Physiology

• Haematopoiesis = production of blood cells.

  Derived from pluripotent stem cells - capable of making all types of blood cell.
• Haematopoiesis Areas =

  Skull

  Ribs

  Sternum

  Pelvis
• Posterior iliac crest = most common biopsy site to get a sample of bone marrow
• Flow cytometry =

  Allows us to define stem cells by specific proteins on cell surface - using flow cytometry
• Granulopoiesis = production of neutrophils

  Driven by two key cytokines = GM-CSF + G-CSF (injections used after chemo)

  Receptors are present on myeloid precursors - signal via JAK/STAT pathway

  Acutely unwell = increased neutrophils + primitive myeloid precursors in blood
• Erythropoiesis order =

  Promonormoblast

  Early normoblast

  Intermediate normoblast

  Normoblast - last one with nucleus

  Reticulocyte

  Erythrocyte
• Erythropoiesis =

  Major cytokine = erythropoietin produced in renal interstital cells (sense blood oxygen tension)

  EPO receptors expressed on early erythroid progenitors - signal via JAK/STAT pathway to stimulate prolifereration
• Where does fetal production of EPO occur?

  Liver
• Acquired activating mutations in JAK signaling pathway most commonest cause of polycythaemia (pathological over production of RBCs).
• EPO injections are used in =

  Renal anaemia

  In chemo - reduce need for transfusions
• Large megakaryocytes develop erythroid progenitors and platelets budding from surface.
• THrombopoiesis =

  Main cytokine = thrombopoietin produced in liver + renal PCT cells

  TPO binds to TPO receptor on progenitor cells - signal to drive proliferation of megakaryocytes
• B- cell lymphopoiesis

  • B cell precursors migrate to lymph nodes
  • Maturing B cells move through lymph node germinal centres - exposed to antigens
  • Ig genes are rearraneed - become specialised with IgM ON SURFACE
  • Class switching Ig heavy chains to D/E/G/A. Leave as mature memory cells - migrate to bone marrow.
• T-cell lymphopoiesis =

  Formed in bone marrow - migrate to cortex of thymus - undergo maturation

  Develop into

  T-helper

  T-cytotoxic

  T-memory

  T-suppressor
• FBC can only be assayed on non-coagulated blood.
• Erythropoiesis = controlled by CNS - sympathetic and parasympathetic systems.
• Old red blood cells =

  Taken up by macrophages

  Globin chains = amino acids

  Heme group = iron + bilirubin
• Glycolysis = Energy of RBC - ATP

  1. maintains glycolysis
  2. synthesis of glutathione - protection of metabolic enzymes + haemoglobin + membrane proteins
  3. purine + pyramidine metabolism
  4. maintenance of haemoglobin iron in ferrous state
  5. preservation of membrane phospholipids
  6. ATP-ase driven Ion pumps
  7. Shape of RBC
  8. ATP = extracellular messenger during hypoxia
• Luebering-Rapaport bypass =

  Regulator of oxygen-carrying pathway. End product = 2,3-DPG
• Penrose phosphate pathway = protection of macromolecules in RBC.

  End product = NADPH

  Keeps glutathione reduced.

  Reduces methaemoglobin (can’t bind oxygen) with Fe3+ into normal haemoglobin Fe2+
• Function of glutathione =

  Reduced glutathione = protects haemoglobin + enzymes + membrane

  NADPH keeps glutathione in reduced form
• CO2 transport in blood =

  1. bicarbonate ion
  2. Bind to haemoglobin
  3. Dissolution directly into blood
• B12 and folate - diet + absorption

  A) Meat and dairy

  B) Liver and Vegetables + cereals

  C) 2-4 years

  D) 4 months

  E) ileum

  F) duodenum and jejunum

  
• B12 deficiency =

  • causes conversion of intracellular folate -> methionine
  • Fall in folate = megaloblastic anaemia
• Vitamine B12 absorption =

  • binds to haptocorrin
  • haptocorrin broken down by pancreatic proteases = allows B12 to bind to IF
  • B12 - IF complex bind to ileum - dependent on Ca
• Causes of B12 deficiency =

  • vegan die
  • bacterial overgrowth in small intestine due to poor motility
  • Crohns disease - affects ileum
  • elderly with poor nutrition
  • pernicious anaemia
• Most common symptoms of B12 deficiency =

  Tiredness - affects oxygen carrying

  Memory loss

  Poor concentration
• Red flags in B12 Deficiency =

  Paraestehsia

  Hyporeflexia - may indicate peripheral neuropathy

  ataxic gait

  reduced muscle power

  SOB

  peripheral oedema

  cognitive impairment

  depression
• Diagnosis of B12 deficiency =

  serum B12 - transport and active forms

  active B12

  Methylmalonic acid = raised in B12 deficiency

  Homocysteine = raised in B12 deficiency

  Auto-antibodies (anti- IF) - more specific for pernicious anaemia
• Blood film B12 deficiency =

  Macrocytic anaemia

  Macro-ovalocytes

  Hypersegmented neutrophils
• Folic acid gets reduced to THF. This is essential for synthesis of purines + pyrimidines - compromises DNA synthesis.
• Causes of folate deficiency =

  Diet - with alcoholism

  Malabsorption - IBD

  Excess utilisation - pregnancy + malignancy

  Drugs that induce CYP450 - anti-convulsant drugs
• Folate deficiency symptoms =

  Sore tongue

  Jaundice

  Anaemia symptoms

  Weight loss

  Diarrhoea
• Pregnant women folate deficiency = neural tube defects

  Spina bifida

  Anencephaly
• Treatment of pernicious anemia = life long B12 supplementation

  No neuro symptoms = IM hydroxoxobalamin 3x for 2 weeks

  Maintenance = IM every 3 months

  Neuro symptoms = alternate day IM hydroxocobalamin

  Maintenance = IM every 2 months
• Vitamin b12 treatment =

  HIgh dose oral vitamin B12

  • used instead of IM with bleeding disorders
  • IM = treatment of choice
• Folic acid treatment =

  Megaloblastic anemia = 5mg for 4 months

  Prevention of NTDs = 5mg daily taken from conception to week 12 of pregnancy

  Prevention of methotrexate induced side effects = 5mg once weekly
• Measuring folate concentration =

  Serum folate = transient

  Red cell folate
• Protection of the fibrin clot =

  Inhibition of plasminogen and plasmin
• Haemostasis counter regulation =

  Plasmin - activates fibrinolysis to make vessels pagent again after healing wall

  Natural anticoagulants = Antithrombin III + Protein C and Protein S