F8vii: Describe the physiology & consequences of abnormal haemoglobins

Abnormal Hb

  1. Structural abnormality of globin chain (haemoglobinopathies)
  2. Globin chain production abnormality (thalassaemia)
  3. Acquired haemoglobinopathies (MetHb, sulfonoglobin, carboxyHb)

Abnormal Globin Chain

Pathology

Consequences

Clinical Features

Abnormal Globin Chain

Sickle Cell Disease

Pathology

Mutation of b globin chain

Glutamic acid → Valine

On posn 6 of globin chain

Causes critical loss in solubility of reduced Hb

HbS

HbSS = sickle cell disease, homozygous (all Hb abnormal)

HbSA = sickle cell trait, heterozygous (half Hb abnormal, half normal)

Consequences

R Shift ODC

Very insoluble at low pO2 tensions with the Hb crystalizing in the RBC → causes its shape to change from biconcave to sickle

Sickle cell shaped RBCs are fragile and hemolyse easily resulting in sickle cell anaemia

RF for sickling: acidosis, sepsis, hypothermia, cellular dehydration

Clinical Features

Increased blood viscocity

Ischaemia

Tissue infarction

Chronic hemolytic anaemia

Jaundice

Splenomegaly

Impaired growth, susceptibility to infection

Acute Chest Syndrome:  vaso-occlusive crisis of pulmonary vessels usually precipitated by lung infection → inflammation, hypoxia, sickling & vasooclusion

Abnormal Globin Chain

Globin Chain Production Abnormality

Thalassa = sea

Aima = blood

‘blood of the Mediterranean’

Pathology

Lack or decreased synthesis of a/b globin chain

Consequences

Clinical Features

Abnormal Globin Chain

β Thalassaemia

Pathology

Abnormal/absent β chain

Consequences

Excess a chains bing to any other globin chain available

HbA2 = 2a+2d

HbF =  2a+2g

Over production of HbF = L shift ODC

Clinical Features

Minor: usually asymptomatic – mild hypochromic, microcytic anaemia

Major:  markedly reduced b chain production.  Failure to thrive, anaemia, jaundice, hepatosplenomegaly, anaemia and regular blood transfusions leading to iron overload

Abnormal Globin Chain

α Thalassaemia

Pathology

Abnormal/absent α chain

Consequences

Four genes code α chain production

Deletion of all four α chain genes = incompatible w life

Three chain deletion = moderate anaemia but not transfusion dependant

Two chain deletion = mild anaemia, usually asymptomatic

Clinical Features

Abnormal Globin Chain

Aquired Haemaglobinopathies

Pathology

Consequences

Clinical Features

Abnormal Globin Chain

MetHb

Pathology

Iron atom is oxidised from

Fe2+ → Fe3+

Forming MetHb

MetHb cannot bind O2

Oxidation of ONE HEME in the tetramer increases the affinity of the other hemes so L ODC shift occurs and they do not give up their O2 readily

Consequences

MetHb forms one of 3 ways:

  1. Auto-oxidation whereby O2 binds Fe2+ there is partial electron transfer to produce superoxoferrihaem (Fe3+O2)

Unloading usually restores Fe2+ ferrous form

Sometimes O2 leaves a superoxide radical (O2) retaining the electron leaves iron in Fe3+ ferric state

This requires NADH & Cytb5 (which exist in mitochondria which RBC don’t have)

  1. Drugs

Nitrites, prilocaine

  1. Congenital

Deficiency of MetHb reductase in RBC

Clinical Features

Spontaneously formed MetHb is reduced by NADH-Methaemaglobin reductase system present in RBC

NADH generated by glycolysis reduces Hb

Allows steady state of <1% MetHb (normal levels)

Another enzyme system NADPH-dehydrogenase in RBC can reduce MetHb using NADPH generated from pentose phosphate pathway

But this is the ‘reserve’ metHb reductase and almost has no effect → but it can reduce methylene blue, the reduced form of which then non-enzymatically reduces MetHb

Abnormal Globin Chain

CarboxyHb

Pathology

CO bind Hb → Carboxyhaemoglobin

Consequences

Reduces O2 availability to tissue by:

  1. Decreasing the O2 carrying capacity of blood

CO has x240 more affinity for Hb than O2

So small amounts of CO can occupy a large portion of Hb and make O2 unavailable for carriage

  1. Increasing the affinity of Hb for O2

Binding CO causes conformational change in Hb structure

Remaining O2 bound to Hb has very high affinity and less likely to offload = L ODC Shift

So an anaemic patient who has 50% normal HbO2 is still better off than a patient that has normal Hb 50% and COHb 50% bc even though they have the same [HbO2] the COHb patient is less likely to release O2 to the tissues

Clinical Features

Death if COHb >70%

= PaCO 0.7mmHg

This is no alteration of RR with CO bc PaO2 & PaCO2 is normal