Hematopoietic and Lymphoid Systems Pathology by Marc Imhotep Cray, M.D.

Hematopoietic & Lymphoid Systems Pathology

Marc Imhotep Cray, M.D.

Marc Imhotep Cray1MD

Companion: The Top Ten Anemias to Know for Boards A Quick Review of High-Yield Anemias Kristine Krafts, M.D. 2nd Edition 2

Blood and Lymphatic System Learning Objectives: a) Red blood cells (anemias): 1. Define anemia and classify anemia on an etiologic and morphological basis and give the major examples in each category. 2. List causes of iron deficiency anemia. 3. Explain the pathophysiologic effects of iron-deficiency anemia. 4. List the major causes of vitamin B12 & folate deficiency. 5. Explain the pathogenesis of megaloblastic anemias. 6. Describe the bone marrow cellularity and peripheral blood counts in aplastic anemia.

Marc Imhotep Cray, M.D.

Blood and Lymphatic System Learning Objectives: a) Red blood cells (anemias) contâ&#x20AC;&#x2122;ed. 7. List the major causes of aplastic anemia. 8. Review the pathogenesis and hematologic findings of anemia of chronic disease. 9. Describe the mechanism of anemia of renal failure and how this differs from all other forms of anemia. 10. Compare and contrast extravascular and intravascular hemolysis. 11. Describe the peripheral blood and bone marrow changes seen in response to excessive red cell destruction.

Marc Imhotep Cray, M.D.

Kibble J , Cannarozzi ML. Pathophysiology Flash Cards. New York: McGraw-Hill, 2013. Marc Imhotep Cray, M.D.

Hematopoiesis The Components of Blood and Their Importance, American Society of Hematology

Online version.

Le T, et al. First Aid for the USMLE Step 1, 2020. New York, NY: McGraw-Hill; 2020, Pg. 406.

Marc Imhotep Cray, M.D.

Hematopoiesis - Formation of Blood Cells, Animation

Online version. Marc Imhotep Cray, M.D.

Erythrocytes (Red Blood Cells) Development  Hematopoietic stem cell  proerythroblast reticulocyte  erythrocyte  Mature erythrocytes contain no nucleus or cytoplasmic organelles thus, energy is derived from anaerobic degradation of glucose  Lifespan is 120 days old erythrocytes are removed from circulation by spleen and liver

Structure  Biconcave disk shape is maintained by submembrane cytoskeleton composed of spectrin, ankyrin, protein 4.1, and other proteins o Biconcave shape results in increased surface area to volume ratio, thereby enhancing gas exchange

Function  Involved in O2 and CO2 transport via hemoglobin (Hgb) Marc Imhotep Cray, M.D.

Erythrocytes cont’ed.  RBCs Carry O2 to tissues and CO2 to lungs  RBCs are anucleate and lack organelles large surface area-tovolume ratio for rapid gas exchange  Source of energy is glucose (90% used in glycolysis, 10% used in HMP shunt)  Membranes contain Cl-/HCO3antiporter, which allow RBCs to export HCO3- and transport CO2 from periphery to lungs for elimination Marc Imhotep Cray, M.D.

 Eryth = red; cyte = cell  Erythrocytosis = polycythemia = Inc. Hct  Anisocytosis = varying sizes  Poikilocytosis = varying shapes  Reticulocyte = immature RBC reflects erythroid proliferation  Bluish color (polychromasia) on Wright-Giemsa stain of reticulocytes represents residual ribosomal RNA

Adult Reference Ranges for Red Blood Cells What is the difference between hematocrit and hemoglobin? ď&#x201A;§ Hemoglobin (Hb) is the protein contained in red blood cells that is responsible for delivery of oxygen to the tissues. ď&#x201A;§ The hematocrit measures the volume of red blood cells compared to the total blood volume (red blood cells and plasma). Learn more: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Ch. 151 Hemoglobin and Hematocrit & Ch. 152 Red Cell Indices Robbins Basic Pathology 10th Ed. ,2018; 443.

Marc Imhotep Cray, M.D.

Normal bone marrow, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Normal bone marrow, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. Marc Imhotep Cray, M.D.

Normal bone marrow smear, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. Marc Imhotep Cray, M.D.

Normal peripheral blood smear, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Rouleaux formation, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Anemia

A condition in which the body lack enough RBCs or hemoglobin to carry adequate O2 to tissues. There are many forms, each with its own cause. It can be temporary or long term, can range from mild to severe, and be gradual or rapid in onset.

The Role of Red Blood Cells in Anemia, American Society of Hematology

Online version.

Diagnosis of anemia in men is based on a hemoglobin of less than 130 to 140 g/L (13 to 14 g/dL); in women, it is less than 120 to 130 g/L (12 to 13 g/dL). Further testing is then required to determine etiology. Marc Imhotep Cray, M.D.

Anemias: Essential Background Information How Red Blood Cell Carry Oxygen and Carbon Dioxide, Animation

Online version.

Marc Imhotep Cray, M.D.

Red Blood Cell Life Cycle and Disorders, Animation

Online version.

Pathology of Anemia Causes: three mechanisms by which body becomes anemic: 1. Blood loss (either acute or chronic) 2. Decreased production of RBCs, and 3. Increased destruction of RBCs (i.e., hemolysis)

Morphology  Microcytic (iron deficiency, thalassemia)  Macrocytic (folate or vitamin B12 deficiency)  Normocytic but w abnormal shapes (hereditary spherocytosis, sickle cell disease) Marc Imhotep Cray, M.D.

Classification of Anemia According to Underlying Mechanism

Robbins Basic Pathology 10th Ed. ,2018; 442.

Marc Imhotep Cray, M.D.

Reticulocytes & Reticulocyte index (RI) Reticulocytes are RBCs that are still developing made in bone marrow and sent into bloodstream mature after 2 days in periphery 

Provide an assessment of BM’s response to anemia

Reticulocyte index, also called corrected reticulocyte count is used to correct falsely elevated reticulocyte count in anemia  Retics. make up a higher % of bld count in anemia makes retic count falsely high needs to be corrected  RI measures appropriate BM response to anemic conditions (effective erythropoiesis) • •



High RI indicates compensatory RBC production Low RI indicates inadequate response to correct anemia

Calculated as: RI = reticulocyte % × actual Hct/normal Hct [normal Hct ≈ 45%]

Marc Imhotep Cray, M.D.

Reticulocyte count Analysis of reticulocyte count helps determine whether an anemia is due to a RBC production defect or to premature hemolysis and shortened survival defect  If there is shortened RBC survival, as in hemolytic anemias, BM tries to compensate by ↑ RBC production to release more reticulocytes into peripheral circulation  Although an ↑reticulocyte count is a hallmark of hemolytic anemias, it can also be observed after acute blood loss

Marc Imhotep Cray, M.D.

Reticulocyte count (2) Chronic blood loss, as against acute, does not lead to an appropriate ↑ in reticulocyte count but rather leads to iron deficiency and a subsequent low reticulocyte count 

Thus an inappropriately low reticulocyte count results from ↓ production of normal RBCs as a result of either insufficient or ineffective erythropoiesis

Marc Imhotep Cray, M.D.

Clinical Manifestations of Anemia  Acute: shortness of breath, organ failure, shock

 Chronic • Pallor, fatigue, lassitude • With hemolysis: jaundice and gallstones • With ineffective erythropoiesis: iron overload, heart and endocrine failure • If severe and congenital: growth retardation, bone deformities due to reactive marrow hyperplasia Marc Imhotep Cray, M.D.

Anemias

Le T, et al. First Aid for the USMLE Step 1, 2020. New York, NY: McGraw-Hill; 2020, Pg. 417. Marc Imhotep Cray, M.D.

Trigger Case 1 A 26-year-old pregnant woman presents to your office for a checkup. She states that her pregnancy has been proceeding smoothly, although she has been feeling more tired than she expected. Her physical examination is largely unremarkable except for marked pallor. You order serum studies and find that she has decreased hematocrit, decreased ferritin, and increased total iron-binding capacity. Her peripheral blood smear shows red blood cells that are both microcytic and hypochromic. You reassure her that these findings are most likely associated with her pregnancy status and recommend iron supplements. What is the Diagnosis? Marc Imhotep Cray, M.D.

Iron Deficiency Anemia  Etiology: Chronic blood loss, most often caused by gastrointestinal bleeding or menorrhagia; dietary deficiency (rare); malabsorption; pregnancy  Pathology: Peripheral blood smear: Hypochromic microcytic erythrocytes  Clinical Manifestations: Fatigue, conjunctival pallor, and dyspnea during exercise, pica (persistent craving and compulsive eating of nonfood substances), spoon nails (koilonychia)  Lab findings: Decreased hematocrit, decreased serum iron, decreased serum ferritin, increased TIBC, decreased Fe/TIBC ratio (< 15%)  Treatment: Iron supplementation; identification of source of occult blood loss Marc Imhotep Cray, M.D.

Iron Deficiency Anemia cont’ed.  Plummer-Vinson syndrome is a disease in which patients present with Triad of iron deficiency anemia, esophageal webs, and glossitis  It is associated with an increased risk for developing esophageal cancer

 Sideroblastic anemia is result of defective heme biosynthesis within erythrocyte precursor cells  It can be caused by hereditary enzymatic defects or acquired defects (ie, alcohol or lead, Myelodysplastic Syndromes (MDS) o Laboratory studies reveal increased iron and ferritin levels, but a normal TIBC o Ringed sideroblasts are present in bone marrow o Treatment is directed at underlying cause and supportive with blood transfusions Marc Imhotep Cray, M.D.

Hypochromic anemia, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

WebPath Hematopathology Index

Normal CBC, diagram

Marc Imhotep Cray, M.D.

CBC with iron deficiency anemia, diagram

Basophilic stippling, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Trigger Case 2 A 46-year-old man presents to your office complaining of weakness and a â&#x20AC;&#x153;pins and needlesâ&#x20AC;? feeling in his extremities. You note that he is ataxic and has decreased vibration and position sense in both his arms and legs. Upon further examination, you also observe that his tongue is red and enlarged. When laboratory tests reveal a positive Schilling test and a macrocytic anemia, you question the patientâ&#x20AC;&#x2122;s diet habits, drinking habits, and history of abdominal surgery. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Megaloblastic Anemias  Etiology: Vitamin B12 deficiency anemia (pernicious anemia): Autoimmune gastritis (results in the failure to produce intrinsic factor); malabsorption or vegetarian diet; gastric resection or resection of the ileum  Folate deficiency anemia: Malabsorption or dietary deficiency (often seen in alcoholics); pregnancy; pharmacologic agents (methotrexate, sulfa drugs, phenytoin, AZT)  Pathology:  Vitamin B12 deficiency: Demyelination of posterior and lateral columns of spinal cord o Peripheral blood smear: pancytopenia; hypersegmented neutrophils; macrocytic erythrocytes  Folate deficiency: Peripheral blood smear: pancytopenia; hypersegmented neutrophils; macrocytic erythrocytes Marc Imhotep Cray, M.D.

Megaloblastic Anemias cont’ed.  Clinical Manifestations:  Vitamin B 12 deficiency: Neurologic abnormalities (ataxia, impaired proprioception, and vibratory sensation); glossitis; symptoms of autoimmune gastritis o Lab findings: Decreased Hct, decreased serum vitamin B 12, anti-intrinsic factor antibodies, abnormal Schilling test (tests for decreased absorption of oral vitamin B12)  Folate deficiency: Glossitis and diarrhea o Lab findings: Decreased Hct, decreased red blood cell folate levels  Treatment:  Vitamin B 12 deficiency: Vitamin B12 supplementation; intrinsic factor supplementation if anemia caused by autoimmune gastritis  Folate deficiency: Folic acid supplementation Marc Imhotep Cray, M.D.

Megaloblastic anemia, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Vitamin B12 deficiency, MRI

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Hereditary Spherocytosis Etiology: Autosomal dominant condition that causes a defect in an erythrocytic membrane protein (usually spectrin or ankyrin) Pathology: Peripheral blood smear: Spherocytes (sphere-shaped erythrocytes with no central pallor) Clinical Manifestations: Splenomegaly; hemolytic anemia, which can lead to jaundice  Lab findings: Increased erythrocyte osmotic fragility, increased MCHC, reticulocytosis, normal MCV, normal Hgb

Treatment: Splenectomy; folate supplementation  Of Note: Paroxysmal nocturnal hemoglobinuria is a stem cell disorder characterized by increased sensitivity of RBCs to complement-mediated lysis  Patients present with episodic morning hemoglobinuria (increased urine hemosiderin), hemolytic anemia, and venous thrombosis  Diagnosis is confirmed by positive Ham (acid serum) test and flow cytometry o Ham Test now an obsolete for Dx of PNH due to its low sensitivity and specificity Marc Imhotep Cray, M.D.

Hereditary spherocytosis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Trigger Case 3 A 35-year-old African American man comes to your office after noticing that his urine has become tea colored. He tells you that he has just returned from a trip to Africa where he had taken primaquine to guard against contracting malaria. Upon finding Heinz bodies on his peripheral blood smear, you suspect that his dark urine will likely resolve on its own shortly. You reassure the patient that his current condition is likely related to the primaquine and recommend no further testing. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Glucose-6-Phosphate Dehydrogenase Deficiency Anemia Etiology and Epidemiology: X-linked recessive disorder resulting in a deficiency of glucose-6-phosphate dehydrogenase (G6PD); Affects 10%–15% of African Americans Pathology and Pathophysiology:  Peripheral blood smear: Bite cells; Heinz bodies (clumps of oxidized hemoglobin within RBC)  Pathophysiology: G6PD is an enzyme involved in production of NADPH in hexose monophosphate shunt pathway o NADPH is necessary for reduced glutathione, which protects hemoglobin from oxidative damage o When G6PD is deficient, reduced glutathione is absent o Without reduced glutathione, hemoglobin is oxidized and forms Heinz bodies in RBC o Heinz bodies cause damage to RBC membrane and these damaged RBCs are removed in spleen, leading to anemia Marc Imhotep Cray, M.D.

G6PD Anemia cont’ed.  Clinical Manifestations: Episodic hemolytic anemia with hemoglobinuria occurring with ingestion of oxidant drugs (eg, primaquine, quinidine, quinine, sulfonamides, anti-TB drugs) or certain foods (ie, fava beans)  Treatment: Avoid oxidant drugs

 Of Note: Increased malarial resistance is noted with G6PD deficiency

Marc Imhotep Cray, M.D.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Trigger Case 4 An 8-year-old African American boy presents to the emergency department complaining of severe pain in both legs. The pain began after the boy attended a pool party and spent much of the day swimming. He reports that he has suffered from severe bouts of back and chest pain in the past owing to a pre-existing medical condition. Routine laboratory studies demonstrate a severe anemia. You place the child on oxygen, begin aggressive intravenous fluid hydration and call the blood bank to prepare for a blood transfusion. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Sickle Cell Anemia Etiology and Epidemiology: Autosomal recessive disorder resulting in production of Hgb S  Hgb S arises from a mutation (substitution of valine for glutamine) in gene coding for β-globin chain of Hgb o 8% of African Americans carry the gene for Hgb S

Pathology and Pathophysiology:  Peripheral blood smear: Crescent-shaped RBCs; Howell-Jolly bodies; reticulocytosis  Pathophysiology: Hgb S polymerizes in hypoxic environments (as caused by infection, exercise, or dehydration) causing RBC shape to become distorted and more susceptible to hemolysis Marc Imhotep Cray, M.D.

Sickle Cell Anemia cont’ed. Clinical Manifestations:  Chronic hemolytic anemia, which may lead to jaundice and leg ulcers  Vaso-occlusive crises o Severe pain in back or limbs b/c of microvasculature blockage by sickled cells  Autosplenectomy caused by repeated infarction  Aplastic crises usually provoked by B19 parvovirus infection  Increased susceptibility to infection by encapsulated organisms (Salmonella) o Imaging: “Crew cut” on skull x-ray b/c of marrow expansion

Marc Imhotep Cray, M.D.

Sickle Cell Anemia cont’ed. Treatment:  Transfusions, fluid resuscitation, pain control, and oxygen during hemolytic and vaso-occlusive crises  plasma exchange for severe vaso-occlusive crises (ie, stroke, acute chest syndrome);  hydroxyurea (increases Hgb F levels) and bone marrow transplant for severe disease Note:  Patients with hemoglobin C disease (different mutation in β-chain of Hgb) and sickle cell trait (heterozygous for Hgb S gene) tend to have milder versions of sickle cell anemia  Hgb S gene provides resistance to Plasmodium falciparum malaria Marc Imhotep Cray, M.D.

https://en.wikipedia.org/wiki/Sickle_cell_disease Marc Imhotep Cray, M.D.

Sickle cells in human blood - both normal red blood cells and sickle-shaped cells are present.

Normal blood cells next to a sickle blood cell, colored scanning electron microscope image

https://en.wikipedia.org/wiki/Sickle_cell_disease Marc Imhotep Cray, M.D.

HBB gene (responsible for sickle cell anemia) is Sickle cell disease is inherited in an autosomal recessive pattern. located on the short (p) arm of chromosome 11 at position 15.5.

https://en.wikipedia.org/wiki/Sickle_cell_disease

Marc Imhotep Cray, M.D.

Distribution of the sickle cell trait, shown in pink and purple

Historical distribution of malaria (no longer endemic in Europe), shown in green

https://en.wikipedia.org/wiki/Sickle_cell_disease

Marc Imhotep Cray, M.D.

Sickle Cell Anemia and its Protection Against Malaria ď&#x201A;§

In series A the red blood cell becomes sickled after interaction with the malarial merozoite, which then begins to multiply in the cell (schizont). Due to the heterozygous nature of the cell, and the hemoglobin inside it causing sickling, likely as a result of the lowering of the pH and deoxygenation, the cell can be targeted and eliminated by macrophages before the infection can reproduce, lowering the overall amount of infected cells in comparison to normal red blood cells.

ď&#x201A;§

In series B the normal red blood cell becomes infected by the merozoite, which multiplies inside the cell, eventually causing hemolysis of the cell, and the offspring go on to infect other cells.

Marc Imhotep Cray, M.D.

https://commons.wikimedia.org/wiki/File:Sickle_Cell_Anemia_and_its_Protectio n_Against_Malaria.svg

Sickle cell anemia, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Sickle Cell Disease, Animation

Online version. Marc Imhotep Cray, M.D.

Sickle cell anemia, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Hemoglobin SC disease, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Hemoglobin electrophoresis, cellulose acetate

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Trigger Case 5 A 10-month-old boy from Greece presents with pallor and failure to thrive. During physical examination, you find that his spleen is enlarged and that he has an abnormal facial structure. You order a peripheral blood smear, which shows a microcytic, hypochromic anemia with target cells. You begin to suspect that this child may need blood transfusions for the rest of his life. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Thalassemias  Etiology and Epidemiology:  α-Thalassemias: Deletion of one or more of four genes coding α-globin chain of Hgb  β-Thalassemias: Point mutation in β-globin gene resulting in reduced or absent synthesis of β-globin chain of Hgb  All thalassemias are relatively more common in people of Mediterranean ancestry  Pathology:  α-Thalassemias: o Peripheral blood smear: hypochromic, microcytic erythrocytes; target cells  β-Thalassemias: o Peripheral blood smear: hypochromic, microcytic erythrocytes; target cells; anisopoikilocytosis Marc Imhotep Cray, M.D.

Thalassemias cont’ed. Clinical Manifestations:  α-Thalassemias: Four clinical variants: (1) α-thalassemia trait w 3–4 normal genes present—asymptomatic; (2) α-thalassemia trait w 2 normal genes present—mild anemia w decreased MCV; (3) Hemoglobin H disease w 1 normal gene present—severe hemolytic anemia w decreased MCV (< 70), presence of Hgb H (aggregation of excess β-chains), splenomegaly; (4) hydrops fetalis w 0 normal genes present stillborn fetus  β-Thalassemias: Two clinical variants: (1) β-thalassemia minor (heterozygosity)—mild anemia w decreased MCV; (2) β-thalassemia major (homozygosity)—severe hemolytic anemia w decreased MCV, presenting in infancy, increased Hgb F, splenomegaly, bony abnormalities (marrow expansion), hemosiderosis (owing to chronic transfusions), heart failure (owing to hemosiderosis) Marc Imhotep Cray, M.D.

Thalassemias cont’ed.  Treatment:  α-Thalassemias: o No treatment needed for α-thalassemia trait; o Transfusions for hemoglobin H disease  β-Thalassemias: o No treatment needed for β-thalassemia minor; o Transfusion and/or bone marrow transplantation for β-thalassemia major

Marc Imhotep Cray, M.D.

Î˛-Thalassemia major, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Î˛-Thalassemia major, hemoglobin electrophoresis

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Î˛-Thalassemia major, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Sebes and Diggs, Radiographic Changes of the Skull in Sickle Cell Anemia AJR; 132, March 1979. Marc Imhotep Cray, M.D.

Î˛-Thalassemia major, radiograph

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. Marc Imhotep Cray, M.D.

Îą-Thalassemia major, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. Marc Imhotep Cray, M.D.

Îą-Thalassemia major, capillary electrophoresis

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Trigger Case 6 A 30-year-old woman arrives at the emergency room complaining of fatigue and dark-colored urine. While obtaining the history of her present illness, you learn that she has been recovering from a recent bout of pneumonia, for which she had been treated appropriately by her primary care physician with a course of antibiotics. Physical examination reveals an enlarged spleen and slight scleral icterus. You obtain a blood sample and decide to order a direct Coomb test. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Autoimmune Hemolytic Anemias Etiology:  Warm antibody autoimmune hemolytic anemia (WAIHA): Caused by IgG antibodies that react against the RBC membrane; reason for formation of IgG antibodies may be idiopathic, or underlying disease such as SLE, CLL, or lymphomas  Cold agglutinin disease (CAD): Caused by IgM antibodies that react against I antigen on RBCs leading to phagocytosis of RBC; reason for formation of IgM antibodies is often idiopathic, or may be a result of Waldenstrom macroglobulinemia, mononucleosis, or Mycoplasma pneumoniae infection  Besides WAIHA and CAD, autoimmune hemolytic anemia can also be induced by pharmacologic agents (sulfa drugs, quinidine, rifampin) Pathology:  WAIHA: Peripheral blood smear: spherocytes (sphere-shaped erythrocytes with no central pallor);reticulocytosis  CAD: Peripheral blood smear: spherocytes (sphere-shaped erythrocytes with no central pallor); reticulocytosis Marc Imhotep Cray, M.D.

Autoimmune Hemolytic Anemias cont’ed.  Clinical Manifestations:  WAIHA: Severe hemolytic anemia, which may lead to jaundice; splenomegaly. Lab findings: Positive direct Coomb test, decreased Hct.  CAD: Mild hemolytic anemia (which may lead to jaundice) upon exposure to cold. Lab findings: Positive cold agglutinin test  Treatment:  WAIHA: Treat underlying disease; steroids and/or splenectomy CAD: Avoid cold environments  Note:  Direct Coomb test checks for presence of antibodies on surface of RBCs. Indirect Coomb test assesses for presence of free antibody in patient’s serum. Marc Imhotep Cray, M.D.

Schematic showing direct and indirect Coombs tests.

Marc Imhotep Cray, M.D.

https://upload.wikimedia.org/wikipedia/commons/1/1c/Coombs_test_schematic.png

Hemolytic anemia, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

More About Hemolytic Anemias Classification and Peripheral Smear Findings:

https://step1.medbullets.com/hematology/107041/autoimmune-hemolytic-anemia

Marc Imhotep Cray, M.D.

Normocytic, normochromic anemias ď ąNormocytic, normochromic anemias are classified as nonhemolytic or hemolytic ď&#x201A;§ hemolytic anemias are further classified according to o cause of hemolysis (intrinsic vs extrinsic to RBC) and by o location of hemolysis (intravascular vs extravascular) ď&#x201A;§ Hemolysis can lead to o increases in LDH, reticulocytes, unconjugated bilirubin, pigmented gallstones, and urobilinogen in urine

Marc Imhotep Cray, M.D.

 Intravascular hemolysis 

Findings: decrease haptoglobin, increase schistocytes on blood smear o



Characteristic hemoglobinuria, hemosiderinuria, and urobilinogen in urine

Causes are mechanical hemolysis (eg, prosthetic valve), paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias

 Extravascular hemolysis  Mechanism: macrophages in spleen clear RBCs  Findings: spherocytes in peripheral smear  Causes: most commonly due to hereditary spherocytosis and autoimmune hemolytic anemia o no hemoglobinuria/hemosiderinuria

 Can present with urobilinogen in urine Note: Nonhemolytic, normocytic anemias include anemia of chronic disease, aplastic anemia, (Iron deficiency anemia) and chronic renal disease To learn more see: First AID for the USMLE Step 1, 2020, Pg.421. Marc Imhotep Cray, M.D.

Intrinsic vs. Extrinsic Anemias Q&A https://www.pathologystudent.com/intrinsic-vs-extrinsic-anemias/ Q. Can you help me understand intrinsic vs. extrinsic anemias? My concept of it is that intrinsic means itâ&#x20AC;&#x2122;s in the blood vessels and extrinsic means itâ&#x20AC;&#x2122;s in the spleen. Is this a correct assumption? Or not necessarily? A. Usually, when we use the words intrinsic and extrinsic in reference to anemias, weâ&#x20AC;&#x2122;re talking about the things that cause hemolytic anemias. Some hemolytic anemias are caused by things intrinsic to the red cell itself (like a problem with the red cell membrane, as is the case in hereditary spherocytosis, or a problem with a red cell enzyme, as is the case in G6PD deficiency) vs. things that are extrinsic to the red cell (like the fibrin strands that rip apart red cells in microangiopathic hemolytic anemia). I think the concepts you are referring to are intravascular hemolysis (which is hemolysis that happens in blood vessels, often due to complement activation) and extravascular hemolysis (which is hemolysis that happens in the spleen, often due to antibodies coating the red cells). Download this eBook from the Pathology Professor who authors Pathology Student. The Top Ten Anemias to Know for Boards: A Quick Review of High-Yield Anemias. Kristine Krafts, M.D. 2nd Edition. Marc Imhotep Cray, M.D.

Trigger Case 7 A 28-year-old woman presents to the hospital in labor with her second child. As you prepare for the delivery, you discover that this woman had pregnancy complications associated with tearing of the placenta during the delivery of her first child. The mother and first child had been blood typed for Rh antigen during their stay at the hospital and records show that the mother is D-negative and the first child was D-positive. Concerned, you decide to administer anti-D IgG antiserum to the mother during her delivery to prevent the possibility of a serious hematologic complication for the second child. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Erythroblastosis Fetalis:

Hemolytic disease of the newborn (HDN) also known as hemolytic disease of the fetus and newborn (HDFN)

 Etiology: ABO incompatibility or Rh antigen incompatibility (usually fetal D antigen) between mother and fetus  Pathology and Pathophysiology: Peripheral blood smear: Erythroblasts; reticulocytosis  Pathophysiology: Maternal alloimmunization to fetal red blood cell antigens (usually caused by exposure to fetal Rh antigens during prior pregnancy) results in maternal antibodies reacting against fetal RBCs  Clinical Manifestations: Severe fetal hemolytic anemia; extramedullary hematopoiesis; increased indirect bilirubin resulting in jaundice and kernicterus; severe cases may result in fetal heart failure with generalized edema or in a stillbirth  Treatment:  Transfusion  Preventive measures include giving anti-D IgG to D-negative mothers during delivery of a D-positive child Marc Imhotep Cray, M.D.

Erythroblastosis Fetalis_Mechanism Explained

https://upload.wikimedia.org/wikipedia/commons/c/ce/1910_Erythroblastosis_Fetalis.jpg

Marc Imhotep Cray, M.D.

Le T, et al. First Aid for the USMLE Step 1, 2020. New York, NY: McGraw-Hill; 2020, Pg. 405.

Marc Imhotep Cray, M.D.

Hemolytic Disease of the Newborn, Animation

Online version. Marc Imhotep Cray, M.D.

Blood type (or blood group) is determined, in part, by the ABO blood group antigens present on red blood cells.

https://en.wikipedia.org/wiki/Blood_type#/media/File:ABO_blood_type.svg Marc Imhotep Cray, M.D.

Red blood cell compatibility chart ď ą In addition to donating to the same blood group; type O blood donors can give to A, B and AB; blood donors of types A and B can give to AB

Marc Imhotep Cray, M.D.

https://en.wikipedia.org/wiki/Blood_type#/media/File:Blood_Compatibility.svg

Main symptoms of acute hemolytic reaction due to blood type mismatch.

Marc Imhotep Cray, M.D.

https://en.wikipedia.org/wiki/Blood_type#/media/File:Main_symptoms_of_acute_hemolytic_reaction.png

Blood Types, Blood Group Systems & Transfusion Rule, Animation

Online version. Marc Imhotep Cray, M.D.

Trigger Case 8 A 15-year-old girl presents to the emergency department with a petechial rash, bleeding of the oral mucosa, fatigue, and a history of recurrent sinus infections over the past 2 months. She does remember having had a bad flulike virus about 3 months ago that caused her to miss 4 days of school. There is no hepatosplenomegaly on examination. Laboratory tests reveal anemia, neutropenia, and thrombocytopenia. There are no abnormal cell types seen on peripheral blood smear. You decide to admit the patient to the hospital and you schedule a bone marrow biopsy. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Aplastic Anemia  Etiology: Idiopathic; radiation, benzene, or drugs (chloramphenicol, alkylating agents); idiopathic autoimmune dysfunction of cytotoxic T cells; viral infection (parvovirus B19, EBV, HIV, hepatitis C); auto-immune disorders (ie, SLE)  Pathology:  Bone marrow: Hypocellular and demonstrating fatty change with no hematopoietic cells  Peripheral blood smear: Pancytopenia  Clinical Manifestations: Anemia presenting with fatigue, malaise, and pallor; neutropenia presenting with infections; thrombocytopenia presenting with mucosal bleeding, purpura, or petechiae; no hepatosplenomegaly  Treatment:  Transfusion; admin. of G-CSF or GM-CSF; allogenic bone marrow transplant; cessation of causative drug; immunosuppression w cyclosporine Marc Imhotep Cray, M.D.

Aplastic anemia

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

Case Trigger 9 A 57-year-old woman with a history of rheumatoid arthritis presents to your office complaining of fatigue upon exertion. You note that she is pale and decide to send her for serum studies. Laboratory results reveal an anemia as well as low serum iron levels, a low TIBC, and mildly increased serum ferritin levels. You tell the patient your diagnosis and begin to discuss whether treatment is necessary. What is the Diagnosis?

Marc Imhotep Cray, M.D.

Anemia of Chronic Inflammation Etiology: Secondary to chronic systemic disorders, including rheumatoid arthritis, chronic infection (ie, HIV), or malignancy Pathology and Pathophysiology: Peripheral blood smear: Normochromic, normocytic erythrocytes Pathophysiology: Increased cytokines and hepcidin in setting of inflammatory state leads to impaired iron utilization by bone marrow with resulting decreased erythropoiesis Clinical Manifestations: Fatigue and pallor associated with anemia Lab findings: Mildly decreased Hct, low serum iron, low TIBC, normal to increased serum ferritin (increased storage iron in marrow macrophages) Treatment: Treat underlying disease; synthetic erythropoietin or blood transfusions if severe

Marc Imhotep Cray, M.D.

Note: Anemia of inflammation, also called anemia of chronic disease or ACD, is a type of anemia that affects people who have conditions that cause inflammation, such as infections, autoimmune diseases, cancer link, and chronic kidney disease (CKD).

Learning Objectives 1. What are the 3 general components of hemostasis? 2. What is the basic sequence of events following vessel injury? 3. What induces the endothelium to switch from an antithrombotic state to a prothrombotic state? 4. What are the antithrombotic properties of endothelial cells? 5. Outline the formation of primary hemostatic plugs (3 main steps) 6. How do thrombocytopenia and thrombocytopathy differ and what lesions are associated with these defects? 7. Outline the formation of a secondary hemostatic plug 8. What is the most important component (outcome ) of the coagulation cascade? 9. What lesions do we see with defects in coagulation? 10. What is DIC? 11. Describe the resolution of hemostatic plugs Marc Imhotep Cray, M.D.

Learning Objectives (2) 12. Discuss the mechanisms that lead to thrombosis (Virchowâ&#x20AC;&#x2122;s triad). List the possible outcomes of thrombosis. 13. Identify and classify thrombi (arterial vs venous, etc) based on location and gross/microscopic features. 14. Describe the causes and consequences of embolism. 15. What materials may form emboli? 16. Which is most common? 17. Describe the pathogenesis of ischemia and infarction.

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Hemostasis: The Prevention of Blood Loss

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Hemostasis Background Video Edu: Hemostasis Primary & Secondary_Amboss Series

Stoppage of bleeding is known as hemostasis Hemostatic mechanisms are most effective in dealing with injuries in small vessels—arterioles, capillaries, and venules most common sources of bleeding in everyday life

In contrast, body usually cannot control bleeding from a medium or large artery (surgical attention required) Marc Imhotep Cray, M.D.

Hemostasis and Clotting Hemostasis Well regulated process  Keeps blood fluid (clot free) within blood vessels  Rapid clot formation (hemostatic plug) occurs with vessel injury Clotting  Hemostatic clot is normal in cases of vessel injury  Thrombosis refers to an inappropriate activation of hemostatic process Marc Imhotep Cray, M.D.

Hemostasis cont’ed. Three components of hemostasis  Endothelial cells  Platelets  Coagulation Cascade Sequence of events in normal hemostasis following vascular injury 1. Arteriolar vasoconstriction  Endothelium 2. Primary hemostasis  Platelets 3. Secondary hemostasis  Coagulation cascade 4. Antithrombotic counter-regulation  Fibrinolytic system Marc Imhotep Cray, M.D.

Normal hemostasis Capsule

Kumar V, Abbas AK, Aster JC. Robbins Basis Pathology, 10th Ed. Philadelphia: Saunders-Elsevier, 2018. Fig. 4.5, Pg. 102.

Marc Imhotep Cray, M.D.

Normal hemostasis Capsule contâ&#x20AC;&#x2122;ed.

Kumar V, Abbas AK, Aster JC. Robbin Basis Pathology, 10th Ed. Philadelphia: Saunders-Elsevier, 2018. Fig. 4.5, Pg. 102.

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Platelet adhesion and aggregation. VWF functions as an adhesion bridge between subendothelial collagen and the glycoprotein 1b (Gplb) platelet receptor. Platelet aggregation is accomplished by fibrinogen binding to platelet Gpllb-llla receptors on different platelets. Congenital deficiencies in the various receptors or bridging molecules lead to the diseases indicated in the colored boxes.

Kumar V, Abbas AK, Aster JC. Robbins Basis Pathology, 10th Ed. Philadelphia: Saunders-Elsevier, 2018. Fig. 4.6, Pg. 103. Marc Imhotep Cray, M.D.

Hemostasis cont’ed. I. Initial response to blood vessel damage is vasoconstriction and sticking together of opposed endothelial surfaces

Formation of a Platelet Plug (Primary Hemostasis) I. Next events are formation of a platelet plug followed by blood coagulation (clotting) II. Platelets adhere to exposed collagen in a damaged vessel and release contents of their secretory vesicles  These substances help cause platelet activation and aggregation  This process is also enhanced by von Willebrand factor secreted by endothelial cells and thromboxane A2 produced by platelets  Fibrin forms bridges betw. aggregating platelets  Contractile elements in platelets compress and strengthen plug

III. Platelet plug does not spread along normal endothelium b/c nml endothelium secretes prostacyclin and nitric oxide both inhibit platelet aggregation Marc Imhotep Cray, M.D.

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Prostacyclin (prostaglandin I2 [PGI2]) and Nitric Oxide (NO), both produced by endothelial cells, inhibit platelet aggregation and therefore prevent spread of platelet aggregation from a damaged site.

From Widmaier EP, Raff H , Strang KT. Vanderâ&#x20AC;&#x2122;s Human Physiology : The Mechanisms of Body Function, 14th ed. New York, NY: McGrawHill, 2016; Fig. 12.71, Pg. 429.

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Hemostasis cont’ed. Blood Coagulation: Clot Formation (Secondary Hemostasis) I. Blood is transformed into a solid gel when, at site of vessel damage, plasma fibrinogen is converted into fibrin molecules, which then bind to each other to form a mesh II. This reaction is catalyzed by the enzyme thrombin, which also activates factor XII, a plasma protein that stabilizes the fibrin meshwork III. Formation of thrombin from plasma protein prothrombin is end result of a cascade of reactions in which an inactive plasma protein is activated and then enzymatically activates next protein in series  Thrombin exerts a positive feedback stimulation of cascade by activating platelets and several clotting factors  Activated platelets, which display platelet factor and binding sites for several activated plasma factors, are essential for cascade Marc Imhotep Cray, M.D.

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Hemostasis cont’ed. Blood Coagulation: Clot Formation cont’ed IV. Cascade usually begins via extrinsic clotting pathway when tissue factor forms a complex with factor VIIa This complex activates factor X which then catalyzes conversion of small amounts of prothrombin to thrombin This thrombin then recruits intrinsic pathway by activating factor XI and factor VIII, as well as platelets, and this pathway generates large amounts of thrombin V. Liver requires vitamin K for normal production of prothrombin and other clotting factors

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Scanning electron micrograph of erythrocytes enmeshed in fibrin.

From Widmaier EP, Raff H , Strang KT. Vanderâ&#x20AC;&#x2122;s Human Physiology : The Mechanisms of Body Function, 14th ed. New York, NY: McGraw-Hill, 2016; Fig. 12.73, Pg. 430. Marc Imhotep Cray, M.D.

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Structure and function of factor Vlllâ&#x20AC;&#x201D;von Willebrand factor (vWF) complex. Factor Vlll and vWF circulate as a complex. vWF also is present in the subendothelial matrix of normal blood vessels. Factor Vlll takes part in the coagulation cascade by activating factor X by means of factor IX (not shown). vWF causes adhesion of platelets to subendothelial collagen, primarily through the glycoprotein 1b (Gplb) platelet receptor.

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Basic Pathology, 10th ed. Philadelphia: Saunders-Elsevier, 2018. Fig 21.31 .Pg. 489. Marc Imhotep Cray, M.D.

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Anti-clotting Systems I. Clotting is limited by three events:  Tissue factor pathway inhibitor inhibits the tissue factor–factor VIIa complex  Protein C, activated by thrombin, inactivates factors VIIIa and Va  Antithrombin III inactivates thrombin and several other clotting factors

II. Clots are dissolved by the fibrinolytic system  A plasma proenzyme, plasminogen, is activated by plasminogen activators to plasmin, which digests fibrin  Tissue plasminogen activator is secreted by endothelial cells and is activated by fibrin in a clot Examples of Anti-clotting drugs I. Aspirin inhibits platelet cyclooxygenase (COX-1) activity thereby inhibiting prostaglandin and thromboxane production—this inhibits platelet aggregation II. Warfarin and heparin interfere with clotting factors— they prevent clot formation. III. Recombinant tissue plasminogen activator (t-PA) is a thrombolytic—dissolves bld clots after they are formed Marc Imhotep Cray, M.D.

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See Video Edu: Coagulation Cascade and Lab. Measurements _Katie Boes 107

Key Laboratory Terms and Definitions Follow

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The Clotting Mechanism

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Test of Clotting Pathway

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Key laboratory terms and definitions: Partial thromboplastin time (PTT) measures overall speed at which blood clots by means of two consecutive series of biochemical reactions intrinsic pathway and common pathway of coagulation  PTT measures following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VIII (anti-hemophilic factor), X (Stuart–Prower factor), XI (plasma thromboplastin antecedent), and XII (Hageman factor).  Thrombin time (TT), aka thrombin clotting time (TCT) measures time it takes for a clot to form in plasma of a bld sample containing anticoagulant, after an excess of thrombin has been added  TT assesses activity of fibrinogen It is used to Dx bld coagulation disorders and to assess effectiveness of fibrinolytic therapy TT is generally <22 seconds (14 to 16 seconds) Marc Imhotep Cray, M.D.

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Key laboratory terms and definitions cont’ed. Prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – are assays evaluating extrinsic pathway and common pathway of coagulation  Also called protime INR and PT/INR  Used to determine clotting tendency of blood, in measure of warfarin dosage, liver damage, and vitamin K status  PT measures following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X (Stuart–Prower factor)

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Key laboratory terms and definitions cont’ed. PTT and activated partial thromboplastin time (aPTT) are used to test for same functions (intrinsic pathway and common pathway ) in aPTT, an activator is added that speeds up clotting time and results in a narrower reference range  Normal aPTT value is 30 to 40 seconds  On heparin, you'd want your PTT 120 to 140 seconds, and your aPTT to be 60 to 80 seconds

Reference range for PT is 11.0-12.5 seconds  Results are given as what is called INR (international normalized ratio)  If not taking oral anticoagulants, such as warfarin, normal range for PT results is: 11 to 13.5 seconds; INR of 0.8 to 1.1 o Adequate anticoagulation is considered PT 1.5 to 2 x normal or INR 2.0 to 3.0 Marc Imhotep Cray, M.D.

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Key laboratory terms and definitions cont’ed. Bleeding time (BT) test determines how quickly blood clots to stop bleeding done to assess platelets function  Involves making small punctures in the skin  Normal BT is 2-7 min

Qualitative platelet disorders suggested by a prolonged bleeding time (abnormal platelet function screen) or clinical evidence of bleeding in setting of a normal platelet count and coagulation studies  most commonly acquired, but can be inherited o Acquired disorders include drugs (most frequent), hematologic diseases, and systemic disorders Learn more: Coagulation and Lab Test_Q&A Driven Learning.pdf Marc Imhotep Cray, M.D.

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Bleeding Diathesis versus Thrombophilia Bleeding diathesis is an unusual susceptibility to bleed (hemorrhage) mostly due to hypocoagulability (a condition of irregular and slow blood clotting), in turn caused by a coagulopathy (a defect in the system of coagulation). Thrombophilia is a condition in which there's an imbalance in naturally occurring blood-clotting proteins, or clotting factors. This can put you at risk of developing blood clots. Marc Imhotep Cray, M.D.

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Bleeding Diathesis  Bleeding diathesis is an unusual susceptibility to bleed (hemorrhage) mostly due to hypocoagulability (a condition of irregular and slow blood clotting) in turn caused by a coagulopathy (a defect in the system of coagulation) • Therefore, this may result in reduction of platelets being produced or clotting factor deficiencies leads to excessive bleeding

 Several types of coagulopathy are distinguished, ranging from mild to lethal  Coagulopathy can be caused by thinning of skin (Cushing's syndrome)such that skin is weakened and is bruised easily and frequently without any trauma or injury to body  Also, coagulopathy can be contributed by impaired wound healing or impaired clot formation Marc Imhotep Cray, M.D.

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Qualitative Platelet Disorder:

 Congenital:  Glanzmann's Thromboasthenia • Rare coagulopathy in which platelets contain defective or low levels of glycoprotein IIb/IIIa (GpIIb/IIIa), which is a receptor for fibrinogen  Bernard–Soulier syndrome • rare autosomal recessive bleeding disorder caused by a deficiency of glycoprotein Ib (GpIb), receptor for von Willebrand factor  Von Willebrand disease • Most common hereditary blood-clotting disorder in humans. Mutation results in impaired synthesis in von Willebrand factor, leading to a qualitative defect in platelet binding and aggregation.  Acquired:  Myeloproliferative disorder  Uremia  Drugs, ie., NSAIDS, Aspirin  Autoantibody Marc Imhotep Cray, M.D.  Fibrin degradation products

Kumar V, Abbas AK, Aster JC. Robbins Basis Pathology, 10th Ed. Philadelphia: SaundersElsevier, 2018. Fig. 4.6, Pg. 103.

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Causes Bleeding Diathesis While there are several possible causes, they generally result in excessive bleeding and a lack of clotting Acquired  Acquired causes of coagulopathy include anticoagulation with warfarin, liver failure, vitamin K deficiency and disseminated intravascular coagulation are common examples  Viral hemorrhagic fevers include dengue hemorrhagic fever and dengue shock syndrome  Leukemia may also cause coagulopathy  Cystic fibrosis has been known to cause bleeding diathesis, especially in undiagnosed infants, due to malabsorption of fat soluble vitamins like vitamin K  Additionally, the hemotoxic venom from certain species of snakes can cause this condition, for example Bothrops, rattlesnakes and other species of viper Marc Imhotep Cray, M.D.

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Causes Bleeding Diathesis (2) Genetic  Some people lack genes that typically produce protein coagulation factors that allow normal clotting  Various types of hemophilia and von Willebrand disease are major genetic disorders associated with coagulopathy  Rare examples are Bernard–Soulier syndrome, Wiskott–Aldrich syndrome and Glanzmann's thrombasthenia  Gene therapy treatments may be a solution as they involve in insertion of normal genes to replace defective genes causing the genetic disorder • Gene therapy is a source of active research that hold promise for the future McCain J (June 2005). "The future of gene therapy". Biotechnology Healthcare. 2 (3): 52–60. Marc Imhotep Cray, M.D.

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Signs and symptoms bleeding diathesis Symptom

Disorders

Petechiae (red spots)

Wiskott–Aldrich syndrome, where they may resemble a few bruises; Acute leukemia; Chronic leukemia; Vitamin K deficiency Acute leukemia; Chronic leukemia; Vitamin K deficiency Wiskott–Aldrich syndrome, especially in infancy Acute leukemia Wiskott–Aldrich syndrome; Acute leukemia; Chronic leukemia Wiskott–Aldrich syndrome

Purpura and ecchymoses Blood in stool Bleeding gingiva (gums) Prolonged nose bleeds Marc Imhotep Cray, M.D.

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Complications of bleeding diathesis The table displays some complications of coagulopathies, some of them caused by their treatments:

Complication

Disorders

Soft tissue bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb

Hemophilia; Von Willebrand disease

Joint damage, potentially with severe pain and even destruction of the joint and development of arthritis

Hemophilia; Von Willebrand disease

Retinal bleeding

Acute leukemia

Transfusion transmitted infection, from blood transfusions given as treatment.

Hemophilia

Adverse reactions to clotting factor treatment.

Hemophilia

Anemia

Von Willebrand disease

Exsanguination (bleeding to death)

Von Willebrand disease; Acute leukemia Vitamin K deficiency

Cerebral hemorrhage

Wiskottâ&#x20AC;&#x201C;Aldrich syndrome

Companion Tutorial: Bleeding from Platelets vs Clotting Factors Marc Imhotep Cray, M.D.

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Thrombophilia  Thrombophilia (sometimes hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases risk of thrombosis (blood clots in blood vessels)  Such abnormalities can be identified in 50% of people who have an episode of thrombosis (such as deep vein thrombosis in the leg) that was not provoked by other causes

 A significant proportion of population has a detectable abnormality, but most of these only develop thrombosis in presence of an additional risk factor  There is no specific treatment for most thrombophilias  but recurrent episodes of thrombosis may be an indication for long-term preventive anticoagulation • First major form of thrombophilia, antithrombin deficiency, was identified in 1965 • Most common abnormalities (including factor V Leiden) were described in the 1990s Marc Imhotep Cray, M.D.

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Causes of Thrombophilia: Congenital or Acquired Congenital  Most common types of congenital thrombophilia are those that arise as a result of overactivity of coagulation factors  They are relatively mild, and are therefore classified as "type II" defects • Most common ones are factor V Leiden (a mutation in F5 gene at position 1691) and prothrombin G20210A, a mutation in prothrombin (at position 20210 in the 3' untranslated region of the gene)  Rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants  They are classified as "type I" and are more severe in their propensity to cause thrombosis • Main ones are antithrombin III deficiency, protein C deficiency and protein S deficiency Marc Imhotep Cray, M.D.

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Causes of Thrombophilia (2) Acquired A number of acquired conditions augment the risk of thrombosis  A prominent example is antiphospholipid syndrome, which is caused by antibodies against constituents of the cell membrane, particularly lupus anticoagulant (first found in people with disease systemic lupus erythematosus)  Heparin-induced thrombocytopenia (HIT) is due to an immune system reaction against anticoagulant drug heparin (or its derivatives) • Though it is named for associated low platelet counts, HIT is strongly associated with risk of venous and arterial thrombosis  Paroxysmal nocturnal hemoglobinuria (PNH) is a rare condition resulting from acquired alterations in PIGA gene, which plays a role in protection of blood cells from the complement system • PNH increases risk of venous thrombosis but is also associated with hemolytic anemia (anemia resulting from destruction of red blood cells)  Cancer  Pregnancy  OCP (Estrogen)  Obesity

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Case-based Discussion of Select Diseases and Disorders

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Case 1 A 32-year-old woman is brought to the emergency room by a friend because of the onset of confusion and disorientation over the past day. Upon physical examination, you discover a generalized petechial rash, fever, and bilateral positive Babinski sign. You immediately order several blood tests, which show an elevated LDH, increased indirect bilirubin, thrombocytopenia, and anemia. Examination of a peripheral blood smear yields multiple reticulocytes and schistocytes. You admit the patient to the intensive care unit and you prepare for emergency plasmapheresis. What is the Diagnosis? Marc Imhotep Cray, M.D.

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Idiopathic and Thrombotic Thrombocytopenic Purpura  Etiology and Epidemiology:  Idiopathic thrombocytopenic purpura (ITP): Antiplatelet IgG antibodies coat platelets leading to phagocytosis by splenic macrophages; occurs in children as acute self-limited reaction to viral infection, or can occur in adults as chronic disease  Thrombotic thrombocytopenic purpura (TTP): Etiology unknown although viral infection, drugs, and autoimmune diseases have been implicated. Occurs most commonly in women between age 20 and 50  Pathology:  ITP: Bone marrow: occasionally there are increased megakaryocytes; Peripheral blood smear: thrombocytopenia with slightly enlarged platelets  TTP: Widespread hyaline microthrombi in microvasculature w no inflammation; Peripheral blood smear: thrombocytopenia; schistocytes; reticulocytosis

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ITP & TTP Clinical Manifestations:  ITP: Mucous membrane bleeding; epistaxis; petechiae; no splenomegaly  Lab findings: Decreased platelets, antiplatelet antibodies, increased bleeding time TTP: Neurologic deficits; fever; renal insufficiency; petechiae; microangiopathic hemolytic anemia  Lab findings: Decreased platelets, increased LDH and indirect bilirubin, azotemia, increased bleeding time, decreased Hct

Treatment:  ITP: Prednisone; splenectomy Marc Imhotep Cray, M.D. TTP: Plasma exchange; steroids

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Microangiopathic hemolytic anemia (MAHA) HUS and TTP share MAHA, thrombocytopenia, HTN and RF, although these features are present to different degrees. Hemolytic–Uremic Syndrome  Typical postdiarrheal HUS features MAHA and acute renal failure, w little or no significant vascular disease outside kidneys  Typical HUS is one of the most common causes of acute renal failure in children Thrombotic thrombocytopenic purpura  In TTP systemic microvascular thrombosis is characterized clinically by thrombocytopenia, purpura, fever and changes in mental status  Unlike HUS, renal involvement is often absent or less important than other organ disease  Bleeding caused by consumptive thrombocytopenia, is also more severe in TTP than it is in HUS  TTP is more common in adults than children Marc Imhotep Cray, M.D.

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Case 2 An 8-year-old boy presents to the emergency department with a swollen right knee. He denies a history of trauma to the knee. Physical examination reveals a warm, swollen, erythematous joint with a significant effusion. Upon taking a family history, you learn that two of the boyâ&#x20AC;&#x2122;s maternal uncles suffer from a bleeding disorder. Laboratory tests reveal a prolonged PTT, a normal PT, and a normal bleeding time. To provide the proper treatment, you immediately order a clotting factor assay. What is the Diagnosis?

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Hemophilias A and B Etiology:  Hemophilia A: X-linked recessive disorder resulting in a deficiency of factor VIII  Hemophilia B: X-linked recessive disorder resulting in a deficiency of factor IX

Pathophysiology: Lack of clotting factor VIII or IX results in an ineffective intrinsic pathway of coagulation Clinical Manifestations: Bleeding into muscles and joints (hemarthrosis); easy bruising; GI bleeding  Lab findings: Prolonged PTT, normal PT, normal bleeding time, normal thrombin time

Treatment: Replace deficient clotting factor

NB: Vitamin K deficiency is most commonly caused by liver disease, malabsorption, or warfarin admin.  Results in a deficiency of factors II, VII, IX, and X and lab. studies demonstrate a prolonged PT Marc Imhotep Cray, M.D.

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Case 3 A 7-year-old girl is brought to the emergency department because of uncontrollable bleeding following a deep laceration to her palm. Further questioning reveals that she has been taking aspirin for a viral illness, that she has a history of prolonged bleeding, and that her brother and mother both suffer from a bleeding disorder. Laboratory tests reveal a prolonged bleeding time, a prolonged PTT, and a normal PT. You suspect that this girl and her family are affected with the most common hereditary bleeding disorder and advise them all to avoid aspirin. What is the Diagnosis?

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von Willebrand Disease Etiology and Epidemiology: Autosomal dominant disease marked by a deficiency in von Willebrand factor (vWF)  Acquired vWF disease is assoc. w malignancy and autoimmune diseases and is related to decreased synthesis and increased clearance of vWF  von Willebrand disease is the most common hereditary bleeding disorder (affects 1% of all people)

Pathophysiology: Lack of vWF results in impaired platelet adhesion to subendothelium during vascular injury thereby resulting in deficient platelet plug formation  b/c vWF also acts as a carrier protein for factor VIII deficient vWF results in a functional deficiency of factor VIII thereby impairing intrinsic pathway of coagulation Marc Imhotep Cray, M.D.

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von Willebrand Disease cont’ed. Clinical Manifestations: Mucosal bleeding  Lab findings: Prolonged PTT, prolonged BT, normal PT, normal TT Treatment: Avoid aspirin and other anticoagulants; desmopressin or factor VIII replacement if necessary Note: There are two bleeding disorders that result from deficiencies in platelet aggregation: (1) Glanzmann thrombasthenia results from a deficiency of GpIIb and GpIIIa, which are receptors for fibrinogen (2) Bernard–Soulier disease results from a deficiency of glycoprotein Ib, which serves as a receptor for vWF factor  Both disorders present w mucosal bleeding, a prolonged BT, and nml PTT and PT Marc Imhotep Cray, M.D.

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Case 4 A 33-year-old woman presents to your office because of a swollen, painful left calf. She denies any sort of recent trauma or fevers. She has no significant past medical history and her only medication is an oral contraceptive. Her family history is notable for the death of her mother at age 55 from a pulmonary embolism. During physical examination, you elicit a positive Homan sign with pain on dorsiflexion. Concerned, you order a Doppler ultrasound of the left lower extremity. What is the Diagnosis?

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Hypercoagulable States Etiology:  Causes of inherited hypercoagulable states include Factor V Leiden (resistance to activated protein C), prothrombin mutation, protein C or S deficiency, antithrombin III deficiency, or antiphospholipid syndrome  Causes of acquired hypercoaguable states include cancer, myeloproliferative disorders, pregnancy, nephrotic syndrome, or estrogens Pathology= Vein: Venous thrombus (dark red w pale gray fibrin strands, firm and attached to vessel wall); venous inflammation Clinical Manifestations: Symptoms of DVT or pulmonary embolism; stroke; recurrent miscarriages  Lab findings: Increased D-dimer levels, increased PTT levels in antiphospholipid syndrome

Treatment: Anticoagulation (heparin for short term, warfarin for long term)

NB: Virchow triad (endothelial injury, hypercoagulable state, venous stasis) predisposes to formation of a deep vein thrombosis (DVT) Marc Imhotep Cray, M.D.

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Case 5 A 28-year-old woman, who is at 33-week gestation, presents to the emergency department with heavy vaginal bleeding. Ultrasound evaluation reveals that she is suffering from abruptio placentae (premature separation of the placenta from the uterus wall). As she is being prepared for delivery, you notice that there is blood seeping from her IV and venipuncture sites and that she has a petechial rash. Concerned, you immediately order several blood tests, which reveal a prolonged PT, prolonged PTT, prolonged bleeding time, prolonged thrombin time, thrombocytopenia, and elevated D-dimer levels. You begin transfusing platelets and fresh frozen plasma in the hope of stabilizing this life-threatening complication. What is the Diagnosis?

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Disseminated Intravascular Coagulation (DIC)  Etiology: Seen in connection with obstetric complications such as abruptio placentae or amniotic fluid embolus, malignancy, sepsis, trauma, acute pancreatitis, shock, and hemolytic transfusion reactions  Pathology and Pathophysiology: Peripheral blood smear: Schistocytes; thrombocytopenia  Pathophysiology: Excess thrombin activity leads to activation of coagulation and fibrinolytic cascades and microthrombi subsequently leads to consumption of platelets, fibrin, and clotting factors thereby leads to bleeding  Vasculature: Microthrombi in microvasculature of multiple organs

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DIC cont’ed.  Clinical Manifestations: Bleeding and thrombosis (manifested by bleeding from venipuncture sites, petechiae, and ischemia of fingers and toes); microangiopathic hemolytic anemia  Lab findings: Prolonged PT and PTT, prolonged bleeding time and thrombin time, increased D-dimer levels, decreased fibrinogen, decreased platelets, decreased Hct  Treatment: Platelet transfusion, fresh frozen plasma and cryoprecipitate transfusion to replenish depleted clotting factors and fibrinogen  Remember: Prolonged PT, PTT, bleeding time, and thrombin time also occur in coagulopathy of liver disease  This disorder is not assoc. w microthrombi and can be Tx w vitamin K Marc Imhotep Cray, M.D.

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Thrombosis & Embolism

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Thrombosis & Thrombus (pl. Thrombi) Thrombosis  Inappropriate activation of hemostasis resulting in formation of a solid mass (thrombus) within blood vessels or heart Thrombus  Aggregate of platelets, fibrin, RBCs/WBCs within blood vessels or heart  Can lead to vascular obstruction and embolism

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Signs and symptoms hypercoagulability  Most common conditions assoc. w thrombophilia are deep vein thrombosis (DVT) and pulmonary embolism (PE) referred to collectively as venous thromboembolism (VTE)  DVT usually occurs in legs, and is characterized by pain, swelling and redness of limb • It may lead to long-term swelling and heaviness due to damage to valves in the veins • Clot may also break off and migrate (embolize) to arteries in lungs • Depending on the size and location of clot, may lead to sudden-onset shortness of breath, chest pain, palpitations and may be complicated by collapse, A right-sided acute deep vein thrombosis (to shock and cardiac arrest the left in the image). The leg is swollen and Marc Imhotep Cray, M.D.

red due to venous outflow obstruction

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Pathogenesis of Thrombosis Virchow’s Triad

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Virchow's triad Describes the three broad categories of factors that are thought to contribute to thrombosis  Hypercoagulability  Hemodynamic changes (stasis, turbulence)  Endothelial injury/dysfunction

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Modern understanding of factors leading to embolism is similar to description provided by Virchowď&#x192; Virchow's triad remains a useful concept in understanding contributors to thrombosis The triad consists of three components: Virchow's

Modern

Phenomena of interrupted Stasis blood-flow

Notes The first category, alterations in normal blood flow, refers to several situations. These include venous stasis, long surgical operations, prolonged immobility (whilst on a long plane or car ride, bed bound during hospitalization), and varicose veins.

Phenomena associated with Endothelial injury irritation of the or vessel wall injury vessel and its vicinity

The second category, injuries and/or trauma to endothelium includes vessel piercings and damages arising from shear stress or hypertension. This category is ruled by surface phenomena and contact with procoagulant surfaces, such as bacteria, shards of foreign materials, biomaterials of implants or medical devices, membranes of activated platelets, and membranes of monocytes in chronic inflammation. The last category, alterations in constitution of blood, has numerous possible risk factors such as hyperviscosity, coagulation factor V Leiden mutation, coagulation factor II Phenomena of G2021A mutation, deficiency of antithrombin III, protein C or S deficiency, nephrotic bloodHypercoagulability syndrome, changes after severe trauma or burn, cancer, late pregnancy and delivery, coagulation race, advanced age, cigarette smoking, hormonal contraceptives, and obesity. All of these risk factors can cause the situation called hypercoagulability (excessively easy clotting of blood). Marc Imhotep Cray, M.D.

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Virchow's triad - Wikipedia

Embolism • An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by blood to a site distant from its point of origin • 99% are Thromboembolus • Rare forms include Fat, Air, Amniotic fluid, tumor, foreign body, atherosclerotic debris (cholesterol emboli) • Consequences of embolus is ischemic necrosis of affected tissue

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Important types • Pulmonary thromboembolism • Systemic thromboembolism • Fat embolism • Air embolism • Amniotic fluid embolism

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Pulmonary Embolism • Most commonly from venous emboli from leg veins • Depending on size of embolus Can occlude main pulmonary artery, impact across bifurcation (saddle embolus), or pass out into smaller, branching arterioles • Multiple emboli or shower of small emboli in small pulmonary arteries • Once a Pulmonary embolus occurs, patient will be prone for recurrent emboli episodes

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Paradoxical embolism â&#x20AC;˘ Rarely, an embolus may pass through an interatrial or interventricular defect to gain access to the systemic circulation

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A 58-year-old man develops deep venous thrombosis during a hospitalization for prostatectomy. He exhibits decreased mental status 10 days postoperatively, with right hemiplegia. A CT scan of the head shows an acute cerebral infarction in the distribution of the left middle cerebral artery. A chest radiograph reveals cardiac enlargement and prominence of the main pulmonary arteries consistent with pulmonary hypertension. Laboratory studies show a serum troponin I of <0.4 ng/mL. Which of the following lesions is most likely to be present on echocardiography? A Coarctation of the aorta B Tetralogy of Fallot C Atrial septal defect D Pulmonic stenosis E Dextrocardia Marc Imhotep Cray, M.D.

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(C). This is the infamous â&#x20AC;&#x153;paradoxical embolusâ&#x20AC;? from right to left. This can only happen if there is a defect that allows passage from right-to left. This can happen across a patent foramen ovale. In this case, the pulmonary hypertension suggests that there may have been a shunt persistent for a long time--a so-called Eisenmenger complex. An atrial or a ventricular septal defect can provide the shunt.

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Pulmonary embolism, gross

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Pulmonary embolism, CT image

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Pulmonary embolism, angiogram

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Pulmonary embolism, V/Q scan

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Pulmonary embolism, microscopic

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Pulmonary infarct, gross

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Pulmonary embolism, microscopic

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Blood & Lymphatic System Learning Objectives b) White blood cells: 1. Leukopenia: i. Define leukopenia; list the causes of neutropenia and its clinical manifestations.

2. Leukocytosis: i. List the major causes of leukocytosis affecting neutrophils, eosinophils, lymphocytes, and monocytes. ii. Explain the terms ‘shift to the left’ or ‘shift to the right’ and describe their significance

c) Lymph nodes: 1. List the causes of lymph node enlargement 2. Describe the causes of acute & chronic no-specific lymphadenitis. Marc Imhotep Cray, M.D.

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Blood and Lymphatic System Learning Objectives contâ&#x20AC;&#x2122;ed. d) Lymphoid Neoplasia: 1. Describe the main categories of lymphoid neoplasia as described in the World Health Organization (WHO) classifications. 2. List the commonly encountered forms of lymphoid neoplasia. 3. Compare and contrast Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL) clinically and histologically. 4. Describe the histologic hallmark of HL. 5. Describe the microscopic features of Reed-Sternberg cell and its variants. Give its likely origin. 6. Describe the basis of the histologic classification of HL and how this relates to the natural history of HL. Marc Imhotep Cray, M.D.

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Kibble J , Cannarozzi ML. Pathophysiology Flash Cards. New York: McGraw-Hill, 2013. Marc Imhotep Cray, M.D.

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Leukocytes GRANULOCYTES Neutrophil Structure: multilobed nucleus; granules containing lysozyme, myeloperoxidase, and hydrolytic enzymes Function: involved in acute inflammatory response Basophil Structure: bilobed nucleus; dark blue granules containing heparin, histamine, leukotrienes Function: involved in mediating allergic reactions Eosinophil Structure: bilobed nucleus; pinkish granules containing major basic protein, histaminase, and arylsulfatase Function: defends against parasitic infections; levels increased in asthma, allergic processes, neoplasm, collagen vascular disease Marc Imhotep Cray, M.D.

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Leukocytes cont’ed. LYMPHOCYTES B Cell Development: develops from lymphoblast in bone marrow; matures in bone marrow Structure: small cell w large, darkly staining nucleus Function: mediates humoral immune response; differentiates into antibody-producing plasma cells; can function as antigen-presenting cell via MHC II T Cell Development: develops from lymphoblast in bone marrow; matures in thymus Structure: small cell with large, darkly staining nucleus Function: mediates cellular immune response; differentiates into cytotoxic T cells (MHC I, CD8), helper T cells (MHC II, CD4), and suppressor T cells Marc Imhotep Cray, M.D.

Lymphoid Structures 1° organs: Bone marrow—immune cell production, B cell maturation Thymus—T cell maturation 2° organs: Spleen, lymph nodes, tonsils, Peyer patches Allow immune cells to interact w antigen

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Normal white blood cells, microscopic

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White Cell Disorders Disorders of WBCs include deficiencies (leukopenias) and proliferations may be reactive or neoplastic  Reactive proliferation in response to a primary, often microbial, disease is common  Neoplastic disorders, although less common, are more ominous: o Cause approx. 9% of all cancer deaths in adults and 40% of cancer deaths in children younger than 15 years of age

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Disorders of WBCs Leukopenia  Leukopenia results most commonly from a decrease in granulocytes most numerous circulating white cells  Lymphopenia is much less common associated with o rare congenital immunodeficiency diseases o advanced human immunodeficiency virus (HIV) infection o treatment with high doses of corticosteroids  Neutropenia/Agranulocytosis o A reduction in number of granulocytes in bld is known as neutropenia or, when severe, agranulocytosis o Neutropenic persons are susceptible to severe, potentially fatal bacterial and fungal infections • Risk of infection rises sharply as neutrophils falls below 500 cells/µL Marc Imhotep Cray, M.D.

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Nonneoplastic Disorders of WBCs Reactive Leukocytosis

Causes of Leukocytosis

 An increase in number of white cells in bld is common in a variety of inflammatory states caused by microbial and nonmicrobial stimuli  Leukocytoses are nonspecific and classified according to particular white cell series that is affected  Some cases reactive leukocytosis may mimic leukemia o Such “leukemoid reactions” must be distinguished from true white cell malignancies

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Leukocytosis, microscopic

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Leukemoid Reaction vs Leukemia

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Leukocyte alkaline phosphatase test, microscopic

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Infectious mononucleosis, microscopic

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Neoplastic Proliferations of WBCs Although there are many reactive types of leukocytosis and leukopenia, neoplastic diseases responsible for leukocytosis and leukopenias are most clinically important  Leukemias are conditions in which neoplastic cells are in blood  Lymphomas are conditions in which neoplastic cells are in lymph nodes o Overlap does occur two conditions are not mutually exclusive See Video Edu: Hematological Malignancies_Amboss

 Symptoms of leukemias and lymphomas relate to cells affected  In leukemia, neoplastic cells replace normal hematopoietic population patients will have anemia (w pallor & fatigue), thrombocytopenia (w bleeding), and leukopenia (w propensity for infections) Marc Imhotep Cray, M.D.

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Leukemia Leukemia is a general term for a group of malignancies of either lymphoid or hematopoietic cell origin number of circulating leukocytes is greatly increased Bone marrow is diffusely infiltrated w leukemic cells with encroachment on normal hematopoietic cell development  Consequent failure of normal leukocyte, red cell, and platelet production can result in infection, anemia, or hemorrhage

Infiltration of leukemic cells in liver, spleen, lymph nodes, and other organs is common Marc Imhotep Cray, M.D.

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Relative proportions of hematological malignancies in the United States Type of hematological malignancy

Percentage

Leukemias

30.4%

Acute lymphoblastic leukemia (ALL)

4.0%

Acute myelogenous leukemia (AML)

8.7%

Chronic lymphocytic leukemia (CLL) sorted under lymphomas according to current WHO classification; called small lymphocytic lymphoma (SLL) when leukemic cells are absent.

10.2%

Chronic myelogenous leukemia (CML)

3.7%

Acute monocytic leukemia (AMoL)

0.7%

Other leukemias

3.1% Lymphomas

55.6%

Hodgkin's lymphomas (all four subtypes)

7.0%

Non-Hodgkin's lymphomas (all subtypes)

48.6%

Myelomas Total Marc Imhotep Cray, M.D.

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World Health Organization (WHO) Classification of Lymphoid & Myloid Neoplasms (Abbreviated) From: Harris NL, Jaffe ES, Diebold J, et al.: The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Modern Pathology 13:193â&#x20AC;&#x201C;207, 2000.

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Leukemia Classification  There are four main types of leukemia:    

Acute lymphoblastic leukemia (ALL) Acute myeloid leukemia (AML) Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML)

 General classification  Clinically and pathologically, leukemia is subdivided into a variety of large groups o first division is betw. its acute and chronic forms Marc Imhotep Cray, M.D.

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Acute leukemia vs Chronic leukemia Acute leukemia: rapid increase in number of immature blood cells  crowding that results makes bone marrow unable to produce healthy blood cells  results in low hemoglobin and low platelets  Immediate treatment is required  b/c of rapid progression and accumulation of malignant cells spill over into bloodstream and spread to other organs of body

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Acute leukemia vs Chronic leukemia cont’ed. Chronic leukemia: excessive buildup of relatively mature, but still abnormal, WBCs  Typically take months or years to progress cells are produced at a much higher rate than normal resulting in many abnormal WBCs  Whereas acute leukemia must be treated immediately, chronic

leukemia is frequently monitored for some time before treatment to ensure maximum effectiveness of therapy Chronic leukemia mostly occurs in older people can occur in any age group Marc Imhotep Cray, M.D.

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lymphoblastic (or lymphocytic) leukemias vs myeloid (or myelogenous) leukemias Leukemias are also subdivided according to which kind of blood cell is affected  lymphoblastic (or lymphocytic) leukemias and myeloid (or myelogenous) leukemias

In lymphoblastic (lymphocytic) leukemias cancerous change takes place in marrow cells that normally go on to form lymphocytes  Infection-fighting immune system cells  Most lymphocytic leukemias involve B cell

In myeloid (myelogenous) leukemias cancerous change takes place in marrow cells that normally go on to form RBCs, other types of WBCs, and platelets Marc Imhotep Cray, M.D.

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Cell Markers and Genetic Abnormalities for Leukemia Form of Leukemia

Cell Markers

Genetic Abnormality

Acute lymphoid (lymphoblastic) leukemia (ALL)

Precursor B-cell

CD10+

Early precursor B-cell Pre–B-cell

CD10Cytoplasmic Ig+

t(12;21) TEL1/AML1 t(9;22)–bcr-abl

Chronic lymphocytic CD 19,20,23, and leukemia (CLL) 5 positive

del 13q12-14 and del 11q, trisomy 12

Acute myelogenous leukemia (AML)

t(15;17)–PML/RARA t(8;21)–CBF /ETO

CD 13,15, 64 positive

Chronic myelogenous leukemia (CML)

t(9;22)–bcr-abl

The Big Picture Series: Pathology, 2008; Pg.190.

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Lymphoid Neoplasms Hodgkin lymphoma (Hodgkin disease) is a malignant neoplasm with features (e.g., fever, inflammatory cell infiltrates) resembling an inflammatory disorder

General considerations  Hodgkin lymphoma characteristically affects young adults (predominantly young men); an exception is nodular sclerosis, which frequently affects young women  Clinical manifestations: include pruritus, fever, diaphoresis, and leukocytosis reminiscent of an acute infection  With modern staging and aggressive therapy, a clinical cure is often achieved  Characterized in all forms by presence of Reed-Sternberg cells  Diagnosis depends on this histologic finding Marc Imhotep Cray, M.D.

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Classification of Hodgkin lymphoma ď ąWHO classification IDs a number of disease variants ď&#x201A;§ First distinction is betw. classical Hodgkin lymphoma (CHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) o Classical Hodgkin lymphoma is further divided into four subgroups: 1. Lymphocyte predominance 2. Nodular sclerosis 3. Mixed cellularity 4. Lymphocyte depletion

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Classification of Hodgkin lymphoma cont’ed Classical Hodgkin Lymphoma Again, all variants of CHL demonstrate Reed-Sternberg cells  Reed-Sternberg cells are derived from B cells, are binucleate or multinucleate, and typically have brightly eosinophilic nucleoli o They are positive for CD15 and CD30 but are negative for CD45 o Number of R-SCs and constituents of background vary across CHL subtypes background lymphocytes usually T-cells Type: Nodular sclerosis (NS) (next slide)most common form of Hodgkin lymphoma o Unlike other forms of Hodgkin lymphoma, it occurs more frequently in young women

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Normal lymph node, microscopic

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Normal lymph node, microscopic

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(A, B) Nodular sclerosis Hodgkin lymphoma. The lymph node is transected by broad bands of fibrous connective tissue.

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Non-Hodgkin lymphomas These malignant neoplasms arise from lymphoid cells or other cells native to lymphoid tissue They originate most frequently within lymph nodes or in other lymphoid areas Tumor involvement of periaortic lymph nodes is frequent WHO classification of lymphoid neoplasms includes Hodgkin lymphoma and all lymphoid neoplasms, including not only the nonHodgkin lymphomas, but also lymphoid leukemias Marc Imhotep Cray, M.D.

From: Harris NL, Jaffe ES, Diebold J, et al.: The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Modern Pathology 13:193–207, 2000.

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Non-Hodgkin lymphomas cont’ed Small lymphocytic lymphoma is a B-cell lymphoma that follows an indolent course and occurs most often in older persons (see next slide for micrograph)  Diffuse effacement of lymph node architecture by small matureappearing lymphocytes is characteristic  widespread nodal involvement and involvement of the liver, spleen, and bone marrow frequently occur  Close relationship to CLL o In WHO classification, this disorder is called B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma o Neoplastic cells express surface immunoglobulin and pan–B-cell markers (e.g., CD19 and CD20) and are positive for CD5 but negative for CD10

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Small lymphocytic lymphoma. This lymph node is replaced by a “sea” of normal appearing, neoplastic small lymphocytes. This appearance is referred to as a “diffuse” pattern of lymph node effacement.

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Non-Hodgkin lymphomas cont’ed Follicular lymphoma is a B-cell lymphoma, often following an indolent course in older persons most common form of non-Hodgkin lymphoma  Proliferation of angulated grooved cells that closely resemble cells of lymphoid follicular center, commonly in a follicular (nodular) pattern is Rubin R, Strayer D, et al., eds.: Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore, Lippincott Williams & characteristic Wilkins, 2012, figure 20-58, p. 1013.

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Case-based Discussion of Select Diseases and Disorders

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Case Trigger 1 A 6-year-old boy presents to your office complaining of fatigue, fever, and a history of recurrent epistaxis (nose bleeds) and urinary tract infections. He has an enlarged liver and spleen and a petechial rash over his entire body. Concerned, you send him for some blood tests, which demonstrate pancytopenia with the presence of multiple blast forms. You fear that a bone marrow biopsy may demonstrate cells that would stain positive for TDT and CALLA. What is the Diagnosis?

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Acute Lymphoblastic Leukemia (ALL) Etiology and Epidemiology:  Risk factors include prior exposure to radiation and chemotherapy Occurs most often in children with a median peak age of 10, but may also occur in elderly (poor prognosis); increased incidence in pts. Down syndrome

Pathology: ALL can be classified as either T cell or early B cell Lymphoblastic surface antigens indicate origin of leukemia Markers  B-cell antigens include CALLA (CD10), CD19, and CD20  T-cell antigens include CD2, CD5, and CD7  Terminal deoxynucleotidyl transferase (TDT) is a marker of immature T and B lymphocytes and is present in 95% of cases  Bone marrow: Hypercellular; composed mostly of lymphoblasts; distorted architecture of BM  Peripheral blood smear: Pancytopenia with lymphocytosis (excess lymphoblasts) Marc Imhotep Cray, M.D.

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Acute Lymphoblastic Leukemia cont’ed. Clinical Manifestations: Fatigue; infections; mucosal bleeding; lymphadenopathy; hepatosplenomegaly; bone pain; cranial neuropathies

Treatment and Prognosis:  Chemotherapy or bone marrow transplant,  Very responsive to therapy with a good prognosis ALL is most common childhood cancer  accounts for 80% of all childhood leukemias

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Acute lymphoblastic leukemia, microscopic

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Lymphoblastic lymphoma, microscopic

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Case Trigger 2 A 52-year-old woman presents to your clinic complaining of a 2-week history of low-grade fever and weakness. Further evaluation reveals that she has suffered from various infections over the past 3 months. Upon physical examination, you note that she is pale with a petechial rash and that she has an enlarged spleen and liver. After a peripheral blood smear demonstrates pancytopenia with multiple myeloblasts, you immediately refer this patient to a hematologist / oncologist. What is the Diagnosis?

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Acute Myelogenous Leukemia (AML) Etiology and Epidemiology:  Risk factors include Down syndrome and exposure to ionizing radiation, benzene, or chemotherapy  Associated with chromosomal translocations: M3-t(15;17), M2-t(8;21)  Occurs most frequently in middle-aged adults

Pathology: There are 8 subgroups (M0-M7), each associated w a specific neoplastic myeloid lineage (myelocyte, monocyte, megakaryocyte, erythrocyte) and a level of maturation; ALL is characterized by a predominance of lymphoblasts in circulating Bld and in BM  Bone marrow: Hypercellular with distorted architecture; myeloblasts specific to subtype; Auer rods (cytoplasmic granules)  especially with M3 (acute promyelocytic leukemia)  Peripheral blood smear: Pancytopenia w myeloblasts Marc Imhotep Cray, M.D.

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Acute Myelogenous Leukemia cont’ed. Clinical Manifestations: Fatigue; infection; bleeding (menorrhagia, nose bleeds); lymphadenopathy; hepatosplenomegaly; stroke caused by leukostasis elevated blast count leads to occluded microcirculation

Treatment and Prognosis:  Chemotherapy or bone marrow transplant;  all-trans retinoic acid for M3 with t(15;17)  Prognosis fair: 60% remission only 25% remain disease free for 5 years o CD10 is a favorable prognostic marker of this disease o mutations in kinase FLT3 suggest a worse prognosis Marc Imhotep Cray, M.D.

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Acute myelogenous leukemia, microscopic

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Acute myelogenous leukemia, microscopic

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Case Trigger 3 A 55-year-old man presents to your office complaining of a feeling of heaviness in his abdomen. He has had several infections over the past 6 months. Physical examination demonstrates a massively enlarged spleen and a peripheral blood smear reveals abnormal cells with filamentous projections. As you refer this patient to a hematologist/oncologist, you reassure him that his disease is very sensitive to treatment. What is the Diagnosis?

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Hairy Cell Leukemia Etiology and Epidemiology: Etiology unknown; 0ccurs mostly in middle-aged men Pathology: Mature B-cell tumor  Bone marrow: dry tap on aspiration; Interstitial infiltrate of hairy cells (B cells with hairlike projections  stain positive for TRAP=Tartrate resistant acid phosphatase )  Peripheral blood smear: Pancytopenia with hairy cells  positive for the B cell markers CD19, CD20, and CD22

Clinical Manifestations: Massive splenomegaly; hepatomegaly (less common); infections; pancytopenia Treatment and Prognosis:  Very sensitive to chemotherapy and other agents (cladribine, pentostatin)  Hairy cell leukemia is of special interest b/c of striking therapeutic efficacy of agents such as α-interferon, 2-chlorodeoxyadenosine, and deoxycoformycin

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Hairy cell leukemia, microscopic

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Hairy cell leukemia, CT image

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Case Trigger 4 A 67-year-old man presents to your office for his annual checkup. You learn that he has been rather tired as of late and has had several nose bleeds over the past 6 months. Physical examination reveals shotty lymphadenopathy and mild hepatosplenomegaly. A complete blood count reveals an extremely high white blood cell count. You order a peripheral blood smear, which demonstrates multiple smudge cells, helping you to make a diagnosis. What is the Diagnosis?

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Chronic Lymphocytic Leukemia (CLL)  Etiology and Epidemiology: Associated with chromosomal abnormalities (trisomy 12, deletions of 13q, deletions of 11q); most often occurs insidiously in men over age of 60  Pathology: Bone marrow: Infiltration with small lymphocytic cells  resembling normal mature B lymphocytes; they express CD5 normally seen in T lymphocytes Peripheral blood smear: Smudge cells (leukemic cells are sensitive to mechanical disruption occurring during slide preparation); lymphocytosis; normochromic, normocytic erythrocytes

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Chronic Lymphocytic Leukemia cont’ed.  Clinical Manifestations: Lymphadenopathy, hepatosplenomegaly, mucosal bleeding, and fatigue; may have few symptoms (indolent course)  Complications include warm AIHA, thrombocytopenia, and hypogammaglobulinemia early in course lead to bacterial infections  Treatment and Prognosis: Chemotherapy to relieve symptoms, but cure is rare  Mean survival is 3–7 years after diagnosis depending on cytogenetic status  much longer symptom-free survivals are not uncommon

Note: CLL is very similar to SLL (small lymphocytic lymphoma)

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Chronic lymphocytic leukemia, microscopic

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Case Trigger 5 A 44-year-old man presents to your clinic complaining of severe fatigue. Physical examination is relatively unremarkable except for an enlarged spleen. You send him to the laboratory for blood tests, which reveal multiple immature granulocytes on peripheral blood smear, a high WBC count, and low leukocyte alkaline phosphatase activity. Based on these test results, you begin to suspect that he may have a chromosomal abnormality. What is the Diagnosis?

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Chronic Myelogenous Leukemia (CML)  Etiology and Epidemiology: Assoc. with Philadelphia chromosome t(9;22), which forms a hybrid gene (bcr-abl) that codes for a protein with tyrosine kinase activity; occurs mostly in middle-aged people  Pathology:  Bone marrow: Hypercellular; increased myeloid precursor cells  Peripheral blood smear: Leukocytosis with a mixture of mature and immature myeloid cells NB: CML is almost invariably marked by finding of Philadelphia chromosome, a small residual chromosome 22 with addition of a small segment of chromosome 9, resulting from a 9;22 translocation Marc Imhotep Cray, M.D.

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Chronic Myelogenous Leukemia cont’ed. Clinical Manifestations: Presents with low-grade fever, fatigue, night sweats, and splenomegaly  Lab findings: Leukocytosis (neutrophils and metamyelocytes), decreased LAP, increased serum B12, hyperuricemia

Treatment and Prognosis: Chemotherapy (hydroxyurea, imatinib [a tyrosine kinase inhibitor]) or bone marrow transplantation  Death usually occurs b/c of transformation into AML (blast crisis) NB: CML is considered a myeloproliferative disorder along with polycythemia vera, essential thrombocythemia, and myelofibrosis

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Chronic myelogenous leukemia, microscopic

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Chronic myelogenous leukemia, microscopic

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Case Trigger 6 A 54-year-old overweight man presents to your office complaining of headache and worsening vision over the last month. His past medical history includes hypertension and a recent hospital admission for deep vein thrombosis. He has no history of COPD, smoking, renal disease, or endocrine abnormalities. Physical examination demonstrates a blood pressure of 130/80, but is otherwise unremarkable. Blood tests reveal an increased hematocrit and increased RBC mass. To confirm your suspicions, you decide to order a test to determine serum erythropoietin levels. What is the Diagnosis?

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Polycythemia Vera (primary polycythemia) Etiology: Myeloproliferative disorder of unknown etiology; occurs most often in middle-aged, obese, hypertensive men Pathology:  Bone marrow: Hypercellular with marked increase in erythroid precursor cells; increase in other hematopoietic elements (megakaryocytes, myelocytes) also present Clinical Manifestations: Splenomegaly; pruritus; symptoms associated with hyperviscosity (headache, blurry vision); thrombosis; bleeding  Lab findings: Increased Hct, increased RBC mass, decreased erythropoietin levels, increased WBCs, increased platelets, increased LAP, increased serum vitamin B12 levels, hyperuricemia  Treatment: Phlebotomy; aspirin; hydroxyurea if thrombosis occurs Marc Imhotep Cray, M.D.

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Polycythemia Vera cont’ed. PV is considered a myeloproliferative disorder along w CML, essential thrombocythemia, and myelofibrosis Essential thrombocythemia is characterized by thrombocytosis and megakaryocytosis and presents w bleeding and thrombosis Secondary polycythemia refers to increased RBC mass owing to increased erythropoietin production caused by chronic hypoxia, renal disease, or Cushing syndrome

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Myeloproliferative disorder, gross

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Myeloproliferative disorder, microscopic

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Essential thrombocytosis, microscopic

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Case Trigger 7 A 51-year-old man presents to the clinic with a chief complaint of increasing fatigue over the past 8 months. He states that he used to be very active, but finds that he tires now from walking up the stairs in his house. Blood tests demonstrate a low hematocrit and a peripheral blood smear reveals teardropshaped erythrocytes, large platelets, and granulocytic precursor cells. You suspect that he may also have extensive extramedullary hematopoiesis in his liver and spleen and fear that he may eventually have to undergo a bone marrow transplant. What is the Diagnosis?

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Myelofibrosis with Myeloid Metaplasia Etiology: Increased secretion of platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) results in fibroblastic proliferation in bone marrow Pathology:  Bone marrow: Replacement of bone marrow cavity with fibrous tissue; loss of hematopoietic precursor cells except for megakaryocytes (which are actually increased)  Liver and Spleen: Extramedullary hematopoiesis (owing to loss of bone marrow)  Peripheral blood smear: Teardrop-shaped erythrocytes; granulocyte precursor cells; nucleated RBCs; thrombocytosis with abnormal-looking platelets

Clinical Manifestations: Anemia presenting with fatigue and pallor; massive splenomegaly  Lab findings: Decreased Hct

Treatment: Bone marrow transplant; supportive care w transfusions Marc Imhotep Cray, M.D.

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Myelofibrosis with teardrop cells, microscopic

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Case Trigger 8 A 22-year-old man presents to your office complaining of a painless lump in his neck. Upon further questioning, you discover that he has had a low-grade fever and drenching night sweats for the past 2 months. He also has lost 14 pounds over the past 8 weeks. Physical examination reveals unilateral cervical lymphadenopathy and splenomegaly. A lymph node biopsy reveals large multinucleated cells with prominent nucleoli resembling owlâ&#x20AC;&#x2122;s eyes. You immediately refer the patient to a hematologist/oncologist. What is the Diagnosis?

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Hodgkin Lymphoma Etiology and Epidemiology: Etiology unknown, but EBV infection has been implicated  Classic presentation is in a 20-year-old man, although Hodgkin actually has a bimodal age distribution of patients with a peak betw. 20–30 and a peak over age 50

Pathology: Lymph node: Reed-Sternberg cell (multinucleated giant cell with eosinophilic nucleoli resembling owl’s eyes, believed to be of CD 30+ and CD 15+ B-cell origin)  Four histologic variants: (1) Lymphocyte predominance: many lymphocytes, few Reed Sternberg cells; (2) Nodular sclerosis: fibrous bands, variants of Reed-Sternberg cells called lacunar cells; o Dx of NS can be based on finding of fibrous bands and lacunar cells (3) Mixed cellularity: eosinophils, plasma cells, Reed-Sternberg cells, fibrosis; (4) Lymphocyte depletion: few lymphocytes, many Reed-Sternberg cells, necrosis Marc Imhotep Cray, M.D.

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Hodgkin Lymphoma cont’ed. Clinical Manifestations: Painless lymphadenopathy usually in neck (localized, single group of nodes); pruritus; splenomegaly  Constitutional symptoms (B symptoms): Low-grade fever, night sweats, weight loss o B symptoms are so called b/c Ann Arbor staging of lymphomas includes both a number (I–IV) and a letter (A or B) • "A" indicates absence of systemic symptoms, while "B" indicates Sx presence

Treatment and Prognosis: Radiation and chemotherapy  Good prognosis (80% cure) associated with nondisseminated disease, absence of B symptoms, and certain histologic types (lymphocyte predominance and nodular sclerosis) although pts w Hodgkin lymphoma are at risk for second malignancies (acute leukemia, breast cancer) Of Note:  HL tends to spread to contiguous lymph nodes  Nodular Sclerosis histologic variant of HL is more common in women Marc Imhotep Cray, M.D.

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Hodgkin lymphoma, gross

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Hodgkin lymphoma, gross

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Hodgkin lymphoma, CT image

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Hodgkin lymphoma, microscopic

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Hodgkin lymphoma, microscopic

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Case Trigger 9 A 57-year-old man presents to your office after noticing a large painless lump in his neck. Upon questioning, he tells you that he has been suffering from a lowgrade fever over the past 3 months. He has also lost 10 pounds during that time. Physical examination reveals painless cervical and inguinal lymphadenopathy and hepatosplenomegaly. Blood tests reveal a mild anemia as well as elevated LDH levels. You decide to send him for a lymph node biopsy. What is the Diagnosis?

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Non-Hodgkin Lymphoma (NHL) Etiology and Epidemiology: Chromosomal translocations: Burkitt lymphoma: t(8;14), results in overexpression of c-myc; follicular lymphoma: t(14;18), results in activation of bcl-2, most common subtype  Viral infection: HIV, EBV (EBV associated with Burkitt lymphoma of the jaw)  Median age at Dx is 65; more common in males

Pathology: Lymph node: (1) Follicular: proliferation of cleaved cells in nodular pattern; (2) Burkitt: starry-sky appearance, noncleaved cells; (3) Small lymphocytic: widespread effacement of lymph node architecture by small mature lymphocytes, related to CLL (also positive for CD5 marker); (4) Diffuse large B cell: large cells with large, round nucleus; (5) other variants include mantle cell, marginal cell, and MALT lymphoma

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NHL cont’ed. Clinical Manifestations: Hepatosplenomegaly; painless lymphadenopathy; fewer B symptoms than Hodgkin lymphoma  Lab findings: Increased LDH (used as prognostic marker), no hypergammaglobulinemia Treatment and Prognosis: Chemotherapy and radiation; bone marrow transplantation for relapsing disease  Median survival is 6–8 years; prognosis worse for the elderly, those with disseminated disease and those with aggressive forms NB: NHL does not spread contiguously. EBV infection is also associated with an increased risk for nasopharyngeal carcinoma Marc Imhotep Cray, M.D.

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Non-Hodgkin lymphoma, gross

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Non-Hodgkin lymphoma, gross

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Question A 10-year-old boy presents with a large abdominal mass. Computed tomography of the abdomen reveals enlarged retroperitoneal and mesenteric lymph nodes. Biopsy of one of the involved lymph nodes shows a â&#x20AC;&#x153;starry-skyâ&#x20AC;? appearance, with prominent debris-containing macrophages. A diagnosis of Burkitt lymphoma is made. Which of the following statements about this disorder is correct? A. The sporadic (Western) form is most frequently associated with EBV B. The disorder is considered to be a derivative of Hodgkin lymphoma, lymphocyte depletion subtype C. The most common cytogenetic change is t(8;14), with increased expression of c-myc D. The tumor cells are derivatives of T lymphocytes E. The tumor most often has an indolent clinical course

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Answer C. The typical cytogenetic change associated with Burkitt lymphoma is t(8;14) with increased expression of the c-myc gene. This disorder is an aggressive B-cell non-Hodgkin lymphoma most commonly affecting children. The endemic (African) form is characterized by the involvement of the maxilla or mandible, whereas the sporadic (Western) form usually involves the abdominal organs. Burkitt lymphoma is generally a rapidly growing neoplasm, and the endemic form has a frequent association with EBV

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Trigger Case 10 A 69-year-old man presents to the emergency department complaining of pain in his neck and back. Upon directed history, he also reveals that he has been extremely tired and has suffered from two urinary tract infections over the past 4 months. An x-ray of his back reveals fractures in the L2 and L3 vertebrae as well as punched-out lytic bone lesions in the posterior skull. Laboratory studies reveal a mild anemia as well as an elevated BUN and creatinine. You decide to admit him to the hematology/oncology service for further evaluation. What is the Diagnosis?

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Multiple Myeloma Etiology and Epidemiology: Tumor cell arises from proliferation of monoclonal plasma cells, which produce IgG; most common in people over age of 60 Pathology:  Bone marrow: Neoplastic plasma cells with fried egg appearance derived from B lymphocytes  Peripheral blood smear: Rouleaux formation of erythrocytes  Long bones: Lytic lesions (produced by osteoclast-activating factor secreted by neoplastic cells)

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Multiple Myeloma cont’ed. Clinical Manifestations: Bone pain and fractures; renal insufficiency; recurrent infections; primary amyloidosis  Imaging: Punched-out lytic lesions on radiographs  Lab findings: Monoclonal immunoglobulin spike (M protein) on serum protein electrophoresis,  Bence-Jones protein (IgG light chains) in urine, anemia, increased ESR, hypercalcemia, hyperglobulinemia (IgG), azotemia

Treatment: Chemotherapy and autologous stem cell transplantation Differential: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic disease characterized by a monoclonal M protein spike < 3 g/dL and is associated w no Bence–Jones proteinuria, no lytic bone lesions, and no renal insufficiency  Pts. w MGUS should be closely monitored at higher risk to develop multiple myeloma or another lymphoproliferative disease Marc Imhotep Cray, M.D.

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Multiple myeloma, microscopic

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Multiple myeloma, gross

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Multiple myeloma, radiograph

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Trigger Case 11 A 72-year-old man presents to your office complaining of fatigue, blurry vision, headaches, and weight loss over the past 6 months. Physical examination reveals hepatosplenomegaly, generalized lymphadenopathy, and retinal vascular dilatation. An abdominal x-ray and urinalysis are normal, although blood tests demonstrate anemia and increased serum viscosity. You decide to send this patient for a bone marrow biopsy.

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Waldenstrom Macroglobulinemia Etiology and Epidemiology: Hyperviscosity syndrome most often associated with IgM-producing plasmacytic lymphocytes (hybrids of plasma cells and B lymphocytes) Most frequently occurs in men over age of 50 Pathology:  Bone marrow: Mixture of small lymphoid cells showing differing degrees of plasma cell differentiation; Dutcher bodies (eosinophilic inclusion bodies in nucleus); Russell bodies (eosinophilic inclusion bodies in cytoplasm)  Peripheral blood smear: Rouleaux formation of erythrocytes

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Waldenstrom Macroglobulinemia cont.  Clinical Manifestations: Fatigue; weakness; weight loss; anemia; hepatosplenomegaly; lymphadenopathy  Complications include hyperviscosity syndrome from circulating IgM (blurry vision, neurologic abnormalities, heart failure), bleeding, and peripheral neuropathy (from IgM deposition)  Lab findings: Monoclonal IgM spike seen on serum protein electrophoresis, increased serum  viscosity, decreased Hct  Treatment: Chemotherapy; periodic plasmapheresis

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THE END

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Study tools and resources Video Edu: Hematology-Oncology_Medicosis Perfectionalis Companion Notes: Hematology and Immunology Rapid Review Q&A Cloud Folders: Hematopoietic and Lymphoid Systems Pathology Textbooks:  Kumar V, Abbas AK, Aster JC. Robbins Basis Pathology, 10th Ed. Philadelphia: Saunders-Elsevier, 2018.  Rubin R, Strayer D (eds.) Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012. Marc Imhotep Cray, M.D.

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