Hematopoetic system: platelet
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Blood liquid contains
plasma and serum
plasma vs serum
plasma: THE FLUID LEFT AFTER BLOOD CELLS ARE REMOVED, CAN CLOT
SERUM = THE FLUID LEFT AFTER THE BLOOD CLOT AND CELLS ARE REMOVED
Different type of plasma proteins
blood cells embryology
3 WEEKS: Yolk Sac (Primitive stem cells)
- 3rd MONTH: Stem cells migrate to the LIVER which is the chief site of blood cell
- formation until birth.
- 4th MONTH: Stem cells migrate to the bone
- marrow and commence hematopoesis.
BIRTH: Bone marrow is the sole source for hematopoesis.
The main source of blood cell in adult
the bone marrow
- the microenvironment for the orderly proliferation, differentiation and release
- of blood cells.
- a normal adult the marrow cavity includes ends of long bones
Blood supply to the bone
- supply. 1. Nutrient artery (enters at
- the center of the bone) -2. Medularly artery – 3. radial artery – 4. cortical
- capillary – 5. endosteal capillary – 6. medullary vascular sinuses – 7. central sinus – 8. efferent vein.
Lymphoid stem cell
myeloid stem cell
Stem Cell produces
common lymphoid stem cell and common myeloid stem cell
Hypercellular bone marrow
inc cell in bone marrow
Erythropoesis is regulated by
- nErythropoietin , a hormone that is
- synthesized in the kidney.
required for red cell production include
Red cell maturation happen in
- discs with an average diameter of 7.2 µm
- lipid bilayer under which is the protein
- cytoskeleton the main being spectrin.
- transport oxygen to peripheral tissues
- Normal life span is 120 days and senescent red cells
- are removed from circulation by the spleen and liver
- As the red cells mature they lose
- the nucleus and become hemoglobinized
- and then enter the circulation.
- Acute blood loss in the presence of a normal
- bone marrow can result in
- hyperplasia of the red cell precursors and lead
- to increased immmature
- red cells in the circulation (reticulocytes)
- immature erythrocyte with residual ribosomal RNA
reticulocyte - normal range
- to 1.5% of reticulocytes refers to a normal, healthy person
the patient is anemic and the marrow response is healthy, reticulocyte lvl
- the % should be much higher, up to 10X higher %.
- 1 %
- reticulocyte count would mean the marrow is not responding to the anemia
3 CBC value of RBC
- RBC count
- PCV - packed cell volume or hematocrit
pathology and morphology
of Anemias - pathology
- red cell production
- red cell destruction (hemolysis)
- Loss , acute or chronic
of Anemias - morphology
- (iron deficiency, thalassemia)
- (folate or B12 deficiency)
- but with abnormal shapes (hereditary spherocytosis, sickle cell disease)
RBC disorder - anemia
- nIs defined as reduced oxygen
- carrying capacity of blood which stems from a reduction in the total
- circulating red cell mass to below the normal amounts.
- nThis results in lower hemoglobin (Hb)
- and Hematocrit
due to decreased red cell production
- –Iron deficiency
- –B12/ Folic Acid deficiency ( megaloblastic
- marrow failure: Aplastic anemia
nErythropoetin deficiency: Renal failure
- of globin synthesis: thalessemia
- protein for iron
- form of iron, levels reflects the iron stores in the body
- nThe amount of iron that the
- transferrin could bind in a fully saturated state; TIBC is high when serum iron
- is low.
common form of nutritional deficiency
iron deficience anemia
best indicator of the body iron stores
Deficiency Anemia cause
- malabsorption due
- to sprue and
- celiac disease, chronic blood loss
- in hypochromic microcytic anemia
- the duodenum iron is absorbed into the epithelial cells Divalent Metal
- Transporter (DMT)
- in the epithelial cells and macrophages releases the iron from the enterocytes
- into hepatic portal system
Hepcidin peptide hormome
- by the liver major role in iron homeostasis
- secretion of ferroportin hence inhibits iron absorption
nHepcidin mutation or hemojuvelin mutation
to iron deficiency in order of occurrence
- serum ferritin is the first response to iron deficiency
- % saturation of transferrin
- red cells (MCV <80)
Hemosiderine - histological slide
- visible brown
- pigment stored in macrophages in the liver,
- spleen and bone marrow
Lab finding - Iron deficiency
- dec serum iron
- inc TIBC
- <10% SAt
Lab finding- anemia of chronic disease
Iron deficiency vs anemia of chronic disease
hypochromic microcytic anemia
Clinical presentation in iron deficiency
Pica; persistent compulsive desire to ingest certain food or non-edible items like ice, clay, plaster.
Sore mouth, angular stomatitis, palor
vitamins that are required for DNA synthesis
Deficiency leads to...?
Both B12 and Folic Acid
MEgaloblastic anemias - pathogenesis & hallmark
- Deficiency leads to impairment in
- DNA synthesis which results in delay in nuclear maturation and cell division in
- comparision to the cytoplasmic elements hence nuclear to cytoplasmic asynchrony effecting all cell lineages.
Hallmark is the presence of megaloblasts
MEgaloblastic anemia - bone marrow finding
Normal cellularity in adults 40-60%. In megaloblastic anemia bone marrow is hypercellular with increased megaloblasts
All hematopoetic lineages show nuclear to cytoplasmic dyssynchrony.
Megaloblastic anemia - peripheral smear finding
macrocytic anemia (MCV >100fL) and hypersegmented neutrophils
Vitamin B12 - dietary source
- Abundant in all animal products and
- is resistant to cooking and boiling.
common cause of B12 deficiency
Dietary B12 deficiency confined to
Pernicious anemia - cause
- Vitamin B12 deficiency resulting from inadequate gastric production or defective
- function of intrinsic factor (IF).
- Intrinsic factor secreted from the parietal
- cells of the stomach that forms a complex with B12 that attaches to the epithelial intrinsic factor receptors present in the ileum which leads to the absorption of Vitamin B12.
The absorbed B12 is bound to the transport protein transcobalmin II which delivers it to the liver and other parts of the body.
Causes for Intrinsic factor deficiency
autoimmune and malabsorption
Causes for Intrinsic factor deficiency - autoimmune
antibodies against the parietal cells
antibodies against IF-B12 complex.
occurrence of PA in patients with other autoimmune conditions such as RA, Diabetes, Hashimoto thyroiditis.
Causes for Intrinsic factor deficiency- Malabsorption
due to gatrectomy, and other small bowel disorders such as Whipple disease, Crohn’s Disease, tropical sprue.
Sources: uncooked fruits and vegetables
Food folates are in the polyglutamate forms and must be split to monoglutamate for absorption in proximal third of the small intestine.
Within cells the monoglutamate form is converted into tetrahydrofolate which is involved in the synthesis of purines and pyrimidines (DNA synthesis)
Causes of Folic Acid deficiency
Diets poor in fresh fruits and vegetables
Alcoholics; alcohol interferes with folate metabolism
Increased metabolic needs: pregnancy and lactation
Drugs: anticonvulsants, antimicrobials, methotrexate
Malabsorption: Celiac disease and Tropical Sprue
Lab findings for B12 and Folic Acid deficiency
Peripheral blood smear- Macrocytic anemia (MCV > 110), hypersegmented neutrophils (> 5 nuclear lobes)
Bone marrow: Hypercellular, megaloblastic changes, erythroid hyperplasia
Response to B12 treatment after therapy in a B12 deficient includes
Increase in reticulocyte count within the first week
Disappearance of hypersegmented neutrophils in 2-3 weeks
Anemia of Chronic Disease - cause
Chronic infections, – TB, osteomyelitis
Chronic immune disorders- Rheumatoid arthritis, regional enteritis
Neoplasms- lymphoma, carcinoma
Anemia of Chronic Disease - pathogenesis
Increased interleukins (IL) which inhibit the release of iron from the stores, decrease the responsiveness of the bone marrow to erythropoetin.
In response to inflammatory cytokines liver produces Hepcidin, which suppresses ferroportin from releasing iron from the enterocytes and macrophages.
- Inflammatorycytokines also blunts bone marrow response to erythropoetin
- SerumFerritin levels are high, TIBC is low
Reticulocytecount is low
Red cell membrane proteins and fxn
Ankyrin, spectrin, protein 4.2, band 3
- - Vertical interactions:
- - Perpendicular to the red cell membrane
- - Stabilize the lipid bilayer
- Trilineage bone marrow hypoplasia due to
- constitutional and acquired causes.
Presentation; Pancytopenia (peripheral blood counts for all three lineages is decreased), bone marrow hypoplasia (cellularity < 10%).
Clinical: Anemia, bleeding, infections.
Aplastic Anemia - cause
Idiopathic: Most common
Infections: Parvovirus, Hepatitis, HIV1, Influenza, EBV
Drugs: Chloramphenicol, chemotherapy, sulfonamides, anticonvulsants
Genetic: Fanconi’s anemia, Familial aplastic anemia, dyskeratosis congenita
Others: Paroxysmal nocturnal hemoglobinuria, pregnancy, immune disorders.
RBC membrane - lipid layer
- The lipid bilayer in the red cells have an outer half that is enriched by phosphatidyl choline and sphingo myelin
- The inner half of the lipid bilayer is enriched by phosphatidyl serine and phosphatidyl ethanolamine
Red Cell Membrane Disorders
nSouth Asian Ovalocytosis
nAcanthocytosis and related disorders
nRh deficiency syndrome
Most common RBC membrane disorder
Spherocytosis - etiology
nDeficiency of one of the cytoskeleton proteins that keep the lipid bilayer intact.
- nThe ensuing destabilisation of the lipid bilayer leads to
- release of lipids from the membrane as microvesicles and surface area deficiency.
nHence RBC’s become non deformable
Spherocytosis - favorable tx
Spherocytosis - genetic cause and presentation
- most patients (70%) autosomal dominant inheritance
Most prevalant in Northern European decent
- as hemolytic anemia
Spherocytosis - dx - clinical feature
anemia, Jaundice, splenomegaly
HereditarySpherocytosis - dx - lab finding
MCV- Low normal
- Hemolysis- LDH, reticulocytosis,
Osmotic fragility test- gold standard
Gold stand for hereditary spherocytosis
Osmotic fragility test
Hereditary elliptocytosis - common in ?/confer resistance to / major defect
- in African and Mediteranean
- resistance to malaria
- of defect is due to spectrin
elongated shaped plasma
Red cell Enzyme disorder - G6PD
housekeeping gene that is essential for basic cellular functions
G6PD generates NADPH which is utilized for glutathione reduction. Reduced glutathione restores hemoglobin in the soluble state and prevents oxidative damage.
G6PD deficiency leads to-
- in the presence of oxidant stress.
- sequel of the oxidative damage to hemoglobin is –Heinz bodies.
- cells are rarely seen
- deficiency confers protection against malaria
G6PD - gene encoded/dx/tx
Gene for G6PD is encoded on the X chromosome
Laboratory diagnosis- Spectrometric analysis
- Avoidance of oxidant stressors medications, fava beans and infections.
Pyrimidine 5’Nucleotidase: genetic/fx
Inherited as an autosomal recessive fashion
Participates in the degradation of RNA in the reticulocytes
the only red cell enzyme deficiency that has a specific consistent
morphological abnormality-basophilic stippling
Basophilic stippling - definition and cause
Ribosomal RNA that is precipitated during staining
Causes heavy metal poisoning, sideroblastic anemias, thalessemia
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