A. Anemia caused by decreased production of red blood cells
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Transcript A. Anemia caused by decreased production of red blood cells
Anemic syndrome
Anca Bacârea, Alexandru Schiopu
Hematopoiesis
Hematopoiesis is the process by which mature blood cells are
generated and functional, assuming the existence of cells of origin
who have a long series of transformations and hematopoetic
microenvironment (composed of stromal cells and stimulating
factors).
Bone marrow (BM) is the central component generating blood cells:
red cells, granulocytes, monocytes, lymphocytes, platelets and
hematopoietic functions are proliferation, differentiation and cell
release into circulation.
BM consists of:
reticulovascular stroma (with supporting role, nutrition and
movement of hematopoietic cells);
medullar parenchyma - composed of active cells forming islands
of hematopoiesis, usually arranged around a trophic cell - "nurse
cell." Nurse cells are involved in erythropoiesis (iron stores) in
myelopoesis and megacaryopoesis (liberate stimulating factors e.g.. IL-3).
Hematopoiesis
Pluripotent
stem cells
(PSCs) are
the cells of
origin of all
blood cells.
Anemic syndrome
Definition
Anemic syndrome is defined as a poly-etiologic syndrome
characterized by decrease in circulating hemoglobin (Hb) below
the normal values.
Anemic syndrome
Adults (>15 years)
Hb (g/dl)
Hb (mmol/l)
Women
12.0
7.4
Men
13.0
8.1
Children
Hb (g/dl)
Hb (mmol/l)
Children < 5 years
11.0
7,1
Children < 15 years
12.0
7.4
Signs and symptoms
Presence of a history of bleeding (not in all cases)
Dyspnea (initial effort)
Pallor
Dizziness
Low grade fever
Compensatory hemodynamic syndrome
Tachycardia
Murmurs
Palpitations
Low blood pressure
Signs and symptoms
Ventilatory changes
Polipnea
Changes in the peripheral nervous system's activity caused by
neuronal hypoxia:
Paresthesia
Neurovegetative dystonia
Changes of reflexes
Positive Babinski sign
Ataxia
Sphincter incontinence
Changes of the senses
Signs and symptoms
Changes in the central nervous system activity - driven by neuronal
hypoxia:
Fatigue
Asthenia
Irritability
Decreased ability to concentrate
Insomnia
Depression, suicide - Vitamin deficiency anemia. B12
Paranoia - Vitamin deficiency anemia. B12
Hallucinations - Vitamin deficiency anemia. B12
Psychosis - Vitamin deficiency anemia. B12
Panic Attacks - Vitamin deficiency anemia. B12
Changes in personality - Vitamin deficiency anemia. B12
Decreased muscle strength - Vitamin deficiency anemia. B12
Impotence - Vitamin deficiency anemia. B12
Signs and symptoms
Trophic disorders of the mucous membranes
Glossitis
Esophagitis
Gastritis
Dyspepsia
Trophic disorders of the skin and appendages
Brittle hair
Digital hypocratism (hippocratic fingers)
Pigmentation of the skin
Leg ulcers
Bone pain
Classification
A. Anemia caused by decreased production of red blood
cells
B. Anemia caused by lost of red blood cells
C. Anemia caused by combined mechanisms
A. Anemia caused by decreased
production of red blood cells
1. Involvement of hematogenous bone marrow (BM):
a. Destructive processes:
Physical factors: ionizing radiation
Chemical factors: drugs (cytostatics, anti-inflammatory phenylbutazone, chloramphenicol, phenytoin), industrial benzene, insecticides;
Biological factors: some viruses (Epstein - Barr virus, hepatitis
C, parvovirus infection, human immunodeficiency virus);
Immune diseases: timom, graft versus
host reaction,
eosinophilic fasciitis;
Unknown etiology
A. Anemia caused by decreased
production of red blood cells
1. Involvement of hematogenous bone marrow (BM):
b. Bone marrow infiltrative processes:
Tumours of the bone marrow (BM): leukemia, lymphoma,
multiple myeloma (MM)
Metastases in BM
Sarcoidosis
Bone marrow fibrosis
Storage diseases (glicogenoze, lipidosis - Gaucher disease)
Bone marrow necrosis
Bone marrow infections: sepsis, miliary tuberculosis, fungal
infections
A. Anemia caused by decreased
production of red blood cells
1. Involvement of hematogenous bone marrow (BM):
c. Low production of erythropoietin:
Anemia of chronic disease (chronic inflammation, chronic
infections, cancers) - inflammatory cytokines (IL1, IL 6, TNF-α) suppresses the synthesis of erythropoietin and erythropoietin increases
resistance to the action;
Kidney disease - chronic renal insufficiency - insufficient production
of erythropoietin due to renal lesions;
Liver disease - by parenchymal liver failure (cirrhosis, hepatice, toxic hepatitis, chronic aggressive hepatitis, etc.) - It
reduces the synthesis of erythropoietin and hemoglobin precursors;
Poliglandular hypofunction - production of erythrocytes is
influenced by thyroid hormones, testosterone, glucocorticoids.
A. Anemia caused by decreased
production of red blood cells
2. Deficiency of forming factors:
a. Protein deficiency:
Low protein intake
Malnutrition - starvation, low protein in food;
Maldigestion - exocrine pancreatic insufficiency, bile salt
deficiency, gastrectomy;
Malabsorption - intestinal resection, bacterial diarrheal
diseases, viral (excluding the time of contact of food with
intestinal mucosa), intestinal parasites;
The reduced synthesis of proteins - parenchymal liver
insufficiency;
The additional consumption of protein - "trap" of protein in endstage of cancer;
Increased protein loss - diarrheal diseases, burns, nephrotic
syndrome;
A. Anemia caused by decreased
production of red blood cells
2. Deficiency of forming factors:
b. Lack of synthesis of purine and pyrimidine derivatives (nucleic
acids, macroergic phosphates)
Lack of vitamin B12
Lack of folic acid (B9)
Other vitamin deficiencies - deficiency of fat soluble vitamins
(A, D, K, E, F), lack of water-soluble vitamins - B thiamine
(B1), riboflavin (B2), niacin (B3), pirodoxina (B6), pantothenic
acid (B5), biotin (B7);
c. Caused by iron deficiency anemia (iron deficiency anemia)
Loss of blood
Low intake
Increased needs
Iron metabolism disorders
B. Anemia caused by lost of red blood cell
mass
1. Bleeding or iatrogenic emissions of blood
2. Increased destruction of erythrocytes - hemolytic syndrome
(prehepatic jaundice)
a. Extracorpusculare causes:
Physical factors
Mechanical
Mechanical cardiac causes hemolytic anemia (acquired
or congenital) - aortic stenosis, coarctation of the aorta,
mitral insufficiency, aortic aneurysm, heart valves;
Thermal – heat
Ultrasound
Radiation - ultraviolet (photodermatosis), high-energy
ionizing radiation;
B. Anemia caused by lost of red blood cell
mass
2. Increased destruction of erythrocytes - hemolytic syndrome
(prehepatic jaundice)
a. Extracorpusculare causes:
Chemical factors
Exogenous - arsenic, copper, lead, etc..
Endogenous - hemolytic anemia in nitrogen retention (renal
failure);
Biological factors
Parasites - Malaria (Plasmodium falciparum), babesiosis
(Babesia genus)
Bacteria
- bacterial toxins (Clostridium, E. Coli,
Streptococci)
Viruses (Epstein Bar, herpes encephalitis virus);
Toxic - venoms (snake, scorpion, spider)
B. Anemia caused by lost of red blood cell
mass
2. Increased destruction of erythrocytes - hemolytic syndrome
(prehepatic jaundice)
a. Extracorpusculare causes:
Autoimmune hemolytic anemia
Hypersplenism
Removal of damaged erythrocytes
Response to bacterial, viral, parasitic
Autoimmune diseases
Metabolic diseases
Tumors
Hemolytic anemia with combined mechanisms - vascular
coagulation (DIC)
DIC is a clinical syndrome (infections, cancers, venoms, autoimmune
diseases, trauma, burns, etc. obsterticale cases.) characterized by
intravascular coagulation, with the formation of thrombosis and necrosis,
accompanied by secondary fibrinolysis and consumption of coagulation
factors, with bleeding.
B. Anemia caused by lost of red blood cell
mass
2. Increased destruction of erythrocytes - hemolytic syndrome
(prehepatic jaundice)
b. Corpuscular causes:
Metabolic - enzyme deficiency:
At the level of glycolysis - glucose 6-phosphate
dehydrogenase (G6PDH) deficiency, pyruvate kinase
deficiency, etc.
In the cycle of glutathione - glutathione synthetase
deficiency, glutathione reductase deficiency;
Lack of heme synthesis (porphyrias)
Lack of globin synthesis (globinopathies)
Lack of hemoglobin synthesis (hemoglobinopathies)
Complications of anemic syndrome
Decreased Hb reduces oxygen to tissues with consequent hypoxia.
The effct of hypoxia depends on cells needs (neurons and muscle
cells have greater needs) and on cell proliferation rate.
Complications of anemic syndrome
Biochemical changes:
Krebs cycle activity is reduced due to low oxygen. Following, the
synthesis of macroergic phosphates (plastic and energetic role)
is reduced.
Reduced Warburg respiratory chain activity with reduced heat
production.
Increased glycolitic activity with accumulation of non-volatile
organic acids (lactic acid, pyruvic acid) flattens the hemoglobin
dissociation curve (oxygen is released more easily to the tissue).
Reduced liver metabolism.
Complications of anemic syndrome
Hemodynamic changes:
Preferential
redistribution of blood flow to vital organs
(catecholamines causes vasoconstriction in the splanhnic and
skin territory) - skin blood flow reduction causes - pallor,
decreased skin temperature, feeling cold, shivering, trophic skin
changes. Onset of symptoms depends on the magnitude and
duration of the anemic syndrome.
Hemodynamic
compensatory hyperkinesia evidenced by:
tachycardia, increased blood flow, increased blood speed,
murmurs, increased circulatory flow.
Hyperkinetic
compensation increases oxygen consumption
which, in time, will lead to cardiac decompensation (dyspnea,
swelling, transudates, etc.)
If there is a preexiting coronary obstruction, anemia and
compensatory tachycardia, may lead to angina or increased
frequency of its manifestation, instable angina or even
myocardial infarction.
Complications of anemic syndrome
Respiratory changes
Compensatory polipnea
Renal changes
Hypoxia stimulates production of erythropoietin
Through hypoxia - induced transcription factor 1 * (HIF -1).
Hypoxia stimulates renal renin → activates the renin angiotensin - aldosterone system → retention of sodium
(electrolyte imbalance).
Complications of anemic syndrome
Alteration of tissue perfusion:
Vasomotor activity and angiogenesis are modiffied.
Promotion of angiogenesis is through vascular - endothelial
growth factor - (VEGF).
Changes in skin and mucous membranes (tissues with increased
cell turn-over):
Glossitis, esophagitis, gastritis, bronchitis, vulvovaginitis
Leg ulcers
Pigmentation
Changes to appendages
Brittle hair, digital hipocratism
Complications of anemic syndrome
Increased production of red blood cells
Stimulation of erythropoietin encoding gene via hypoxia-induced
transcription factor (HIF-1), results in increased synthesis of
erythropoietin.
* HIF-1 functions as a regulator of adaptive responses induced
by hypoxia. Under conditions of hypoxia it activates
transcription of over 40 genes, including those responsible for
synthesis erythropoietin, glucose transporters, glycolitic
enzymes, vascular - endothelial growth factor (VEGF) and
other proteins that facilitate metabolic adaptation to hypoxia.
Increasing production of red blood cells is mediated by
erythropoietin. Rates of synthesis of erythropoietin is in inverse
relationship with Hb concentration. Erythropoietin concentration
can increase 1000 times in severe anemia.
It enhances erythropoiesis, with expandation of erythropoietic
tissue, possibly with sternal pain or diffuse bone pain.
Complications of anemic syndrome
Immune system abnormalities:
Hipoxia lowers the defense capacity of the immune system,
especially related to protection of mucosas;
Anemic patient is prone to infections;
Endocrine changes:
Pituitary hypofunction
Thyroid hypofunction
Gonadal hypofunction
Changes in menstrual cycle
Amenorrhoea
Impotence
Particular form of anemia - Iron deficiency
anemia
Iron deficiency is the most common cause of anemia.
20% of women (50% of pregnant women) and 3% of men do not
have enough iron in the body.
Disruption of iron metabolism causes anemia and disturb
cytochromes activity (cell respiration).
Iron is obtained through dietary intake (muscle, liver) and iron
absorption requires the presence of HCl and transferrin.
Iron deficiency anemia - causes
Loss of blood:
Bleeding
Menstrual loss
Frequent blood emission
Polycythemia vera (PV) –
therapy
Blood donors
Neoplasms
Inadequate intake:
Vegetarian diet
Global malabsorption /
selective for iron
Aclorhydria
Resected stomach
Celiac disease
Parasitosis
Iron metabolism disorders
Lack of transferrin
Congenital
Hepatic
Nephrotic syndrome
Defective / deficient transferrin
receptors
Increased needs: pregnancy,
lactation, gemelarity, prematurity,
sports performance
Iron deficiency anemia - causes
Laboratory data
Low Hb
Normal or low number of reticulocytes
Low sideremia
Increased total iron binding capacity
Elevated transferrin
Low ferritin
Absent iron reserves in the bone marrow (Perls staining)
Blood smear
CBC
Microcytosis
Hypochromia
Pokylocitosis
Low Hb, MCV ↓, MCH ↓, MCHC ↓
WBC count normal or slightly decreased
Frequently thrombocytosis
Bone marrow
Red series hyperplasia with iron deficiency erythroblasts
Blood smear
Blood smear
Anemia of chronic disease
It is a normochromic, normocytic or hypochromic, microcytic anemia,
which develops through multiple mechanisms.
Newest name, inflammation associated anemia, is more
representative because it reflects pathophysiological mechanisms.
It secondary appears in:
Chronic inflammation (infections, tuberculosis, endocarditis,
abscesses);
Collagen diseases (SLE, RA, SS);
Malignancy (carcinoma, multiple myeloma, lymphoma)
Elderly anemia.
Pathogenesis
This type of anemia is characterized by the inability of the body to
increase red cell production, to compensate for red cell destructions
more or less increased.
Sustained stimulation of monocytic-macrophage system because of
chronic inflammation, autoimmune diseases or tumors, decrease life of
erythrocytes by increasing phagocytosis.
During inflammation, iron releasing from macrophages and liver
deposits is significantly inhibited.
Interleukin 6 (IL-6) produced during inflammation induces the synthesis of
hepcidine (iron regulating hormone), which in turn inhibits iron release from
macrophages and hepatocytes, with consequent decreasing sideremia.
Hepcidine binds the feroportin molecules from the membrane,
molecules responsible for iron export, leading to their internalization
and intracellular degradation. In this way iron stuck in macrophages and
can not be used for Hb synthesis.
It is known that iron is incorporated into protoporphyrin IX and zinc may
substitute iron for its synthesis.
Pathogenesis
Another mechanism mediated through inflammation mediators (IL-1,
interferon alpha) is low compensation capacity through
erythropoietin by decreasing its synthesis.
Finally there is a decreased iron in serum and erythrocyte
precursors, with increased reserves of iron. The lifespan of red
blood cells decreases without adequate compensation.
Inflammatory cytokines promote the production of white blood cells.
Other anemia with low erythropoietin
Kidney disease - chronic renal insufficiency - insufficient production
of erythropoietin due to renal lesions;
Liver disease - by parenchymal liver failure (cirrhosis, toxic hepatitis,
chronic aggressive hepatitis, etc.) - It reduces the synthesis of
erythropoietin and hemoglobin precursors;
Poliglandular hypofunction - production of erythrocytes is influenced
by thyroid hormones, testosterone, glucocorticoids.
Laboratory data
Low Hb;
Low number of reticulocytes;
Low sideremia;
Low total iron binding capacity;
Increased ferritin;
Perls staining of bone marrow shows reduced number of
syderoblast and a high amount of hemosiderine in the
macrophages.
Megaloblastic anemia
Anemia is normochromic, macrocytic defined by increasing MCV
over 100 fl.
Macrocytosis is typical in:
Megaloblastic anemia
Alcoholism
Liver disease
Megaloblastic anemia is characterized by nucleo-cytoplasmic
asincronism due to deficiency in DNA synthesis with normal RNA
and protein synthesis (immature nuclei and mature cytoplasm).
The most common cause is vitamin B12 deficiency and / or folic acid
deficiency.
A common cause of B12 deficiency is Biermer anemia. It is believed
that the mechanism is immune, mediated by antibodies to intrinsic
factor (IF) or / and anti gastric parietal cells. Thus vitamin B12
absorption disorder is secondary to lack of IF.
Megaloblastic anemia
Folic acid:
It is found in fresh vegetable products, liver;
The daily necessary amount is about 100 mg, normal diet
providing much more than this amount;
The total reserve is up to 5 mg, enough for 3-4 months;
Normal serum level is - 5 to 20 ng / ml;
It is absorbed in the proximal jejunum;
Vitamin B12:
Food sources are animal products;
B12 absorption occurs in the terminal ileum;
The daily necessary is 1μg;
B12 liver reserves are sufficient for 3-5 years;
Serum B12 level is 200-600 pg / ml;
Absorption is only in the presence of intrinsic factor (IF),
glycoprotein produced by gastric parietal cells.
Causes of B12 deficiency
Deficient intake (malnutrition, vegetarian);
Malabsorption:
Inadequate production of IF (pernicious anemia), gastrectomy,
congenital deficiency;
A disease of the terminal ileum: celiakie, Crohn's disease,
intestinal resection, intestinal neoplasms, selective malabsorption
of B12;
An intestinal consumption of B12: parasites, bacteria
Drugs that interfere with B12 absorption: neomycin
Deficiency in transportation and use of B12 : congenital deficiency of
transcobalamin II (TC), excess of I and III TC, enzyme deficiency.
Causes of folic acid deficiency
Deficient intake : alcoholism, low-vegetable diet, infancy, prematurity
Increased needs:
Pregnancy
Childhood
Malignancies
Intense hematopoiesis
Chronic skin exfoliation (psoriasis)
Malabsorption
Drugs - barbiturates
Signs and symptoms
Depression
Paranoia
Hallucinations
Psychosis
Panic Attacks
Changes in personality
Suicide
Decreased muscle strength
Impotence
Laboratory data
Low Hb
Low / normal number of reticulocytes
CBC
MCV > 100 fl
Leucopenia
Moderate thrombocytopenia
Blood smear
Macrocytosis (macrocytic anemia) , macro-ovalocytes,
megalocytes
Hypersegmented neutrophils (from 5 lobes)
Bone marrow
Hyperplasia, predominantly in red blood cells with asincronism in
maturation of the hematopoetic precursors
Laboratory data
Biochemistry:
Low serum cobalamin <100 pg / ml
Increased level of intrinsic factor antibodies and anti-parietal cells
Increased lactate dehydrogenase
Increased or normal serum iron
Schilling test positive - no excretion of radiolabelled B12
Atrophy of gastric mucosa at endoscopy
Laboratory data
Principles of treatment
Treatment and management of underlying disease
Blood transfusion
Recombinant erythropoietin administration
Vitamin B12/folate administration
Iron preparations
Dietary therapy
Food acidification
Stopping alcohol intake
Vitamin supplementation
Glucocorticoids
Immunosuppressive drugs
Splenectomy
Marrow transplantation
Phototherapy in newborn