126 Flashcards
Epo signalling
Binds to a blast cell.
Through Janus kinase 2 (Jak2), signals.
Process of erythropoiesis
1
2
3
1) Proerythroblast
2) Polychromatic erythrocytes
3) Erythrocytes
Outcome of erythrocytes having no nucleus or mitochondria
Obligate anaerobes. Make lactate continuously.
How quickly do blast cells mature to erythrocytes?
~7 days
Rate at which RBCs are made in adults
~2 million per second
Where is EPO synthesised?
Kidney
Epo function
Erythropoietin (Epo) is required
for survival, proliferation and
differentiation of committed
erythroid progenitor cells.
Met-haemoglobin
Hb with Fe3+ (Fe2+ has been oxidised).
How is RBC lifespan determined?
Give chromium 51 to random sample of RBCs, infuse.
Over ~120 days the label is removed.
120 days is the maximum lifespan. Many things can shorten lifespan.
Vitamin B12 role in RBC maturation
Methylation step in haemoglobin synthesis
What happens when a RBC has ~15% met-Hb?
Macrophages in spleen, liver, red bone marrow phagocytoses RBC
What converts haeme to biliverdin?
Haem oxygenase
Where does the Fe from metabolised Hb go?
Stored in transferrin, which goes to the liver.
Transfered to ferritin.
Spleen microscopic structure
White pulp - Immune cells
Red pulp - is a system of blood vessels arranged to facilitate removal of old or damaged red blood cells from the circulation. The removal is performed by macrophages.
Mononuclear phagocyte system of the spleen 1 2 3 4 5 6
1) Performed by monocytes/macrophages in spleen, lymph nodes. Also by Kupfer cells in the liver.
2) Formation of new RBCs and WBCs (in embryo).
3) Destruction of old RBCs and WBCs.
4) Formation of antibody
5) Formation of plasma proteins.
6) Formation of bile pigments.
Examples of altered surface molecules on RBCs that macrophages can recognise
Exposure of phosphatidyl serine, reduced content of sialic acid anchored to glycophorin.
Surface protein on RBCs that determine immunogenicity
Carbohydrates (neuraminic acid, also called sialic acid) attached to glycophorin.
How does the body determine age of RBCs?
Neuraminidase in body slowly cleaves off sialic acid while RBC circulates. After maximum 120 days, enough has been removed for macrophages to phagocytose RBC.
As the RBC ages, more phosphatidylserine flips to the outer
side of the membrane. Eventually it reaches equilibrium, and this is a signal for destruction.
Causes of haemolysis
1
2
3
1) External attack on RBC (EG: strep, enterococcus)
2) Parasitic haemolysis (EG: malaria)
3) Congenital or genetic factors
Haptoglobin
Plasma protein that binds haemoglobin (repurposed serine protease).
Cleaves tetrameric structure of Hb, binds to it.
This signals to a macrophage to phagocytose Hb-Hp.
What happens when haptoglobin is depleted?
Get Hb in the urine, as haptoglobin isn’t degrading Hb
What to suspect when there is low haptoglobin?
Haemolytic anaemia, as this depletes haptoglobin
Protein that carries haeme to liver
Hemopexin
Why does haeme need to be removed from the blood?
It is neurotoxic
Role of hemopexin
Takes up free haeme in blood, transfers it to the liver
Signs of haemolytic anaemia
Low haemopexin, haptoglobin
Consequences of haemolysis 1 2 3 4
- Unconjugated (indirect) hyperbilirubinemia. Jaundice occurs when the conversion of Hb to bilirubin exceeds the liver’s capacity to conjugate and excrete bilirubin.
- Increased stercobilin (brown) in the stool and urobilinogen in the urine.
- Sometimes cholelithiasis (gall stones from bile acids).
- Reticulocytosis when the bone marrow responds to the excess loss ofRBCs by accelerating production and release of RBCs
Signs and symptoms of haemolysis
Pallor, fatigue, dizziness, possible hypotension.
If very severe, haemolytic crisis.
Haemolytic crisis
It may be accompanied by chills, fever, pain in the back and abdomen, prostration, and shock. Severe hemolysis can cause jaundice and splenomegaly. Hemoglobinuria causes red or reddish-brown urine.
Endogenous production of carbon monoxide
When haeme is broken down, NADPH and O2 react with products to form Fe3+, CO and NADPH
Enzyme that converts biliverdin to bilirubin
Biliverdin reductase
Timeline of bruises 1 2 3 4 5
1) First presentation is reddish as the blood is trapped in interstitial tissue.
2) 1 -2 days: bruise turns bluish-purple or even blackish (deoxy and met-Hb).
3) 5 -10 days: bruise turns greenish or yellowish (biliverdin).
4) 10 -14 days: yellowish-brown or light brown (bilirubin).
5) >14 days the bruise fades away
What can serum albumin bind?
Highly-hydrophobic bilirubin
What happens to bilirubin after it has been formed?
Released from organ that formed it.
Binds serum albumin in the blood.
Transferred to the liver
What happens to bilirubin in the liver?
Bilirubin UDP-transferase makes bilirubin more hydrophilic by conjugating to a hydrophilic gluconurate.
It can be excreted by the kidneys.
cMOAT
Canalicular multispecific organic anion transporter.
Actively transports bilirubin diclucuronide into the liver canaliculi.
Syndrome from cMOAT deficiency
Dubin-Johnson syndrome
Dubin-Johnson syndrome
Failure to export dihydropurinides into bile.
Can lead to hyperbilirubinaemia, but this is normally asymptomatic.
Dihydropurinides are non-toxic, so not really dangerous.
Name for syndrome with deficiency in UDP gluconyltransferase 1 family
Crigler-Najjar syndrome
Crigler-Najjar syndrome
In Crigler-Najjar patients the transferase is either inactive (type I) or severely reduced (type II). Bilirubin cannot be excreted into the bile and remains in the blood. The high plasma level of unconjugated bilirubin presents as persistent jaundice.
Some patients exhibit kernicterus (bilirubin encephalopathy and brain damage) due to bilirubin toxicity. Kernicterus can produce hypotonia, lethargy, deafness and oculomotor palsy.
Treatment of Crigler-Najjar syndrome
Must begin early to protect brain
Children given 10-12 hours treatment/day.
Exposed to blue light (phototherapy).
How does phototherapy work for Crigler-Najjar syndrome?
1
2
3
Some of the double-bonds in bilirubin isomerize cis/trans when exposed to light.
The Z,Z-isomer flips to E,Z and E,E-isomers and bilirubin becomes more soluble.
E,E form is more soluble, can be excreted.
Proportion of bile that bile salts are
~4.4%. Higher in haemolysis.
Enterohepatic urobilinogen cycle
Resorption of uribilinogen in gut and excretion by kidney.
Conjugated bilirubin is secreted in bile into gut.
Bacterial enzymes convert conjugated bilirubin into urobilinogen, 90% of which is excreted in faeces. The rest is taken up by the portal vein, and 9% of this is excreted again in bile. 1% enters blood, is excreted by the kidneys.
What is the most common cause of low urobilinogen?
Gallstone blocking bile duct.
What can increased urobilinogen in urine mean?
Increased values indicate RBC breakdown (haemolytic
disease), hematoma, poisoning and liver cirrhosis.
Urobilin
Urobilinogen slowly converts to urobilin in the presence of O2.
Major colourant of faeces
Stercobilin, which is deep red-brown.
