RED BLOOD PATHOLOGY

ANEMIAS

Plurpotential stem cells

Common myeloid stem cells Lymphopoietic stem cells

Commited progenitors of erythrocytes, granulecytes, monocytes, megakariocytes

Commited progenitors of B-lymphocyte and T-lymphocyte classes

Immature hemopoietic precusors

Immature lymphocyte precusors

Mature functional blood cells Mature functional lymphocytes

ROLE of ERYTHROPOIETIN in REGULATION of ERYTHROPOIEsIS

Decreased production of mature RBC-s Decreased Hb synthesis, Decreased blood flow , Hemorrhages, Increased oxygen consumption by tissues.

Decreased arterial PO2 ↓ O2 content in tissue cells

Hypoxia of kidney ↑ secretion of erythropoietin by UGA of kidney

↑ proliferation of erithroblasts in bone marrow

↑ population of reticulocytes in circulation

↑ arterial PO2

↓ secretion of erythropoietin

↑ mature erythrocytes in circulation

Erythrocyte sedimentation rate - ESR Panchenkov method, Westergren method

AGE Children WOMEN MEN

Midle age 10 -12 mm/h 2 – 20 mm\h

8-10 mm/h 1 – 10 mm/h

>50 women > 60 men

15 mm/h (avar) 14 -25 -30 mm/h

18-20 mm/h

1 month 1 - 6 years old > 8 years old

2 – 30 mm/h 1 – 12 mm/h as in adult

Causes of ↑ESR : inflammation, intoxication, acute , chronic infections, trauma, myocardial infarction, autoimmune diseases, anemia, blood loss, tumor diseases, pregnensy Causes 0f ↓ESR: ↓ body mass, dehydration, glucocorticoids , starvation, Poyicytemia Vera.

PRICE – JOHNS’s CURVE

normal size of erythrocyte

macrocytes megalocytes Diameter

microcytes

FOOD SOURCES of the major HEMATINICS

(all uncooked mean values) Products Fe

mg/100g FOLATE mg/100g

VITAMINE B12

MEAT 3 10 5

LIVER 10 300 100

FLOUR 1,5 - 7 14 - 20 0,4

GREEN VEGETABLES 10 50 0

MILK 0,2 0,2 0,2 – 0,6

EGGS 2 8 1/egg

ANEMIA - is a clinic –hematologic syndrome which characterized by decreasing in hemoglobin and/or Erythrocyte number in the unit of blood volume

ANEMIA commonly result from : 1. Impaired erythrocyte production , 2. blood loss (acute or chronic) 3. increased erythrocyte destruction 4. combination of these three

RI Reticulocytic index

Color index

CI normal = 0.86 – 1.05

RI normal = 2

CLASSIFICATION OF ANEMIA DUE TO TYPE OF ERYTHROPOEISIS:

MEGALOBLASTIC anemia: B12 - folate deficiency, - Folate deficiency NORMOBLASTIC : all others anemia

DUE TO the level of saturation of erythrocyte with hemoglobin

- Normochromic normal MCHC= 31-36 gm/dl (hemolytic A) CI = 0.85 -1.05 - Hypochromic MCHC < 31 gm/l ( iron-deficiency A) CI < 0.85 -Hyperchromic MCHC > 36 gm/l (B12 -folate deficiency A) CI > 1.05

DUE TO SIZE of ERYTHROCYTES: -Normocytic MCV = 86 -100fi (hemolytic anemia) - Microcytic MCV < 86 fi (iron deficiency anemia) - Macrocytic MCV > 100 fi (B12 folate deficiency anemia

DUE TO REGENERATIVE ABILITY OF BONE MARROW

Hypo-regenerative IR < 2, Regenerative IR =2, HYper-regenerative IR > 2

CLASSIFICATION of ANEMIAS: DUE TO ETIOLOGY AND PATHOGENESIS:

Anemia (A) of impaired erythropoiesis: - Altered hemoglobin synthesis: iron deficiency A, Thalassemia, - Sideroblastic A , Sickle-cell A - A of chronic diseases - Altered DNA synthesis: B12 –deficiency, Folate-deficiency A - BONE MARROW FAILURE (or replacement): - Aplastic anemia, - Myeloproliferative leukemia - Anemia of increased erythrocyte destruction :

Hemolytic anemia - ANEMIA OF BLOOD LOSS: acute post-hemorrhagic A , chronic post-hemorrhagic A

POSTHEMORRHAGIC ANEMIAS CAUSES: acute or chronic blood loss

STAGES of acute post hemorrhagic anemia

1. Hidden A. or DUE TO reflex OF SYMPATHETIC NERVOUS SYSTEM – (hours/1day) ↓ blood volume, ↓erythrocytes

and leukocytes, MCH, MHCH , Ht, color index are N

2. Hydremic – ( 1-2 days) blood volume restored due to plasma - oyigocytemia normovolemia, ↓ Er, ↓ Hb, ↓ Ht , ↓Rt

3. REGENERATIVE or activation of bone marrow regeneration – (4-5 days) - hypoxia of kidney → activation of UGA → →↑erythropoietin → activation of bone marrow regeneration → ↑ Rt, but ↓Hb, ↓Ht,↓ color index neutrophilia with regenerative shift to the left, thrombocytosis.

Acute post hemorrhagic anemia

is normoblastic,, normochromic - color index –N, MCH, MCHC – N normocytic –MCV-N, regenerative (reticulocytosis, neutrophilia with regenerative shift to the left, thrombocytosis in 3-d stage

CHRONIC POST HEMORRAGIC ANEMIA Appear due to repeated insignuficant blood loss. Causes: hemorrhoid, uterine blood loss, ulcer disease and ets. Consequence : ↓ iron stores in organism (iron deficiency anemia) and impaired regeneration capacity of bone marrow.

IRON (Fe) CICLE

Bone marrow

erythrocytes

secreted with bile

blood stream aged, abnormal or damaged erythrocytes

macrophages in spleen, liver, bone marrow

IRON + TRANSFERRIN

Hb

bilirubin Fe

heme globin

storage in liver

release

IRON reused in the synthesis of new erythrocytes

storage in spleen

≈ 67 % of total body iron is bound to heme in erythrocytes and muscle cells ≈30 % is stored bound to ferritin of hemosiderin in macrophages ≈ 3 % (less than 1 mg) is lost daily in urine, sweat, bile, epithelial cells shed from GIT. IRON not lost is continiously recycled

METABOLISM OF IRON

Causes of iron deficiency anemia

Impaired of Fe reabsorbton: gastroectomia, diseases of thin intestine, SPROU, achlorhydria

Chronic BLOOD LOSS: ulcer diseases, excessive menorrhages, Kron’s disease, tumors in GIT, hematuria

Insufficient dietary intake of Fe

Chronic diseases

↑ demand for iron

- Acute erosious Gastritis -Duodenal ulcer -Fe malabsorption -severe vegetarian

Causes of iron deficiency anemia

Causes of iron deficiency anemia

DEFICITE OF IRON IN ORGANISM

↓ ham synthesis

↓ Hb formation

↓ synthesis of Fe-containing enzymes, myoglobin

ANEMIA

Damaged organs and tissue

↓ activity of antioxidant system

↑ lipid peroxydation

hypochromic er.

IRON DEFICIENCY ANEMIA poikilocytosis –various shape

anisocytosis – various size

IRON DEFICIENCY ANEMIA

HYPOCHROMIA, MICROCYTOSIS, single target shape erythrocyte

IRON DEFICIENCY ANEMIA

CLINICAL SYMPTOMS and SIGNS: - Fatigue and sleepiness - Dyspnea - Brittle nails - Koilonychias (spoon-shaped nails) - Sore tongue - Angular stomatitis - ( Indolent crackings at the corner of the mouth) - Dysphagia - Pica (abnormal taste) - Pallor

IRON DEFICIENCY ANEMIA. CLINICAL manifestations

SYNDROME of SIDEROPENIA: Dry skin, early loss of hear, glossitis, “pica chlorotica” - abnormal taste. Kollonychias The nail s are brittle, thin, spoon-shaped as a result of impaired capillary circulation and cellular breathing (↓ activity of enzyme- cytochromoxydase ).

Atrophic changes in GIT : gastritis, enteritis, ↓HCl secretion → malabsorption

Pallor of the skin and mucous membrane.

Symptoms of IRON deficiency ANEMIA

Treatment of IDA

1. To identify and eliminate the sources of blood loss. 2. Iron replacement therapy is very effective in the treatment of IDA and usually continued for 6 - 12 moths after bleeding. Iron preparation are administrated orally, i/v, i/m 3. Take iron tablets with vitamin C 4. Diets with ↑ iron in products only for

prophylactic IDA

SIDERBLASTIC ANEMIA Hereditary (linked with X chromosome) Acquired due to poisoning by lead (Pb) or hypovitaminosis B6 ,

intake of drugs (untituberculosis), alcoholism, copper deficiency.

Pathogenesis: hereditary or acquired deficit of enzymes , which take part in porfirin and protoporfirin synthesis

SIDEROBLASTIC ANEMIA IS NORMOBLASTIC< HYPOREGENERATIVE MICROCYTIC HYPOCHROMIC

CLINICAL MANIFESTATION: hypoxic syndrome , impaired function of organs , in which appear hemosiderosis and dystrophy

HEME STRUCTURA

HEME SYNTHESIS

SUKcinil KoA + glycin ð –aminolevulinat

PB syntase ð –aminolevulinic acid porfobilinogen synthasa Porphobilinogen Uroporphinogen 111 CO2 decarboxylase Coproporphinogen 111 oxidase Vit.B6 Protoporphinogen 1X Oxidase Protoporphirine 1X Fe ferrohelatase HEME

mito

cho

nd

ria cytop

lasm

Lead poisoning - sideroblasts – ring form

Peripheral blood in Sideroblastic anemia: myicrocytic, hypochromic, Hyporegenerative, normoblastic

COMPARISON of IRON –DEFICIENCY and SIDEROBLASTIC anemia

Laboratory test Iron deficiency anemia

Ring-form

serum iron ↓ < 12 µm ↑ > 30 µm

Total iron binding capacity ↑ ↓

Ferritin in serum ↓ ↑

Transferrin saturation ↓ ↑

Siderophags in blood stream ↓ ↑

Sideroblasts in bone marrow ↓ ↑ ring - form

Treatment of sideroblastic anemia.

Imdividuals with hereditary SBA are usually treated with pyridoxine therapy in doses of 50 up 200 mg per day . One third of persons with hereditary SBA respond to this therapy. For individuals who do not respond to pyridoxine, blood transfusion are necessary . Individuals who demonstrate evidence of iron overload need to iron depletion therapy to prevent organ damage. Individuals with acquired SBA respond to pyridoxine

HEMOLYTIC ANEMIAS

CLASSIFICATION: HEMOGLOBINOPATHIES: Thalassemia α and β (congenital) Sickle cell anemia ENZYMOPATHIES: Glucose- 6-phosphate dehydrogenase (congenital) deficiency MEMBRANOPATHEIS (ERYTHROCYTOPATHIES): (plasma membrane of erythrocyte is affected) Hereditary form: Acquired forms Spherocytosis - immune : Drug-induced forms (hapten model) - hemolytic anemia of newborn (mother Rh “-”, fetus Rh “+” ) - Non- immune: -Transfusion reactions, caused by ABO incompatibility - Idiopathic hemolytic anemia

Hemolytic anemia: normocyting (MCV)

normochromic (MCHC), Hyper regenerative

Hemoglobinuria leg ulcers

gall stones

anemia Jaundice Splenomegaly

Cranial overgrowth

extension of bone marrow

Feature s of hemolysis: reticulocytosis, ↑ iron + ↑bilirubin ↓ osmotic resistance

PERIPHERAL BLOOD. RETICULOCYTOSIS

RETICULOCYTOSIS is CHARACTERISTIC of ALL HEMOLYTIC ANEMIAS

reticulocyte

Sickle cell anemia

Sickle cell anemia is a hereditary disease characterized by the presence of abnormal form of hemoglobin - Hb-S. Hb S is formed by genetic mutation in recessive allele which encode the β- chain of protein hemoglobin: amino acid –valin- replaces glutamic acid.

Hb S → deoxygenation → hypoxia → dehydration → solidifying → stretching of erythrocyte into elongated sickle shape

Causes: spontaneous mutation and deletion of ß – globin gene on 11 chromosome lead to HbS synthesis .

SICLE CELL ANEMIA

Brain: hemorrhage thrombosis

- splenic infarcts -skeletal defects -kidney hematuria - abdominal infarcts

-Dactylitis bone infarcts osteomyelitis - leg ulcers

SICKLE – CELL ANEMIA

Hypoxia, Acidosis Abdominal pain Fever Strokes Painful swelling of the hands and feet Dehydratio n Thrombotic crisis

Sickling

Clinical manifestations

PATHOGENESIS of sickle –cell anemia

Replacement of glutamic acid to valin in b- chain of HB

Formation of hemoglobin -S

Aggregation and solidifying of Hg under the influence of hypoxia → sickle shape of erythrocytes

Rapid damage of erythrocytes. Disturbance of microcirculation

Anemia Stasis Microthrombi in lung and kidney Hepatomegaly, splenomegaly

Hypoxia stimulates bone marrow → activation of erythropoesis

Heperplasia of bone marrow. Pain syndrome

MICROCPHEROCYTOSIS - hereditary hemolytic anemia

spectrin

ankirin

erythrocyte plasma membrane

glyciforin

actin

Spherosytosis appears due to mutation of gens, which controls the proteins in erythrocyte membrane: spectrin and ankerin. These proteins make contacts with cellular membrane and cytockeleton. When spectrin and ankerin are defected or absent affected erythrocytes decrease the length of plasma membrane ( ↓ cellular diameter) and increase permeability for Na.

MICROSPHEROCYTOSIS : normoblastic,

hyperregenerative

Deficiency in membrane proteins leads to a very low erythrocytes deformity → they destroy in spleen → splenomegaly

APLASTIC ANEMIA PANCYTOPENIA - reduction or absent of all three types of blood cells. It results from failure or suppression of bone marrow to produce an adequate amounts of blood cells

Aplastic anemia : normoblastic, a (hypo)-regenerative, normocytic, normochromic (MCV, MCH, MCHC –N) CAUSES: radiation, toxic substances, some drugs, severe viral infections, metastasis of tumor cells, autoimmune process, mediated by TNF and INFÝ product of T-lymphcyts and NK. CLINICAL MANIFESTATIONs appear due to tree syndromes - hypoxic (↓ Er, ↓Hb), - hemorrhagic (↓Trc) - immuno-depression (↓NP, ↓LP)

Bone marrow NORMAL APLASTIC ANEMIA – pancytopenia

CLINICAL MANIFESTATIONS: Hypoxic syndrome Hemorrhagic syndrome Immunodepressive syndrome -pallor, -severe weakness, -hemorrhaging, infections.

Normal bone marrow Bone marrow in Aplastic anemia

B12 – FOLATE DIFICIENCY ANEMIA

↑MCV - macroergic, ↑MCH –C hyperchromic, hyporegenerative

PERIPHERAL BLOOD: ↓erythrocytes (macrocytes, megalocytes), ↓ reticulocytes, ↓ plateletes, ↓ lymphocytes, ↓ osmotic resistance, Jolly bodies, Cabot rings, ↑ Fe + ↑billirubine→ Hemolysis BONE MARROW: packed with red cell precursors , megaloblasts

B 12 – DEFICIENCY FOLATE DEfICIENCy Absorption: terminal ileum jejunum B12 + intrinsic factor

CLINICAL MANIFESTATIOS: megaloblastic anemia, jaundice, Disturbance in gastro-intestinal tract: -glossitis (tongue is glazed, beefy) - atrophic gastritis (autoimmune atrophy of fundice glands)

NEUROLOGIC SYMPTOMS -----------------------

VITAMIN B12

Methylcobalamine Adenosilcobalamine

FOOD FOLATES

Methyl THF Uridine nonophosphate

THYMIDINE synthesis

PYRIMIDINE

DNA SYNTHESIS

THF

Methylmalonic KoA

Cuccinyl KoA

Krebs cycle

Succinic acid

Methylmalonic acid

B12 - and Folates metabolism are interrelated

CAUSES of B12 –deficiency anemia

INADEQUATE INTAKE: severe vegetarianism Extreme malnutrition MALABSORPTION gastric: - gastric atrophy, - congenital intrinsic factor deficiency -partial or total gastroectomia 0 cancer of the stomach MALABSORPTION intestinal: ileum resection, - Tropical sprue, - fish tapeworm ( diphillobothrium) - - Kron disease, - deficit of receptors for B12 + IF

B12 deficiency anemia. Symptoms

Gray hair Blue eyes Reticulopathy Jaundice Sore, smooth tongue Tiroid disease

splenomegaly Addison’s disease ? Diabetes ? Vitiligo

GLOSITIS . Tongue of patient with B12 (folate) deficiency anemia appear due to loss of DNA synthesis → reduced proliferation of tongue epithelium. NEUROLOGIC SYMPTOMS in patient with B12 deficiency anemia are the result of nerve demyelination or nerve cell death due to toxic effect of metylmalonic acid

Pernicious anemia is the most common type of B12 megaloblastic

anemia

CAUSE of pernicious anemia - absent of intrinsic factor - an enzyme required for absorption of dietary vitamin B 12

Autoimmunity plays a significant role in the development Of pernicious anemia, characterized by the presence of autoantibodies to gastric parietal cells, which can secrets intrinsic factor.

DIPHILLOBOTRIOSIS

Disbacteriosis

Disturbance of vitamin B 12 biosynthesis

Absorption of vitamin B 12 by parasites

Aditional factors: unbalance feeding, decreased synthesis of intrinsic factor, fever, pregnansy

Hypovitaminosis B 12

B 12 deficiency anemia

B12 -FOLATE DEFICIENCY ANEMIA

PERIPHERAL BLOOD

1- Macro,- megalocytes, 2 – erythrocytes with Jolly bodies, 3- normocytes, 4- Poly chromic erythrocytes

Blue bone marrow B 12 deficiency anemia

Cabot ring

Jolliy body

Hyper--segmented NP

Hyperchromic erythrocytes

B12 (folate) deficiency anemia

Treatment of B12 - Folate - deficiency anemia

Replacement of vitamin B12 (cobalamine) oral Individuals with atrophic gastritis need to i/v injection of vitamin B 12

Individuals with Folic deficiency anemia require daily oral administration of folate preparations 1 mg/day

POLYCYTHEMIA VERA

is a neoplastic, nonmalignant chronic myeloproliferative disease, which characterized by abnormal proliferation of bone marrow stem cell despite normal to below normal erythropoietin level . Mutation s in JAK2, CALR, rarely LVK in hematopoietic stem cells.

The most likely cause of PV is acquired genetic alterations in the stem cell leading to disturbance of normal cellular growth.

↑RBC, ↑WBC, ↑ platelets

POLYCYTHEMIA VERA

Bone marrow Peripheral blood

Hemoblastosis - instant erythremia

Polycythemia vtra

Clinical manifestations: Erythrocyanosis, ↑BP, thrombosis, bleeding ↑Er, ↑ granulocytes, ↑Ht, ↑ platelets, ↓ESR Hepatomegaly, splenomegaly