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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