27. 11. 2020 Anemic syndrome and white blood cells disorders Kristína Repová, M.D., PhD. [email protected] Institute of Pathophysiology, Faculty of Medicine, Bratislava Prepared exclusively for the purposes of distance education at the Faculty of Medicine, Comenius University in Bratislava in 2020/21 Hematopoeisis • Hematopoietic organs: • Bone marrow: • forming of erythrocytes, granulocytes, monocytes, thrombocytes, partially lymphocytes • Thymus: • forming of T-lymphocytes • Lymphatic nodes, tonsils, spleen: • forming of B-lymphocytes lymphoid multipotent stem cell pluripotent progenitor cell precursor cell stem cell myleoid multipotent stem cell 1 27. 11. 2020 Hematopoeisis 3 Pluripotent hematopoietic stem cell (self-renewal) Myeloid multipotent Lymphoid multipotent stem cell stem cell Megacaryocyte and Granulocyte and T-cell and NK B-cell erythroid progenitor Macrophage progenitor cell progenitor progenitor Megacaryocyte Erythrocyte Granulocyte Monocyte progenitor progenitor progenitor progenitor (CFU-Meg) (CFU-E) (CFU-G) (CFU-M) Myeloblast NK-cell Proerythroblast Monoblast Lymphoblast Lymphoblast Promyelocyte Megacaryoblast Erythroblast Myelocyte Promonocyte Prolymphocyte Prolymphocyte Megacaryocyte Reticulocyte Metamyelocyte Monocyte T-cell B-cell Thrombocyte Erythrocyte Band cell Basophil Eosinophil Macrophage Dendritic cell Neutrophil 2 27. 11. 2020 I. Disorders of red blood cells II. Disorders of white blood cells III. Myeloproliferative and lymphoproliferative disorders I. Disorders of red blood cells 1. Anemia 2. Polycythemia 3 27. 11. 2020 • Hemoglobin (Hb): • F: 120 - 160 g/l M: 140 - 180 g/l • ”: polycythemia, dehydration • ‘: anemia, hyperhydration • Red blood cells (RBC): • F: 4,2 - 5,4 x 10 12 /l M: 4,6 - 6,2 x 10 12 /l • ”: polycythemia, dehydration • ‘: anemia, hyperhydration • Hematocrit: • volume percentage of red blood cells in blood • F: 39±4 % (0,39±0,04) M: 44±5 % • ”: polycythemia, dehydration • ‘: anemia, hyperhydration • Reticulocytes: • 0,5 – 1,5 % • ”: bleeding, haemolysis (bone marrow compensation) • ‘ - 0: poor RBC production, aplastic anemia • Erythropoietin: • ”: secondary polycythaemia, ‘ paO2, sideropenic and some haemolytic anemias • ‘: renal diseases, deficit of proteins, ” paO 2, polycythaemia vera • MCV – mean cell volume: • 87,5 fl (80-96 fl) • to differentiate normo-, micro- and macrocytic anemias • MCH – mean cell hemoglobin: • 29 pg (28-33 pg), 18 fmol • ”: hyperchromic anemias • ‘: hypochromic anemias 4 27. 11. 2020 1. Anemias = ‘ plasma hemoglobin concentration: ♀ < 120 g/l, ♂ < 140 g/l = ‘ hematocrit = ‘ RBCs • mild > 100 g/l • moderate 80 – 100 g/l • severe ˂ 80 g/l • a sign (symptom) of other diseases • normal paO2, in arteries, Hb fully saturated by O2 • Dilutive (relative) anemia: anemia caused by ” plasma volume Anemic syndrome • symptoms often present during ‘ Hb concentration in blood 1. ‘ O2 transport: • shortness of breath during exertion • weakness, fatigue • dizziness • angina • organ disorders • pallor: pale skin, lining mucosa, conjunctiva and nail beds 2. ‘ plasmatic volume: • pale or yellowish skin • postural hypotension 3. ” cardiac output: • palpitations • flow murmurs • tachycardia 5 27. 11. 2020 Adaptation to anemia ‘ blood viscosity tissue hypoxia ” Epo production ” 2,3-DPG in RBCs vasodilation ‘ peripheral resistance ‘ O affinity ” cardiac output 2 ” erythropoiesis (shift to the right of the (hyperkinetic circulation) dissociation curve) • fast adaptation, during exercise • develops within 24 h Morphologic classification of anemias according to MCV and MCH • • Normocytic: • after acute bleeding • Normochromic: after acute • aplastic anemia bleeding • hemolytic anemia: sickle cell anemia, • Hypochromich: ‘ Fe, thalassemia enzymatic defects, antibodies • Hyperchromic: ‘ VT B 12 • Microcytic: • ‘ Fe • β-thalassemia major • hereditary spherocytosis • chronic infections • Macrocytic: • megaloblastic: ‘ folate, VT B 12 • hypothyreosis, chronic liver failure 6 27. 11. 2020 Morphologic classification of anemias • Acute bleeding • Hemolysis • ↓ B12 • Bone marrow aplasia • ↓ folate ‘ Fe • Bone marrow infiltration Chronic disease ↓ MCV MCV and MCH ↑ MCV ↓ MCH normal ↑ MCH • Macrocytic Microcytic Normocytic hyperchromic hypochromic normochromic anemia anemia anemia • Megaloblastic anemia Pathophysiologic classification of anemias A. Anemias due to B. Anemias due to ‘ RBCs production: ” RBCs loss: • ‘ Erythropoietin (Epo): • acute / chronic • severe renal dysfunction hemorrhage • severe protein deficiency • hemolytic anemias • chronic inflammatory diseases • ‘ factors essential for erythropoiesis: • ‘ Fe • ‘ folate, VT B 12 • ‘ proteins • cellular dysfunction of hematopoietic Reticulocytes? tissues: • aplastic anemia • myelodysplastic sy. • leucemias • infiltration of hematopoietic tissue • fibrosis of bone marrow 7 27. 11. 2020 Pathophysiologic classification of anemias ↓ Hb ” RBCs loss ‘ RBCs production ‘ abnormal ” blood loss - hemorrhage Cytoplasmatic Nuclear Haemolytic defect defect anemias ↓ Fe ↓ B 12 Posthemorrhagic Aplastic anemia anemias Bone marrow infiltration A. Anemias due to ” RBCs loss A-a) Acute / chronic hemorrhage A-b) Hemolytic anemias 8 27. 11. 2020 A-a) Anemias due to blood loss • Acute hemorrhage: 1. hypovolemia (not anemia) • blood loss > 500 ml g severe anemia and Fe loss 2. regulatory mechanisms g ” plasma volume g hemodilution g ‘ hematocrit g anemia 3. ‘ Hb g ” Epo g ‘ apoptosis of progenitor cells CFU-E in hematopoietic tissues g 1 CFU-E forms in 2-3 days 60-120 reticulocytes • 4-5 days after acute hamorrhage g ” reticulocytes in blood • Chronic hemorrhage: • loss of x10 ml blood/day g cumulative iron loss • if the loss of Fe exceeds increased resorption g restriction of erythropoiesis g iron deficiency anemia A-b) Hemolytic anemias A. Extravascular hemolysis: • in spleen, liver, bone marrow • Fe and globin reutilize => no Fe deficiency, hemoglobinuria or hemosiderinuria • hem g bilirubin => ” indirect, nonconjugated bilirubin g jaundice, gallstones B. Intravascular hemolysis: after transfusion, artificial heart valves, PNH, cold aglutinins • hemoglobin binds haptoglobin g macrofages g prevent hemoglobin loss • if the haptoglobin capacity is exceeded, in kidneys: • passing glomerular membrane g hemoglobinuria g Fe loss • fagocytosis by tubular cells: Hb g hemosiderin g after 3-4 days hemosiderinuria , may injure tubules, acute renal failure • fragments of RBCs g trombosis, embolism g cerebral, myocardial, renal ischemia • ‘ plasma haptoglobin, takes x days to produce by liver • ” plasma lactate-dehydrogenase from RBCs 9 27. 11. 2020 A-b) Hemolytic anemias 1.Intracorpuscular: • membrane defects • hereditary spherocytosis, elliptocytosis, paroxysmal nocturnal hemoglobinuria (PNH) • enzymopathies • defects of glucose-6-phosphate dehydrogenase (G6PD), pyruvate kinase • hemoglobinopathies • sickle cell anemia, thalassemia 2.Extracorpuscular: • physical and toxic injury • mechanic, heat, bacterial toxins, malaria • antibodies • agglutinins, auto-antibodies, anti-Rh antibodies Hemolytic anemias intracorpuscular – membrane defects • Hereditary spherocytosis, elliptocytosis • AD, cytoskeletal and membrane defect with spectrin deficiency • vesicles form in membrane, when passing through spleen, RBCs are loosing part of membrane g spherical, ellipsoid shape of RBCs with ‘ deformability g hemolysis CP: anemia, splenomegaly, jaundice, gallstones Lab: ” reticulocytes, ” Epo Th: splenectomy • Paroxysmal nocturnal hemoglobinuria (PNH) acquired chronic HA, mutation of PIG-A gene in RBCs g lack of protecting proteins against complement on the membrane of RBCs (CD55, CD59) • ‘ pH during sleep stimulates complement g hemolysis CP: nocturnal/morning hemoglobinuria, hemosiderinuria, anemia (normocytic, normochromic), aplastic anemia , pancytopenia, venous thrombosis (complement activates aggregation of Thro) 10 27. 11. 2020 Hereditary spherocytosis Hereditary elliptocytosis Hemolytic anemias intracorpuscular – enzymopathies • Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency: • inherited, X chromosome, G-6-PD defends cells against oxidative stress • the most common enzyme deficiency in humans fava beans (= favism), infections, drugs (antimalarials, sulphonamides) g ” ox. stress g hemolysis CP: malaise, weakness, abdominal or lumbar pain, jaundice, dark urine (hemoglobinuria) • Pyruvate kinase deficiency: • AR, rare • ATP deficiency g ” K+ loss, Na + accumulation g rigid RBCs g hemolysis CP: neonatal jaundice, anemia 11 27. 11. 2020 Hemolytic anemias intracorpuscular – hemoglobinopathies • normal Hb: HbA = α2β2 • 2-3% HbA 2 = α2δ2 • fetal Hb = α2γ2 • Sickle cell anemia: • AD, usually Africans, resistance to malaria mutation in the β-globin gene that changes the 6th amino acid from glutamic acid to valine => HbS • HbS polymerizes reversibly when deoxygenated g ‘ deformability of RBCs g sickle shape g microvascular vasoocclusion • HbS denaturates in RBCs g membrane injury g macrophages g chronic hemolytic anemia • sickle cell crisis : intermittent episodes of vasoocclusion in connective and musculoskeletal structures g painful ischemia: acute pain and tenderness, fever, tachycardia, anxiety • repeated micro-infarction: lungs (pulmonary hypertension), kidneys (renal papillary necrosis), bone and joint (aseptic necrosis), skin (ulcerations), CNS (stroke), spleen (calcification) Lab, CP: ” reticulocytes, ” Epo, ” nonconjugated bilirubin, jaundice, gallstones Sickle cell anemia 24 12 27. 11. 2020 Hemolytic an emi as intrac orpus cular – hemoglobinopathies