Blood transfusion and haematopoietic stem cell transplantation

History of blood transfusions
1. First recroded use in 17th Century - between animals; and animals to humans
  1. Unsuccessful - as many died (rejection of transfusion)
  2. 1901: Blood groups first identified by Karl Landsteiner (A, B, AB, O system)
    1. 1940's: Rhesus groups identified
      1. Storage was a problem (due to lack of anticoagulants etc.)
        Anticoagulants and dextorse increase shelf life
        1922: First blood bank
        1946: National blood service
2. Other milestones/achievements
  1. Fractionation of blood
    1. Clotting factors
    2. Anti-D (to prevent Rhesus haemolysis in newborns)
    3. Human albumin (for restoring blood volume, without adding cells)
    4. Cell separators (1968)
      1. Freezing blood for long term storage (in glycerol)
        Autologous blood transfusion
        Removing a patient's blood prior to surgery, then using to transfuse during blood loss)
        Useful for transfusion of rare groups
Blood groups
1. 23 blood group systems
  1. e.g. ABO, Rh, Kell, MNS, Duffy
    1. Each is a series of antigens - determined by single gene locus or closely linked loci)
      1. 400 antigens to date
2. ABO system
  1. Most important grouping system
  2. RBCs can express either; A, B, no (O) or both (AB) antigens
    1. Plasma contains naturally occuring Ab's to these antigens
      1. Present without previous exposure to the blood group antigen
        Only blood grouping system to do this
        All others generate Ab's after an initial exposure
      2. These Ab's are IgM (pentamer Ig units)
        Capable of activating the MAC directly
        Others (e.g. IgG) can only activate C3/4 of the complement cascade
  3. Genotypes -> phenotypes
    1. Genotypes
      1. AA
        BB
        AB
        OO
        AO
        BO
      2. Phenotypes
        A
        B
        AB (universal recipient)
        O (Universal donor)
        A
        B
        Associated natural Ab's
        Anti-B
        Anti-A
        None
        Anti-A and Anti-B
        Anti-B
        Anti-A
  4. Ethnic differences
    1. Caucasian (44% O; 34% A; AB = rarest)
    2. Black (49% O; 19% A; 19% B; AB= rarest)
    3. Oriental (43% O; 27% A; 25% B; AB = rarest)
    4. Indian (22% O; 22% A; 40% B; 15% AB)
    5. Australian aborigne (44% O; 56% A)
3. Rh group
  1. Second most important group system
  2. Found in 83% caucasians (Rh(D)+)
  3. Highly immunogenic
    1. 1mL of RBCs will generate Ab response
      1. Following an Rh(D)+ mismatched transfusion there is 90% chance of Anti-D Ab formation
        Rh(D) not the only antigen - 45 Rh antigens known (commonest = D, C, c, E and e)
Blood groups = RBC antigens
1. Maybe expressed soley on RBCs (e.g. Rh)
2. Or shared between RBCs and tissue (e.g. MNS)
3. Some are protein alone (e.g. Rh)
4. Some are glycoproteins (e.g. ABO)
  1. Sugar moiety which determines A, B, or O group (modification determined by allele expressed)
5. Lacking an antigen may be beneficial sometimes
  1. Duffy blood group (Fy)
    1. Glycoproteins Fy(a) and Fy(b)
      1. Cell receptor acts as malarial entry receptor
    2. Duffy negative individuals are protected from malaria
6. Function of blood groups
  1. Convinient in transfusion - aids selection of appropriate blood
  2. But, they are functional proteins
    1. e.g. Band 3 protein forms; Diego and Wr
      1. Form an RBC anion channel protein (transport Cl(-) and HCO3(-)
    2. e.g. Rh proteins control RBC lipid asymmetry
Antibodies and their relevance to transfusion
1. Immunoglobins (Ig's)
  1. IgG, IgA, IgM, IgE, IgD
    1. IgM's are a large molecule (x5 Ig's together in pentamer form) - activate the complement cascade better than IgG
      1. IgG single Ig molecule - activates the complement cascade
        IgG can cross the placenta, whilst IgM cannot (IgG can cause foetal problems when raised against foetal Rh(D)
        Anti-D neutralising Ab's can be given (= Rhogam)
    2. Ab's made by B lymphocytes
      1. Alloantibodies -> Ab's against foreign molecules
        Autoantibodies -> Ab's against self molecules
        Both auto-and alloantibodies encountered in transfusion
2. Ab's against blood groups (ABO)
  1. People who are blood group A have anti-B Ab's
    1. People who are blood group B, have anti-A Ab's
      1. These Ab's are present without an initial exposure to the offending blood type
        How?
        Naturally occuring Ab's vs. immune Ab's
        Naturally occurring Ab's
        Not present at birth
        Appear by 3-6 months of life
        Where do they come from?
        Exposure to bacterial and food proteins stimulate their production
        If sterile environment -> no anti-A or anti-B Ab's produced
        Most naturally occurring Ab's are cold Ab's
        Cold Ab's
        Warm Ab's
        Immune Ab's are warm
        Produced in response to sensitisation to blood group antigen
        Work at body temperature (37*C)
        Potentially dangerous
        Subtle RBC destruction by the reticuloendothelial system (RES), spleen etc.
        Extravascular haemolysis
        E.g. Anti-D in rhesus disease (aka haemolytic disease of newborn)
        E.g. mismatched transfusion
        All IgG Ab's
        Usually IgM
        Work better at 0-4*C (many don't work at 37*C)
        Most naturally occuring Ab's are cold Ab's
        BUT.... anti-A and anti-B have a wider thermal range and are active at 37*C
        Cause (when mismated transfusion)
        Activation of the complement cascade
        RBC lysis
        Dramatic intravascular haemolysis
        Ab's that are not activated >30*C are of no clinical significance
        Immune Ab's
        Are warm Ab's
        ->
Blood collection and processing
1. UK blood source
  1. Homologous blood (from donors)
    1. Aged 17-70yrs
    2. Max = 2 donors per year
  2. Standar interview with tick box questionaire to determine fitness
    1. Ask about transfusion-transmitted diseases (HIV, HBV etc.)
  3. Copper sulfate test (drop of blood -> tests for anaemia)
2. The blood itself
  1. 450mL of whole blood collected into 63mL anticoagulant
  2. Sterile, closed system
  3. RBCs, plasma and platelets separated (by centrifugation)
  4. WBCs removed (leukodepletion)
  5. Labelled
  6. ABO and Rh groups checked
  7. Shelf-life = 5 weeks
3. Processing
  1. Whole blood
    1. Cellular components
      1. RBCs, WBCs and platelets
    2. Plasma
      1. Plamsa for clinical use
        Fresh frozen plasma
        Cryoprecipitate / cryroprecipitate depleted plasma
        Single donor plasma
      2. Fractionation for plasma products
        Clotting factors (VIII and IX)
        Ig's (specific and non-specific)
Compatability testing
1. Ag test
  1. Direct Ag test
    1. Detects Ab's bound to RBCs
      1. Wash patients RBCs (from a collection)
        Add anti-human globulin (Ab against human Ab)
        Watch for agglutination (Anti-human Ab binds to Ab's on RBCs and causes aggregation)
        Positive in: Haemolytic disease of the newborn; autoimmune haemolytic anaemia and haemolytic transfusion reaction
  2. Indirect Ag test
    1. Detects Ab's in patients serum
      1. Test (control) RBCs are incubated in patient's serum
        Anti-human globulin added
        Watch for agglutination of test cells
        Detects anti-RBC Ag's in patient's serum
        Positive in: alloantibodies in patient's serum
        Important because it excludes incompatibility

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Blood transfusion and haematopoietic stem cell transplantation

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