陳玉昆教授 : 高雄醫學大學 口腔病理科 07-3121101~2755 yukkwa@kmu.tw

1. 口腔病理科 Diseases of blood andblood-forming organs 血液與造血器官疾病 陳玉昆教授: 高雄醫學大學 口腔病理科 07-3121101~2755 yukkwa@kmu.edu.tw

2. 學 習 目 標 Understanding: • Diseases of blood • Diseases of blood-forming organs

3. 參考資料 • Patton KT. Thibodeau GA. Anatomy & Physiology. 7th edition, St. Louis, Mosby, 2010 • http://zh.wikipedia.org/wiki/File:Erythropoietin.png • Damjanov I, Lindor J. Anderson’s Pathology, 10th edition, St. Louis, Mosby, 1996 • Raven PH, Johnson GB. Biology, 5th edition, NY, McGraw-Hill, 1999 • 2008 EdNurses, Inc. • asanagi987.blog27.fc2.com • www.mun.ca • www.lookfordiagnosis.com • Pathologyatlas.com • es.wikipedia.org • medcell.med.yale.edu • Neville BW, Damm DD, Allen CM, Bouquot JE. Oral & Maxillofacial Pathology, 3rd edition, St. Louis, Saunders WB, 2009 • commons.wikimedia.org • www.studyblue.com • 自我學習: 紅血球 studentaddomum.blogspot.com

4. (1) Homeostasis Composition of blood: whole blood, plasma, proteins Plasma(percent by volume) Proteins Whole Blood(% by volume) Albumins 57-60% Globulins 38% Fibrinogen 4% Prothrombin 1% Protein7% Blood 8% Water 92% Other solutes Ions Nutrients Waste products Gases Regulatory substances Plasma55% Other solutes 1% Other fluids& tissues 92% Platelets 140,000-340,000 Buffy coat Leukocytes Formedelements 45% Leukocytes 5,000-10,000 Neutrophils40-60% Lymphocytes 20-40% Erythrocytes 4.2-6.2 million Total Body Weight Monocytes 2-8% Centrifugedsample of blood Eosinophytes 2-4% Basophils 0.5-1% Formed elements(No./mm3) Ref. 1 Homeostasis (dynamic equilibrium: 動態平衡)

5. (1) Homeostasis Compensation mechanisms 1. Decreased RBCs 2. Decreased hemoglobin synthesis 3. Decreased blood flow 4. Hemorrhage 5. Increased O2 consumption by tissues 1 5  EPO 2 Bonemarrow  O2 3 4 6 9 Kidney Erythrocytes  EPO 8  O2 7 EPO (erythropoietin): 紅血球生成素 Refs. 1, 2

6. (1) Homeostasis Clotting cascades (級聯) • Three components - Vasculature (endothelial cells) - Blood proteins (clotting factors) - Platelets (vasospasm) • Basic blood clotting mechanism - Injured tissue & activated platelets - Chemical reactions: result in formation of thrombin - Formation of fibrin, trapping of RBC to form clot (凝血酶)

7. (1) Homeostasis Clotting cascades Extrinsic Pathway Intrinsic Pathway • Activated by 2 ways • Extrinsic- tissue trauma • Intrinsic- vascular damage • All routes lead to initiation of Factor X & thrombin blood clot Damage to tissueoutside theblood vessel Damage tothe blood vessel InactiveFactor X Cascade of clotting factors TissueThromboplastin (凝血酶) ActivatedFactor X Thrombin Prothrombin Factor XIII Fibrinogen Fibrin Blood Clot RBCs enmeshed(捲入)in fibrin Damaged tissue cells 2. Prothrombin Injury Extrinsic 3 Prothrombinactivator Clottingfactors Fibrin smesh(Blood clot) Calcium Blood clot Intrinsic Thrombin 1 Fibrinogen Fibrin Sticky platelet Ref. 1 Platelet plug

8. PGI2(前列腺素): an unstable metabolite synthesized by arachidonate cyclooxygenase pathway 結構 1.為一不飽和脂肪酸，共含20個碳 2. 必有一個五碳環，且上圖第7、8碳或是第12、13碳之間至少要有一個是雙鍵 (1) Homeostasis Clotting cascades (7-step) Endothelial sloughing I. Subendothelial exposure Platelets • Occurs after endothelial sloughing(塌陷) • Platelets begin to fill endothelial gaps • Promoted by thromboxane A2 (TXa2) • Inhibited by prostaglandin I2 (PGI2, prostacyclin) • Platelet function depends on many factors, esp. Ca2+ Collagen II. Adhesion • Initiated by loss of endothelial cells, which exposes adhesive glycoproteins such as collagen & von Willebrand factor (vWF) in the subendotheliuim • vWF in plasma deposit on the damaged areas • Platelets adhere to subendothelium through receptors that bind to the adhesive glycoproteins (GPIb, GPIa/IIa, GPIIb/IIIa) Stickyplatelets Collagen ACTIVATION Collagen Collagen III. Activation Platelets • After platelets adhere, they are activated to have a conformational changein GPIIb/IIIa receptors, resulting in their ability to bind adhesive proteins, including fibrinogen & vWF • Changes in platelet shape • Formation of pseudopods • Activation of arachidonic pathway Collagen Ref. 1

9. (1) Homeostasis Clotting cascades (7-step) RBC Platelets IV. Aggregation • Induced by release of TXa2 • Adhesive glycoproteins bind simultaneously to GPIIb/IIIa on two different platelets • Stabilization of the platelet plug (blood clot)occurs by activation of coagulation factors, thrombin, & fibrin • Heparin neutralizing factor enhances clot formation Fibrinmesh Fibrin Thrombin V. Platelet plug formation • RBCs and platelets enmeshed(捲入)in fibrin Platelet plug (blood clot) Fibrin degradation Thrombin VI. Clot retraction & dissolution Plasmin Plasminogen activators Activated protein • Clot retraction, using large number of platelets, joins the edges of the injured vessel • Clot dissolution is regulated by thrombin and plasminogen activators Thrombin:凝血酶 Ref. 1

10. (1) Homeostasis Normal destruction of RBCs • Old RBCs - Sequestered(隔離) & destroyed in spleen - In liver- if no spleen - Globin chains- broken down  amino acids - Reduced to bilirubin  liver & secreted in bile • Aging-RBCs replaced more slowly - Iron depletion(消耗) -  total serum iron, iron-binding capacity, & intestinal iron absorption • Lymphocyte function decreases Bilirubin(膽紅素): an orange-yellow pigment formed in liver by breakdown of hemoglobin & excreted in bile

11. (1) Homeostasis Engulfment of RBCs by macrophage 低倍 中倍 ScanningElectronMicroscope 高倍 R: RBCP: pseudopod M: macrophage Ref. 1

12. Etiologic events (erythropoiesis) (blood loss) (destruction) Red blood cells, hemoglobin(anemic condition) Oxygen-carrying capacity(hypoxemia) Liver(fatty changes, fattychanges can also occurin heart and kidney) Ischemia Tissue hypoxia Central nervous system(dizziness, fainting,lethargy)(頭暈，昏厥，嗜睡) Respiratory (respiratory rate, depth,exertional dyspnea)) Claudication(跛行) (muscle) Weakness (Fatigue) Pallor (skin/mucous membrane) Compensatorymechanisms Heart(angina) Capillarydilation Renal Heart rate Cardiovascular DPG in cells Renin-aldosteroneresponseSalt and H2OretentionExtracellular fluid Oxygen demandsfor work of heart SV Erythropoietin Extracellularfluid Hyperdynamiccirculation Stimulatesbone marrow High-outputcardiac failure Release of oxygenfrom hemoglobin in tissues Cardiacmurmurs (2) Anemia Generalized introduction 2,3-diphosphoglycerate (2,3-DPG):binds with greataffinity to deoxygenated HB,  the release ofthe remaining O2boundto the Hb 1 1 2 2,3-DPG 2 Diastolic volume Ref. 1

13. (2) Anemia Classification (1) • Classified by: - RBC sizeMacrocytic, microcytic, normocytic - HemoglobincontentNormochromic, & hypochromic • Symptoms based on severity & compensation • Classic symptoms - Fatigue, weakness, dyspnea(呼吸困難), & pallor(蒼白)

14. (2) Anemia Classification (2) • Macrocytic normochromic (megaloblastic) - Pernicious, folate (vitamin B12) deficiency • Microcytic hypochromic -Iron deficiency, sideroblastic(鐵粒幼細胞), Thalassemia(Mediterranean) • Normocytic normochromic - Aplastic, hemolytic,sickle(鐮刀型) cell "hair-on-end" appearance Ref. 12

15. (2) Anemia Causes (1) • ANEMIAS WITH DISTURBED IRON METABOLISM - Iron deficiency anemia - Sideroblastic anemia • MEGALOBLASTIC ANEMIAS -Cobalamin (B12) deficiency (pernicious anemia) - Folic acid deficiency • DISORDERS OF HEMOGLOBIN - Sickle cell anemia - Thalassemia (鐵粒幼細胞)

16. (2) Anemia Causes (2) • ANEMIAS ASSOCIATED WITH CHRONICDISORDERS - Anemia of chronic infection (infective endocarditis, osteomyelitis, lung abscess, pyelonephritis) - Anemia of inflammatory connective tissue (rheumatoid arthritis, lupus erythematosus, sarcoidosis, temporal arteritis, regional enteritis) - Anemia associated with malignancy - Secondary to chronic bleeding - Myelophthisic anemia - Anemia of uremia - Anemia of endocrine failure - Anemia of liver disease

17. (2) Anemia Causes (3) • HEMOLYTIC ANEMIAS - Extrinsic causes - Splenomegaly - Red cell antibodies - Trauma in circulation - Direct toxic effects (various microorganisms, copper salts, venom of some snakes) - Membrane abnormalities - Spur cell anemia(刺激細胞性貧血) - Paroxysmal nocturnal hemoglobinuria (陣發性睡眠性血紅蛋白尿) - Hereditary spherocytosis(球形紅細胞增多症) - Hereditary elliptocytosis - Disorders of interior of red cell - Defects in Embden-Meyerhof pathway - Defects in hexose monophosphate shunt

18. (2) Anemia Physiologic response & Compensatory • Physiologic response to anemia - Oxygen-carrying capacity of blood - Tissue hypoxia • Compensatory - Plasma volume - Thinner blood - Blood flow - Heart rate & stroke volume - Cardiac & pulmonary symptoms - Breathing rate & depth - Short of breath & dizziness(頭暈)

19. (2) Anemia Iron deficiency- Generalized introduction • Most common form • Populations at risk - Individuals living in poverty, women of childbearing age, children - Inadequate iron intake - Poor dietary conditions & malnutrition - heart rate & stroke volume - demand for iron during infancy & pregnancy

20. (2) Anemia Iron deficiency anemia- Manifestation • Bleeding that results in iron loss- usually gradual & occult (e.g., peptic ulcers, colonic tumors), menorrhagia • Manifestations - Pallor, ineffective erythrocytes - Generalized anemia S/S - Brittle & malformed nails - Neurologic symptoms (e.g., numbness, paresthesia, headache, confusion)

21. (2) Anemia Sickel cell anemia- Generalized introduction • Inherited types of hemolytic anemia • Autosomal recessive- abnormality in hemoglobin synthesis • U.S.  African-Americans • Worldwide- Mediterranean South America • India- natural protective adaptation against malaria(瘧疾) Slight "hair-on-end" appearance Ref. 12

22. (2) Anemia Sickel cell anemia- Two major forms • Sickle cell trait- one defective gene (heterozygous) - Often asymptomatic (carrier) or experience recurrent episodes associated with pain & tissue ischemia • Sickle cell anemia- defective gene from both parents (homozygous) has disease - Life threatening, pain crises, organ infarction, profound destruction of erythrocytes (aplastic crisis) Ref. 13

23. (2) Anemia Sickle cell trait- 1 defective gene (heterozygous) if only 1allele is affected(carrier), only 40-50% Hb isabnormal 未患病(carrier)(Father) 未患病(carrier)(Mother) 未患病(1/4機率) 未患病(carrier)(2/4機率) 患病(1/4機率) Ref. 14

24. (2) Anemia Sickel cell anemia- Cell morphology Cell changes shape,releases heme, andbecomes stiff-and-curved (sickle) (低氧血症) Hypoxemia Hemoglobin “lines up”and changes theshape of the RBC Ref. 1

25. Normal red cell Sinusoid Siickel cell Pointmutation Macrophage Splenic cord Valine Glutamic acid Endothelium infarction HbS solution HbS polymers Spleen  Hemolysis, congestion, infarction Oxygenated Deoxygenated Irreversiblysickled Infarct (e.g. lung) Infarct (e.g. bone marrow) Transudation(滲出) of fluid inflammation Reversibly sickled Membrane changesincreased adhesiveness Increased RBC transitmess in inflammed tissues Cell adhesion Microvascular occlusionby sickle cells Microvascular occlusionby sickle cells Sicklederythrocytes: more fragile than normal & block capillariesbecause of their shape & adherenceproperties (2) Anemia Sickel cell anemia- Sicklecell HbA HbS Ref. 14

26. (2) Anemia Sickle cell anemia- Sickle cell crisis • Dehydration • Stress or strenuous(費勁) exercise • Infection • Fever • Bleeding • Acidosis • Hypoxia (smoking) • Cold weather • Pregnancy Ref. 15

27. (2) Anemia Sickle cell anemia- Presentation • Bone crisis • Acute chest syndrome (vaso-occlusive crisis of the pulmonary vasculature; commonly manifests with pulmonary infiltrate on a chest x-ray) • Abdominal crisis • Joint crisis • Bleeding • Jaundice(黃疸), bruising(瘀傷), blood in urine Jaundice: yellowing of skin or whites of eyes, arising from excess of pigment bilirubin & caused by obstruction of bile duct, by liver disease, or by excessive breakdown of RBCs.

28. (2) Anemia Pernicious anemia- Generalized introduction • Most common type of macrocytic anemia • Caused by vitamin B12 deficiency & underlying absence of intrinsic factor - Enzyme required for gastric absorption of vitamin B12 - Vitamin B12 required for DNA synthesis - Congenital, autoimmune - Bariatric(減肥) surgery patients at risk due to gastrectomy- removal of parietal cells(胃壁細胞: secrete HCl & an intrinsic factor that forms a compound with vitamin B12) Refs. 10, 11

29. (2) Anemia Hemolytic anemia- Generalized introduction • Acquired- infection, systemic, liver, kidney disease, toxins • Hemolysis - Hemolysis of RBCs • Splenomegaly, jaundice from RBC destruction

30. (3) Myeloproliferative RBC disorders Generalized introduction • Polycythemia (abnormally increased Hb conc. through either (i) plasma volume or (ii) RBC no. )(紅血球增多症) • Relative polycythemia - Result of dehydration/fluid loss - Blood is viscous, hypercoagulable, thrombi • Absolute polycythemia - Secondary * (i) Increase in EPO to chronic hypoxia or (ii) response to EPO-secreting tumors EPO (erythropoietin): 紅血球生成素

31. (4) WBC disorders Generalized introduction • Leukocytosis (白血球增多) - Normal protective physiologic response to physiologic stressors • Leukopenia - Leukopenia is not normal & not beneficial - Low WBC predisposes to infection

32. (4) WBC disorders Granulocyte disorders- Classification • Granulocytopenia (agranulocytosis) - Hematopoiesis, immune mechanisms, chemo & radiation • Granulocytosis (neutrophilia) - 1st stage of infection/inflammation - Demand beyond supply-immature neutrophils (bands) - WBC differential = termed a “shift to the left” • Neutropenia - circulating neutrophils - Causes * Prolonged severe infection * Decreased production * Abnormal distribution & sequestration

33. Normal WBC Count 4,000 – 10,000 cells/mL Bands Neutrophils Lymphocytes Monocytes Eosinophils Basophils <1% 55% 36% 3-8% 1-4% 0.5% WBC elevated with bacterial infection“Shift to left” – increase in bands & neutrophils Bands Neutrophils Lymphocytes Monocytes Eosinophils Basophils 5% 75% 12% 4% 3% 0.3-0.5% (4) WBC disorders Granulocyte disorders- WBC differential Bands: immature neutrophils Ref. 1

34. (4) WBC disorders Leukemia- Introduction & classification • Malignant disorder of blood & blood-forming organs • Excessive WBC proliferation • Based- cell of origin - Myeloid(骨髓) - Lymphoid(淋巴) • Manifestations - Anemia, petechiae(瘀斑), ecchymosis(瘀斑), thrombosis, hemorrhage, DIC (disseminated intravascular coagulation),infection, weight loss, bone pain, liver, spleen, lymph nodeenlargement, pancytopenia (deficiency of all 3 cellular components of blood (RBCs, WBCs, & platelets), fatigue

35. (4) WBC disorders Acute leukemia- Generalized Introduction • Acute: rapid growth of immature/undifferentiated blood cells (blast cells) • Onset rapid & abrupt •  survival time- 85%: B-cells; 50%: > 50-year-old

36. (4) WBC disorders Acute leukemia- Classification • Acute lymphocytic leukemia (ALL) - Least common overall– common in children(78%) • Acute myelogenous leukemia (AML) - More common in adults - 20% survival rate

37. (4) WBC disorders Chronic leukemia- Generalized Introduction • Chronic- slow growth of more differentiated/ mature cells • Do not function normally • Gradual onset • Longer disease course • Longer survival time, mostly 60-80 years old • Arise from many different mature WBCs

38. (4) WBC disorders Chronic leukemia- Classification • Chronic lymphocytic leukemia (CLL) - More commonly in elderly adults - 73% survival rate • Chronic myelogenous leukemia (CML) - Mostly adults

39. (4) WBC disorders Leukemia- Summary Pluripotential stem cell Acute undifferentiated leukemia Lymphoid stem cell Acute erythroleukemia Acute megakaryocytic leukemia Acute myelogenous leukemia (AML) Acute lymphocytic leukemia(ALL) Erythroid stem cell Granulocyticstem cell Megakaryocyticstem cell Chronic lymphocyticleukemia, non-Hodgkin lymphoma(CLL) Chronic myelogenousleukemia Promonocyte Monocyte Chronic myelogenousleukemia(CML) Polycythemia,chronic myelogenousleukemia T cell B cell Erythrocyte Megakaryocyte Eosinophil Myeloblast Multiplemyeloma Solitaryplasmacytoma Platelet Basophil Promyelocyte Non-Hodgkin lymphoma Plasma cell Myelocyte Humoral immunity (antibody)IgG, IgM, IgA, IgD, IgE Metamyelocyte Cell-mediated immunity,graft vs host response Segmented neutrophil Ref. 1

40. (4) WBC disorders Leukemia- Etiologies • Genetic aberrations - Translocations (Philadelphia chromosome: 95% CML & 30% adults with ALL) - Errors in protein • Certain hereditary tendencies: - Down syndrome & immune deficiencies • Environmental factors: - Cigarette smoke - Ionizing radiation - Cancer treatments, other cancers - HIV, hepatitis C - Drugs

41. (4) WBC disorders Leukemia- Philadelphia translocation ChangedChromosome 9 NormalChromosome 9 ChangedChromosome 22(Philadelphiachromosome) NormalChromosome 22 BCR (q11) (q34)ABL Chromosomesbreak BCR-ABL Translocations Ref. 7

42. (4) WBC disorders Lymphoid disorders- Types • Lymphocytosis - Acute viral infections • Lymphocytopenia - Immune deficiencies, drug destruction, viral destruction • Lymphomas - Malignant transformation of a lymphocyte in lymphoid tissues - Two major categories * Hodgkin lymphoma(有Reed-Sternbergcell) * Non-Hodgkin lymphoma(無Reed-Sternbergcell) Ref. 8

43. (4) WBC disorders Hodgkin lymphoma(Reed-Sternbergcell) Refs. 8, 9

44. (4) WBC disorders Lymphoid disorders- EM photo Ref. 4

45. (4) WBC disorders Non-Hodgkin lymphoma- Generalized Introduction • Diverse group of lymphomas - Based on etiology, features, & response to therapies • Linked to: - Chromosome translocations - Viral & bacterial infections, environmental - Immunodeficiencies, autoimmune - Clonal expansion of B cells, T cells, and/or NK (natural killer) cells - Changes in proto-oncogenes and tumor- suppressor genes   malignant cells

46. (4) WBC disorders Multiple myeloma- Generalized Introduction • B-cell cancer • ~60years old males, blacks 2 times > whites, ~17000 cases yearly • Infiltrates bone marrow & aggregate into tumor masses in skeletal system • Hypercalcemia, renal failure, bone lesions

47. (4) WBC disorders Lymphadenopathy- Generalized Introduction • Enlarged lymph nodes- palpable/tender(壓痛) • Local - Drainage of inflammatory lesion located near enlarged node • General Ref. 12

48. (5) Splenic disorders Splenomegaly- Generalized Introduction • Splenomegaly - Idiopathic - Sign of underlying disease - Hypersplenism: overreactive splenic function - Causes: * Inflammation, infection, congestive disorders, tumors or cysts - Clinical signs * Splenic sequestering of RBCs, WBCs & platelets anemia, leukopenia, thrombocytopenia

49. (5) Splenic disorders RBCs in the spleen Ref. 1

50. (6) Platelets disorders Generalized Introduction • Acquired (common)/congenital - Drugs:heparin(肝素〔抗凝血藥〕), ASA(aspirin 抗凝血 ), NSAIDS(non-steroidal anti-inflammatory drugs) - Systemic conditions: Chronic renal disease, liver disease, iron & foliate deficiencies,… - Heme alteration: leukemia, … • Alteration of platelet function - Factor deficiencies (glycoprotein & von Willebrand) - Petechiae(瘀斑), purpura(紫癜), mucosal bleeding, gingival bleeding, & spontaneous bruising(瘀傷)