Anemic syndrome and white blood cells disorders...• defects of glucose-6-phosphate dehydrogenase(G6PD), pyruvatekinase • hemoglobinopathies • sickle cell anemia, thalassemia

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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

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


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



• Hematocrit:

• volume percentage of red blood cells in blood

• F: 39±4 % (0,39±0,04) M: 44±5 %



• 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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↓ 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. 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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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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32

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B. Anemias due to � RBCs production

• � erythropoietin (Epo):





• � Fe


• � proteins

• cellular dysfunction of hematopoietic tissues:

• aplastic anemia


• leucemias



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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• 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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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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A. Anemias due to � RBCs loss:

• acute / chronichemorrhage

• hemolytic anemias

Reticulocytes?

B. Anemias due to � RBCs production:

• � Erythropoietin (Epo):





• � Fe


• � proteins

• cellular dysfunction of hematopoietic

tissues:

• aplastic anemia


• leucemias







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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





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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


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


70

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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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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


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)


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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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)


• 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-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

Documents

Anemic syndrome and white blood cells disorders...• defects of glucose-6-phosphate dehydrogenase(G6PD), pyruvatekinase • hemoglobinopathies • sickle cell anemia, thalassemia