Understanding the adverse consequences of blood transfusion, including that of massive blood transfusion

Production and Storage of Blood Products

Red cells, platelets, and FFP have different storage requirements.

Red Blood Cells

  • Stored blood decays over time - this is known as a storage lesion
    Preservatives are used to extend the time blood can be stored:
    • Kept at ~4°C (balance between freezing and being too warm)
      • Reduces cellular metabolic requirement
      • Inhibits bacterial growth
    • Collected in an aseptic fashion
    • Stored in special solutions:
      • SAGM is currently used by the Australian Red Cross:
        • Saline
        • Adenine
          Substrate for ATP synthesis
        • Glucose
          Substrate for RBC glycolysis
        • Mannitol
      • CPDA1 (citrate-phosphate-dextrose-adenine) was traditionally used
        • Citrate binds calcium, preventing clotting
        • Phosphate acts as a buffer and phosphate source for metabolism
        • Dextrose
        • Adenine
  • A storage lesion describes the changes that occur in stored blood:
    • Loss of 2,3 DPG
      Less of a factor in CPDA1 blood.
    • Haemolysis
    • Hyperkalaemia
      Typically not clinically relevant as potassium is taken up into red cells when metabolism resumes.
    • Acidaemia
    • Hyponatraemia
      Not clinically significant.
  • Blood can be stored for up to 35 days, which corresponds to 70% survival


Platelets require particular storage conditions to remain functional:

  • Temperature ~22°C
    Below this, platelets deform and become non-functional
  • Gas exchange
    Platelets are stored in a bag which allows gas exchange to occur, minimising lactic acid and carbon dioxide production
  • Agitation
    Platelets are stored on an agitator which prevents clotting and ensures the platelets are well mixed, which maximises the diffusion gradient for gas exchange
  • pH control
    pH is kept between 6.2 to 7.8 to prevent degranulation.

As platelets do not contain antigen, there is not a strict requirement for platelets to be type matched. However:

  • Rh(+) platelets should be avoided in Rh(-) patients
    The small amount of contaminating red cells may precipitate rhesus disease.
  • Plasma incompatibility should be avoided as this may lead to haemolysis of recipient red cells
    • Children are at greater risk due to their proportionally smaller blood volume

Fresh Frozen Plasma

Fresh Frozen Plasma is:

  • Prepared either via:
    • Separation from whole blood
    • Apheresis
      Removal of a large volume (typically 800ml) of plasma from a single patient, with return of red cells to the donor.
  • Once collected, it is frozen and re-thawed in a water bath prior to use


Cryoprecipitate is prepared by removing the precipitate from FFP which forms at 1–6°C. Cryoprecipitate contains predominantly:

  • Fibrinogen
  • Fibronectin
  • vWF
  • Factor VIII
  • Factor XIII

Whole Blood

Whole blood undergoes additional changes:

  • White cells become nonfunctional within 4-6 hours of collection, though antigenic properties remain
  • Platelets become non-functional within 48 hours of storage at 4°C
  • Factor levels decrease significantly after 21 days

Blood Groups

Blood groups refer to the expression of surface antigens by red blood cells, as well as any antibody in plasma. Blood groups can be divided into three types:

  • ABO
  • Rhesus
  • Other antibodies These are additional antibodies that a patient may express in plasma, and include Kell, Lewis, Duffy, etc.


The ABO blood group is:

  • A complex carbohydrate-based antigens series
    These may be either A or B antigen, and patients may express one, both, or neither, giving four blood groups (A, B, AB, O).
  • Expressed on the H-antigen stem of RBCs, and on the surface of tissue cells.
    • The Bombay Blood Group (or hh or Oh group) describes individuals who do not express the H antigen
      These individuals:
      • Don't express A- or B-antigen (as there is no H-antigen stem) and are 'universal donors'
      • Express H-antibody
        Can only receive blood from other individuals with the Bombay phenotype
  • Individuals express IgM antibody to foreign blood groups
    This develops within 6 months of birth, likely due to environmental exposure to similar antigens.
  • Associated with a severe hypersensitivity reaction if an ABO-mismatch occurs
Group RBC Plasma
A A-antigen B-antibody
B B-antigen A-antibody
O - A-antibody
AB A-antigen


The Rhesus blood group is the next most important group after ABO. The Rhesus system:

  • Consists of ~50 different antigens, the most important of which is D
    Rhesus status is therefore expressed as positive (D - 85% of the population) or negative (anything-but-D).
  • Rhesus antibody does not naturally occur in Rh(-) individuals
    • This is relevant in Rhesus disease
      A Rh(-) mother exposed to Rh(+) blood will develop Anti-D antibody, which can cross placenta and induce abortion in a future Rh(+) foetus. This can occur with:
      • Incompatible transfusion
      • Foetal-maternal haemorrhage

Compatibility Testing

Donor blood must be tested with recipient blood to avoid a transfusion reaction. This involves three steps:

  • Blood Typing (ABO/Rh)
    • Patient's blood is mixed with samples of plasma known to contain Anti-A, Anti-B, or Anti-AB antibodies.
    • Agglutination occurs when antibodies in the plasma react with the antigen on the RBC surface, and indicates a mismatch
  • Antibody Screen
    For minor (non-ABO/Rh) group antibodies.
    • Testing is similar to ABO screening, but now patient plasma is mixed with several samples of red cells which contain a known non-ABO/Rh antigen (e.g. Kell, Duffy), and monitored for agglutination
  • Cross-match
    Two methods:
    • Electronic cross-match
      Used if the antibody screen is negative and the patient has had no previous blood transfusion, as it is quicker and cheaper.
    • Serological cross match
      Indicated if the antibody screen is positive, or the patient has had previous exposure to blood (prior transfusion, pregnancy), as this gives the patient a risk of exposure to non-ABO or Rh antigens.
      • Performed by mixing patient plasma with a small sample of donor RBC and monitoring for agglutination If there is no agglutination, the transfusion can proceed with the tested specimen only.

Indirect Coomb's Test

Method of cross-matching that is now deprecated as it provides negligible additional safety over the above processes. Testing identifies IgG antibody in host plasma which would haemolyse transfused red cells, and involves:

  • Incubating
    Binds IgG Ab to antigen on RBC membrane.
  • Washing
    Removes serum and unbound IgG.
  • Testing with an antibody to IgG, known as antiglobulin serum.
    • A positive test will cause clumping of red cells, as each antiglobulin serum will bind two IgG molecules, which have in turn been bound to red cells
    • A negative test will cause no agglutination, as the IgG has not been bound to red cells
    • If negative, the antiglobulin serum is re-used on a control sample to ensure that it is not a false negative

Transfusion Reactions

An adverse event associated with the transfusion of whole blood or one of its components. Can be classified as either acute (< 24 hours) or delayed (> 24 hours), and as immunological or non-immunological.

Immunological Acute Reactions

Reaction Incidence Mechanism
ABO Mismatch 1:40,000 ABO incompatibility causing rapid intravascular haemolysis, which may cause chest pain, jaundice, shock, and DIC. RhD-reactions tend to cause extravascular haemolysis.
Haemolytic (acute) 1:76,000 (1:1.8 million fatal) Immunological destruction of transfused cells (Type II hypersensitivity). Presents with fever, tachycardia, pain, progressing to distributive shock
Febrile, non-haemolytic ~1:100 Cytokine release from stored cells causing a mild inflammatory reaction, with temperature rising to ≥38ºC or ≥1ºC above baseline (if >37ºC). Benign - but requires exclusion of a haemolytic reaction.
Urticaria 1:100 Hypersensitivity to plasma proteins in the transfused unit
Anaphylaxis 1:20,000 Type I hypersensitivity reaction to plasma protein in transfused unit
TRALI Variable Donor plasma HLA activates recipient pulmonary neutrophils, causing fever, shock, and non-cardiogenic pulmonary oedema

Non-Immunological Acute Reactions

Reaction Incidence Mechanism
Massive Transfusion Complications Variable See below
Non-immune mediated haemolysis Rare Due to physicochemical damage to RBCs (freezing, device malfunction). May lead to haemoglobinuria, haemoglobinaemia, tachycardia and fevers.
Sepsis 1:75,000 (platelets), 1:500,000 (RBC) Contamination during collection or processing. Most common organisms are those which use iron as a nutrient and reproduce at low temperatures, e.g. Yersinia Pestis.
Transfusion Related Circulatory Overload (TACO) < 1:100 Rapid increase in intravascular volume in patients with poor circulatory compliance or chronic anaemia. May result in pulmonary oedema and be confused with TRALI.

Delayed Immunological Reaction

Reaction Incidence Mechanism
Delayed haemolytic transfusion reaction 1:2,500 Development of sensitisation with the reaction occurring 2-14 days after a single exposure. Typically Kidd, Duffy, Kell antibodies.
Post-transfusion Purpura Rare Alloimmunisation to Human Platelet Antigen causing sudden self-limiting thrombocytopenia
TA-GVHD Rare Transfused lymphocytes recognise host HLA as positive causing marrow aplasia, with mortality >90%
Alloimmunisation 1:100 (RBC antigens), 1:10 (HLA antigens) Previous sensitisation leading to antibody production on re-exposure.
Transfusion-related Immune Modulation Not known Transient immunosuppression following transfusion potentially due to cytokine release from leukocytes

Delayed Non-Immunological Reaction

Reaction Incidence Mechanism
Iron Overload Chelation after 10-20 units, organ dysfunction 50-100 units Each unit of PRBC contains ~250mg of iron, whilst average excretion is

Complications of Massive Transfusion

A massive transfusion is one where:

  • Greater than one-half of circulating volume in 4 hours
  • Whole circulating volume in 24 hours

Risk of complication from a massive transfusion is influenced by:

  • Number of units
  • Rate of transfusion
  • Patient factors
Complication Mechanism
Air embolism Inadvertent infusion
Hypothermia Cooled products
Hypocalcaemia Consumption with coagulopathy and bound to citrate added to transfused units
Hypomagnesaemia Bound to citrate in transfused units
Citrate toxicity Citrate is added to stored units as an anticoagulant
Lactic acidosis Hyperlactataemia due to anaerobic metabolism in stored units
Hyperkalaemia Potassium migrates from stored erythrocytes into plasma whilst in storage


  1. Blood Service. Classification & Incidence of Adverse Events. Australian Red Cross.
  2. National Blood Authority. Patient Blood Management Guidelines. Australian Red Cross.
  3. Chambers D, Huang C, Matthews G. Basic Physiology for Anaesthetists. Cambridge University Press. 2015.
Last updated 2021-07-14

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