anemic syndrome and white blood cells disorders...• defects of glucose-6-phosphate...
TRANSCRIPT
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Anemic syndrome and white blood cells disorders
Kristína Repová, M.D., PhD.
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
pluripotent
stem cell
lymphoid
multipotent
stem cell
myleoid
multipotent
stem cell
progenitor cell precursor cell
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Hematopoeisis
3
Pluripotent hematopoietic stem cell (self-renewal)
Myeloid multipotent
stem cell
Lymphoid multipotent
stem cell
Megacaryocyte and
erythroid progenitor
Granulocyte and
Macrophage progenitor
Erythrocyte
progenitor
(CFU-E)
Megacaryocyte
progenitor
(CFU-Meg)
Monocyte
progenitor
(CFU-M)
Granulocyte
progenitor
(CFU-G)
T-cell and NK
cell progenitor
B-cell
progenitor
T-cell B-cell
NK-cell
Dendritic
cell
Thrombocyte Erythrocyte
Neutrophil
Basophil Eosinophil Macrophage
Monocyte
Megacaryoblast
Megacaryocyte
Monoblast
Promonocyte
Proerythroblast
Erythroblast
Reticulocyte
Myeloblast
Promyelocyte
Myelocyte
Metamyelocyte
Band cell
Lymphoblast
Prolymphocyte
Lymphoblast
Prolymphocyte
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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
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• 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 1012/l M: 4,6 - 6,2 x 1012/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, � paO2, 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
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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
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Adaptation to anemia
� blood viscosity tissue hypoxia
vasodilation
� peripheral resistance
� cardiac output
(hyperkinetic circulation)
• fast adaptation, during exercise
� 2,3-DPG in RBCs
� O2 affinity
(shift to the right of the
dissociation curve)
• develops within 24 h
� Epo production
� erythropoiesis
Morphologic classification of anemias
• according to MCV and MCH
• Normochromic: after acute
bleeding
• Hypochromich: � Fe, thalassemia
• Hyperchromic: � VT B12
• Normocytic:
• after acute bleeding
• aplastic anemia
• hemolytic anemia: sickle cell anemia,
enzymatic defects, antibodies
• Microcytic:
• � Fe
• β-thalassemia major
• hereditary spherocytosis
• chronic infections
• Macrocytic:
• megaloblastic: � folate, VT B12
• hypothyreosis, chronic liver failure
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Morphologic classification of anemias
� Fe
↓ MCV
↓ MCH
Microcytic
hypochromic
anemia
Chronic
disease
• Acute bleeding
• Hemolysis
• Bone marrow aplasia
• Bone marrow infiltration
MCV and MCH
normal
Normocytic
normochromic
anemia
• ↓ B12
• ↓ folate
↑ MCV
↑ MCH
• Macrocytic
hyperchromic
anemia
• Megaloblastic
anemia
Pathophysiologic classification of anemias
A. Anemias due to � RBCs loss:
• acute / chronichemorrhage
• hemolytic anemias
Reticulocytes?
B. Anemias due to � RBCs production:
• � Erythropoietin (Epo):
• severe renal dysfunction
• severe protein deficiency
• chronic inflammatory diseases
• � factors essential for erythropoiesis:
• � Fe
• � folate, VT B12
• � proteins
• cellular dysfunction of hematopoietic
tissues:
• aplastic anemia
• myelodysplastic sy.
• leucemias
• infiltration of hematopoietic tissue
• fibrosis of bone marrow
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Pathophysiologic classification of anemias
↓ Hb
� blood loss -
hemorrhage
Posthemorrhagic
anemias
� RBCs loss
Haemolytic
anemias
� RBCs production
� abnormal
Aplastic anemia
Bone marrow infiltration
Cytoplasmatic
defect
↓ Fe
Nuclear
defect
↓ B12
A. Anemias due to � RBCs loss
A-a) Acute / chronic hemorrhage
A-b) Hemolytic anemias
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A-a) Anemias due to blood loss
• Acute hemorrhage:
1. hypovolemia (not anemia)
• blood loss > 500 ml � severe anemia and Fe loss
2. regulatory mechanisms �� plasma volume � hemodilution �
� hematocrit � anemia
3. � Hb �� Epo �� apoptosis of progenitor cells CFU-E in hematopoietic tissues � 1 CFU-E forms in 2-3 days 60-120 reticulocytes
• 4-5 days after acute hamorrhage � � reticulocytes in blood
• Chronic hemorrhage:
• loss of x10 ml blood/day � cumulative iron loss
• if the loss of Fe exceeds increased resorption � restriction of erythropoiesis � 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 � bilirubin => � indirect, nonconjugated bilirubin � jaundice, gallstones
B. Intravascular hemolysis:after transfusion, artificial heart valves, PNH, cold aglutinins
• hemoglobin binds haptoglobin � macrofages � prevent hemoglobin loss
• if the haptoglobin capacity is exceeded, in kidneys:
• passing glomerular membrane � hemoglobinuria � Fe loss
• fagocytosis by tubular cells: Hb � hemosiderin � after 3-4 days hemosiderinuria, may injure tubules, acute renal failure
• fragments of RBCs � trombosis, embolism � cerebral, myocardial, renal ischemia
• � plasma haptoglobin, takes x days to produce by liver
• � plasma lactate-dehydrogenase from RBCs
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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 � spherical, ellipsoid shape of RBCs with � deformability �
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 � lack of protecting
proteins against complement on the membrane of RBCs (CD55, CD59)
• � pH during sleep stimulates complement � hemolysis
CP: nocturnal/morning hemoglobinuria, hemosiderinuria, anemia (normocytic,
normochromic), aplastic anemia, pancytopenia, venous thrombosis
(complement activates aggregation of Thro)
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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) �
� ox. stress � hemolysis
CP: malaise, weakness, abdominal or lumbar pain, jaundice, dark urine
(hemoglobinuria)
• Pyruvate kinase deficiency:
• AR, rare
• ATP deficiency �� K+ loss, Na+ accumulation � rigid RBCs � hemolysis
CP: neonatal jaundice, anemia
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Hemolytic anemias intracorpuscular –hemoglobinopathies
• normal Hb: HbA = α2β2 • 2-3% HbA2 = 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 �� deformability of RBCs �
sickle shape � microvascular vasoocclusion
• HbS denaturates in RBCs � membrane injury � macrophages � chronic
hemolytic anemia
• sickle cell crisis: intermittent episodes of vasoocclusion in connective and
musculoskeletal structures � 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
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Hemolytic anemias intracorpuscular –hemoglobinopathies
• Thalassemia: inherited, disorders of α (4 allels) or β (2 allels) -globin
biosynthesis
• α-thalassemia: α –chain deficiency, 4 grades
• 3 loci deleted (HbH disease): severe hemolytic anemia
• 4 loci deleted: hydrops fetalis, HbH (β4) – precipitates in RBCs
• β-thalassemia: mutations � quantity of β-chains (β+) or they lack (β0)
• thalassemia major (β0/β0): α –chains precipitate in RBCs, kill developing erythroblasts
in the marrow = ineffective erythropoiesis, severe HA (microcytic, hypochromic), HbF,
HbA2
• massive bone marrow expansion � maxillary marrow hyperplasia and frontal
bossing, thinning and pathologic fracture of long bones and vertebrae � growth
retardation; hepatosplenomegaly
Th: RBCs transfusion � Fe overload � damage liver (cirrhosis), pankreas (DM 1.
type), myocardium (fibrosis, heart failure)
• thalassenia intermedia (β+/β+): anemia
• thalassemia minor (β0/β or β+/β0): none / mild anemia
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β-thalassemia
Facial bone abnormalities:
-Bossing of the skull
-Hypertrophy of maxilla
-Exposure of upper teeth
-Depression of nasal bridge
-Periorbital puffiness
Distribution of sickle cell anemia and thalassemia
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Sposi: Interaction between Erythropoiesis and Iron Metabolism in Human β-Thalassemia - Recent Advances and New Therapeutic Approaches. Inherited Hemoglobin
Disorders. 2015. https://doi.org/10.5772/61716.
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Hemolytic anemias extracorpuscular
• Mechanical injury:
thrombotic thrombopenic purpura, hemolytic-uremic syndrome, disseminated
intravascular koagulation, transplant rejection: firbrin, aggregated Thro in arteriols or
capillaries � fragmentation RBCs, endothelial dysfunction� microangiopathic hemolytic
anemia
marathon, barefoot ritual dancing (march hemoglobinuria)
prosthetic heart valves
• Toxic agents: Clostridium perfringens toxin, spider, snake toxins, malaria
• Heat: > 49°C, burns
• Drugs: - penicilin, ampicilin, cephalosporins � haptens on RBCs surface � antibodies
- phenacetin, chinidin, rifampicin � bind plasmatic proteins and then complement
binds RBCs
- methyldopa � chronic production of autoAb against RBCs
Hemolytic anemias extracorpuscular –autoimmune (AIHA)
• Warm antibody hemolytic anemia:
SLE, lymphoma, chronic lymphocytic leukemia
• 37°C, IgG with Fc fragment binds RBCs
� macrophages in spleen phagocyte RBCs � extravascular hemolysis
� activation of complement � intravascular hemolysis (rare)
• Cold agglutinin disease:
mycoplasmal pneumonias, infectious mononucleosis, lymphoproliferative disorders
• 4-30°C, IgM
• hemolysis in the extravascular mononuclear phagocyte system of the liver
• RBCs agglutinate in circulation � obliteration of colder acral parts = akrocyanosis
• Paroxysmal cold hemoglobinuria:
• Ab binds to red cells only at a low temperature (4°C) � warming � lysis of RBCs in the
presence of complement � intravascular hemolysis
CP: pallor, jaundice, abdominal pain, fever
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Hemolytic anemias extracorpuscular –autoimmune (AIHA)
• Rh incompatibility :
• mother Rh neg. and fetus Rh posit.
• hemolysis usualy in 2nd pregnancy
• hemolytic anemia, jaundice of the newborns, hydrops fetalis
• AB0 incompatibility:
• acute hemolytic reaction
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B. Anemias due to � RBCs production
• � erythropoietin (Epo):
• severe renal dysfunction
• severe protein deficiency
• chronic inflammatory diseases
• � factors essential for erythropoiesis:
• � Fe
• � folate, VT B12
• � proteins
• cellular dysfunction of hematopoietic tissues:
• aplastic anemia
• myelodysplastic sy.
• leucemias
• infiltration of hematopoietic tissue
• fibrosis of bone marrow
Lab: � reticulocytes in blood
B-a) Anemia due to erythropoietin deficiency
bilateral nephrectomy, bilateral chronic renal failure
chronic disease (rheumatoid arthritis), malignant diseases:
• inflammatory cytokines (IL-1, TNF, IFN-γ) � renal reactivity to hypoxia ��
Epo
• Fe deficiency (accumulation in macrophages, Fe for immunity)
• shorter life of RBCs
• � EPO � apoptosis of CFU-E, � CFU-E in bone marrow, � reticulocytes in
blood
• Epo is partialy produced in liver
• normocytic, normochromic anemia
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B-b) Iron deficiency anemia – iron metabolism
• 3,5–5 g iron (Fe)
• iron stores: ferritin and hemosiderin
• Ferritin: �: iron overload, liver disease, malignancies
�: iron deficiency anemia
• transport iron: transferrin
• �: iron deficiency � negative feedback �� transferrin synthesis in
hepatocytes
• �: impaired proteosynthesis, malnutrition, loss (proteinuria), acute /
chronic inflammation (negative acute phase reactant)
• transferrin saturation: �: 80–90 % in hereditary hemochromatosis
�: iron deficiency
• functional iron: hemoglobin, myoglobin, cytochromes, katalases, peroxidases
B-b) Iron deficiency anemia
Iron deficiency:
• blood loss: UGS (menorrhagia, renal hemorrhagia), GIT (ulcers, varices,
hemorrhoids, ...)
• impaired iron recycling: chronic infections (does not release from
macrophages)
• insufficient iron intake: malnutrition
• impaired resorption: achlorhydria (atrofic gastritis), malabsorption (celiac
disease, ulcerative colitis, phytates in grains, tannins in tea)
• increased demand for iron: rapid growth in infancy or adolescence,
pregnancy, lactation
1. prelatent iron deficiency (negative iron balance): demands for (or losses of)
iron exceed the body's ability to absorb iron from the diet, enough iron for
erythropoiesis
2. latent iron deficiency (iron deficient erythropoiesis): iron stores depleted, �
marrow iron stores, erythropoiesis present
3. manifest iron deficiency: iron deficiency anemia - microcytic hypochromic
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B-b) Iron deficiency anemia
B-b) Iron deficiency anemia
• erythroblasts mature longer in BM, they can undergo more divisions �
microcytes
CP: smooth red tongue, angular stomatitis, spoon nails, infections
Lab: - � reticulocytes
- � ferritin (iron stores depleted)
- � serum iron
- � transferrin
- � transferrin saturation
- � Epo
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B-b) Iron deficiency anemia
smooth red tongue,
angular stomatitis
spoon nails (koilonychia)
pale conjunctiva
Microcytic and hypochromic red cells
smaller than the nucleus of a
lymphocyte associated with marked
variation in size (anisocytosis) and
shape (poikilocytosis).
B-c) Megaloblastic anemia –Folate and cobalamin deficiency anemia
defects in DNA synthesis, the cell cycle is slowed down during formation of
RBCs, granulocytes and megakaryocytes
• Hb synthesis in the cytoplasm continues unchanged=> megaloblasts in BM and
megalocytes in blood
• premature destruction of megaloblasts in bone marrow=> inefficient erythropoiesis
• shortened life-span of the megalocytes=> premature hemolysis
Lab: - � reticulocytes in blood
- pancytopenia
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B-c) Folate deficiency anemia
Folate deficiency:
• dietary
• � utilization: growth, pregnancy, malignancies
• malabsorption: small intestine diseases, methotrexate
• cobalamin deficiency (VT B12)
• folate: thymidine synthesis for DNA
• deficiency manifests after x weeks – months
• in vegetables (long cooking destroys folate)
B-c) Vitamin B12 (cobalamin) deficiency anemia
Vitamin B12 deficiency:
• dietary: vegans
• intrinsic factor (IF) deficiency: IF is secreted by parietal cells of stomach, in
duodenum IF binds VT B12, in lower ileum IF-VT B12 is absorbed and in
enterocyte B12 binds transcobalamin II � plasma): atrophic gastritis =>
pernicious anemia megaloblastic, macrocytic
• � bacterial consumption of VT B12 in intestine: blind loop syndrome,
diverticulosis, Crohns disease
• loss (inherited / resection) or inflammation of terminal ileum
• deficiency manifests after x years
• in meat, fish, and dairy products
• B12 is needed to form tetrahydrofolate during conversion of homocystein to
methionin
CP: - homocysteine accumulation => thrombi
- damage to NS (can be permanent): methionine deficiency � axonal
demyelization, neuronal loss => paresthesia, impaired reflexes, balance,
cognition
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B-c) Megaloblastic anemia
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B-d) Aplastic anemia• pancytopenia with bone marrow hypocellularity - bone marrow failure
• Idiopatic aplastic anemia:
• 50-65% aplastic anemias, more severe than secondary
viral infections, drugs (chloramphenicol)
autoimmune defect of pluripotent stem cells or BM stroma
• Secondary aplastic anemia:
cytostatic drugs – transient anemia
parvovirus B19 infection
myelotoxic drugs: benzene, pesticides
CP: - anemia – pallor, fatigue, tachycardia, hyperkinetic circulation
- thrombocytopenia – petechiae, hematomas, bleeding from gums, GIT,
menorrhagia
- granulocytopenia – bacterial, fungal infections
Lab: - BM: � erythroblasts, megakaryocytes, granulocytes precursors
- blood: pancytopenia – anemia, leukopenia, thrombocytopenia, �
reticulocytes
B-d) Aplastic anemia
• Fanconi’s anemia:
• aplastic anemia with pancytopenia
• AR, chromosomes are peculiarly susceptible to DNA cross-linking agents � malignancy
• congenital developmental anomalies involving the thumb, radius, and genitourinary tract
• growth and mental retardation
• skin hyperpigmentation - café au lait spots
• Myelophthisis:
• fibrosis of the bone marrow
invading tumor cells
osteopetrosis
infection of mycobacteria (both Mycobacterium tuberculosis and M. avium), fungi, or HIV, and in sarcoidosis
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B-d) Aplastic anemia
• Pure red cell aplasia:
• isolated absence of RBCs precursors
• antibodies against Epo
• Diamond-Blackfan sy.:
• AD, severe macrocytic anemia, in BM � reticulocytes and erythroblasts
• Pure red cell aplasia (PRCA):
• acquired, idiopatic
thymom, lymphatic malignities, lupus erythematodes, rheumatoid
arthritis, infections (parvovirus B19, HIV, EBV)
B-e) Anemia of chronic disease
• inflammation, infection, tissue injury, cancer � proinflammatory cytokines
chronic infections: TBC, pulmonary inflammation, subacte bacterial
endocarditis, osteomyelitis, AIDS
chronic inflammation: ulcerative collitis, rheumatic, systemic diseases
autoimmune diseases
malignancies: carcinoma, lymphoma, leukemia, myeloma
chronic renal failure (� Epo)
trauma, postoperative state
• anemia: normocytic, normochromic �� hypochromic a microcytic
• Mechanisms:
• shortened life-span of RBCs (macrophage activation)
• � proliferation and differentiation of erythroid precursors
• � Epo production / resistance of erythroid precursors to Epo
• changed iron metabolism, specific deficit for erythropoiesis
• inflammatory cytokines (IL-1β, IL-6, TNFα, IFNγ)
• primary disease (hemorrhage, malnutrition, …)
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Zarychanski, CMAJ 2008,179(4):333-337
B-e) Anemia of chronic disease – iron
• Functional iron deficiency: not enough of iron for erythropoiesis, BUT it is sequestrated in macrophages
• Hepcidin:
• sequestration of iron within macrophages (essential nutrient for the growth of microorganisms, promotes infection and facilitates the growth of malignant cells)
• stimulated by inflammation (IL-6)
• rapidly � serum iron
• � iron resorption in duodenum
Anemia of
chronic disease
Iron deficiency
anemia
Serum iron � �
Transferrin � - normal �
Transferrin saturation � �
Ferritin normal - � �
Soluble transferrin receptor normal �
Cytokine levels � normal
Weiss, Goodnough, N Engl J Med 2005;352:1016
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B-f) Renal anemia
Chronic kidney disease
� Epo from kidneys uremic toxins
� RBCs survival
� filtration and removal
of phosphates
hyperphosphatemia
phosphates + calcium �
calciumphosphate komplex
accumulation in
joints and bones
hypocalcemia
stimulates parathyroid
glands � parathormone
� BM sensitivity to Epo
� erythropoiesis in BM
• normocytic
normochromic anemia
• � reticulocytes
2. Polycythemia
• Cellular disorders of hematopoietic tissue:
• polycythaemia vera rubra (� Myeloproliferative diseases)
• Polycythemia due to � Epo stimulation:
tissue hypoxia: high altitude, pulmonary diseases, right-to-left
shunts, carbon monoxide intoxication
ectopic Epo production: tumors of kidneys, liver, uterus
• Relative (stress) polycythemia (Gaisbock sy.):
• � plasma volume
arterial hypertension, obesity, smoking
dehydration
severe burns
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Pathophysiologic classification of anemias
A. Anemias due to � RBCs loss:
• acute / chronichemorrhage
• hemolytic anemias
Reticulocytes?
B. Anemias due to � RBCs production:
• � Erythropoietin (Epo):
• severe renal dysfunction
• severe protein deficiency
• chronic inflammatory diseases
• � factors essential for erythropoiesis:
• � Fe
• � folate, VT B12
• � proteins
• cellular dysfunction of hematopoietic
tissues:
• aplastic anemia
• myelodysplastic sy.
• leucemias
• infiltration of hematopoietic tissue
• fibrosis of bone marrow
I. Disorders of red blood cells
II. Disorders of white blood cells
III. Myeloproliferative and
lymphoproliferative disorders
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II. Disorders of white blood cells
1. Leukopenia
2. Leukocytosis
3. Disorders of granulocyte function
Normal values:
Leukocytes: 4-10 x 109/l
Neutrophils: 65% 3,9 x 109/l
Eosinophils: 3% 1,8 x 108/l
Basophils: 0,5% 3 x 107/l
Monocytes: 4% 2,4 x 108/l
Lymphocytes: 27,5%
Neutrophil pool
1. bone marrow (90%)
2. circulation (2–3% ):
• circulating pool (1/2): not in contact with the endothelium
• marginated leukocytes: are in close physical contact with the
endothelium
3. tissues
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1. Leukopenia
• Neutropenia:
often, severe infections: fever, fatigue, anorexia, sore throat, otitis media,
inflammation of UGS
� production:
• iatrogenic injury to BM: cytotoxic or immunosuppressive therapies
• aplastic anemia, myelofibrosis
• folate, VT B12 deficiency
• infections: tuberculosis, brucellosis, tularemia, infectious mononucleosis,
malaria, viral hepatitis, leishmaniasis, AIDS
• cyclic neutropenia: � neutrophils in 20 days cycles
Peripheral Pooling (Transient Neutropenia):
• hypersplenism
• overwhelming bacterial infection (acute endotoxemia)
Peripheral Destruction:
• antineutrophil antibodies
• rheumatoid arthritis, lupus erythematosus
1. Leukopenia
• Eosinopenia: acute bacterial infection
treatment with ACTH and glucocorticoids
• Basopenia: treatment with ACTH and glucocorticoids
• Lymphopenia: � ACTH
radiation
cytostatic therapy
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2. Leukocytosis
• Neutrophilia:
� production:
• glucocorticoids, G-CSF (release from BM); infection (bacterial, fungal);
inflammation (thermal injury, tissue necrosis, myocardial and pulmonary
infarction); myeloproliferative diseases (myelocytic leukemia, myeloid
metaplasia, polycythemia vera)
� marrow release:
• glucocorticoids, acute infection (endotoxin), inflammation (thermal
injury)
� or defective margination:
• drugs (epinephrine, glucocorticoids, NSAIDs); stress, excitement, vigorous
exercise; leukocyte adhesion deficiency syndrome
acute hemorrhage or hemolysis, ketoacidosis, acute poisoning
• Leukemoid reaction: physiological response to stress or infection,
neutrophilia with mature neutrophils and marked “left shift”=> benign
2. Leukocytosis
• Eosinophilia: parasite, helminthic infection
allergies: hay fever, asthma, eczema
allergic reaction to drugs: iodides, aspirin, penicillins, cephalosporins
rheumatoid arthritis
malignancies: Hodgkin's disease, chronic myeloid leukemia
• Basophilia: ulcerative collitis, rheumatoid arthritis, tumors
CML, Hodgkin's disease
estrogens
• Lymphocytosis: viral infections: infectious mononucleosis, CMV
ALL, CLL
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3. Disorders of granulocyte function
• Leukocyte adhesion deficiency – LAD:
AR, impaired phagocyte adherence, aggregation, spreading, chemotaxis
• � or absence of marginal pool � neutrophilia
• granulocytes are not able to concentrate in inflammatory sites � recurrent
infections of skin and mucosa, gingivitis, periodontal disease
• Abnormal chemotaxis: Chédiak-Higashiho sy.:
� chemotaxis and phagolysosome fusion � recurrent pyogenic infections,
especially with S. aureus
• Disorders of Phagocyte Function:
• Chronic Granulomatous Diseases:
no respiratory burst in neutrophils, monocytes, and eosinophils � severe
infections of skin, ears, lungs, liver, and bone (catalase-positive
microorganisms: S. aureus, Aspergillus spp.) � granulomas, can obstruct
GI or GU tracts
• Myeloperoxidase Deficiency:
• MPO forms hypochlorous acid, defect compensated by NADPH oxidase
activity � systemic candidiasis
I. Disorders of red blood cells
II. Disorders of white blood cells
III. Myeloproliferative and
lymphoproliferative disorders
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III. Myeloproliferative and lymphoproliferativediseases
1.Myeloproliferative:a) Myelodysplastic syndrome (MDS)
b) Acute myeloid leukemia (AML)
c) Chronic myeloid leukemia (CML)
d) Polycythaemia vera rubra (PVR)
e) Essential thrombocythemia
f) Idiopathic myelofibrosis
g) Mastocytosis
2.Lymphoproliferative :a) Acute lymphoid leukemia (ALL)
b) Chronic lymphoid leukemia (CLL)
c) Hodgkin's lymphomas
d) Non-Hodgkin's lymphomas
e) Plasma cells disorders
Pluripotent hematopoietic stem cell (self-renewal)
Myeloid multipotent
stem cell
Lymphoid multipotent
stem cell
Megacaryocyte and
erythroid progenitor
Granulocyte and
Macrophage progenitor
Erythrocyte
progenitor
(CFU-E)
Megacaryocyte
progenitor
(CFU-Meg)
Monocyte
progenitor
(CFU-M)
Granulocyte
progenitor
(CFU-G)
T-cell and NK
cell progenitor
B-cell
progenitor
T-cell B-cell
NK-cell
Dendritic
cell
Thrombocyte Erythrocyte
Neutrophil
Basophil Eosinophil Macrophage
Monocyte
Megacaryoblast
Megacaryocyte
Monoblast
Promonocyte
Proerythroblast
Erythroblast
Reticulocyte
Myeloblast
Promyelocyte
Myelocyte
Metamyelocyte
Band cell
Lymphoblast
Prolymphocyte
Lymphoblast
Prolymphocyte
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1. Myeloproliferative diseases
• primary proliferation of hematopoietic myeloid stem cells in bone
marrow and extramedullary (spleen, liver)
a) Myelodysplastic syndrome (MDS)
b) Acute myeloid leukemia (AML)
c) Chronic myeloid leukemia (CML)
d) Polycythaemia vera rubra (PVR)
e) Essential thrombocythemia
f) Idiopathic myelofibrosis
g) Mastocytosis
1-a) Myelodysplastic syndrome
mutation of pluripotent myeloid stem cell � monoclonal pathologic
hematopoiesis � refractory anemias
• acquired genetic alterations / immune response � apoptosis of marrow cells
� ineffective hematopoiesis
• BM is normo-/hyper-cellular (not aplastic), but part of the cells are pathologic
(dysplastic) blood cell precursors
RF: Down sy., Fanconi`s anemia, alkylating agents, radiation, benzene
CP: severe anemia, can progress to AML (preleukemic state), infections,
hemorrhages
Lab: blood: � RBCs, reticulocytes, granulocytes, monocytes, thrombocytes =
pancytopenia
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1-b) Acute myeloid leukemia (AML)
• males > 65 r.
pathologic monoclonal hematopoiesis from different genetic disorders (t(15;17),
t(8;21), inv(16), ...) in one of myeloid cells
• rapid and uncontrolled proliferation of malignant hematopoietic cell
• later defect of maturation and differentiation (accumulation of blasts)
• inhibited apoptosis
Lab: - blood: - hiatus leukemicus – presence of blasts and completely mature
elements, without intermediate forms
- � leukocytes, absolute count are leukemic blasts
- BM: > 20% blasts from all nuclear cells in BM, uniform, morphology
depends on the type of AM
1-b) Acute myeloid leukemia (AML)
CP: - fatigue, weakness, anorexia, weight loss, fever
-� erythropoiesis: normochromic normocytic anemia,
� reticulocytes
- � normal granulocytes and monocytes: infections – bacterial
and fungal inf. of skin, mucosa, lungs
- trombocytopenia: hemorrhage, in CNS (neurologic signs)
- � blasts in blood: DIC
- infiltration of organs by pathologic blasts: spleno-, hepato-
megaly, lymphadenopaty, skin, gingivnal mucosa, testes
RF: - acquired AML: mutagens – alkylating agents, radiation, benzene
- inherited predisposition to AML: Down sy., neurofibromatosis 1.
type, Fanconi`s anemia
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Clinical presentation of AML
gingival infiltrations infiltrations of the tongue
1-b) Acute myeloid leukemia (AML)
70
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1-b) Acute myeloid leukemia (AML)
71
1-c) Chronic myeloid leukemia (CML)
• males > 50 y.
• higher grade of maturation of myeloid granulocytes than in AML
t(9,22) - translocation between chromosomes 9 (protooncogene c-abl) and 22
(gene bcr) = Philadelphia chromosome � fusion gene bcr/abl � protein p210
BCR-ABL constitutively active as a tyrosine kinase enzyme:
• � resistance to apoptosis
• � proliferation � supresses normal hematopoiesis
• inhibits DNA repair � genomic instability � the cell more susceptible to
developing further genetic abnormalities � malignant clones replace
normal cells � malignant phase = blast crisis
• � adhesion to marrow stromal cells
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1-c) Chronic myeloid leukemia (CML)
Lab: - blood: �� dysfunctioned granulocytes (Leu: > 100 x 109/l), � infections
- � Leu �� blood viscosity � leukostasis
- � Tro � thrombi
1. chronic phase: < 10% blasts, 85% of patients
2. accelerated phase: 10 – 19% blasts
3. blast crisis: > 20% blasts
CP: - fatigue, anemia, dyspnoe, weight loss, fever, sweating
- infections, thrombosis, bleeding
- leukostasis � vasoocclusive disease, cerebrovascular accidents, myocardial
infarction, venous thrombosis, priapism, visual disturbances, pulmonary
insufficiency
- splenomegaly
1-c) Chronic myeloid leukemia (CML)
74
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1-d) Polycythaemia vera rubra (PVR)
• clonal disorder of a multipotent hematopoietic progenitor cell � accumulation
of phenotypically normal RBCs, granulocytes, and platelets
acquired clonal mutation in JAK2 �� sensitivity of progenitor cells to growth
factors (Epo, IGF, IL-3, GM-CSF), some BFU-E differentiate without Epo
CP: - hypervolemia �� BP, kompensatory vasodilation (warm skin)
- aquagenic pruritus
- � bleeding (in CNS!, GIT, UGT, epistaxis)
- � hematocrit �� blood viscosity � thrombosis, � cardiac
performance
- splenomegaly
Lab: - � RBCs (6-8 x 1012/l), Hb, hematocrit
- � Leu, Thro
- normal O2 saturation
- � Epo
1-e) Essential thrombocythemia
Lab: - BM: � megakaryoblasts a megakaryocytes
- blood: Thro: 3000 x 109/l, but defective
CP: - trombosis
- bleeding: epistaxis, GIT
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1-f) Idiopathic myelofibrosis
megakaryocytes produce growth factors (PDGF) � fibroblast
proliferation � bone marrow fibrosis
• gradual loss of marrow hematopoiesis, activation in spleen, liver
=> extramedullary hematopoiesis
CP: - anemia, trombocytopenia,
granulocytopenia
- splenomegaly, hepatomegaly
Lab: - Teardrop-shaped RBCs,
nucleated red cells,
myelocytes, and
promyelocytes
1-g) Mastocytosis
• clonal expansion of mast cells in BM, skin, gastrointestinal mucosa,
liver, and spleen
CP: - histamin � pruritus, flushing, palpitations and vascular collapse,
gastric distress, lower abdominal crampy pain, and recurrent
headache
- � cell burden � urticaria pigmentosa (lesions of darker skin and
very bad itching) at skin sites, bone pain and malabsorption
- fibrotic changes in liver, spleen, and bone marrow
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2. Lymfoproliferative diseases
• malignant diseases of lymphoid cells:
• disseminated form – lymphatic leukemia
• localized form – lymphoma
• from B-cells
• from T-cells
a) Acute lymphoid leukemia (ALL)
b) Chronic lymphoid leukemia (CLL)
c) Hodgkin's lymphomas
d) Non-Hodgkin's lymphomas
e) Plasma cells disorders
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2-a) Acute lymphoid leukemia (ALL)
• children, 4 y.
• blocked differentiation and clonal expansion of lymphoid cells on
different grade of differentiation, in 80 – 90% B-cells
EBV, carcinogens, inherited syndromes (Fanconi`s anemia, Down sy.,
neurofibromatosis)
genetic aberrations:
• chromosome count (hyperdiploidity)
• chromosome structure (t(9;12), t(8;14) – protooncogene deregulation,
c-myc – uncontrolled proliferation, Ph-chromosome)
2-a) Acute lymphoid leukemia (ALL)
CP: - fatigue, weakness, bleeding, anemia
- adenomegaly, splenomegaly, hepatomegaly
- periostal infiltration – pain in joints and bones
- meningeal infiltration – neurologic symptoms, �
intracranial pressure
- infiltration of n. opticus – visual disturbances
Lab: - blood: leukocytosis
- BM: lymfoblast infiltration (> 30%)
- anemia, trombocytopenia (suppressed formation)
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2-a) Acute lymphoid leukemia (ALL)
85
2-b) Chronic lymphoid leukemia (CLL)
• > 50 y., males, most frequent type of leukemia
• especially from B-cells
� bcl-2 expression � disorders of apoptosis � accumulation of pathologic
clones of lymfocytes, extravascular infiltration (lymph nodes, liver, spleen)
disorders of differentiation and maturation � infections, autoimmune diseases
CP: - malaise, weight loss, nocturnal sweating, fever
- lymphadenopathy, splenomegaly, hepatomegaly
Lab: - leukocytosis 15 – 200 x 109/l
- massive marrow infiltration � suppressed remained hematopoiesis �
anemia, granulocytopenia, trombocytopenia
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2-b) Chronic lymphoid leukemia (CLL)
87
2-c-d) Lymphomas
• malignancies of the lymphocyte system (BM, thymus, lymphaticnodes, spleen, lymphatic tissue of resp. system, GIT, ...) and its precursor cells
• constitutive "B" symptoms:
• weight loss > 10% in the last 6 months
• temperatures ≥ 38 ° C
• sweating
88
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2-c) Hodgkin's lymphomas
• males, 15 – 30 y., > 50 y.
EBV
CP: - cervical, axillary, inguinallymphadenopathy
- cytokines irritate the nerves in the skin
� itching of the skin
- splenomegaly
- enlarged lymph nodes in mediastinum �cough, superior vena cava syndrome
Lab: Reed-Sternberg cells (esp. B-cells)
2-c) Hodgkin's lymphomas
90
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2-d) Non-Hodgkin's lymphomas (NHL)
• 20 – 40 y.
• clonal expansion of malignant lymphocytes, with preserved function and
migration
EBV (Burkitt's lymphoma), HTLV-1 (Adult T cell leukemia/lymphoma),
immunodeficiency
t(14;18) � bcl-2 expression � inhibits apoptosis of pathological clone �
accumulation
• Nodular forms: primary in lymph nodes
CP: - lymphadenopathy (Waldeyer`s ring, cervical, axillary, inguinal)
- fever, sweating
• Extranodular forms:
• also progression of nodular forms NHL; in GIT, skin, CNS, orofacial area, ...
• maltomas: lungs, small intestine, pharynx; stomach (H. pylori), thyroid
gland (Hashimoto's thyroiditis)
2-d) Non-Hodgkin's lymphomas (NHL)
• Indolent:
• grow very slowly
• follicular lymphoma
• Aggressive:
• may develop rapidly
• Diffuse large B-cell lymphoma (DLBCL)
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Lymphadenophy in B-NHL
2-d) Non-Hodgkin's lymphomas (NHL)
2-e) Plasma cells disorders
• monoclonal gammopathy: � production of pathologic Ig (paraprotein)
• � production of normal Ig � bacterial infections
• Multiple myeloma:
• diffuse, accumulation of pathological cells in bone marrow, pathological fractures of vertebrae and ribs
• � bone reabsorption by osteoclasts � osteoporosis, hypercalcemia(lethargy, depression, renal injury)
• myeloma kidney: selective proteinuria (light Ig chain lambda), pyelonephritis
• anemia
• Waldenström`s macroglobulinemia:
• pathologic clone in BM, spleen, liver, lymph nodes, blood