Hematology_Pathophysiology_Lecture_Notes, Exams of Nursing

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Hematology Pathophysiology Basics of Anemia Alteration in Erythrocytes  Normal RBC count is 12- 18 g/dL  Polycythemias- too many cells  Anemias- too few cells  Polycythemias and Anemias are r/t erythropoiesis that is directed by erythropoietin (hormone released by kidney when low oxygen is sensed)  RBC production (Erythropoiesis) is determined by o Low oxygen o Perfusion to the kidneys o Amount of erythropoietin  Important vitamins need to make RBCs o Vitamin B12 and Folic acid  Important for development of hemoglobin o Iron Anemia  Reduction in the o total # of erythrocytes circulating OR o in the quality OR quantity of hemoglobin  Causes o Impaired RBC production o Bleeding; acute or chronic o Increased RBC destruction  Hereditary hemolysis (breakdown or RBC)  Sickle cell trait or disease  Acquired hemolysis  Immune mechanisms (blood transfusion reaction) o Antibodies from donor’s blood attack recipient’s RBCs  Infection o Malaria, clostridial  Drugs o Quinidine, penicillin, methyldopa  Liver or kidney disease  Toxins o Chemical, venoms  Classifications o Etiologic factor (cause) o Size  -cytic  Macrocytic- large  Microcytic- small  Normocytic- normal o Hemoglobin content  -chromic  Hypochromic- decreased amount  Normochromic- normal amount  Anisocytosis o RBCs are present in various sizes  Poikilocytosis o RBCs are present in various shapes  S/S of Anemia o Hypoxia  Caused by reduced oxygen carrying capacity  All s/s of anemia are r/t hypoxia (low O2 in tissues) o Syncope, angina, compensatory tachycardia, and organ dysfunction  Syncope; low O2 to brain  Angina; low O2 to chest o Classis s/s: Fatigue, weakness, dyspnea, elevated HR, and pallor  Lab Studies of Anemia o CBC  Hgb: Hemoglobin- the protein that carries oxygen in RBCs  Hct: Hematocrit- the % of blood volume that is occupied by RBCs  RDW: Red cell distribution- looks at RBC size  MCV: looks at RBC size  Normocytic, macrocytic, microcytic.  MCHC: looks at weight of hemoglobin  MCH: looks at size and concentration of hemoglobin in RBCs  Reticulocytes: looks at how many new RBCs are being produced Microcytic Anemias Microcytic- Hypochromic Anemias (small size RBC and low hgb content)  Characterized by RBCs that are small and contain reduced amounts of hemoglobin  Causes: stem from issues r/t hemoglobin production o Iron metabolism disorders o Porphyrin and heme synthesis disorders o Globin synthesis disorders  Iron Deficiency Anemia o Most common anemia o For men and postmenopausal women IDA is a good indicator of malignancy and needs to be further investigated! o If Ringed sideroblasts are seen in the bone marrow aspiration= a diagnostic test  Will see Iron deposits around nucleus within the RBC  Sideroblasts: erythroblasts contain iron granules that have not been synthesized into hemoglobin o S/S  Moderate reduction in Hct 20-30%  MCV usually normal, can be increased or decreased  Serum iron is elevated  Transferrin saturation is high; TIBC is low  Iron overload (hemochromatosis)  Enlarged spleen (splenomegaly)  Enlarged liver (hepatomegaly)  Thalassemia o Anemia d/t Autosomal recessive blood disorder  25% of offspring affected, 25% offspring unaffected, and 50% offspring unaffected carriers if both parents are unaffected carriers o Diagnostic test is hemoglobin electrophoresis o Characterized by abnormal formation of hemoglobin  Results form mutation that causes loss of one or both of alpha globin chains or one or both of beta globin chains  Abnormal hemoglobin formed results in improper oxygen transport and destruction of RBCs; resulting in anemia o Microcytic hypochromic (low MCV, low MCH) o Target cells may be seen o Complications  Iron overload  Bone deformities  CV illness o Confers a degree of protection against malaria Microcytic- Hypochromic Anemias (small size RBC and low hgb content)  Iron Deficiency Anemia vs Thalassemia Macrocytic- Normochromic Anemias (large size RBC and normal hemoglobin content) Also called Megaloblastic anemias  Types Iron Deficiency Anemia Thalassemia Low Ferritin level Normal Ferritin level Serum Iron decreased Normal Serum Iron Elevated TIBC Normal TIBC Decreased MCHC MCHC: looks at weight of hemoglobin Normal MCHC Normal Hgb electrophoresis Abnormal electrophoresis Common in anyone Common among Asia, Mediterranean, North Africa, and Middle East. o Folate, B12 deficiency, poisons, some antiviral drugs, and some chemo agents  Patho: o DNA synthesis is defective d/t to deficiencies in vitamin B12 or folate o RBCs do not form sufficiently and are released prematurely  Large, structurally abnormal, immature RBS  Vitamin B12 (Cobalamin) Deficiency o All B12 comes from diet: animal products o Functions  Keeps nervous system functioning properly  Necessary in the formation of blood  Involved in metabolism of every cell but especially affecting DNA synthesis and regulation o Liver can store a 3-year supply o It is very unusual to develop a B12 deficiency d/t diet  Except strict vegan diet o Lab findings  MCV high (large RBC)  MCH normal  Peripheral blood smear  Anisocytosis, poikilocytosis, macro-ovalocyte (characteristic of this), hyper-segmented neutrophils  Low reticulocyte count initially; will increase with Vitamin B12 supplementation  Pancytopenia if severe  Vitamin B12 is important with formation of blood cells; if Vitamin B12 is low reduction in all blood cell lines can occur  BM  Marked erythroid hyperplasia, megaloblastic changes  Elevated LDH and slight increase in indirect bilirubin d/t intramedullary destruction  LDH is an enzyme that helps to produce energy in the body. It is important in almost all body tissues. LDH will be elevated whenever there is injury to a cell.  Abnormally low serum B12  Serum B12 can be normal in 5% of pts with B12 deficiency, so antibodies and urine methylmalonic acid (MMA) is also checked  Elevated anti- parietal and anti- intrinsic factor antibodies  Elevated MMA  Pernicious Anemia o Most common macrocytic anemia o Caused by a Vitamin B12 deficiency o Lack intrinsic factor from the gastric parietal cells  Required for vitamin B12 absorption o May be congenital or autoimmune disorder  Auto-antibodies against intrinsic factor which is released from the parietal cells in the fundus of the stomach (anti-parietal antibodies) o Conditions that increase risk include:  Past infections with Helicobacter pylori  d/t damage to parietal cells  Gastrectomy  d/t removing part of the stomach and therefor parietal cells  Proton-pump inhibitors  Decreased stomach acid which is important r/t breaking vitamin B12 away from dietary source in the stomach o S/S  Weakness, fatigue  Paresthesia’s of the feet and fingers  Loss of appetite, abd pain, weight loss  Sore tongue that is smooth and beefy red, secondary to atrophic glossitis  “Lemon yellow” (sallow) skin as a result of a combination of pallor and icterus  Yellow/ jaundice/ pale skin  Neurologic symptoms from nerve demyelination  Ataxia, decreased or lack of DTRs, pathologic reflexes; babinski’s, severe paresis  Not reversible, even with treatment. BUT progress can be stopped. o Schilling Test  Test that localizes the site of pathology of the B12 deficiency  Phase 1:  Pt gets IM injection of nonradioactive B12 o Pt’s B12 receptors become saturated  Pt ingests radioactive B12  NORMAL pt will find radioactive B12 in the urine  Pt with pernicious anemia there is no intrinsic factor, so the ingested B12 is never absorbed so it is never excreted in the urine.  Phase 2:  Phase 1 plus additional step  Pt is also given intrinsic factor  If the problem is pernicious anemia, exogenous intrinsic factor should correct it and radioactive B12 will now appear in the urine  Folate (folic acid) Deficiency Anemia o Folate is an essential vitamin for RNA and DNA synthesis o Absorption of folate occurs in the upper small intestine; it is NOT dependent on any other facilitating factors o Is common in alcoholics and individuals with chronic malnourishment o S/S  May be asymptomatic  Jaundice (icterus)  Splenomegaly  d/t destruction and hemolysis, the spleen has to clean out RBCs  Autoimmune Hemolytic Anemia o Antibodies attack RBCs and shorten the RBCs life o Warm reactive antibody type o Cold agglutinin type o Cold hemolysin type (paroxysmal cold hemoglobinuria) o Based on the optimal temperature at which the antibody binds to the erythrocytes  Some antibodies like cold temps, some like warm temps  Drug-induced Hemolytic Anemia o Form of immune hemolytic anemia that is usually the result of an allergic reaction against foreign antigens o Called the hapten model o Penicillin, cephalosporins (90%+), hydrocortisone  G6PD Deficiency Hemolytic Anemia o Hereditary enzyme defect; X-linked recessive  G6PD is located on the X chromosome  Male XY o G6PD Normal XY o G6PD Deficient XY  Female XX o G6PD Normal XX o G6PD Intermittent XX  Heterozygous o G6PD Deficient XX  Homozygous; lack G6PD gene on both X chromosomes o Most common enzyme related hemolytic anemia o G6PD is an enzyme that works within the pentose phosphate pathway. Pentose pathway is essential in creating and maintaining the sugars needed to make up the backbone of DNA and RNA. o Pentose pathway does not require energy from ATP. o Inability of the NADPH in the pentose pathway  NADPH functions to protector the cell against oxidants  Lack of NADPH leads to the loss of the cells ability to protect itself from oxidants or stressors.  NADPH is important within the RBC… lack of NADPH allows for oxidation of the protein groups within the hemoglobin that causes proteins to denature and target the RBC  Leading to premature removal of RBCs from circulation  Shortened lifespan of RBC leads to anemia o Episodic hemolytic anemia in response to triggers that result in  Oxidative stress and damaged RBCs. o When hemoglobin is oxidized it denatures and forms a precipitant called Heinz bodies  Heinz bodies are clusters within RBC made up of the denatured hemoglobin  Heinz bodies damage the cell membrane and lead to destruction of RBC o Many variants of the disorder that have varying severity o Triggers that result in oxidative stress and damaged RBCs  Fava beans  Disorder called favism d/t consuming fava beans  Acute hemolytic anemia  Fava beans contain a strong oxidative agent that triggers hemolysis of RBC  Infection  R/t reactive oxygen species by the immune system  Drugs  Antimalarials  Chemotherapy agents  Sulfonamides (tx bacterial infections)  Antipyretic (reduces fever)  Analgesic (relieve pain)  Diabetic agents  Gout meds o Treatment  Avoid known triggers  Episodes are self-limiting o S/S  Usually healthy  Hemolysis only with oxidative stress (infection or drug exposure)  Common causative drugs: dapsone, primaquine, quinidine, quinine, sulfonamides, macrodontia  Episodes are self- limiting o Lab findings  Normal between episodes (ie no exposure to triggers and no development of oxidative stress)  During episodes  Reticulocytosis  Increased indirect bilirubin (jaundice)  Blood smear non-diagnostic but may show bite cells or blister cells  Heinz bodies  G6PD Assay  May be low, but misleading at or directly after episode when the enzyme deficient group of cells has been removed and results may be misleading low  Should be repeated several weeks after hemolysis resolves (6-8 weeks) o If G6PD Assay is low outside of a hemolytic episode, it confirms the deficiency  Sickle Cell Hemolytic Anemia o Autosomal recessive- homozygous inheritance of the mutated B globin chain gene o Mutation of the B globin chain of hemoglobin results in production of defective Hgb  Designated HemoglobinS (HgbS)  The entire hemoglobin is now called α2β2S  Those homozygous for mutation have sickle cell anemia  HbSS  Those heterozygous for mutation have sickle cell trait  HbASt o o The mutated part of the RBC, HgbS, is unstable and not elastic. When HgbS is exposed to acidosis or oxidative stress (hypoxia) the RBC collapses or “sickles” o The sickling is permanent, shortens the RBC life, and can lead to occluded vessels o Sickled RBCs cannot change their shape which prevents them from passing through narrow capillaries  Leads to occlusion and tissue ischemia. This is where most of the s/s complications stem from. o Sickled cells survive between 10-20 days  Remember a healthy RBC survives 100-120 days o Lab findings  Laboratory test is hemoglobin electrophoresis o Begins as a normocytic anemia and progresses to microcytic anemia as the chronic disease progresses o Usually patients have mild to moderate anemia o Severity of anemia corresponds to severity of underlying disease  Erythrocytes typically normocytic, normochromic  1/3 of pts will have microcytic anemia o Pathophysiology  Likely secondary to chronic inflammatory response  Inflammatory response  Releases chemicals called cytokines and interleukin (IL-6) o Stimulates hepcidin release from liver  Key regulator to entry of iron into circulation o Iron is therefore trapped in macrophages and liver cells and decreased gut absorption of iron  Overall, leads to dysfunctional iron utilization o Results in low access of iron in circulation o Decreased erythropoiesis: decreased RBCs and decreased availability of iron o S/S  With impaired release of iron  What happens to TIBC and ferritin? o Ferritin is the storage of iron  So if there is impaired release of iron, the iron is stored in excess or inappropriately  Ferritin is therefore elevated o TIBC decreases with anemia of chronic diseases  The body produces less transferrin and more ferritin  The body likely does this to keep the iron away from the pathogens that require it for their metabolism.  Hepcidin is released from the liver and regulates iron metabolism  Often a normocytic anemia (MCV normal)  However, if severe can have microcytic  Ferritin increased  TIBC decreased  Transferrin saturation can be very low (misleading to dx of IDA. Not a good indicator)  RBC morphology nondiagnostic  Bone marrow can distinguish between IDA and ACD o Mild-to-moderate anemia from decreased erythropoiesis  AIDS, malaria, rheumatoid arthritis, lupus, erythematosus, hepatitis, renal failure, and malignancies o Pathologic mechanisms  Decreased RBC lifespan  Suppressed production of erythropoietin  Remember erythropoietin is the hormone that go to the bone marrow and stimulates erythropoiesis  Ineffective bone marrow response to erythropoietin  Altered iron metabolism  iron sequestration in macrophages, iron stored in excess. o S/S  S/S are related to the causative disease  Similar to IDA  Mild (Hgb 10-12): o likely no symptoms  Moderate (Hgb 7-11): o Palpitations, dyspnea, exercise intolerance, angular stomatitis, glossitis, pallor, Koilonychia  Severe (Hgb <7): o Postural HoTN, dizziness, weak, gastritis, paresthesia, lethargy Myeloproliferative RBC Disorders  Polycythemia o Overproduction of RBCs  Increased # of RBCs causes the blood to become thicker o Relative polycythemia  RBC number does not increase just appears to be d/t dehydration  Fluid loss results in relative increase of RBC counts and hemoglobin and hematocrit values  Resolves with fluid intake o A hyper-proliferative state of the bone marrow or excess erythropoietin secretions could lead to polycythemia  Remember that normally the RBC production occurs in the bone marrow under the stimulation of erythropoietin o Polycythemia vera also called Primary Polycythemia  Myeloproliferative disease that increases production of RBCs  Chronic neoplastic, nonmalignant condition  Characterized by production of hematopoietic stem cells resulting in overproduction of all blood cell lines especially RBCS  Overproduction of RBCS (frequently with increased levels of WBCs and platelets  Splenomegaly  Spleen becomes enlarged, frequently with abd pain and discomfort  As the disease progresses, blood cellularity and viscosity increases  Ie the blood thickens. Most s/s are r/t thick blood d/t increased RBCs.  Intense, painful itching is intensified by heat or exposure to water (aquagenic pruritus)  More common in elderly  S/S  Itching and severe burning pains in hands and feet with reddish or blueish discoloration of skin.  Pts with Primary Polycythemia are likely to develop gouty arthritis  Pathophysiology  Acquired mutation in Janus Kinase 2 (JAK2) o Normally the JAK2 gene functions to allow erythropoietin receptors to be active AND it has the ability to turn off when not needed o When JAK2 is mutated, the erythropoietin receptors are constantly on and stimulate erythropoiesis regardless of the erythropoietin levels  Key to remember that patho involves EPO receptor being constantly on; patho is not r/t EPO levels!  Negates the self-regulatory activity of JAK2 that allows the erythropoietin receptor to be constitutively active, regardless of the level of erythropoietin  Disease can convert into acute myeloid leukemia  What would you expect to happen to erythropoietin in this disease?  If RBC count is inappropriately high, this should normally send negative feedback to the kidneys to stop producing erythropoietin, and thus erythropoietin level is low in primary polycythemia vera o In other words, increased RBCs results in compensatory suppression of erythropoietin levels  Key to remember that patho involves EPO receptor on the bone marrow being constantly on; patho is not r/t EPO levels! o Secondary Polycythemia  Elevated erythropoietin  D/t appropriate need for more RBCs or inappropriate o Appropriate  Chronic hypoxia r/t disease will causes increase in RBC to compensate  Leads to an appropriate secondary polycythemia o Inappropriate  Excessive bleeding during a menstrual period (menorrhagia) and/or bleeding between periods (metrorrhagia) o Platelet problem  P, P, P = petechiae, platelet dysfunction, low platelets  Remember that petechiae are pinpoint red dots on the skin o Coagulation factor disorder  Deep bleeding  Decreased Coagulation Factors o Clotting factors are proteins synthesized mostly in the liver (2, 7, 9, and 10)  They need vitamin K for synthesis o Deficiency in clotting factors result from:  Liver failure  Where clotting factor is made  Vitamin K deficiency  Needed for clotting factor synthesis  Genetic mutation leading to dysfunction protein or inadequate amount  Hemophilia is an X-linked genetic disease that leads to clotting factor deficiency o Hemophilia A (Classic) is deficiency of Factor 8 o Hemophilia B (Christmas disease) is a deficiency of Factor 9  Decreased Platelet Function or Number o Normal platelet count is 150,000- 400,000 o Pathology can occur at any step in the function of platelets o Von Willebrand’s Disease  There is a decrease in or absence of Von Willebrand factor  Results in decreased ability of platelets to bind to vessel wall o Remember: Von Willebrand factor is the protein that stabilizes Factor 8. If there is a deficiency in vWF it can lead to a decrease in Factor 8 causing hypo-coagulable state or propensity to bleed. So, Von Willebrand disease is a genetic disorder caused by missing or defective Von Willebrand Factor protein (which is a clotting factor). vWF is carried on chromosome 12. vWF binds with Factor 8 and platelets in blood vessels walls to form platelet plug and fibrin clot during the coagulation process. o Bernard-Soulier Syndrome  There is a defect in GP 1b-IX (the link to Von Willebrand factor)  Results in decreased ability of platelet to bind to vessel wall o Storage Pool Diseases  There is a decrease in storage pool of signaling molecules that are normally released by platelets o Thrombocytopenia  Platelet count <150,000  <50,000: hemorrhage from minor trauma  <15,000: spontaneous bleeding  <10,000: severe bleeding  Result of  Decreased production of platelets o Bone marrow failure r/t malignancy, radiation, drugs, infection  Platelets are loss/destruction o Infection, drugs, autoimmunity, TTP, DIC o Immune (idiopathic) Thrombocytopenic Purpura (ITP)  Low platelet count with normal bone marrow and absence of other causes of thrombocytopenia; so it is autoimmune  IgG antibodies target platelet glycoproteins  Remember: glycoproteins are found on the surface of platelets  Antibody-coated platelets are sequestered and removed from the circulation  The coating of the platelets and IgG renders them susceptible to being engulfed by tissue macrophages within the spleen or the immune like cells in the liver called Kupffer cells  The acute form of ITP that often develops after a viral infection is one of the most common childhood bleeding disorders  S/S  Petechiae and purpura  Progressing to major hemorrhage o Thrombotic Thrombocytopenic Purpura (TTP)  A thrombotic microangiopathy (damage to microvasculature)  Platelets aggregate, form microthrombi, and cause occlusion of arterioles and capillaries  widespread ischemia  S/S: widespread ischemia  Classic fever, purpura, altered mental status, neuro signs, renal dysfunction, thrombocytopenia, hemolytic anemia  Lab findings  Thrombocytopenia  Hemolytic anemia (increased RBCs, increased reticulocytes, schistocytes on smear, elevated LDH)  Coagulation factors are not affected o PT and PTT will be normal  TTP can be fatal if plasmapheresis (plasma exchange) is not initiated immediately and continued until s/s improve o Hemolytic Uremic Syndrome (HUS)  Type of TTP: same underlying pathophysiology as TTP  But HUS is generally r/t syndrome that occurs following a diarrheal illness such as E. coli or Shigella  HUS is more common in children o Essential (Primary) Thrombocythemia (Thrombocytosis)  Thrombocythemia/ thrombocytosis is the presence of high platelet counts in the blood  Platelet count >600,000  Primary (Essential)  Secondary (Reactive)  Myeloproliferative disorder of platelet precusor cells  Megakaryocytes in the bone marrow are produced in excess  Microvasculature thrombosis occurs (clots)  S/S  Often asymptomatic  Often occurs in tandem with inflammatory disease o Stimulates of platelet production are elevated  Can occur with polycythemia vera  Alterations of Coagulation o Vitamin K Deficiency  Vitamin K is necessary for synthesis and regulation of prothrombin, the prothrombin factors (2, 7, 10 and 11) and protein C and S (anticoagulants) o Liver Disease  Liver disease causes a broad range of hemostasis disorders  Defects in coagulation  Fibrinolysis  Platelet number and function  Disseminated Intravascular Coagulation (DIC) o Complex, acquired disorder in which clotting and hemorrhage simultaneously occur dysregulated o Does not occur by itself  Infections (gram negative sepsis, malaria), massive trauma or surgery, neoplastic disease, chronic inflammatory diseases, complication of child birth o DIC is the result of increased protease activity in the blood caused by unregulated release of thrombin with subsequent fibrin formation and accelerated fibrinolysis (clot breakdown). So the clotting factors become depleted which leads to excessive bleeding o Significant endothelial damage is the primary initiator of DIC o Critically ill pts o By activating the fibrinolytic system (plasmin), the pt’s fibrin degradation product (FDP) and D-dimer levels will increase  Remember: