Bone marrow

Red

Yellow

Bone

Fat

Reticulin

Haematopoiesis – red, white, platelets

lymphoid

Normal red cells

Central pale area

Red cellsMen 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

Red cellspathological conditions:

I. 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 =erythrocytosis=polyglobuly

Polycythemia=increased concentration of red cells

• RELATIVE - decreased plasma volumedehydration, stress• ABSOLUTEprimary – neoplastic= polycythemia vera

= myeloproliferative neoplasm

secondary - increased erythropoietin stimulationAppropriate

reactive – low levels of oxygen in the PB (heart disease, high altitude)

Inappropropriate

Red cells• Normal: uniform in size and shape

• Pathologic: variation in size, shape, inclusions

• Variation

• size - anisocytosis

• Shape – poikilocytosis

Red cells - functions

• Deliver oxygen to the tissues

• Anemia - reduction

• of the total number of red cells

• amount of hemoglobin

• circulating red cell mass

Consequences of anemia - symptoms

• ???????????

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

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

Anemia

• Not a diagnosis per se

• Look for an underlying problem

• History, physical examination

Anaemiadecrease 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)

M

A

Y

C

O

M

B

IN

E

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

Blood loss•acute or chronic•internal or external

Iron deficiency anemiamechanism: blood loss, decreased production

body iron = functional + storage

F - 2g, M - 6ginadequate 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, GYNmost important cause of iron deficiency

in the Western world

Hypochromic microcytic sideropenic anemia

Scattered fully hemoglobinized cells - blood transfusion

Small hemoglobinization(narrow Hb rim -periphery)Small red cellsIron deficiency

PB: ery pale + small

BM: erythroid hyperplasia, loss of iron

alopecia, koilonychia, atrophy of tongue, gastric mucosa

Plummer-Vinson (Kelly-Patterson) syndrome: siderop.an., atrophic glossitis, esophageal webs

Iron deficiency anaemia

Pallorconjunctiva

skinpale palmar creases

Iron deficiency anaemiakoilonychianails concave (or flat), ridged, brittle

Iron deficiency anaemiaangular cheilosisfissuring and ulceration; pallor

Iron deficiency anaemiaflattening and loss of papillaebald, fissured tongue

Causes of hypochromic anemia1. Disorders of iron metabolism

2. Disorders of heme synthesis

3. Disorders of globin synthesis (thalassemia)

Ad 1. Iron deficiency

• Blood loss

• Poor intake - growth, pregnancy, lactation

• Malabsorption

• Chronic infections or inflammatory states

• neoplasia

Anaemiadecrease in the total circulating red cell mass

(hematocrit, hemoglobin concentration)

Classification: A. underlying mechanism blood loss

→ increased destruction

decreased production

Increased destruction=lysis of red cells=hemolysis• 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 anemiaAbnormality: intracorpuscular or extracorpuscular hereditary (intra) or acquired (extra)

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 symptomsanemia, splenomegaly, jaundice; gallstones

Haemolytic anaemiasplenomegaly and jaundice

Haemolytic anaemiajaundice normal

Increased destruction of ery=hemolysisI. Intrinsic (intracorpuscular) causes

A. hereditary • membrane – cytoskeleton, lipid synthesis• enzymes – deficiencies - G6PD, glutathione

synthetase, pyruvate kinase• hemoglobin - deficient synthesis of globin,

structurally abnormal HbB. acquired

• membrane defect: paroxysmal nocturnal hemoglobinuria

• II. Extrinsic (extracorpuscular) causes• antibodies, trauma, infection, chemical injury

sequestration

Examples of hemolytic anemia

• Membrane defects –

• Proteins underlying the red cell membrane

• Shape, stability, flexibility

Hereditary spherocytosis (peripheral smear)

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

Hereditary spherocytosisAD (AR, sporadic);most common her. hemol. A.

Membrane defect – cytoskeleton – protein spectrin (and ankyrin) deficiencyRound erythrocyte= spherocyte, less deformableVulnerable to spleen sequestration and destruction

Main clinical symptomsanemia, splenomegaly, jaundice; gallstonesChronic hemolytic anemia (mild to normal)Acute anemic episodes:aplastic crisis (parvovirus)hemolytic crisis

Table 13-2. Adult Reference Ranges for Red Blood Cells*

A red cell squeezing from the red pulp cordsinto the sinus lumen. Note the degree of deformability required for red cells to passthrough the wall of the sinus.

Splenic sinus

Mutations weakening interactions involving α-spectrin, β-spectrin, ankyrin, band 4.2, or band 3 cause the normal biconcave red cell to lose membrane fragments and become sphericalspherocytic cells: less deformable than normal, become trapped in the splenic cords, phagocytosed by macrophages.

Red cell membrane cytoskeleton Alterations leading to spherocytosis and hemolysis

Pathophysiology of hereditary spherocytosis

Haemolytic anaemia: reticulocytes

precip. RNA

Hereditary elliptocytosis

Usually mild, rarely severe

Hemolytic anemia

• Intracorpuscular

• Enzyme deficiencies

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

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

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"

Increased destruction of ery=hemolysisI. Intrinsic causes

A. hereditary membrane – cytoskeleton, lipid synthesisenzymes – deficiencies - G6PD, glutathione

synthetase, pyruvate kinase

→hemoglobin – abnormal

quantity (deficient synthesis of globin)

quality (structurally abnormal Hb)

• Shape: sickle

• Hereditary hemoglobinopathy

• Structurally abnormal hemoglobin HbS

• abnormal physiochemical properties

• B-globin – 6th position,

• Molecular defect: point mutation

• valine for glutamic acid

Sickle cell anemia (PB)

Sickle cell anemia Hemolysis, microvascular occlusion

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

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

Sickle cell anemia - clinical manifestation1. chronic hemolytic anemia (ery survival 20 days)

chronic hyperbilirubinemia, Hbemia, jaundice, gallstonesaplastic crisis

2. occlusion of small vessels → thrombosis, ischemia, necrosis

painful crises

3. splenomegaly4. increased susceptibility to infections

5. activation of the bone marrow, extramedullary haematopoiesis

Diagnosis

• Clinical, laboratory – blood smear

• HbS - electrophoresis

• Clinical course variable

• Therapy symptomatic

Thalassemia

• Deficient synthesis of globin chains• Globin chain absent or amount reduced• β - major, minor (more common), intermedia• β +,0

• Homo/heterozygous

• α +,0

Scleral jaundiceHaemolytic autoimmune anaemia

Pathogenesis of β-thalassemia major

aggregates of unpaired α-globin chains not visible Blood transfusions correct the anemia reducethe stimulus for marrow expansion,but add to systemic iron overload

Thalassemia major: gallbladder - bilirubin gallstones

Immunohemolytic anemia

• Antibodies

• Coombs test

Raynaud phenomenonautoimmnune haemolytic anaemia

Erythroblastosis fetalis

Decreased production of red cellsDeficiency of vital substrates disorders of proliferation and differentiation stem cells erythroblastsImpaired: DNA synthesis – B12, folic acid – megaloblastic hemoglobin synthesis - heme

(lack of iron)

- globin Others: anemia of chron. dis., AA, PRCA

Megaloblastic anemia

• impaired DNA synthesis

• characteristic morphologic changes

blood (macrocytes), bone marrow (megaloblasts)

• Deficiency of vit. B12

• Folic acid

Megaloblastic anaemia

Vitamin B12 absorption

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

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

Pernicious anemia

• Older people

• Autoimmune Ab

• Poss. with autoimmune thyroiditis, adrenalitis

Megaloblastic anaemia

Acute leukaemia

Diffferential diagnosis

Megaloblastic anaemiahypersegmented neutrophils (macropolycyte)

Megaloblastic anaemia - perniciouslemon-yellow appearancepallor (anaemia) + jaundice (ineffective erythropoiesis)

Pernicious anaemia (38 ys.)premature greying, blue eyes, vitiligo

Beefy tongueatrophic glossitis(Hunter)vit. B12 deficiency

Pernicious anaemiaDorsolateral spinal cord demyelination

Folate deficiency• Decreased intake• Increased requirements• Impaired use

• Relative deficiency

• Megaloblastic anemia; no neurological symptoms• Cheilosis, glossitis, dermatitis

Anemia of chronic disease

*Infections

*immunologic

*neoplasms

Mechanism: defect in reutilization of iron (transfer, cytokines)

! abundant storage iron

Anemia: normo, normo or hypo, micro

Aplastic anemia• Failure or suppression of myeloid stem cell• PANCYTOPENIA• primary OR secondary - drugs , chemicals

infectionsirradiationinherited – Fanconi

Or cause unknown…BM: hypocellular, PB: pancytopenia,

symptomsspleen normal

Special subgroup: pure red cell anemia

Aplastic anemia Markedly hypocellular marrow

contains mainly fat cells.