Chapter 21

Hematopathology

Nam Deuk Kim, Ph.D.

Pusan National University

1 Contents I. Red blood cells II. Hemostasis III. White blood cells IV. Disorders of the lymphopoietic system V. Spleen VI. Thymus

2 THE HEMATOPOIETIC SYSTEM Composition of Human Blood Blood • Transports oxygen, nutrients, hormones, leukocytes (white cells), red cells, platelets and antibodies to tissues in the body and carbon dioxide and other waste products of cell metabolism to the excretory organs of the body • Volume of blood: Represents about 8% of total body weight • approximately 5 quarts, but it varies according to size of individual (5 liters in women; 5.5 liters in men) • Almost half of the blood consists of cellular elements suspended in plasma (viscous fluid) 3 4 Hemopoiesis Cellular differentiation and maturation of the lymphoid and myeloid components of the hematopoietic system. Only the precursor cells (blasts and maturing cells) are identifiable by light microscopic evaluation of the bone marrow. BFU = burst-forming unit; CFU = colony-forming unit (Ba = basophils; E = erythroid; Eo = eosinophils; G = polymorphonuclear leukocytes; GM = granulocyte-monocyte; M = monocyte/macrophages; Meg = megakaryocytic); EPO = erythropoietin; Gm-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; NK = natural killer; SCF = stem cell factor; TPO = thrombopoietin.

5 Composition of Human Blood • All blood cells arise from precursor cells within the bone marrow, called stem cells • These undergo further differentiation to form red cells, white cells, and platelets The cellular elements are: • Red cells • Leukocytes . Neutrophils . Monocytes . Eosinophils . Lymphocytes . Basophils • Platelets

6 Composition of Human Blood • Red cells • Are primarily concerned with transport of oxygen • Most numerous cells • Survival 4 months (120 days) • Erythroblast is precursor cell in bone marrow • is the oxygen-carrying protein that is formed by the developing red cell • ~5 million cells/microliter • Leukocytes • Less numerous • Different types • Survival from several hours to several days, except for lymphocytes

7 Normal Leukocyte Cell Counts Mean Number Normal Per Microliter Range WBC (leukocytes) 7,400 4,500-11,000 Neutrophils 4,400 1,800-7,700 Eosinophils 200 0-450 Basophils 40 0-200 Lymphocytes 2,500 1,000-4,800 Monocytes 300 0-800

8 Composition of Human Blood • Lymphocytes may last for 2. Monocytes several years • Actively phagocytic • Lymphocytes are also • Increased in certain types of produced in the bone marrow chronic infection but are mainly produced in the lymph nodes and spleen 3. Eosinophils Types of Leukocytes • Increase in allergic reactions 1. Neutrophils • Increase in the presence of • Most numerous in adults animal-parasite infections • Comprise about 70% of total 4. Lymphocytes circulating white cells • Next most common in adults • Actively phagocytic • Predominant leukocyte in • Predominant in inflammatory children reactions

9 Composition of Human Platelets Blood: Lymphocytes • Are essential for blood • Mostly located in the lymph coagulation nodes, the spleen, and other • Are much smaller than lymphoid tissues leukocytes • Take part in both the cell- mediated and humoral defense • They represent bits of the reactions cytoplasm of megakarocytes, which are the largest precursor cell in the bone marrow • Have a relatively short survival, about 10 days • ~250,000 cells/microliter

10 NORMAL HEMATOPOIESIS Factors that may cause white Hematopoiesis: the formation cell production and development of blood • Products of cell necrosis cells • Hormone secretion by the • The bone marrow replenishes adrenals and other endocrine the blood cells glands • Substances necessary for hematopoiesis Red cells – Protein • Red cells develop from erythroblasts, which are large – Vitamin B12 – Folic acid (one of the vitamin precursor cells in the bone B group) marrow – Iron • Hemoglobin, formed by • Red cell production is developing red cells, is a regulated by the oxygen tetramer composed of four content of the arterial blood different subunits, each one • White cell production is not consisting of heme and globin well understood

11 Normal Hematopoiesis • Heme is a porphyrin ring that contains an iron atom • Globin forms the largest part of the hemoglobin, that forms different chains designated by Greek letters such as alpha, beta, gamma, delta, and epsilon • The heme and the globin are synthesized separately in different locations within the Heme b group erythoblast • The porphyrin ring is produced by the mitochondria; then the iron is inserted to form heme • The globin chains are produced by the ribosomes, and are joined to heme to form a hemoglobin unit Biliverdin 12 Normal Hematopoiesis • Finally, the four subunits aggregate to form the complete hemoglobin tetramer • The developing red cell accumulates increasing amounts of hemoglobin as it matures • The nucleus is extruded when 80% of its total hemoglobin has been synthesized • The cell is discharged from the bone marrow into the circulation, where it completes its maturation process within the next 24 hours • A newly formed red cell that lacks a nucleus but retains some of its organelles can be identified by special strains and is called a reticulocyte • After about 24 hours, it becomes a mature red cell where it survives in the circulation for about four months.

13 Normal Hematopoiesis Regulation of Hematopoiesis • The worn out red cells are • The red cell production is removed in the spleen regulated by the oxygen • The hemoglobin is content of the arterial blood degraded • A decreased oxygen supply stimulates erythropoiesis • The globin chains are broken down and their • The low oxygen tension does products used to make not act directly on the bone other proteins marrow • It is mediated by the kidneys • The iron is extracted and which produce erythropoietin, saved to make new which is a hormone-like hemoglobin erythrocyte-stimulating • The porphyrin ring cannot material be salvaged and is excreted by the liver as bile pigment

14

Bilirubin metabolism and elimination. 1. Normal bilirubin production from heme (0.2 to 0.3 gm/day) is derived primarily from the breakdown of senescent circulating erythrocytes, with a minor contribution from degradation of tissue heme-containing proteins. 2. Extrahepatic bilirubin is bound to serum albumin and delivered to the liver. 3. Hepatocellular uptake and (4) glucuronidation in the endoplasmic reticulum generate bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile. 5. Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and excretion into urine.

15 1. A decrease in red blood cells or a subnormal level of hemoglobin • Anemia: “without blood” • Two different methods of classification are used 1. Etiologic classification: the factor responsible for anemia (Table 20-1) a. Acute blood loss b. Decreased production c. Ineffective hematopoiesis d. Increased destruction 2. Morphologic classification: shape and appearance of red cell

16 17 Etiologic Classification of Anemia

1. Inadequate production of red 2. Excessive loss of red cells cells • External blood loss • Insufficiency of raw materials: (hemorrhage)

iron deficiency, Vitamin B12 • Shortened survival of red cells deficiency, folic acid in circulation, with defective deficiency red cells as in hereditary • Inability to deliver adequate • Accelerated destruction of red cells into circulation cells as caused by anti-red because of marrow damage antibodies, or by mechanical or destruction (as in aplastic trauma to circulating red cells anemia), or by the replacement of marrow by

foreign or abnormal cells (as in bone marrow replacement anemia) 18

Morphologic Classification of Anemia • (정상혈구빈혈): appearance and size of cells is normal • (대적혈구빈혈): cells larger than normal • (소적혈구빈혈): cells are smaller than normal • (저색소성빈혈): reduced hemoglobin content • Hypochromic microcytic anemia (저색소성, 소적혈구빈혈): smaller than normal and reduced hemoglobin content • Classification of anemia based on red cell appearance is useful since it suggests the etiology of the anemia.

19 Morphologic Classification of Anemia • Iron deficiency anemia = hypochromic microcytic

• Vitamin B12 or folic acid deficiency anemia = macrocytic anemia • Most other types of anemia = normocytic Macrocytic- normochromic Anemia

20 Major examples of with morphological changes • Macrocytic-normochromic anemias : pernicious and folate-deficiency • Microcytic-hypochromic anemias : iron-deficiency, sideroblastic, • Normocytic-normochromic anemias : aplastic, post- hemorrhagic, hemolytic, chronic disease, sickle cell

21 A. (disturbance in DNA synthesis) B. Iron deficiency (disturbance in hemoglobin synthesis; lack of iron): Hypochromic, microcytic erythrocytes C. (membrane defect): Spherocytes D. Hereditary elliptocytosis (membrane defect): Elliptocytes E. Hemoglobin C disease (abnormal globin chain): Target cells, rhomboid crystals F. Acanthocytosis (membrane lipid defect, e.g., abetalipoproteinemia): Irregular spiculation G. Disseminated intravascular coagulation (DIC), thrombocytic thrombocytopenic purpura (TTP), heart valve prosthesis sequela (mechanical damage to erythrocytes): Schistocytes H. (abnormal globin chain): Sickle cells I. Thalassemia (disturbance in hemoglobin synthesis): Hypochromic, microcytic erythrocytes, poikilocytosis, basophilic stippling 22 A. Iron-Deficiency Anemia The characteristic laboratory • Most common anemia profile of iron deficiency anemia is low serum ferritin and serum • Hypochromic microcytic anemia iron but a much higher than normal serum iron-binding • Pathogenesis protein with a much lower than – Inadequate iron intake in normal percent iron saturation diet, as in infants during periods of rapid growth or • Clinical features: with adolescents subsisting - Atrophic glossitis (위축성혀염) on an inadequate diet - Angular stomatitis (입꼬리염) – Inadequate reutilization of iron present in red cells due - Koilonychia (숟가락손발톱) to chronic blood loss • Treatment: Laboratory Tests - Primary focus is to learn the • Serum ferritin cause of the anemia • Serum iron - Then direct treatment towards • Serum iron-binding capacity the cause rather than the symptoms

- Supplementary iron 23 Examples • Infant with a history of poor diet • In adults: a common cause is chronic blood loss from the gastrointestinal tract, as may be caused by a bleeding ulcer or an ulcerated carcinoma of the colon • In women: excessive menstrual blood loss • Too frequent blood donations

24 By chronic iron deficiency

25 B. Anemia of chronic disease C. (골수무형성빈 • Arises in association with chronic 혈, 재생불량빈혈) inflammatory & malignant • A disorder of pluripotential stem conditions cells that leads to bone marrow • Pathogenesis: ineffective use of failure iron from macrophage stores in • Pathogenesis: the bone marrow  resulting in a - results from injury to bone functional iron deficiency marrow stem cells • Pathology: - Causes: idiopathic or two main - mild to moderate anemia mechanisms - RBCs are often microcytic a.A predictable, dose-dependent, - Successful treatment of the toxic injury, typified by exposure underlying disease restores to certain chemotherapeutic normal hemoglobin levels drugs, chemicals, & ionizing radiation b.Idiosyncratic, dose-independent, immunologic injury, as seen in idiopathic cases or after certain drug exposures or vial infections c. Rarely, aplastic anemia (e.g., ) may be inherited. 26 • Clinical features: - Pancytopenia  namely weakness, fatigue, infection, & bleeding - Untreated aplastic anemia  3- to 6-month median Aplastic anemia. The bone marrow consists largely of fat cells and lacks survival normal hematopoietic activity. - Only 20% of patients survive • Pathology: variably reduced longer than 1 year. cellularity, depending on the - Bone marrow or stem cell clinical stage of the disease transplantation may be - Anemia, leukopenia (mainly curative. granulocytopenia), & thrombocytopenia - Despite elevated EPO levels, reticulocytosis is not present. 27 D. (PRCA, 적 혈구무형성증) E. Anemia of renal disease (콩 • A selective suppression of 팝병의 빈혈) committed erythroid precursors in • Chronic renal insufficiency  the bone marrow decreased production of EPO • WBC & platelets: unaffected • Pathogenesis: results from • Pathology: normocytic & immune suppression of red cell normochromic production; unknown causes; secondary to viral infection (parvovirus B19) or thymic F. Anemia of lead poisoning (납 lesions (e.g., thymoma, thymic hyperplasia) 중독에 의핚 빈혈) • Diamond-Blackfan syndrome: a • Lead poisoning  anemia by heritable type of PRCA interfering with several • Clinical features: enzymes involved in heme - Acute self-limited illness: often due to parvovirus B19 synthesis - Chronic relapsing process: idiopathic or associated with an underlying thymic lesions

28 3) Ineffective red cell production • The mature red cells are larger is characterized by circulating erythrocytes than normal and are called • Due to ineffective macrocytes; the anemia is hematopoiesis called macrocytic anemia. • Sufficient erythrocyte precursors are formed in the bone marrow, but erythrocytes do not enter the circulation A. Megalobastic anemias (거대적 혈모구빈혈) • Caused by impaired DNA synthesis, usually because of a deficiency in V-B12 or folic acid. Megaloblastic anemia. A bone marrow • Vitamin B : found in meat, aspirate from a patient with vitamin B12 12 deficiency (pernicious anemia) shows liver, and other foods rich in prominent megaloblastic erythroid animal protein precursors (arrows). • Folic acid: found in green leafy vegetables and other animal protein foods, such meat & eggs 29 Folic Acid Deficiency Anemia - The atrophy also causes the • Is relatively common lack of secretion of acid and • The body has very limited digestive enzymes stores - Vitamin B12 not absorbed , which rapidly become - Sometimes develops in depleted if not replenished middle aged and elderly continually individuals • Pathogenesis - Often associated with – Inadequate diet: autoantibodies directed encountered frequently in against gastric mucosal cells chronic alcoholics and intrinsic factor (IF) – Poor absorption caused by Other Causes of Vitamin B12 intestinal disease Deficiency Anemia – Occasionally occurs in • Following gastric resection to pregnancy, which increases treat ulcer disease or to treat folic acid requirements gastric cancer • Following gastric bypass • Pernicious Anemia- Vitamin procedures to treat obesity B12 deficiency macrocytic • Due to distal small bowel anemia resection or disease (because – Lack of intrinsic factor, not Vitamin B12 is absorbed in the secreted because of gastric ileum) mucosal atrophy 30 • Clinical features: B. Thalassemia (지중해빈혈) - In general, folate deficiency • Results from defective globin develops more rapidly (months) chain synthesis than doesV-B12 deficiency • Ineffective hematopoiesis (years) results from precipitation of - Neurologic symptoms by V- abnormal within B12 deficiency  irreversible newly formed RBCs & change if not treated properly; increased erythrocyte fragility, Not encountered with folate features that lead to deficiency erythrocyte destruction in the marrow. • Treatment : • Epidemiology: - Intramuscular administration of - Most common around the Mediterranean Sea (Italy, Vitamin B12 Greece), Middle East, India, Southeast Asia, & China (malaria endemic areas) - A heterozygous state for thalassemia  protective effect against malaria

31 • Pathogenesis: Defective • Pathology & clinical features: hemoglobin synthesis: in a) Homozygous-β-thalassemia thalassemia, the globulin (Cooley’s anemia) chains (α & β chains) are - If both alleles have thalassemia normal but their synthesis mutations. defective; found - A severe microcytic, hypochromic predominantly in persons of anemia Greek and Italian ancestry; - Untreated, it causes anemia, thalassemia minor (mild splenomegaly, and severe bone anemia) and thalassemia deformities. major (severe anemia) - It progresses to death before age a. β-Thalassemia (β-지중해빈혈) 20. - A heterogeneous group of - Treatment consists of periodic disorders caused by point blood transfusion; splenectomy if mutations in the β globin gene splenomegaly is present, and treatment of transfusion-caused - The total annual incidence of iron overload. symptomatic individuals: 1 in - Cure is possible by bone marrow 100,000 throughout the world transplantation. - Cooley's anemia is named after Thomas Benton Cooley.

32 • α-Thalassemia (α-지중해빈혈) - Pathogenesis: a form of thalassemia involving the genes HBA1 & HBA2. - α-thalassemia is due to impaired production of 1,2,3, or 4 alpha globin chains (gene deletion), Thalassemia. The peripheral blood erythrocytes are leading to a relative excess of hypochromic and microcytic and show anisocytosis, beta globin chains. poikilocytosis, and target cells (arrows). - The degree of impairment is based on which clinical b) Heterozygous β-thalassemia phenotype is present (how many - Associated with microcytosis & chains are affected). hypochromia - Pathology & Clinical features: - Often an accompanying • Silent carrier α-thalassemia: no erythrocytosis (increased RBC anemia, asymptomatic count) but minimal anisocytosis • α-thalassemia trait: mild - Target cells, basophilic stippling, microcytic anemia & a mild increase in hemoglobin A2 are present. • Hemoglobin H disease: moderate microcytic anemia - Most patients are entirely asymptomatic. • Homozygous (four genes affected) α-thalassemia: hydrops fetalis (fatal) 33 4) Hemolytic anemias feature A. Erythrocyte membrane defects • Alterations in any portion of the increased red cell destruction red cell membrane  susceptible • Genetically determined to hemolysis abnormalities of red cells a. Hereditary spherocytosis (HS) 1.Abnormally shaped cells: most - A heterogeneous group of common is hereditary inherited disorders of the RBC spherocytosis cytoskeletons, characterized by a deficiency of spectrin or another 2.Red cell enzyme deficiencies: cytoskeletal component (ankyrin, very common one is deficiency protein 4.2, b and 3) of an enzyme called glucose-6- - Moderate normocytic & phosphatase dehydrogenase, hyperchromatic anemia where the enzyme is unstable - Clinical features: splenomegaly and does not function normally due to chronic extravascular 3.Abnormal hemoglobins: hemolysis Hemoglobin S (sickle hemoglobin) is an important one; another one is hemoglobin C; both found predominantly in persons of African descent • Hemolytic anemias  extravascular hemolysis & intravascular hemolysis Hereditary spherocytosis. The peripheral blood smear shows frequent spherocytes with decreased diameter,34 intense staining and lack of central pallor (arrows). b. Hereditary elliptocytosis (HE, 유 c. Acanthocytosis (가시적혈구증 전성타원적혈구증) 가증) - A heterogeneous group of - the condition with inherited disorders involving the acanthocyte-like red blood erythrocyte cytoskeleton cells (spur cells) - “Horizontal” abnormality within - a form of that the cytoskeleton are spiked, or possess - Pathology & clinical features: various abnormal thorny mild normocytic anemia; projections asymptomatic - Most common cause: liver disease - Mild hemolysis & anemia

Acanthocytes. The red cells lack central pallor and display irregular spikes on the surface.

Hereditary elliptocytosis. A peripheral blood smear reveals that virtually all of the erythrocytes are elliptical with parallel sides. 35 B. Enzyme defects: glucose-6- • G6PD deficiency is most prevalent in phosphate dehydrogenase areas where malaria is historically deficiency endemic, notably Africa & the Mediterranean region. • X-linked recessive hereditary • G6PD deficiency is closely linked to disease characterized by favism (치명적 용해), a disorder abnormally low levels of glucose- characterized by a hemolytic reaction 6-phosphate dehydrogenase to consumption of broad beans, with (abbreviated G6PD or G6PDH), a name derived from the Italian name a metabolic enzyme involved in of the broad bean (fava). the pentose phosphate pathway, • Classification & Epidemiology: especially important in red blood - Severe deficiency (<10% activity) cell metabolism. G6PD with chronic (nonspherocytic) deficiency is the most common hemolytic anemia human enzyme defect. - Severe deficiency (<10% activity), • Individuals with the disease may with intermittent hemolysis exhibit nonimmune hemolytic - Mild deficiency (10-60% activity), anemia in response to a number hemolysis with stressors only of causes, most commonly - Non-deficient variant, no clinical infection or exposure to certain sequelae medications or chemicals. - Increased enzyme activity, no • Hereditary nonspherocytic clinical sequelae anemia

36 C. (헤모글로빈병증) • Caused by point mutations in the β- globin chain gene a. Sickle cell disease(낫적혈구병) • Occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria is or was common. • In areas where malaria is common, there is a fitness benefit in carrying only a single sickle-cell gene (). Those with only one of the two alleles of the sickle-cell disease, while not totally resistant, are more tolerant to the infection and thus show less severe symptoms when infected

Sickle cell anemia. Sickled cells (straight arrows) and 37 target cells (curved arrows) are evident. Pathogenesis of the vascular complications of sickle cell anemia. Substitution of valine for glutamic acid leads to an alteration in the surface charge of the hemoglobin molecule. Upon deoxygenation (-O2), sickle hemoglobin (HbS) tetramers aggregate to form poorly soluble polymers. The erythrocytes change shape from a biconcave disk to a sickle form with the polymerization of HbS. This process is initially reversible upon reoxygenation (+O2), but with repeated cycles of deoxygenation and reoxygenation, the erythrocytes become irreversibly sickled. Irreversibly sickled cells display a rearrangement of phospholipids between the outer and inner monolayers of the cell membrane, in particular an increase in aminophospholipids in the outer leaflet. + Potassium (K ) and water (H2O) are lost from the cells. The erythrocytes are no longer deformable and are more adherent to endothelial cells, properties that predispose to thrombosis of small blood vessels. The resulting38 vascular occlusions lead to widespread ischemic complications. • Clinical features: “Sickle cell crisis” = • Clinical features of organs: several independent acute conditions a. Heart: chronic demand for occurring in patients with sickle cell increased cardiac output  disease. Most episodes of sickle cell cardiomegaly and congestive crises last between five and seven days. heart failure a. Aplastic crisis (골수무형성위기): acute b. Lungs: acute chest syndrome worsening of the patient's baseline c. Spleen: splenomegaly anemia, producing pallor, tachycardia, and fatigue. Triggered by parvovirus d. Brain: inability to form B19, which directly affects concentrated urine, renal infarcts, erythropoiesis (production of red blood & papillary necrosis cells) by invading the red cell e. Liver: increased levels of precursors and multiplying in them and unconjugated (indirect) bilirubin destroying them.  pigmented bilirubin gallstones b. Sequestration crisis (격리위기): are f. Extremities: cutaneous ulcers acute, painful enlargements of the spleen. Sudden pooling of the blood * Heterozygotes for hemoblobin S into the spleen and circulatory defect (sickle cell trait) do not develop leading to sudden hypovolaemia  red cell sickling and are clinically hypovolemic shock  the most normal. frequent cause of death early in life. 39 • b. Hemoglobin C disease D. Immune hemolytic anemias • an abnormal hemoglobin in • Hemolysis caused by which substitution of a antibodies against antigens at the erythrocyte surface that glutamic acid residue with a may be allo- or autoimmune in lysine residue at the 6th origin position of the β-globin chain • The site of hemolysis may be has occurred (E6K extravascular or intravascular. substitution). • Autoantibodies can be • Increased erythrocyte rigidity classified as either warm or and mild chronic hemolysis cold antibodies a. Warm-antibody autoimmune c. Other hemoglobinopathies hemolytic anemia (WAIHA, 온 난항체 자가면역 용혈성 빈혈) • Several hundred additional • the most common of the hemoglobin variants in α- or autoimmune hemolytic β–globin genes diseases

40 • Antibody is IgG, though sometimes b. Cold-antibody autoimmune IgA is found. hemolytic anemia (CAIHA) • The IgG antibodies attach to a red • an autoimmune disease blood cell, leaving their FC portion characterized by the presence of exposed with maximal reactivity at high concentrations of circulating 37°C (versus cold antibody induced antibodies, usually IgM or IgG, hemolytic anemia whose antibodies directed against red blood cells. only bind red blood cells at low body • It is a form of autoimmune hemolytic temperatures, typically 28-31°C). anemia, specifically one in which • The FC region is recognized and antibodies only bind red blood cells grabbed onto by FC receptors found at low body temperatures, typically on monocytes and macrophages in 4°C (39.2°F) the spleen. • Pathology & clinical features: • Drug-induced WAIHA - uncommon - Hapten mechanism - more likely to develop peripheral - Immune complex mechanism vascular symptoms (Raynaud - Autoantibody mechanism phenomenon) upon cold exposure • Pathology & clinical features: because of red cell agglutination - normocytic or occasionally macrocytic anemia, with spherocytes, & polychromasia • Treatment: immunospuuressive agents or splenectomy

41 c. Cold hemolysin disease (저온 헤모 E. Mechanical red cell 리싞병 ) fragmentation syndromes • Cold hemolysins (Donath- • Intravascular hemolysis Landsteiner antibodies): usually IgG & directed against the P antigen • Pathogenesis: according to the system on red cells site of hemolysis • Paroxysmal cold hemoglobinuria: the a. Macroangiopathic (large vessels) sudden presence of hemoglobin in hemolytic anemia: most often the urine (called hemoglobinuria), reflects direct red cell trauma typically after exposure to cold from an abnormal vascular temperatures  most often follows a surface (e.g., prosthetic heart viral illness  immunosuppressive valve, synthetic vascular graft) therapy & splenectomy are usually ineffective, and supportive therapy is b. Microangiopathic (capillaries) required. hemolytic anemia: more d. Hemolytic disease of the newborn frequently results from abnormalities in the • Incompatibility of blood types between a mother & her fetus microculation, such as disseminated intravascular • Erythroblastosis fetalis (싞생아 용혈 성질환 coaggulation (DIC) & thrombotic thrombocytopenic purpura (TTP)42

• PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to absence of protective proteins on the membrane). • It may develop on its own ("primary Microangiopathic hemolytic anemia (MAHA). PNH") or in the context of other bone Irregular, fragmented erythrocytes (schistocytes, curved arrows) are seen in the blood smear of a marrow disorders such as aplastic patient with disseminated intravascular anemia ("secondary PNH"). coagulation. Howell-Jolly bodies are also • Only a minority have the telltale red present (straight arrows). urine in the morning. c. Paroxysmal nocturnal hemoglobinuria • Clinical features: (PNH, 발작 야간 혈색뇨증) - Intermittent intravascular hemolysis • a rare, acquired, potentially life- - Nocturnal in only a minority of cases threatening disease of the blood - Thrombocytopenia  lead to characterized by complement-induced bleeding intravascular hemolytic anemia (anemia due to destruction of red blood cells in the bloodstream), red urine (due to the appearance of hemoglobin in the urine) 43 and thrombosis. 2. (적혈구증가증) • Relative polycythemia: characteristic Treatment of dehydration • Many patients develop • Absolute polycythemia: thromboses due to the a. Primary/ (PV) increased blood viscosity and – Is a manifestation of a diffuse hyperplasia of bone marrow of elevated platelet count unknown etiology, characterized • Primary Polycythemia: drugs by overproduction of red cells, that suppress bone marrow white cells, and platelets; some overactivity patients eventually develop granulocytic leukemia • Secondary Polycythemia: b. Secondary : Compensatory periodic removal of excess increase in red blood cells (increased blood erythropoietin production by EPO- dependent stimulation) as a response to low arterial O2 that may accompany underlying disease, such a emphysema, pulmonary fibrosis; and other conditions that impair the oxygenation of blood; some types of congenital heart disease 44 Hematocrit Under Various Conditions

Hematocrit under various circumstances.

45 II. Hemostasis (지혈) 1. Hemostatic disorders (혈액응고장애) • Hemostasis: a process which causes bleeding to stop; platelets, endothelium, & coagulation factors are involved.

Hemostasis and thrombosis. Following injury to a vessel, rupture of an atherosclerotic plaque or the presence of major inflammation, coagulation is initiated when tissue factor (TF) binds to circulating factor VII, a small proportion of which is activated (VIIa). TF is located on cells (subendothelial or activated endothelial cells or leukocytes) or circulating microparticles. The TF/VIIa complex is activated by localizing to an activated phospholipid surface (PL*) such as that provided by activated platelets. TF/VIIa activates factor X to form Xa (1) and IX to form IXa (2). However, TF pathway inhibitor (TFPI) inhibits both (1) and (2). Sustained amplification is achieved through the actions of factors XI, IX and VIII. Factor XI is activated through the small amount of initial thrombin formed and, to a limited extent, by autoactivation or factor XIIa. Cofactors V and VIII, when activated by thrombin, form complexes with X (Xa/Va) and IX (IXa/VIIIa), respectively, on activated PL surfaces. Note the central and multiple roles for thrombin (4), which converts fibrinogen to fibrin, activates cofactors V and VIII (5), activates factors XI and XIII (3) and activates platelets. Fibrinogen binds to the Gp IIb/IIIa integrin receptor on activated platelets (P*). Note the extensive control in time and space of46 these concerted surface reactions. The combined result is the platelet:fibrin thrombus. Schematic illustration of some of the pro- and anticoagulant activities of endothelial cells. Not shown are the pro- and antifibrinolytic properties. vWF, von Willebrand

factor; PGI2, prostacyclin; NO, nitric oxide; t-PA, tissue plasminogen activator. Thrombin receptor is referred to as protease activated receptor (PAR).

The fibrinolytic system, illustrating the plasminogen activators and inhibitors.

47 Virchow triad in thrombosis. Endothelial integrity is the single most important factor. Note that injury to endothelial cells can affect local blood flow and/or coagulability; abnormal The central roles of thrombin in hemostasis and cellular blood flow (stasis or turbulence) can, in turn, activation. In addition to a critical function in generating cross- cause endothelial injury. The elements of the linked fibrin (via cleavage of fibrinogen to fibrin and activation of factor XIII), thrombin also directly induces platelet aggregation triad may act independently or may combine to and secretion (e.g., of TxA2). Thrombin also activates cause thrombus formation. endothelium to generate leukocyte adhesion molecules and a variety of fibrinolytic (t-PA), vasoactive (NO, PGI2), or cytokine (PDGF) mediators. Likewise, mononuclear inflammatory cells may be activated by the direct actions of thrombin. ECM, extracellular matrix; NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostacyclin; TxA2, thromboxane A2; t-PA, tissue type plasminogen activator. 48 • Hemostatic disorders & 2) Common platelet disorders thrombotic disorders: failure of the hemostatic system to restore impair hemostasis the integrity of an injured vessel • Decreased production causes bleeding  inability to maintain the fluidity of blood • Increased destruction results in thrombosis • Impaired function 1) Hemostatic disorders of blood vessels reflect dysfunction of A. Thrombocytopenia(저혈소판증) extravascular or vascular tissues A. Extravascular dysfunction resulting in hemostatic defects • Scurvy • Senile purpura (노년 자색반병) B. Vascular dysfunction resulting in hemostatic defects • Intrinsic genetic defects • Vasculitis • Deposition of immunoglobulin fragments in the vessel wall

49 • Normal platelets: 250,000/μL  • Pathology: under 150,000/μL - Platelets in acute IPT: less than a. Decreased platelet production: 20,000/μL caused by bone marrow - Platelets in chronic IPT: vary from a infiltration with leukemic cells or few thousand to 100,000/μL metastatic cancer, which impair • Clinical features: megakaryopoiesis • Sudden onset of petechiae & purpura b. Increased platelet destruction: • Spontaneous recovery occurs within may reflect immune-mediated 6 months in more than 80% of cases damage & removal of circulating platelets, as in idiopathic C. Drug-induced thrombocytopenia thrombocytopenic purpura & • Many drugs cause immune-mediated drug-induced thrombytopenia platelet destruction: quinine, quinidine, heparin, sulfonamides, gold salts, antibiotics, sedatives, B. Immune thrombocytopenic tranquilizers, & anticonvulsants (ITP, 면역혈소판감소자색반) purpura • Chemotherapeutic agents, ethanol, & • a decrease in blood platelets thiazides causes thrombocytopenia caused by antibodies against by suppression of platelet production platelet or megakaryocytic • Heparin-induced thrombocytopenia: antigens 25% of patients  mild, transient • Two forms: thrombocytopneia within the first 2 to 5 days of treatment initiation a. Acute ITP: children b. Chronic ITP: adults 50