Describe RBC formation:
a) before birth
b) after birth
a) mesoblastic stage (3w, nucleated RBC form in yolk sac and mesothialial layers of placenta) -> hepatic stage (6w, erythropoiesis mainly in liver and spleen) -> myeloid stage (3m, bone marrow becomes principle RBC source)
b) up to 5y: bone marrow in all bones
5 - 20-25y: marrow of long bones
25+y: marrow of membranous bones e.g. vertebrae, sternum, ribs, cranial bones, ilium
Describe bone marrow.
Describe the erythropoiesis to form a RBC.
Soft, spongy, divided into red marrow where most erythropoiesis occurs, and yellow marrow which contains large amounts of fat droplets and cells.
NB: bone marrow = myeloid tissue
Haematopoietic SC (haemocytoblast) in marrow -> common myeloid progenitor (proerythroblast) -> early erythroblast (ribosome synthesis) -> late erythroblast (Hb accumulation) -> Normoblast (ejection of nucleus) -> reticulocyte -> erythrocyte
What's a RBC's diameter and stained with?
What is a reticulocyte?
Roughly how many RBC are in an adult? What is their lifespan? What are the normal ranges per microlitre for a male and female?
Some ribosomes or rRNA in them which shows as dark markings to seperate them from erythrocytes. Normally about 1% of RBC.
24 trillion, 120 days, male = 5.2 x 106/ul, female = 4.7 x 106/ul
What kind of cell is this?
Why is the proerythroblast also called a common myelin precursor?
What else can haemocytoblast SC form apart from myeloid progenitors?
Can differentiate into other blood cells: megakaryocyte, erythrocyte, mast cell, myeloblast (-> granulocytes and leucocytes)
Lymphoid progenitors which differentiate into different types of lymphocytes
Describe the development of myeloblasts.
Turn into granulated white cells (granulocytes or granulated leukocytes), which are part of the innate immune system. They secrete granules to attack invaders.
Basophils (associated with mast cells and help with helminths)
Neutrophils (make up majority of granulocytes)
Eosinophil (associated with allergies, allow WBC access to tissues)
Monocyte -> macrophage (engulfs and digests)
Describe lymphocytes and their development.
Part of adaptive immune response, no granules except NK cell
Haemocytoblast -> common lymphoid progenitor -> NK cell OR small lymphocyte
Small lymphocyte -> T lymph OR B lymph
B lymphoctye -> plasma cell
These cells have nuceli, and NK cells release granules when triggered by other lymphocytes
What controls erythropoiesis and where is it found?
Why is it found there?
What effect does hypoxia have?
Erythropoietin (EPO) produced in fibroblast interstitial cells in the kidney around the proximal tubule.
Kidney has tightly regulated glomeular filtration rate and steady O2 usage. O2 levels in and around proximal tubule not affected by exercise/BP - O2 level mainly determined by amt of Hb in arterial blood
Hypoxia = reduced O2 carriage = stimulates EPO release -> acts on erthropoietic SC (stimulates erythroblast maturation in red bone marrow) to increase TBC production
What is the erythrocyte sedimentation rate, what is it a marker of and how?
How are 120d old senescent RBCs removed from the blood?
Erythrocytes have -ve surface charge (salic acid on membrane glycoproteins) = ensure they electrostatically repel each other and don't stick. Inflammatory reactions/bacteria in blood release molecules that bind to RBC membrane and reduce the charge, enabling RBC to stick together in stacks = rouleaux, which settle faster in a blood test = increased ESR = non specific marker of infection.
By macrophages as they pass through spleen. Maybe cell surface antigens in old RBCs are diff to those in young. Or old = lack of deformablity = entrapped in spleen capillaries.
Describe the breakdown of RBC once engulfed by splenic macrophages.
Broken open by osmotic lysis -> haem prosthetic goups removed from globin proteins.
Globin proteins broken down to aa for reuse
Haem broken open by haemoxygenase enzyme and Fe atom removed for reuse. The opened phorphyrin ring (minus Fe) = biliverdin (greenish) -> converted to bilirubin by bilirubin reductase
Biliruin bound to albumin -> released to blood = unconjugated bilirubin
Reaches liver and attached to glucuronic acid by hepatocytes to make it more soluble = conjugated bilirubin (norm level in blood = 0.1-0.3mg/dl - test of spleen function)
Passes in bile to small intestine where it emulsifies fats, then bacteria convert it to urobilirubin. Most exits in faeces but 10% passes back in portal vein to liver -> blood -> kidney -> urine (yellow colour)
What is the total body Fe and how much is absorbed/day?
What form is most body iron in?
Where is the majority of digested iron absorbed in and by?
3-5g. 1mg (and 1 mg excreted so body balanced - urine, faeces etc.).
Duodenum by enterocytes of duodenal lining.
Describe how iron is absorbed from digested food.
What forms can dietry iron be absorbed in?
Why is Fe dangeous in the free form?
What are transferrins?
Enterocytes of duodenal lining have transporter proteins for Fe transport. Fe is taken up from enterocytes by transferrin and transported in blood to bone marrow and other cells.
Fe2+ or as part of a protein e.g. haeme. Free iron must be in Fe2+ form. Ferric reductase enzyme on enterocytes' brush border can reduce Fe3+ to Fe2+.
Iron-binding blood plasma glycoproteins that control level of free iron in plasma and other extracellular fluids. Each molecule can carry 2 iron atoms in Fe3+ form.
How does transferrin release it's Fe ions?
Where is iron stored and how is it released?
What can you measure in cases of suspected iron deficiency anaemia/iron overload disorders?
Transferrin protein loaded with iron will bind to a transferrin receptor on cell surface (e.g. erythroblast) and is then transported into cell by endocytosis where it releases its Fe ions which are taken up by ferritin and stored for future use. Receptor/transferrin complex transported back to cell surface and transferrin released to repeat.
In cells in ferritin: v large hollow globular protein. Released in controlled fashion when needed. Buffers against iron deficiency and overload. Ferritin is found in most tissues as a cytosolic protein, and small amounts in serum where it's an Fe carrier
Serum transferrin level, serum ferritin level (indirect marker of total amount of stored in body)
What are some symptoms and signs of anaemia?
Hb level below reference levels for age and gender, commonest blood disorder.
Adult male: <13.5g/dl, Adult female: <11.5g/dl, 6-14yrs: <12g/dl, 6m-6y: <11g/dl
Symptoms: tiredness, fainting, SoB, worsening angina/claudication, palpitations
Signs: pallow, rapid HR, bounding pulse, systolic flow murmur, cardiac failure
What are the 3 main reasons for anaemia (and causes of these reasons)?
Give the 3 types of anaemia.
1) decreased production of RBC: iron deficiency, B12/folate deficiency, marrow infiltration e.g. cancer, chronic disease e.g. rheumatoid, cancer, infections e.g HIV
2) increased destruction of RBC: disorders of RBC membrane/enzyme/Hb, immune destruction
3) increased loss of RBC (bleeding) - internal hemorrhage e.g.
Microcytic (<76fl), Normocytic (76-96fl), Macrocytic (>96fl)
Describe iron-deficiency anaemia and its causes.
Commonest nutritional deficiency worldwide, RBCs and microcytic and hypochromic, main cause = low Fe intake and excess Fe ions. No-meat diets can cause it b/c many plants contain iron but absprption limited by low solubility and chelators. Major source = foods of animal origin - haeme iron has high bioavailability.
List some factors:
a) enhancing Fe absorption
b) impairing Fe absorption
What effect can PPIs have?
a) Haeme iron (meat), ferrous salts (Fe2+), acid pH in stomach, Fe deficiency, pregnancy, hpoxia
b) non-haeme iron (veg), ferric salts (Fe3+), alkaline pH, Fe overload, inflammatory disorders
Used for acid reflux/indigestion, may reduce stomach acid and decrease Fe absorption
List the risk factors for developing iron deficiency.
List some causes of iron deficiency anaemia.
Age (elderly/prematurity), Sex (female>male), reproduction (menorrhagia), GI (weight changes, bowel habit change, rectal bleeding), drugs (aspirin, NSAIDs), social (diet - vegans), physiological (pregnancy, infancy, adolesence, breastfeeding)
menorrhagia, GI tract bleeding (varices, ulcer, inflamm bowel, cancer), GI tract malabsorption (coeliac), physiological (pregnancy), dietry (old, vegans), worldwide (hookworm)
List 4 ways you would confirm iron deficiency anaemia.
List 4 ways you would treat iron deficiency anaemia.
1. FBC (low RBC number)
2. Blood film (microcytic, hypochromic RBC)
3. Serum ferritin (low)
4. Serum iron total iron binding capacity (TIBC) (are they low?)
1. improve diet
2. iron tablets (ferrous sulphate)
3. avoid blood transfusions
4. once Hb returned to normal continue iron supplements for 3m