Medical Pathology: Hematologic Disorders I PDF

Medical Pathology: Hematologic Disorders I CHRIS BORGMAN, OD ASSOCIATE PROFESSOR [email protected] WIL MCGRIFF, OD, MPH ASSOCIATE PROFESSOR [email protected] Lecture Objectives — Understand pathophysiology, multiple causes, and clinical findings of anemias/hemoglobinopathies. ¡ ¡ Iron deficiency...

Medical Pathology: Hematologic Disorders I CHRIS BORGMAN, OD ASSOCIATE PROFESSOR [email protected] WIL MCGRIFF, OD, MPH ASSOCIATE PROFESSOR [email protected] Lecture Objectives — Understand pathophysiology, multiple causes, and clinical findings of anemias/hemoglobinopathies. ¡ ¡ Iron deficiency, lead, aplastic, B12 deficiency, folate deficiency, anemia of chronicity Hemoglobinopathies: sickle cell disease & thalassemias — Understand pathophysiology, causes, and clinical findings of polycythemia. — Understand general principles of complete blood count lab test & be able to interpret results. NBEO Outline — Hematopoietic and Lymphoid System ¡ 1. Epidemiology ¡ 2. Symptoms and signs of common blood disorders a. Non-neoplastic disorders of blood cells ÷ b. Neoplastic disorders of blood cells ÷ c. Non-neoplastic disorders of lymph nodes ÷ d. Neoplastic disorders of lymph nodes ÷ ¡ ¡ 3. Diagnostic testing and imaging 4. Pathophysiology and diagnosis Blood = “liquid tissue” — Cells ¡ ¡ ¡ Erythrocytes Leukocytes Thrombocytes — Plasma ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ Water Proteins Glucose Cholesterol Calcium Hormones Metabolic waste Antibodies Many others… Erythrocytes — Non-dividing cells ¡ *Transport O2 and CO2 ÷ Filled w/ Hemoglobin ¢ ¢ ¡ ¡ ¡ 250 million Hgb per RBC! 1 billion O2 molecules per RBC! No nucleus No mitochondria Rapid turnover — Adult sites of production ¡ Vertebrae ¡ Pelvis ¡ Sternum ¡ Ribs — Lifespan of 90-120 days ¡ HbA1c in DM (see DM #1 lecture) — Removed by mononuclear phagocyte system (MPS) ¡ ¡ ¡ Spleen Liver Lymph nodes Fun Fact: One RBC will circulate the entire circulatory system in approximately 20 secs! Erythropoiesis = RBC production — Regulated by O2 levels in blood — Stimulated by hypoxia ¡ Peritubular cells of the kidney produce erythropoietin • See Lecture 19 - Kidneys ¡ ¡ Erythropoietin induces RBC production in bone marrow Process takes ~4 days Erythrocytes — *Growth requirements ¡ Iron ¡ Protein ¡ Vitamins ÷ Folate ÷ B12 — Stimulating factors ¡ Hemorrhage ¡ Damage to bone marrow ¡ High altitude ¡ Exercise ¡ Hemolytic disease Deficiencies lead to impaired ¡ Low hemoglobin levels DNA synthesis in RBC’s Deficiencies lead to reduced ability to carry O2 Hematocrit — Defn: % of blood that are RBCs ¡ ¡ Convenient way to determine if RBC count is normal Blood sample is centrifuged and measured Note: Higher testosterone in males increases EPO output in kidneys à higher hematocrit Anemia — Defn: Reduced circulating RBC levels ¡ <42% hematocrit (males) ÷ ¡ Hb <13.0 g/100 mL <39% hematocrit (females) ÷ Hb <12.0 g/100mL — *Reduced O2 carrying capacity ¡ Bottom Line à Ischemia! — Causes: ¡ Iron deficiency* (30-50%) ¡ Blood loss ¡ Nutritional deficiencies ¡ Medications/Drugs/Chemo ¡ Autoimmune disease ¡ End stage renal failure ¡ Cancers ¡ GI absorption disorders ¡ Bone marrow disorders ¡ Splenomegaly — 5.6% of Americans have anemia ¡ In 2018 à ~18.32 million Americans! — Symptoms (mildàsevere) ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ Overall weakness Tachycardia Fatigue Dyspnea Palpitations Angina Pallor Myelin degeneration — Dx: ¡ CBC with differential — Tx: ¡ ¡ ¡ Supplements Medications Manage underlying disorder Source: Le CHH. NHANES 2003-2012. PLoS One. 2016;11:e0166635. 3 Main Ways To Get Anemia 1. 2. 3. Reduced RBC production Excessive blood loss/hemorrhage Increased RBC destruction 3. 1. 2. Epidemiology of Anemia • Prevalence/incidence of anemia depends on where you live in the world! — Worldwide ¡ 25% population ¡ 42% pregnant women ¡ 30% non-pregnant women ¡ 13% men — United States ¡ 5.6% population ÷ ¡ ¡ ¡ ~18.32 million people 8.8% pregnant women 5-7.6% non-pregnant women 2-3.5% men • AA (15%) > Hispanic (5%) > White (4%) • de Benoist B, et al. Worldwide prevalence of anaemia 1993-2005. World Health Organization, 2008. • Le CHH. The prevalence of anemia and moderate severe anemia in the US population (NHANES 2003-2012). PLoS One. 2016. Anemias to know for this class… …and your career… — There are 400+ types of anemia! — Let’s just focus on these though: ¡ **Iron Deficiency Anemia (IDA) (50%) ¡ *Anemia of Chronic Disease (ACD) (33%) ¡ Pernicious Anemia (PA) (2%) ¡ Folate Deficiency Anemia (FDA) (<1%) ¡ Lead Poisoning Anemia (LPA) ¡ Aplastic Anemia (AA) ¡ Hemolytic anemia (HA) ÷ Sickle Cell Anemia (SCA) Le CHH. The prevalence of anemia and moderate severe anemia in the US population (NHANES 2003-2012). PLoS One. Nov 2016. Anemia in the USA Folate Deficient <1% Types of Anemia in USA Other 14% Pernicious 2% Chronic Disease 33% Iron Deficient 50% Iron Deficient Chronic Disease Pernicous Folate Deficiency Other 5.6% population ~18.32 million people Le CHH. The prevalence of anemia and moderate severe anemia in the US population (NHANES 2003-2012). PLoS One. Nov 2016. Anemia Classification — Etiology ¡ Hypoproliferative ¡ Hemolytic — Size ¡ Macrocytic ÷ ¡ Microcytic ÷ ¡ B12, folate Iron, lead Normocytic ÷ Sickle cell — Hemoglobin content ¡ Normochromic ÷ ¡ B12, folate, sickle cell Hypochromic ÷ Iron, lead Microcytic (MCV <80fL) Normocytic (MCV 80-100 fL) Macrocytic (MCV >100 fL) Iron deficiency Hemolytic Folate (B9) deficiency Sideroblastic SS/SC Anemia B12 deficiency Lead (Pb) Aplastic Copper deficiency Thalassemias Chronic Renal Disease Drug-induced Posthemorrhagic EtOH abuse Anemia of Chronic Liver disease Disease Hypochromic Normochromic Hyperchromic Iron deficiency B12 deficiency Does not exist Lead (Pb) Folate (B9) deficiency Sideroblastic SS/SC Anemia Thalassemias Aplastic Posthemorrhagic Hemolytic Anemia of Chronic Disease Microcytic – Hypochromic Anemias Iron Deficiency Anemia (IDA) — Microcytic, hypochromic anemia ¡ Fe à needed for hemoglobin molecule — **Most common type of anemia worldwide & USA** ¡ ~20% of the world affected — Risk groups: poor, women, and children ¡ Can cause cognitive impairment in children — Main causes à Fe is unable to be recycled ¡ ¡ ¡ ¡ *Pregnancy and heavy menstruation (females) *Chronic, slow GI bleeds (men) Poor GI absorption (ie. Celiac disease) Poor diet — Dx: CBC c diff à hematocrit — Tx: address bleeding & iron supplementation Lead Poisoning — Microcytic, hypochromic anemia — MOA: Inhibits heme & globin synthesis of RBC’s à anemia — Children at highest risk ¡ Ingestion of lead containing paint chips — Early signs and symptoms ¡ Pallor ¡ Abdominal pains ¡ Irritability — Late signs and symptoms ¡ Lethargy ¡ Anorexia ¡ Ataxia ¡ Slurred speech, and convulsions — Tx = remove lead source and/or chelation Macrocytic – Normochromic Anemias Pernicious Anemia — Macrocytic, normochromic anemia — *Reduced Intrinsic Factor (IF) à vitamin B12 deficiency ¡ IF = transporter for B12 in gut to bloodstream ¡ More common than folate deficiency ¡ Mean patient age ~60 yrs ¡ MOA: Impairs DNA synthesis during erythropoiesis — Other causes: ¡ Autoimmune & malabsorption disorder ÷ ¡ ¡ ¡ ¡ (Crohn’s, Celiac disease, etc) H. pylori infection ETOH abuse PPI use Diet (vegetarians) — Treat w/ B12 injections Folate Deficiency Anemia — Macrocytic, normochromic anemia — Folate (Vit. B9) obtained through dietary sources ¡ ¡ B9 = Coenzyme involved with DNA synthesis in RBCs Also associated with neural tube defects in fetuses Impairs DNA synthesis during erythropoiesis — Rare in USA due to dietary regulations — Causes — MOA: ¡ ¡ ¡ Poor diet* Autoimmune & malabsorption disorders ETOH abuse — Tx ¡ Oral supplements and/or diet changes Normocytic – Normochromic Anemias Anemia of Chronic Disease (ACD) — Normocytic, normochromic anemia à usually mild anemia — *2nd most common cause of anemia in world & USA — Usually occurs in older adults (common in nursing homes) ¡ 24% of adults >65 yo have anemia — Many causes: chronic inflammatory diseases slowly impact RBC health ¡ AIDS ¡ Autoimmune: RA or SLE ¡ DM ¡ Hepatitis ¡ Chronic kidney disease — Associated with: ¡ ¡ ¡ Decreased RBC lifespan Suppressed production of EPO Altered iron metabolism — Tx à treat underlying condition and/or oral EPO Aplastic Anemia (AA) — Normocytic, normochromic anemia — MOA: Bone marrow replaced with fibrous, fatty tissue Abrupt onset of low blood cell counts à pancytopenia ¡ Increased incidence of infections and hemorrhages ¡ Often occurs in otherwise healthy young adults ¡ — Etiology: *Idiopathic (75%) ¡ Secondary (Drugs/Virus/Autoimmunity) ¡ ÷ ie. *chloramphenicol, arsenic, chemo — Treatment ¡ Bone marrow transplant Hemolytic Anemias — Normocytic, normochromic anemia most commonly à SCD ¡ However, Hb size/Hb amounts can vary (ie. micro/macro, normo/hypo) — Defn: Premature destruction of RBC’s — Signs and symptoms ¡ Fatigue ¡ Jaundice ¡ Red-brown urine — Two main types: ¡ *Intrinsic à Inherited deficiencies *Hemoglobinopathies à Sickle Cell Disease (SCD) & Thalassemias ÷ RBC membranes ÷ Enzyme defects ÷ ¡ Extrinsic à Toxic/antibody damage to the circulating RBC *Autoimmune/Medications (ie. *cephalosporins, NSAIDs, SLE) ÷ Mechanical damage (ie. heart valve abnormalities, other trauma) ÷ Incorrect blood type (A,B,O) transfusionà severe ÷ Hemoglobinopathies Hemoglobinopathies — Inherited disorders affecting hemoglobin formation: 1. 2. *Sickle Cell Anemias (SS, SC, CC, AC, AS) Thalassemia (α-thal, β-thal) — Sickle Cell Trait (AS) ¡ 8% of African Americans in the U.S. ÷ ¡ ¡ ~1 in 12 African-Americans Usually asymptomatic due to one good “A” gene Confers “fitness benefit” against malarial infections? Sickle Cell Genotypes Sickle Cell Genotypes Genotype ~Percentage AS 66% AC 16.60% Thalassemia trait 12.45% SS 3% SC 2% Thalassemia 0.36% ~83% sickle cell “trait” • • SS Thal. SC Thal. Trait AC AS SS SC AS AC Thalassemia Thalassemia trait Saraf, SL, et al. Differences in the clinical and genotypic presentation of sickle cell disease around the world. Paediatr Respir Rev. 2014;15:4-12. Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med. 2013;3. Sickle Cell Anemia Disorders — *Most common inherited blood disorders ¡ ¡ ¡ ¡ ¡ Normocytic-normochromic anemia Autosomal recessive Abnormal hemoglobin synthesis 70,000 cases in the U.S. More common in individuals of African and Hispanic descent ÷ 1 out of 500 African Americans have SCD — Life expectancy ¡ ¡ 50-60 years on average 90% live to adulthood — Complications: ¡ ¡ ¡ Hemolytic anemia Intermittent painful “crises” Multiple organ damage possible (spleen, GI, brain, heart, etc.) Sickle-Cell Anemia (SCA) — Single point mutation ¡ Beta-globulin gene — Stress causes “sickling” ¡ ¡ ¡ ¡ Viral illness Dehydration Hypoxia Exertion — Effects ¡ ¡ *Microvascular occlusion Hemolysis à anemia — Bottom Line? à ischemia! Sickle Cell Retinopathy — 5 Stages: 1. 2. 3. 4. 5. Peripheral arteriolar occlusions Peripheral AV anastomoses “Sea-fan” neovascularization Vitreous hemorrhage Traction or rhegmatogenous retinal detachment ***Highest Risk of Sickle Cell Retinopathy = SC > SS > AS Thalassemias — Another inherited hemoglobinopathy ¡ ¡ Pathophysiology à Absent or reduced globin chains in hemoglobin Compared to SCD, “sickling” of RBC’s does not occur — Microcytic-hypochromic anemia à severe ¡ ¡ Unstable globin chains damage the RBC membrane à hemolytic anemia Other clinical disorders: ÷ Cardiac, splenomegaly, endocrine, hepatic, and iron overload Alpha-thalassemia 1. ¡ ¡ Less severe More common in South Asian and West African nations Beta-thalassemia 2. ¡ ¡ Severe Often fatal in childhood (Avg: 17 YO) ÷ ¡ ¡ Cardiac complications in ~71% Common around the Mediterranean More likely to be seen in USA than α-thal Ocular Manifestations of Anemia Ocular Manifestations of Anemia — Uncommon finding in anemics; unless severe ¡ Occurs in 10% of patients with only anemia ¡ Occurs in 40%-70% of patients with anemia and thrombocytopenia — Signs ¡ *Conjunctival pallor (75% cases) ÷ ¡ If RBC count is 50% of normal. *Anemic retinopathy (16-28%) Flame-shaped or dot-and-blot hemorrhages ÷ Cotton-wool spots ÷ Roth’s Spot ÷ ¡ Optic nerve/posterior pole pallor (14%) Anemic Retinopathy Polycythemia Polycythemia — Defn: An increase in the RBC mass ¡ ¡ ¡ ≥51% hematocrit (men) ≥48% hematocrit (women) Aka: “erythrocytosis” *Primary polycythemia (57%) 1. ¡ ¡ Proliferative disease of the bone marrow (neoplastic) aka: “Polycythemia Vera” Secondary polycythemia 2. ¡ Increased EPO levels caused by hypoxic conditions ÷ ÷ ÷ ¡ *Disease (COPD, sleep apnea, CHF) Toxins (smoking, carbon monoxide) Adaptation (high altitude) Tx à manage underlying condition Relative polycythemia 3. ¡ ¡ Loss of vascular fluid (dehydration or diuretics) Tx à hydration Polycythemia à Increased Thrombosis Risk! • *Elevated risk for thrombotic events • MOA: elevated hematocrit à hematic hyperviscosity See Lecture 4 – Fluid & Hemodynamics lecture Polycythemia vera — Neoplastic — Incidence: 2.8/100k men, 2.3/100k women — Prevalence: 22/100k population — Gene mutation at JAK2 locus in 95% cases (found 2005) ¡ Uncontrolled RBC hyperproliferation in bone marrow — 50% risk of acute myeloid leukemia (AML) over 20 yrs — Dx: blood test (CBC w/ differential) — Tx: ¡ ¡ ¡ Phlebotomy à bloodletting (>60-65% hematocrits) Anticoagulants Medication: Jakafi (ruxolitinib) à inhibits JAK enzymes Bloodletting Ocular Manifestations of Polycythemia — Ocular complications ~14% ¡ *Transient vision loss (40%) ¡ Retinal vascular occlusions ¡ ION ¡ Papilledema ¡ Diplopia ¡ VF defects ÷ 2’ cerebral CVA Lab Tests: Anemia and Polycythemia Diagnoses Lab Test: “Complete Blood Count w/ Differential” — Broad screening test to check general health status — aka: à “CBC with diff” ¡ ¡ ¡ ¡ ¡ ¡ Anemia Infection Inflammation Bleeding disorders Leukemia More… — Uses ¡ Monitor treatment ¡ Diagnose ¡ Check general health status — Test includes: ¡ WBC count Neutrophils ÷ Lymphocytes ÷ Monocytes ÷ Eosinophils ÷ Basophils ÷ ¡ RBC count Hemoglobin ÷ Hematocrit ÷ Size, volume, shape, etc. ÷ ¡ Platelet count ÷ Size, volume, shape, etc. TEST WBC Count RBC Count Platelet Count HIGH LOW “Leukocytosis” “Leukopenia” • • • • • • • • • • *Infection (viral/bacterial) Inflammation Leukemia Myeloproliferative disorders Allergies Intense exercise/stress *Immunosuppression Bone marrow disorders Lymphoma Severe infection (sepsis) “Polycythemia” “Anemia” • • • • • • • • **Polycythemia vera *Chronic hypoxia Dehydration Lung disease Excess EPO production Smoking High altitude living • • • • *Nutritional deficiency --Fe, B12, folate, etc. Acute/chronic bleeding Hemolytic anemia Bone marrow disorder Chronic renal disease “Thrombocytosis” “Thrombocytopenia” • • • • • • • • • • • • **Tissue damage --surgery, trauma, fractures *Infection Cancer Autoimmune Hemolytic anemia Myeloproliferative disease *Immune Drugs (APAP, sulfa) Sepsis Leukemia Lymphoma Chemo/Radiation CBC w/ diff example….77 yo AAM Anemia à Normal MCV & à Normocytic-Normochromic à most likely Normal MCHC ACD or CRD Anemia Microcytic (MCV <80fL) Normocytic (MCV 80-100 fL) Macrocytic (MCV >100 fL) Iron deficiency Hemolytic Folate (B9) deficiency Sideroblastic SS/SC Anemia B12 deficiency Lead (Pb) Aplastic Copper deficiency Thalassemias Chronic Renal Disease Drug-induced Posthemorrhagic EtOH abuse Anemia of Chronic Disease Liver disease Hypochromic Normochromic Hyperchromic Iron deficiency B12 deficiency Does not exist Lead (Pb) Folate (B9) deficiency Sideroblastic Hemolytic/SCD Anemia Aplastic Posthemorrhagic Chronic Renal Disease Anemia of Chronic Disease Questions??? — [email protected] — Office 932 in Tower