Bone marrow

1
Bone marrow

• Red
• Yellow
• Bone
• Fat
• Reticulin
• Haematopoiesis red, white, platelets
• lymphoid

2
Normal red cells
Central pale area
3
Red cells

• Men Women
• Hemoglobin (g/l) 140-180 120-160
• Hematocrit () 40-52 36-48
• Red cell count (1012/l) 4.5-6.5 3.9-5.6
• Reticulocyte count () 0.5-1.5
• Mean cell volume (fl) 80-95
• Mean corpuscular hemoglobin (pg) 27-33
• Mean corpuscular hemoglobin concentration (gm/dL)
  33-37

4
Red cells

• pathological conditions
• decrease in the circulating red cell mass
• (poss. with structural abnormalities)
• very common - anaemia
• II. increase in the circulating red cell mass
• less common
• polycythemia erythrocytosispolyglobuly

5
Polycythemiaincreased concentration of red cells

• RELATIVE - decreased plasma volume
• dehydration, stress
• ABSOLUTE
• primary neoplastic polycythemia vera
• myeloproliferative neoplasm
• secondary - increased erythropoietin stimulation
• Appropriate
• reactive low levels of oxygen in the PB
• (heart disease, high altitude)
• Inappropropriate

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Red cells

• Normal uniform in size and shape
• Pathologic variation in size, shape, inclusions
• Variation
• size - anisocytosis
• Shape poikilocytosis

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Red cells - functions

• Deliver oxygen to the tissues
• Anemia - reduction
• of the total number of red cells
• amount of hemoglobin
• circulating red cell mass

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Consequences of anemia - symptoms

• ???????????

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Dg. of anemia - history

• Age of onset
• Duration of illness
• Prior therapy of anemia
• Suddennes or severity of anemia
• Chronic blood loss
• Hemolytic episodes
• Toxic exposures
• Dietary history
• Family history, racial background
• Underlying diseases

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Anemia consequences, symptoms

• Fatigue, syncope, dyspnea
• Impairment of organ function due to hypoxia
• Pallor, postural hypotension )decreased blood
  volume)
• Heart murmurs, heart failure . Increased cardiac
  output

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Anemia

• Not a diagnosis per se
• Look for an underlying problem
• History, physical examination

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Anaemia

• decrease in the total circulating red cell mass
• (hematocrit, hemoglobin concentration)
• Classification A. underlying mechanism
• blood loss
• increased destruction
• decreased production
• B. morphology of erythrocytes
• size (micro-, macro-, normocytic)
• shape (spherocytosis, stomato-,...)
• color (degree of hemoglobinization normo-
  hypo-, hyperchromic)

MAYCOMBINE
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• Blood loss
• acute or chronic
• internal or external

• Acute
• Hypovolemia shock
• Anemia normocytic normochromic
• Shift of water hemodilution ? hematocrite
• Compensatory increase of red cell production
• Reticulocytes
• Chronic ? loss of iron? iron deficiency
• hypochromic sideropenic anemia

14
Iron deficiency anemiamechanism blood loss,
decreased production

• body iron functional storage
• F - 2g, M - 6g
• inadequate intake for metabolic demands
• Lack in diet or low absorption
• most common nutritional disorder in the world
• 2. Increased requirement (children, pregn., lact)
• !!!3. Chronic blood loss!!! - GIT, GYN
• most important cause of iron deficiency
• in the Western world

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Hypochromic microcytic sideropenic anemia
Small hemoglobinization (narrow Hb rim
-periphery) Small red cells Iron deficiency
Scattered fully hemoglobinized cells - blood
transfusion
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PB ery pale smallBM erythroid hyperplasia,
loss of ironalopecia, koilonychia, atrophy of
tongue, gastric mucosaPlummer-Vinson
(Kelly-Patterson) syndrome siderop.an.,
atrophic glossitis, esophageal webs
17
Iron deficiency anaemia
Pallor conjunctiva skin pale palmar creases
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Iron deficiency anaemia koilonychia nails concave
(or flat), ridged, brittle
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Iron deficiency anaemia angular
cheilosis fissuring and ulceration pallor
20
Iron deficiency anaemia flattening and loss of
papillae bald, fissured tongue
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Causes of hypochromic anemia

• Disorders of iron metabolism
• Disorders of heme synthesis
• Disorders of globin synthesis (thalassemia)
• Ad 1. Iron deficiency
• Blood loss
• Poor intake - growth, pregnancy, lactation
• Malabsorption
• Chronic infections or inflammatory states
• neoplasia

22
Anaemia

• decrease in the total circulating red cell mass
• (hematocrit, hemoglobin concentration)
• Classification A. underlying mechanism
• blood loss
• ? increased destruction
• decreased production

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• Increased destruction
• lysis of red cellshemolysis
• intravascular rare - mechanical injury
  artificial valves or microthrombi, exogenous
  toxic agents, complement fixation (transfusion of
  mismatched blood)
• extravascular - more common, when red cells
  considered foreign or less deformable
• Hemolytic anemia
• Abnormality
• intracorpuscular or extracorpuscular
• hereditary (intra) or acquired (extra)

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Hemolytic anemia

• premature destruction of red cells
• accumulation of the products of the hemoglobin
  catabolism
• BM increased erythropoiesis, extreme
  extramedullary hematopoiesis
• PB reticulocytosis
• high bilirubin gallstones jaundice, blr in
  urine
• chronic duration hemosiderosis

Main clinical symptoms anemia, splenomegaly,
jaundice gallstones
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Haemolytic anaemia splenomegaly and jaundice
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Haemolytic anaemia jaundice normal
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Increased destruction of eryhemolysis

• I. Intrinsic (intracorpuscular) causes
• A. hereditary
• membrane cytoskeleton, lipid synthesis
• enzymes deficiencies - G6PD, glutathione
  synthetase, pyruvate kinase
• hemoglobin - deficient synthesis of globin,
  structurally abnormal Hb
• B. acquired
• membrane defect paroxysmal nocturnal
  hemoglobinuria
• II. Extrinsic (extracorpuscular) causes
• antibodies, trauma, infection, chemical injury
• sequestration

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Examples of hemolytic anemia

• Membrane defects
• Proteins underlying the red cell membrane
• Shape, stability, flexibility

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Hereditary spherocytosis (peripheral smear)
anisocytosis and several dark-appearing
spherocytes with no central pallor. Howell-Jolly
bodies (small dark nuclear remnants)
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Hereditary spherocytosis

• AD (AR, sporadic)most common her. hemol. A.
• Membrane defect cytoskeleton protein spectrin
  
• (and ankyrin) deficiency
• Round erythrocyte spherocyte, less deformable
• Vulnerable to spleen sequestration and destruction

Main clinical symptoms anemia, splenomegaly,
jaundice gallstones Chronic hemolytic anemia
(mild to normal) Acute anemic episodes aplastic
crisis (parvovirus) hemolytic crisis
31
Splenic sinus
A red cell squeezing from the red pulp cordsinto
the sinus lumen. Note the degree of
deformability required for red cells to
pass through the wall of the sinus.
32
Red cell membrane cytoskeleton Alterations
leading to spherocytosis and hemolysis
Mutations weakening interactions involving
a-spectrin, ß-spectrin, ankyrin, band 4.2, or
band 3 cause the normal biconcave red cell to
lose membrane fragments and become
spherical spherocytic cells less deformable than
normal, become trapped in the splenic cords,
phagocytosed by macrophages.
33
Pathophysiology of hereditary spherocytosis
34
Haemolytic anaemia reticulocytes
precip. RNA
35
Hereditary elliptocytosis
Usually mild, rarely severe
36
Hemolytic anemia

• Intracorpuscular
• Enzyme deficiencies

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G6PD deficiency

• enzymes protecting the red cell against the
  oxidative stress
• G6PD deficiency ? loss of protection ? oxidant
  injury
• infections, drugs, beans (favism)
• ? hemolysis otherwise normal
• morphologic changes of chronic HA rarely present
• hundreds of genetic forms of G6PD
• common pathologic alleles G6PDA-, G6PD
  Mediterranean
• X-linked? males homozygous, women heterozygous
• Mediterranean, Middle East, Africa
• Protection against malaria

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G6PD deficiency

• Clinical and laboratory findings
• Episode of acute hemolytic anemia in anotherwise
  healthy person neonatal jaundice
• following oxid. injury drug (antimal.
  primaquine, sulfoamides, nitrofurantoin,
  nalidixic acid TNT, , infections, food
• Variable severity

39
Enzyme deficiency G6PD deficiency effects of
oxidant drug exposure (PB)
Red cells with precipitates of denatured globin
(Heinz bodies) splenic macrophages pluck out
these inclusions ? "bite cells"
40
Increased destruction of eryhemolysis

• I. Intrinsic causes
• A. hereditary
• membrane cytoskeleton, lipid synthesis
• enzymes deficiencies - G6PD, glutathione
  synthetase, pyruvate kinase
• ?hemoglobin abnormal
• quantity (deficient synthesis of globin)
• quality (structurally abnormal Hb)

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Sickle cell anemia (PB)

• Shape sickle
• Hereditary hemoglobinopathy
• Structurally abnormal hemoglobin HbS
• abnormal physiochemical properties
• B-globin 6th position,
• Molecular defect point mutation
• valine for glutamic acid

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Sickle cell anemia Hemolysis, microvascular
occlusion
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Sickle cell anemia

• Oxyg. HbS liquid
• Deoxyg.viscous gel ?fibers
• HbS - aggregation and polymerization
• Sickle shape Initially reversible (with
  oxygenation)
• Repeated irreversible sickling
• Membrane damage

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Rate and degree of sickling

• 1. Amount of HbS
• Heterozygotes HbS and HbA only sickle cell
  trait
• (sickling when marked hypoxia)
• Homozygotes severe anemia
• 2. Hemoglobin concentration
• the higher, the worse
• 3. Fall in pH ? deoxygenation

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Sickle cell anemia - clinical manifestation

• chronic hemolytic anemia (ery survival 20 days)
• chronic hyperbilirubinemia, Hbemia, jaundice,
  gallstones
• aplastic crisis
• 2. occlusion of small vessels
• ? thrombosis, ischemia, necrosis
• painful crises
• 3. splenomegaly
• 4. increased susceptibility to infections
• 5. activation of the bone marrow,
• extramedullary haematopoiesis

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Diagnosis

• Clinical, laboratory blood smear
• HbS - electrophoresis
• Clinical course variable
• Therapy symptomatic

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Thalassemia

• Deficient synthesis of globin chains
• Globin chain absent or amount reduced
• ß - major, minor (more common), intermedia
• ß ,0
• Homo/heterozygous
• a ,0

48
Scleral jaundice Haemolytic autoimmune anaemia
49
Pathogenesis of ß-thalassemia major
aggregates of unpaired a-globin chains not
visible Blood transfusions correct the anemia
reduce the stimulus for marrow expansion, but
add to systemic iron overload
50
Thalassemia major gallbladder - bilirubin
gallstones
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Immunohemolytic anemia

• Antibodies
• Coombs test

52
Raynaud phenomenon autoimmnune haemolytic anaemia
53
Erythroblastosis fetalis
54

• Decreased production of red cells
• Deficiency of vital substrates
• disorders of proliferation and differentiation
• stem cells
• erythroblasts
• Impaired
• DNA synthesis B12, folic acid megaloblastic
• hemoglobin synthesis - heme
• (lack of iron)
• - globin
• Others anemia of chron. dis., AA, PRCA

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Megaloblastic anemia

• impaired DNA synthesis
• characteristic morphologic changes
• blood (macrocytes), bone marrow (megaloblasts)
• Deficiency of vit. B12
• Folic acid

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Megaloblastic anaemia
57
Vitamin B12 absorption
58
Deficiency of vit. B12

• 1. Decreased intake diet, vegetarianism
• 2. Impaired absorption
• Intrinsic factor deficiency pernicious anemia,
• gastrectomy
• Malabsorption
• Intestinal dis., resection of ileum
• Parasitic uptake, bacterial overgrowth
• 3. Increased requirement
• pregnancy, hyperthyroidism, disseminated cancer

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Vit. B12 deficiency

• BM and blood, CNS, (pernicious GIT)
• GIT beefy tongue atrophic glossitis
• CNS spinal cord - myelin degenaration
  laterodorsal tracts balance, motoric, sensitive
• Pernicious stomach chronic gastritis,
  intestinal metaplasia, higher risk of carcinoma

60
Pernicious anemia

• Older people
• Autoimmune Ab
• Poss. with autoimmune thyroiditis, adrenalitis

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Megaloblastic anaemia
Acute leukaemia
Diffferential diagnosis
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Megaloblastic anaemia hypersegmented neutrophils
(macropolycyte)
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Megaloblastic anaemia - pernicious lemon-yellow
appearance pallor (anaemia) jaundice
(ineffective erythropoiesis)
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Pernicious anaemia (38 ys.) premature greying,
blue eyes, vitiligo
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Beefy tongue atrophic glossitis (Hunter) vit. B12
deficiency
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Pernicious anaemia Dorsolateral spinal cord
demyelination
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Folate deficiency

• Decreased intake
• Increased requirements
• Impaired use
• Relative deficiency
• Megaloblastic anemia no neurological symptoms
• Cheilosis, glossitis, dermatitis

68
Anemia of chronic disease

• Infections
• immunologic
• neoplasms
• Mechanism defect in reutilization of iron
  (transfer, cytokines)
• ! abundant storage iron
• Anemia normo, normo or hypo, micro

69
Aplastic anemia

• Failure or suppression of myeloid stem cell
• PANCYTOPENIA
• primary OR secondary - drugs , chemicals
• infections
• irradiation
• inherited Fanconi
• Or cause unknown
• BM hypocellular, PB pancytopenia,
  symptoms
• spleen normal
• Special subgroup pure red cell anemia

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Aplastic anemia Markedly hypocellular marrow
contains mainly fat cells.