness, vasculitis, malignancy, or long tern exposure to environmental conditions, such as cold or vibrating machinery. Raynaud Disease is a primary vasospastic disorder of unknown origin. Blood vessels in affected individuals demonstrate endothelial dysfunction with an imbalance in endothelium-derived vasodilators (nitric oxide) and vasoconstrictors (endothelin-1). Platelet activation also may play a role; Tends to affect young women and to consist of vasospastic attacks triggered by brief exposure to cold or by emotional stress.

5. What are Reed-Sternberg cells? (Pg. 1024)

Reed-Sternberg cells are present in Hodgkins lymphoma. RS cells represent the malignant transformed lymphocyte. They are often large and binucleate, with occasional mononuclear variants. RS cells are hallmark sign of HL and are necessary for dx of HL, but not specific to HL. In rare instances, cells resembling them can be found in benign illness, as well as other forms of cancer.

6. Know Burkitt lymphoma: patho, clinical manifestations, diagnostics, treatment and complications. (1029-1030)

See above for further explanation. 7/4c.

33. Know function of lymph nodes. How are they affected by inflammation/infection? Why? (P. 952-954)

Structurally, lymph nodes are part of the lymphatic system. Lymphatic vessels collect interstitial fluid from the tissues and transport it, as lymph, through vessels of increasing size to the thoracic duct, which drains into the superior vena cava returning the lymph to the circulation. Lymph nodes are distributed throughout the body and provide filtration of the lymph during its journey through the lymphatics. Functionally, lymph nodes are part of the hematologic and immune systems and are the primary site for the first encounter between antigen and lymphocytes. Lymphocytes enter the lymph node from the blood through the postcapillary venules by means of diapedesis across the endothelial lining. B lymphocytes tend to migrate preferentially to nodes in the cortex and medualla, whereas T lymphocytes predominantly migrate to the paracortex (see Figure 27-7). Macrophages reside in the lymph node; help filter the lymph of debris, foreign substances, and microorganisms; and provide antigen-processing functions. The dendritic cells encounter and process antigens and microorganisms in other tissues, enter the lymph node through the afferent lymph vessels, and migrate throughout the nodes. The reticular network provides adhesive surfaces for trapping large numbers of phagocytes and lymphocytes and facilitating their organization into follicles or primary nodules. The presence of antigen, either removed from the lymph by macrophages or presented on the surface of dendritic cells, results in the production of secondary nodules containing germinal centers. In the germinal centers lymphocytes, particularly B cells, respond to antigenic stimulation by undergoing proliferation and further differentiation, including class- switch, into memory cells and plasma cells. Plasma cells migrate to the medullary cords. The B-lymphocyte proliferation in response to great deal of antigen (eg during infection) may result in lymph node enlargement&tenderness (reactive lymph node) (P. 1023) Lymphadenopathy is characterized by enlarged lymph nodes. Lymph node enlargement is caused by an increase in size and number of its germinal centers caused by proliferation of lymphocytes and monocytes. Normally, lymph nodes are not palpable or are barely palpable. Enlarged lymph nodes are characterized by being palpable and often also may be tender or painful to touch, although not in all situations (see Figure 29-6). Localized lymphadenopathy usually indicates drainage of an area associated with an inflammatory process or infection (reactive lymph nodes). Generalized lymphadenopathy is generally a result of malignant or nonmalignant disease, particularly in adults. Palpable nodes, however, do not always indicate serious disease and may indicate only a reaction to minor trauma or infection of a specific structure. In general, lymphadenopathy results from one of four types of conditions, one being immunologic or inflammatory conditions.

17b. THE HEART (pg. 1085)

THE HEART (PG. 1085) - The structures of the heart can be categorized by function: - Structural support of heart tissues and circulation of pulmonary and systemic blood through the heart. This category includes the heart wall and fibrous skeleton, which enclose and support the heart and divide it into four chambers; the valves that direct flow through the chambers; & the great vessels that conduct blood to & from heart. - Maintenance of heart cells. This category comprises vessels of the coronary circulation (the arteries and the veins that serve the metabolic needs of all the heart cells), and the lymphatic vessels of the heart. - Stimulation and control of heart action. Among these structures are the nerves and specialized muscle cells that direct the rhythmic contraction and relaxation of the heart muscles, propelling blood throughout the pulmonary and systemic circulatory systems. Structures that direct circulation through the heart: HEART WALL - has three layers (epicardium, myocardium, and endocardium) and is enclosed in a double-walled membranous sac, the pericardium. The pericardial sac has several functions: (1) prevents displacement of the heart during gravitational acceleration or deceleration, (2) acts as a physical barrier that protects the heart against infection & inflammation from the lungs & pleural sac, (3) contains pain receptors and mechanoreceptors that can elicit reflex changes in blood pressure and heart rate. The outer layer of the pericardium, the parietal pericardium, is composed of a surface layer of mesothelium over a thin layer of connective tissue. The visceral pericardium, or epicardium, is the inner layer of the pericardium. At one point the visceral pericardium folds back and becomes continuous with the parietal pericardium, allowing the large vessels to enter and leave the heart without breaching the pericardial layers. The visceral and parietal pericardia are separated by a fluid containing space called the pericardial cavity. The pericardial fluid, which is secreted by cells of the mesothelium, lubricates the membranes that line the pericardial cavity, enabling them to slide over one another with minimal friction as the heart beats. The amount and character of pericardial fluid are altered by inflammation of the pericardium. The outer layer of the heart, the epicardium, provides a smooth surface that allows the heart to contract and relax within the pericardium with a minimal amount of friction. The thickest layer of the heart wall, the myocardium, is composed of cardiac muscle and is anchored to the heart's fibrous skeleton. The thickness of the myocardium varies tremendously from one heart chamber to another. Thickness is related to the amount of resistance the muscle must overcome to pump blood from the different chambers. The internal lining of the myocardium is composed of connective tissue and a layer of squamous cells called the endocardium. The endocardial lining of the heart is continuous with the endothelium that lines all the arteries, veins, and capillaires of the body, creating a continuous, closed circulatory system.

18. Know the Electrical activity of heart as displayed on the EKG- ex-what does the QRS represent, etc. (PG. 1095)

The P wave represents atrial depolarization. The PR interval measures time from onset of atrial activation to onset of ventricular activation. (Normal = 0.12 - 0.20 seconds) The PR interval represents the time necessary to travel from the sinus node through the atrium, AV node, and His-Purkinje system to activate the ventricular myocardial cells. The QRS complex represents the sum of all ventricular muscle cell depolarizations. (Normal = 0.06 - 0.10 seconds) The configuration and amplitude of the QRS complex may vary considerably among individuals. During the ST interval the entire ventricular myocardium is depolarized. The QT interval is sometimes called the "electrical systole" of the ventricles, it represents the time for both ventricular depolarization and repolarization to occur. (Normal = 0.04 seconds, but varies inversely with heart rate)

19. Know coronary artery blood flow and effects of occlusions-which part of the heart is affected by occlusion in each coronary artery. (PG. 1090 - 1091)

The major coronary arteries are the right coronary artery (RCA) and the left coronary artery (LCA). These arteries traverse the epicardium and branch several times. The right coronary artery has greater flow than the left in 70% of individuals, the left greater than the right in 10%, and equal flow in each is found in 20% of individuals. The pattern of branching through the visceral pericardium differs among individuals. The branches of the coronary arteries enter the myocardium and endocardium and branch further to become arterioles and then capillaries. The coronary arteries are smaller in women than in men, a fact that is attributed to differences in heart weight. The left coronary artery arises from a single ostium (opening) behind the left cusp of the aortic semilunar valve. This artery ranges from a few millimeters to a few centimeters in length. It passes between the left atrial appendage and the pulmonary artery and generally divides into two branches—the left anterior descending artery and the circumflex artery. Other branches of the left main coronary artery are distributed diagonally across the free wall of the left ventricle. The left anterior descending (LAD) artery delivers blood to portions of the left and right ventricles and much of the interventricular septum. The left anterior descending artery initially travels in a groove between the left and right ventricles down the anterior surface of the interventricular septum toward the apex of the heart. The circumflex artery travels in a groove called the coronary sulcus, which separates the left atrium from the left ventricle, to the left border of the heart. It supplies blood to the left atrium and the lateral wall of the left ventricle. The circumflex artery often branches to the posterior surfaces of the left atrium and left ventricle. The right coronary artery originates from an ostium behind the right aortic cusp, travels behind the pulmonary artery, and extends around the right heart to the heart's posterior surface, where it branches to the right atrium and ventricle. The three major branches of the right coronary artery include the conus, which supplies blood to the upper right ventricle; the right marginal branch, which traverses the right ventricle to the apex; and the posterior descending branch, which lies in the posterior interventricular sulcus and supplies smaller branches to both ventricles.

17e. BLOOD FLOW DURING THE CARDIAC CYCLE (PG. 1088)

The pumping action of the heart consists of contraction and relaxation of the heart muscle or myocardium. Each ventricular contraction and the relaxation that follows it constitute one cardiac cycle. During the period of relaxation, termed diastole, blood fills the ventricles. The contraction that follows, termed systole, propels the blood out of the ventricles and into the pulmonary and systemic circulations. Contraction of the LV occurs slightly earlier than contraction of the RV. During ventricular systole, blood from the veins of the systemic circulation enters the thin walled RA from the superior and inferior vena cava. Venous blood form the coronary circulation enters the RA through the coronary sinus. The RA fills, which, along with the falling RV pressures, allows the AV (tricuspid) valve to open and fill the RV during ventricular diastole (occasionally called atrial systole). The same sequence of events occurs a split second earlier in the left heart. The four pulmonary veins, two from the right lung and two from the left lung, carry blood from the pulmonary circulation to the LA. As the LA fills and LV pressure falls, the mitral valve opens and blood flows into the LV. LA contraction, termed "atrial kick," provides significant increases in the volume of blood entering the LV at the end of diastole. Filling of the RV and LV occurs during one period of diastole. Five phases of the cardiac cycle can be identified: Phase 1: Ventricular diastole or atrial systole begins with the opening of the mitral and tricuspid valves and then ventricular filling from the atria occurs. The ventricles fill rapidly in early diastole and again in late diastole when atria contract. Phase 2: Ventricular systole begins with "isovolumetric contraction," so called because ventricular volume is constant since both the AV and semilunar valves are closed. The first detectable rise in ventricular pressure occurs during isovolumetric contraction. This contraction pushes the AV valves shut. Their cusps bulge slightly in the atria but are prevented from opening back into the atria by their anchors, the chordae tendineae. Phase 3: When ventricular pressure reaches and then slightly exceeds that of the pulmonary artery and aorta, the semilunar valves open and ventricular ejection occurs. Intraventricular pressure and ventricular volume decrease rapidly. Phase 4: With ventricular relaxation and decreased ventricular pressure, the aortic valve closes and "isovolumetric relaxation" occurs. Both the AV and semilunar valves are closed during this phase. Phase 5: When LV pressure falls below atrial pressure, mitral & tricuspid valves open & passive ventricular filling occurs. As blood is pushed through the inflow and outflow tracts of the ventricles, it flows around the crista supraventricularis - the muscle that separates the inflow from the outflow tracts - and is mixed by passing through the strands of the trabeculae carneae. (PG. 1089, Figure 31 - 6) Phases of the cardiac cycle: 1. Atrial systole. 2. Isovolumetric ventricular contraction. Ventricular volume remains constant as pressure increases rapidly. 3. Ejection. 4. Isovolumetric ventricular relaxation. Both sets of valves are closed, and the ventricles are relaxing. 5. Passive ventricular filling. The AV valves are forced open, and the blood rushes into the relaxing ventricles.

32. Know function of the spleen. What happens when a patient has a splenectomy? (P. 951, 1036-1037)

The spleen is the largest of the secondary lymphoid organs. It is a site of fetal hematopoiesis; its mononuclear phagocytes filter and cleanse the blood; its lymphocytes mount an immune response to blood-borne microorganisms; and it serves as a blood reservoir. The spleen is not absolutely necessary for life or for adequate hematologic function. However, splenic absence from any cause (atrophy, traumatic injury, or removal because of disease) has several secondary effects on the body. For example, leukocytosis (high levels of circulating leukocytes) often occurs after splenectomy, suggesting that the spleen exerts some control over the rate of proliferation of leukocyte stem cells in the bone marrow or their release into the bloodstream. Circulating levels of iron may also decrease, reflecting the spleen's role in the iron cycle. The immune response to encapsulated bacteria (e.g., streptococcus pneumonia [pneumococcus], Neisseria meningitides [meningococcus], haemophilius influenzae), which is primarily an IgM response, may be severely diminished, resulting in increased susceptibility to disseminated infections. Loss of the spleen results in an increase in morphologically defective blood cells in the circulation, confirming the spleen's role in removing old or damaged cells. (P. 1036 and 1037). The spleen is a useful organ, but its functions overlap those of other organs so that one is capable of living a normal, healthy life without the spleen. Individuals are able to lead normal live after splenectomy, but hematologic abnormalities often exist after removal of the spleen. The red blood cells become thinner, broader, and wrinkled as a result of increased in surface area and membrane lipids. The white blood cell count increases dramatically 1 week after removal and then stabilizes to approximately 40% greater than normal. Platelet numbers also rise immediately after surgery and then equilibrate to above-normal levels for the duration of the individual's life. Increased platelet levels have been implicated in ischemic heart disease in males because of increased thrombocytosis and hypercoagulability. A major postoperative complication following splenectomy is overwhelming post-splenectomy infection (OPSI). Unless treated in time, OPSI may rapidly progress to septic shock and possibly disseminated intravascular coagulation (DIC). Initial statistics indicate a death rate of 50% to 70%, with most deaths occurring within the first 48 hours after hospitalization. Prompt medical attention can reduce the death rate to 10%.

20. Know Beta 1, Beta 2 and Beta 3 receptors of the heart and how medications affect each. (PG. 1097)

The β1 receptors are found mostly in the heart, specifically the conduction system (AV and SA nodes, Purkinje fibers) and the atrial and ventricular myocardium. The β2 receptors are found in the heart and also on vascular smooth muscle. Stimulation of both the β1 and β2 receptors results in an increase in heart rate (chronotropy) and force of myocardial contraction (inotropy). In addition, stimulation of the β2 receptors results in vasodilation because of the location of the receptors on vascular smooth muscle. Overall β1 and β2 stimulation enables the heart to pump more blood and β2 stimulation also increases coronary blood flow, and β3 receptors are also found in the myocardium and coronary vessels. In the heart, stimulation of these receptors opposes the effects of β1- and β2-receptor stimulation and decreases myocardial contractility (negative inotropic effect). Thus β3 receptors may provide a "safety mechanism" to prevent overstimulation of heart by sympathetic nervous system.

36. Know all about vitamin B12-how it's given, how do you know vitamin B12 administration is effective? (Pg. 988)

Treatment of choice for Pernicious Anemia (not curable). Initial injections of vitamin B12 (cobalamin) are administered weekly until the deficiency is corrected, followed by monthly injections for the remained of the individual's life. The effectiveness of cobalamin replacement therapy is determined by a rising reticulocyte count. Within 5-6 weeks, blood counts return to normal.

38. What happens to leukocytes during a Type I allergic reaction? (Pg. 949)

Type 1 hypersensitivity allergic reactions and asthma are characterized by high numbers of circulating eosinophils, which may be involved in a dual role of regulation of inflammation and may contribute to the destructive inflammatory processes observed in the lungs of persons with asthma. Eosinophil granules contain a variety of enzymes (histamines) that control inflammatory process. Release leukotrienes, prostaglandins, platelet-activating factor, and a variety of cytokines (IL-1, IL-6, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, and chemokines [IL-8]) that augment the inflammatory response