National License: Infectious disease

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NL: Hematology and RE system.. Encoded by Waen32, Tai231, New73 MED34Printed by Ying246, Nan247, and Chi-mo unions MED34

Overview

2 Term 2 Serum ( Coagulating factors) Plasma ( Coagulating factors )

Serum expose Coagulating factor Clot Coagulating factors Fibrinogen Plasma Anticoagulant RBC Buffy coat WBC platelet plasma Coagulating factor

Vascular mesoderm Hemangioblast mesenchymal cell differentiation Growth factors Growth factor 2 series Myeloid/Erythroid series Lymphoid series 2 series mature cell Cell Myeloid series Erythrocyte RBC Serie Myeloid cell Megakaryocyte Cell Cytoplasm platelet thrombocyte

Granulocyte neutrophil, monocyte, eosinophil, basophil lymphoid sense bone marrow differentiation lymphocyte B lymphocyte plasma cell immunoglobulin ( Ig light chain-heavy chain ) lymphocyte thymus gland T lymphocyte NK Cell lymphoid stem cell

Erythrocyte (RBC) O2 Tissue Aerobic respiration ATP Cell Cell RBC Anemia Tissue O2 metabolism anemic symptoms

Megakaryocyte Cytoplasm platelet Hemostasis Mast Cell eosinophil allergen Neutrophil lysosome cell lysosome enzyme cell margination migration inflammation enzyme neutrophil Oxidation free radical signs of acute inflammation Monocyte Neutrophil phagocytic activity monocyte Chronic inflammation (neutrophil acute inflammatory process ) monocyte tissue macrophage dendritic cell macrophage Kpffer cell Langerhans cellB lymphocyte lymphoid cell bone marrow plasma cell immunoglobulins antibodies organism HIR autoantibodies SLE T lymphocyte lymphoid cell bone marrow mature thymus CMIR T lymphocyte CMIR defect intracellur organism HIV infection CD4+ T cell AIDS PCP (Pneumocystis carinii pneumonia) Pneumocystis jiroveci CMIR CMIR

8 yolk sac liver bone marrow bone marrow long bone flat bone bone marrow flat bone skull, sternum, pelvis

bone marrow biopsy pelvic bone histology bone marrow fat cell red bone marrow fat yellow marrow massive blood loss acute hemolysis yellow marrow red bone marrow

Red bone marrowWhite (Yellow) bone marrow

bone marrow () bone marrow fetus thalassemia hemolysis RBC bone marrow bone marrow liver spleen hyperplasia hepatosplenomegaly extramedullary hematopoiesis

RBC bone marrow 120 spleen mature RBC biconcave shape nucleus membrane structure cytoskeleton actin myosin RBC 7 m small lymphocyte

RBC nucleus DNA RNA mitochondria RBC Glycolysis anaerobic respiration pathway Pentose-Phosphate pathway (PPP)

Enzyme PPP G-6-PD enzyme NADP+ NADPH free-radical G-6-PD deficiency Oxidative stress G-6-PD enzyme antioxidant metabolite free radical infection oxidative stress sulfa free-radical acute hemolytic crisis

RBC membrane cytoskeleton ABO antigen glycoprotein blood group

antibody antigen blood transfusion O

RBC O2 condition O2 tissue RBC O2 tissue O2 O2 O2 tissue O2 RBC O2 (O2 affinity) O2 dissociation curve

Oxyhemoglobin hemoglobin O2 (hemoglobin O2 deoxyhemoglobin) deoxyhemoglobin 48 g/litre cyanosis

Oxyhemoglobin O2 saturation sigmoid curve 2,3-DPG

2,3-DPG Hb Hb O2 Hypoxia acidosis H+ RBC O2 O2 alkalosis ,H+ Hb O2

Structure Hemoglobin Heme globin chain heme protoporphyrin Fe2+ Fe2+ RBC globin malnutrition globin

Globin protein , , , globin liver, yolk sac, spleen Hb F bone marrow , Hb A Hb F Hb A

, RBC morphology spleen gene thalassemia 2 globin , chain DNA nucleotide Hb E

-gene -globin -globin -thalassemia -gene mutation -globin -thalassemia thalassemia imbalance , -thalassemia ,

Pathophysiology of -thalassemia -thalassemia -gene -globin Hb A Hb F U -thalassemia Hb F U hemolysis structure RBC extravascular hemolysis hypersplenism anemia RBC Heme porphyrin metabolism bilirubin organ jaundice blood transfusion RBC hemolysis anemia iron overload organ organ dysfunction hemochromatosis pancreas chronic pancreatitis B-cell, liver liver cirrhosis, Heart failure, pituitary gland Hypopituitarism

RBC hemolysis RBC bone marrow (BM), liver, spleen BM Bone Thalassemia hemochomatosis DM pituitary gland GH Sex hormone sex organ

X-ray linear fracture

ANEMIA

Anemia criteria WHO condition Hb Hct Testosterone RBC Hb 13 mg% 12 mg% 11 mg% Blood volume

Mechanism Anemia 3

1. RBC BM aplastic anemia RBC histopathology fat BM Renal failure Erythropoietin hormone RBC anemia of chronic kidney disease

RBC Iron deficiency, Folic deficiency, B12 deficiency DNA Malnutrition: globin chain RBC 2. RBC hemolysis hemolysis 2 UIntravascular hemolysisU RBC RBC membrane G-6-PD deficiency malaria

UExtravascular hemolysisU RBC Thalassemia

3. Blood loss UAcute blood lossU trauma UChronic blood lossU GI bleeding NSAIDs, aspirin Gastritis Blood smear Hypochromic-microcytic RBC Iron deficiency Blood smear iron deficiency CA Colon Bleeding Tumor

anemia sign & symptom 2 CVS CNS fatigue, dyspnea on exertion, (RBC, (carry O2, tissue hypoxia, pump O2 Heart failure

CNS O2 Dizziness Confusion Coma (Onset) Trauma bleeding anemic symptom

Anemia 2 Onset Acute () Chronic () 3 acute 3 Chronic Acute acute blood loss acute hemolysis RBC 120 Chronic

acute blood loss (epistaxis), GI bleeding oxidation coffee ground melena

acute hemolysis jaundice Direct bilirubin urobilinogen Intravascular hemolysis Hb Hemoglobinuria G-6-PD with acute hemolysis

Chronic anemia chronic blood loss BM failure aplastic anemia WBC infect platelet 2 precursor iron deficiency, chronic renal failure, vitamin B12 defect megaloblastic anemia [ Nucleus RBC Cytoplasm nucleus RBC Cytoplasm ] vitamin B12 jejunum absorb malabsorption Capillaria philippinensis malnutrition diarrhea ileum TB infect vitamin B12

Chronic hemolysis thalassemia autosomal recessive (G-6-PD deficiency X-linked recessive )Clinical manifestations of anemia

: mucous membrane conjunctivae , , systemic hypertension Tachycardia compensate O2 tissue requirement1. Glossitis () Folic acid Vitamin B12

2. Koilonychia (spoon shape nail) iron deficiency

** Glossitis Koilonychia iron deficiency**3. Angular dermatitis nutritional deficiency anemia 2

4. Petechiae hemorrhage petechiae bone marrow

** (anemia) petechiae Bone marrow failure**

Icteric scleraMongoloid facies

Hemolytic jaundice hemolytic anemia chronic extravascular hemolytic anemia Thalassemia Thalassemic facies Mongoloid facies

Hemolytic blood picture: hemolysis spherocyte central pallor polychromasia

thalassemia hemolysis spherocyte polychromasia Iron deficiency anemia hypochromic-microcytic RBC (microcytic) RBC MCV (Mean corpuscular volume) 80-100 fL , clinical CBC CBC, blood smear microcyte iron deficiency, thalassemia, lead poisoning macrocytic MCV > 100fL megaloblastic anemia B12, folate deficiency

hypersegmented PMN B12 deficiency

Pernicious anemia B12 Intrinsic factor Parietal cell stomach megaloblastic anemia ( Intrinsic factor)

UU B12 (cobalamine) R factor pancreatic enzyme R factor B12 B12 Intrinsic factor terminal ileum absorption , enzyme , Terminal ileum Vitamin B12 deficiency UClinical B12 deficiencyU: , neurologic symptom

BLEEDING DISORDERS

hemostasis 2 Primary hemostasis platelet plug vasoconstriction blood flow contact collagen tissue platelet platelet aggregation platelet plug Secondary hemostasis coagulative pathway intrinsic extrinsic fibrin fibrinolysis clot

coagulation cascade natural anticoagulant clot endothelial injury natural anticoagulant endothelial injury clot

hemostasis platelet, blood vessels coagulation normal physiology injury expose collagen platelet platelet coagulation factors intrinsic extrinsic factors

platelet aggregation 2 1. platelet von Willebrand factor factor VIII vWF deficiency vWF renal failure von Willebrands disease type 1 platelet coagulogram PTT prolong factor VIII 2. platelet Thromboxane A2 metabolism arachidonic acid cyclo-oxygenase ( COX-1 COX-2 ) COX-1 COX-2 inhibit COX inflammation COX-2 COX-1 IL-1 normal function platelet barrier mucous cell mucosa COX aspirin ( COX-1 COX-2) COX-1 platelet dysfunction atherosclerosis Ischemic heart disease Acute myocardial infarction Coronary syndrome bleeding aspirin TA2 aspirin PGE2 COX-1 gastritis mucous secretion gastric mucosa PGE2 prostaglandin renal function

COX-1 bleeding gastritis, peptic ulcer renal dysfunction renal failure inhibit COX-2 aspirin side effect aspirin selective COX-2 inhibitor COX-1 peptic ulcer COX-2 COX-1 TXA2 platelet clot selective COX-2 inhibitor Myocardial infarction platelet vWF, TXA2, ADP ( platelet) factors Coagulation cascade intrinsic extrinsic pathway

pathway interpret lab intrinsic pathway PTT extrinsic pathway PT common pathway factor pathway pathway

Prolong PTT, Normal PT = intrinsic pathway

Prolong PT, Normal PTT= extrinsic pathway

Prolong PT PTT = common pathway

common pathway factor X factor II ( factor II (prothrombin) factor IIa (Thrombin)) fibrinogen fibrin polymer clot fibrinogen Thrombin time

3-4 factor Coagulation pathway factor VII tissue factor tissue injury tissue factor factor VII factor X common pathway thrombin platelet factor VII coagulation pathway factor VII fibrin tissue plasminogen activator (tPA) plasminogen activated form plasmin fibrin natural anticoagulant

Natural anticoagulant clot DIC clot O2 anaerobic respiration lactic acidosis

Natural anticoagulant clot Protein C, Protein S, Antithrombin III Coagulation factors

Procoagulants regulators coagulation coagulants coagulants anticoagulants clot deep vein thrombosis coagulation anticoagulation bleeding

bleeding primary hemostasis secondary hemostasis fibrinolysis activity ()1) UPrimary hemostasisU: platelet dysfunction onset mucosal bleeding mucous membrane (petechiae) superficial ecchymosis platelet pancytopenia aspirin platelet dysfunction

2) USecondary hemostasisU: coagulation process Hemophilia mucosal bleeding (hemarthrosis) visceral organs deep ecchymosis, hematoma

clinical presentation (petechiae) conjunctiva hypermenorrhea clot clot (Venous stasis) clot endothelial injury vasculitis clot hypercoagulable stage activity clot Risk factors vascular thrombosis UVirchows triad clot thrombophilia (thrombo- = thrombus, philia = ) congenital natural anticoagulant ( Protein C, Protein S, Antithrombin III) acquire thrombophilia condition thrombosis venous thrombosis Antithrombin III nephrotic syndrome proteinuria natural anticoagulant thrombosis Deep vein thrombosis clot emboli deep vein thrombosis pulmonary embolism

deep vein thrombosis emboli cerebral stroke vein common carotid artery venous site venous emboli capillary arterial site arterial occlusion Right-to-left shunt ASD Venous thrombi venous site left atrium left ventricle systemic circulation stroke stasis intravenous pressure tissue tissue ulcer

Venous ischemic ulcerHemophilia

hemophilia clinical (hemarthrosis) coagulation

Hemophilia coagulation defect 2 type A factor VIII type B factor IX type A X-link recessive

factor VIII factor IX intrinsic pathway PTT prolong hemophilia activity factor ( factor 15-45%) bleed injury factor activity 1 diaphragm

Stage 3: lymphoma 2 diaphragm

Stage 4: lymphoma

Leukemia

2 type Leukemia myeloid lymphoid tissue type acute chronic acute leukemia blast cell BM >20% ALL AML ALL AML Bone Marrow failure syndrome anemia bleeding

Organomegaly tumor cell deposit monoblastic leukemia

Hyperuricemia cell (note: cell hyperuricemia )

Bone pain tumor cell BM

Note: APL (acute promyelocyctic leukemia AML type M3) DIC ( Auer rods)

UU: BM transplant, chemotherapyMultiple myeloma (MM)

Second most common hematologic malignancy ( lymphoma, leukemia) plasma cell bone marrow (BM) Bone marrow biopsy plasma cell

Note: tumor plasma cell organ Bone Marrow plasmacytomaU Multiple MyelomaU:

plasma cell BM monoclonal Ab (M protein) serum monoclonal Ab Ab heavy chain light chain light chain light chain urine Bence Jones protein Bence Jones protein acute renal failure plasma cell BM cell BM (bone marrow failure) WBC , RBC anemia, platelet bleeding plasma cell BM cytokine TNF osteoclast , Ca2+ hypercalcemia cytokine Light chain Ab amyloid deposit amyloidosis organomegaly ( deposit ), UNoteU: clinical Multiple Myeloma CRAB (C = hypercalcemia, R = renal involvement, A = anemia, B = bone pain)UU: plasma cell bone marrow > 10%, serum monoclonal Ab ( Ig G Ig A, Ig M, Ig E, Ig D ), Bence Jones proteinUU: BM transplant, chemotherapyMyeloproliferative disorder

4 CML (WBC ), polycetemia vera [PV] (RBC ), essential thrombocytosis [ET] (platelet ), myelofibrosis extramedullary hematopoiesis myeloproliferative disorder normal differentiation blast cell

Chronic Myeloblastic Leukemia

myeloproliferative disorder WBC translocation (9;22) Philadephia chromosome BCR-ABL gene gene tyrosine kinase myeloid cell

CML 3 phase 1. chronic phase organomegaly ( ) peripheral blood smear blast cell

2. accelerated phase 3. blastic phase blast cell BM >20% acute leukemiaUU: Philadephia chromosome [ BCR-ABL gene ]UU: chemotherapy, targeted therapy imatinib tyrosine kinase tyrosine kinase cellPolycythemia Vera

RBC erythropoietin RBC RBC (erythrocytosis)

UClinicalU: erythrocytosis hyperviscosity syndrome O2 (hypoxia) O2 , nerve O2 nerve nerve () blood clot UU: erythrocytosis serum erythropoietin ( RBC erythropoietin erythropoietin) erythrocytosis hypoxia ( COPD) erythropoietin serum erythropoietin Essential ThrombocytosisUU: platelet platelet

UClinicalU: platelet hyperviscosity syndrome hypoxia blood clot ( - -) bleeding platelet von Willebrand factor von Willebrand factor deficiency Platelet dysfunction

UU: ET blood clot bleeding Practice

1. Clinical

a. Red blood cell

b. White blood cell

c. Platelet

d. Coagulation

lingual papilla glossitis (spoon-nail) Iron deficiency RBC

Clinical signs Thalassemia RBC

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Histology Parietal cell RBC intrinsic factor Vitamin B12 Megaloblastic anemia

muscle wasting wrist drop Clinical presentation Lead poisoning RBC

Axillary node enlargement RE system WBC

deep vein thrombosis coagulation cellulites

Jaundice CT infiltration Cholangiocarcinoma obstructive jaundice Biliary tract Bleeding disorder Vitamin K deficiency Coagulation

2. WBC

Acute appendicitis neutrophil

Trichinellosis encapsulated cyst cross-section

eosinophil allergy asthma eosinophil infiltration eosinophil

Caseous granulomatous inflammation monocyte lymphocyte Granuloma TB infection Langhans giant cell

3. 55 GI Hb 10 mg/dL MCV 72 fL, serum iron TIBC saturation ferritin A. RBC folate

B. Iron absorption studies

C. Colonoscopy

D. Bone marrow examination

Colonoscopy CA colon bleeding Anemia4. 60 2 Lost proprioception in lower extremities positive Romberg sign, vitamin A. Folic acid

B. Thiamine

C. Vitamin K

D. Vitamin B12

Vitamin B12 deficiency Romberg test proprioceptive sensation posterior column of spinal cord sensory ataxia peripheral neuropathy loss of proprioception

Folic acid megaloblastic anemia

Thiamine Beri-beri, Wernicke-Korsakoff syndrome

Vitamin K Bleeding5. 25 5 CBC: platelet count 230,000 PT PTT mildly prolong A. Hemophilia

B. vWF disease

C. ITP

D. Cirrhosis

Hemophilia hypersplenism mucosal bleeding Platelet Platelet dysfunction mild PTT prolong vWF disease vWF Factor VIII intrinsic pathway Factor VIII PTT prolong6. A 14-year-old boy present with laceration on his hand that has become badly infected. He has felt fatigued for sometime. Physical examination reveals pallor of the mucous membranes in addition to bleeding on the inside of his cheeks. He has petechiae covering his body, and patches of purpura on his thighs, trunk, and arms. Relevant laboratory findings are WBC count 2,700 cells/mm3, Hct 22% and Platelet 4,800 cells/mm3A. Aplastic anemia

B. Acute leukemia

C. lymphoma

D. Megaloblastic anemia

WBC abnormal bleeding CBC Aplastic anemia

Acute leukemia WBC Blast cell 7. A 42-year-old man presents to ER department with sudden onset of shortness of breath. He complains of feeling fatigued and weak, and notes he saw blood in his urine. He is being treated with cotrimoxazole for UTI. Physical examination reveals mild icteric sclera and tachycardia, no hepatosplenomegaly

A. G-6-PD deficiency with crisis

B. Hb H with crisis

C. Aplastic anemia

D. Iron deficiency

G-6-PD deficiency with crisis

Hb H with crisis 8.

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Lead poisoning basophilic stipping Lead line fatigue wasting, neuropathy extensor area wrist drop wrist drop

organomegaly

extramarrow cellular infiltrate

Infection bleeding

leukemic cells in peripheral

anemia thrombocytopenia neutropenia

abnormal adhesion molecules

bone pain

ineffective hematopoiesis

Acute marrow expansion and replacement of blastic cells

(Bone marrow failure)

hypercellular marrow with < 5-10% blasts

myeloproliferative

disorders

hypercellular marrow with predominantly immature form >20%

acute leukemia

Abnormal proliferation

and differentiation

Myeloid stem cells

organomegaly

thrombosis bleeding extramedullary hematopoiesis

cytopenia, extramedullary hematopoiesis (organomegaly)

myelofibrosis

CML, PV, ET

Infection, anemia, hemorrhage

peripheral cytopenia with varying blasts and without organomegaly

chronic marrow expansion with released cells to periphery

hypercellular marrow with excessive blasts 5-20%

dysplastic changes, apoptosis

myelodysplastic syndrome

lymphoma / leukemia

Abnormal proliferation

and differentiation

Abnormal proliferation

Normal differentiation

Normal proliferation

Abnormal differentiation

Lymphoid stem cells

Hematopoietic stem cells

Chronic Lead Poisoning