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Red Cell Components

The transfusion of red cells has the ability to save lives and markedly improve survival rates and morbidity in patients being treated for a wide range of medical and surgical conditions. A review of patients who declined blood transfusion showed an increasing morbidity and mortality in proportion to reducing haemoglobin level below 8g/dl. Therefore, for each patient, depending on co-morbidities, a transfusion threshold for red cell transfusion should be determined.

The transfusion of blood should be managed in such a way that the most favourable outcome for the patient is achieved, using the optimal (minimal) amount of allogeneic red cells. Clinicians should focus on guideline-driven, appropriate use of banked blood, utilize pharmaceutical preparations that prevent, minimize, or control blood loss (particularly in the surgical setting), and employ other blood conservation methods whenever appropriate.

1. Indications for Red Cell Components

The primary indication for red blood cell (RBC) transfusion is the restoration of oxygen-carrying capacity. Whole blood or red cell concentrates are used to improve tissue oxygenation when this is impaired by haemorrhage or anaemia.

a. Acute blood loss
An acute blood loss of greater than 20% of blood volume (about 1000-1200ml of blood in an adult) will often result in the need for a red cell transfusion. There must be no delay in ordering blood in situations where blood loss is acute and rapid or where there is a possibility of recurrence or continuation of bleeding. Crystalloid solutions should be used initially in volume resuscitation.

b. General surgery
Consider transfusion if:

• The pre-operative haemoglobin level is less than 8g/dl and the surgery is associated with major blood loss (>500ml).
• The intra- or post-operative haemoglobin falls below 7g/dl. A higher haemoglobin level may be indicated in patients who are at risk for myocardial ischaemia or who are >60 years of age.

Pre-operative anaemia must be investigated in every case, as medical management to raise the haemoglobin level may be more appropriate than transfusion.

In surgical patients, the effect of plasma and blood volume expansion should be taken into account when determining the red cell transfusion threshold based on haemoglobin concentration only, and the limitations of the haematocrit level should be taken into account when assessing the need for red cell transfusion in hypovolaemic anaemic patients. In situations of massive transfusion, the number of red cell units transfused can be used as a surrogate for determining the transfusion requirements of fresh frozen plasma (FFP), platelet concentrate and cryoprecipitate.

c. Anaemia in Acute Coronary Syndromes (ACS)
In patients with ACS there is evidence that a haemoglobin level below 8g/dl may be deleterious. Transfusion to a haemoglobin level of 10g/dl is considered acceptable but the effect of each unit transfused must be evaluated for the risk of heart failure due to fluid overload.

d. Anaemia
The aetiology of anaemia should be investigated and, as far as possible, a definitive diagnosis should be made in every case. Medical management will be determined by the cause of the anaemia. Appropriate alternatives to blood transfusion must be considered. Consider transfusion in normovolaemic patients only if they are severely symptomatic e.g. shortness of breath at rest, angina, incipient cardiac failure.

Patients with a haemoglobin level below 7g/dl often require a transfusion. The target (post-transfusion) haemoglobin level will be determined by many factors, including the primary diagnosis. The target haemoglobin will be higher in individuals who require chronic red cell transfusions (such as patients with thalassaemia). In general, the target haemoglobin level will be higher in patients with a "medical" anaemia as apposed to patients with a "surgical" anaemia with blood loss. In the latter, the bone marrow is usually normal; whereas in the former, the bone marrow and other organs may be impaired. The patient's clinical condition should be reassessed after each unit transfused and the need to continue transfusion therapy should be evaluated. In many cases, transfusion can be stopped when a haemoglobin level is reached where the patient is asymptomatic.

e. Cardiac Surgery
Pre-operative clinical variables have been identified that independently predict the likelihood of exposure to blood transfusion of patients undergoing cardiac surgery. These variables include: pre-operative haemoglobin, weight, female gender, age, non-elective procedure, pre-operative creatinine, previous cardiac surgical procedure, and non-isolated procedure (e.g. CABG and valve repair). They constitute the clinical predictive index (TRUST). Making use of this scoring tool enables clinicians to stratify patients according to their likelihood of exposure to blood transfusion. It provides patients with important information about their transfusion-related needs, helps the medical team anticipate the patient’s transfusion needs, transfusion needs, and guides the clinician in the ordering of additional tests.

f. Obstetric haemorrhage
During an obstetric haemorrhage, red cells should be administered to maintain the patient free of signs and symptoms of inadequate tissue oxygen delivery. The haemoglobin should be maintained between 6 and 10g/dl during the resuscitation phase.

2. Red Cell Compatibility

Red cell transfusions must be ABO compatible. As far as possible, red cell transfusions should also be Rh-D compatible although, in an emergency, in situations of massive blood transfusion, or when there is a shortage of Rh-D negative blood, Rh-D positive blood may be transfused to Rh-D negative patients provided that the patient does not have preformed anti-Rh-D antibodies. Rh-D positive blood should also be avoided in females of childbearing age who are Rh-D negative. Antigen negative blood should always be transfused to patients with specific and clinically significant red cell antibodies. As far as possible, compatibility tests (a 'crossmatch') should be performed prior to transfusion of red cells.

3. Storage of red cells

Red cell products are preserved and stored at between 1° and 6 °C for up to 42 days. During the storage of banked blood, changes occur which may be clinically significant. The characteristics of stored blood should be taken into account when transfusing red cell products and the following are some of the impacting factors.

a. Anticoagulant
Donated blood is collected into a solution containing sodium citrate. Citrate is a stable, minimally toxic anticoagulant with pH buffering properties. Citrate is metabolized in the Krebs cycle of respiration and, after transfusion, is rapidly metabolized by most cells in the body, particularly in the liver, muscle and renal cortex. However, certain clinical conditions such as liver disease, hypothermia and hyperparathyroidism may place patients at risk for 'citrate toxicity' during rapid transfusion of whole blood or fresh frozen plasma. Newborns without adequate calcium stores, and with immature livers, are also at risk. In these circumstances, citrate has been considered to be the cause of cardiac arrhythmias due to its ability to decrease plasma ionized calcium through chelation. The flow rate of citrate determines the degree of toxicity. A rate corresponding to 0.04mmol/kg/min. is associated with a significantly increased plasma citrate level and a prolonged QT interval. This situation may arise in massive, rapid transfusion of whole blood especially and, to a lesser extent, red cell concentrates. If possible the ionized calcium levels should be monitored and 10ml of 10% calcium gluconate administered intravenously ( a rule of thumb is 10 ml for every 2 units whole blood given in under 10 minutes). Calcium and any other drug or solution should never be directly added to blood components.

b. 2,3 Diphosphoglycerate (2,3 DPG).
The concentration of erythrocyte 2,3 DPG decreases with storage. The function of 2,3 DPG is to facilitate oxygen transport. The binding of 2,3 DPG with deoxyhaemoglobin, and its interaction with oxyhaemoglobin, shifts the oxygen¬dissociation curve to the right, decreasing oxygen affinity of haemoglobin and enhancing oxygen delivery to tissues. With significantly decreased 2,3 DPG levels, as occurs in stored blood after approximately one week of storage, the oxygen¬dissociation curve is shifted to the left, decreasing oxygen delivery to tissues.

After transfusion, levels of 2,3 DPG are, however, regenerated in-vivo, with approximately 50% being regenerated within 7 hours, although full restoration of RBC 2,3 DPG can take up to 72 hours. In clinical situations of hypoxia and lactic acid production, and with decreasing pH, the oxygen dissociation curve is also shifted to the right, increasing oxygen delivery. Increased oxygen delivery also occurs with an increase in cardiac output. It is therefore generally considered that low 2,3 DPG levels in stored blood are not usually clinically significant. For example, fresh blood and aged stored blood have been shown to be equally efficacious in immediately reversing anaemia-induced brain oxygenation deficits in humans and lower 2,3 DPG red cell concentrations during the first 24 hours of intensive care are not associated with higher ICU mortality.

However, in certain clinical situations, such as in those patients in shock who cannot increase cardiac output to compensate, patients receiving large volumes of stored blood such as occurs in massive transfusion, or in patients undergoing red cell exchange procedures, transfusion of blood which has been stored for less than 5 days may be optimal.

c. Preservative solutions
Red cell concentrates (RCC's) are prepared by the removal of most of the plasma, and the removal of the buffy layer(which is rich in leucocytes and platelets), from a unit of whole blood. A preservative solution (111 ml volume) is added to the residual red cells. It contains adenine which helps maintain ATP levels during storage; glucose, which provides a substrate for RBC energy pathways plus saline and mannitol which reduces the haemolysis of the banked red cells during the 42 day storage period. Separating off the buffy layer results in the removal of approximately 70-80% of leukocytes present in the original whole blood donation and significantly decreases the occurrence of non-haemolytic febrile transfusion reactions. The volume of a unit of red cell concentrate is approximately 300¬-350ml (including the adenine additive solution) and the haematocrit is between 0.55 and 0.70. One unit of red cell concentrate (at a dose of 4ml/kg) can be expected to increase the haemoglobin level of an average (70kg) adult by approximately 1-2g/dl. Stored red cells experience loss of deformability and, on day 42 of storage, about 75% of red cells are viable.

Hyperglycemia has been observed in certain clinical situations such as massive transfusion in orthotopic liver transplantation, or following cardiac surgery in infants, and has been attributed to the high glucose concentration in red cell concentrates stored in adenine additive solutions.

d. Electrolyte changes
Red cell concentrates must be stored between 1^o and 6 ^oC. At these temperatures, the sodium-potassium pump is essentially non-functional and intracellular and extracellular levels gradually equilibrate. Plasma potassium concentration increases nearly eightfold over 28 days of storage although, at expiry, the total potassium load in red cell concentrates is only about 5.5mEq. Therefore, the potassium load is rarely a clinical problem except in the setting of pre-existing hyperkalaemia. In these situations fresh (<5 days) or washed red cell concentrates should be used.

e. Plasticizer
The plasticizer di (2-ethylhexyl) phthalate (DEHP) has been shown to leach from the plastic container into stored blood and, as storage time increases, the amount of DEHP detectable ranges from 6.8 to 36.5 µg/ml in red cell concentrates. The potential toxicity of transfused DEHP remains under investigation, but to date no studies have emerged indicating clinically significant effects.

4. Leucocyte, depleted red cells

For characteristics and indications see guidelines for leucocyte depletion by clicking here.

5. Washed red cells

Washed red cells are prepared by the removal of plasma, and the buffer layer, from whole blood donations. The residual red cells are suspended in isotonic saline and centrifuged; the saline from the first saline 'wash' is then removed, and the red cells re-suspended in isotonic saline. Because washed cells are manipulated in an open system, with a possibility of bacterial contamination, they must be transfused within 24 hours of preparation.

a. Indications for washed red cells

• Patients who have experienced severe, recurrent, allergic transfusion reactions not prevented by antihistamines.
• Patients with known IgA deficiency who have formed anti-IgA antibodies. Patients with IgA deficiency may experience an anaphylactic reaction if transfused with blood products containing plasma (even minute amounts of plasma containing IgA protein).
• Patients with paroxysmal nocturnal haemoglobinuria (PNH). Traditionally, washed cells have been recommended for red cell transfusions in these patients. However, recent evidence suggests that transfusing washed cells in patients with a diagnosis of PNH is not necessary. Washing of red cells is therefore no longer recommended provided that donor red cells of the same A80 group as the patient are transfused.
• Neonates with T-activated red cells. Immune-mediated haemolysis may occur following transfusion of plasma-containing blood components to patients whose red cell T-crypt antigens have been exposed by bacterial infection. T-activation occurs when bacterial neuraminidase removes N-acetyl neuraminic acid and exposes red cell T-crypt antigens. These antigens are then susceptible to IgM anti-T which is prevalent in normal plasma, leading sometimes to severe haemolysis. This is particularly associated with necrotizing enterocolitis. However there is so little plasma in red cell concentrates that it is probably unnecessary to provide washed red cells as a routine to all patients with evidence of T-activation of red cells.
• Stored red cells which have been gamma irradiated. Plasma potassium concentrations increase significantly after 12 hours following a gamma irradiation dose of 25Gy. In patients where a high potassium concentration in transfused blood may be clinically significant, red cells which have been gamma irradiated can be washed shortly before transfusion. However, in practice, this can best be managed by ensuring that irradiated whole blood is transfused within 24 hours of irradiation.

In general, blood should not be warmed when individual units are being transfused slowly (over a period of 2-4 hours per unit). Blood should be warmed to between 35 ^o and 37 ^oC when large volumes of blood are being transfused rapidly.

Transfusing ice cold blood rapidly has been associated with an increased incidence of cardiac arrest. Blood should also be warmed when transfused to patients with identified, strongly reacting, cold agglutinins. The best method of warming blood is to use a heat exchanger in which coils of tubing are warmed by electric heating plates. Microwave ovens must never be used to warm blood for transfusion.

Whole blood is a complex tissue from which clinically appropriate components are processed. Many of the components, particularly platelets and clotting factors, deteriorate in whole blood within hours of donation. It is therefore necessary to physically separate the components soon after donation so that they are available for use in the appropriate clinical situation. The clinical indications for using whole blood are limited since red cell concentrates are more appropriate in most situations where 0₂-carrying capacity needs boosting.

• Exchange transfusion in neonates
• Massive haemorrhage

The replacement of the equivalent of the total blood volume in 24 hours with red blood cells and crystalloid and/or colloid solutions is defined as massive transfusion. Massive transfusion can also be defined as transfusion of 50% of total blood volume within 3 hours.

In massive transfusion, when blood loss is being replaced by red cell concentrates (packed cells), it may be necessary for red cell transfusions to be supplemented with fresh frozen plasma, cryoprecipitate and platelet concentrates. Whenever possible, the haemostatic profile of the patient should be monitored and the above components transfused only if there is a specific haemostatic defect.

Massively transfused patients manifest a profound haemostatic disorder as demonstrated by prolonged PT, APTT and thrombocytopenia less than 50x10⁹/µL, which is, in part, due to haemodilution. Increases in PT or APTT greater than 1.5 to 1.8 times control values are associated with decreases in some coagulation factors, particularly fibrinogen, FV and FVIII, and should be treated with FFP, especially if there is active bleeding.

Although FFP contains fibrinogen, the amount provided in FFP is usually insufficient to maintain adequate levels and cryoprecipitate should be given early in the course of massive haemorrhage, along with FFP. In general, FFP and cryoprecipitate should be considered when more than 50% of blood volume has been replaced, and it is mandatory when more than 120%-150% of the blood volume has been replaced with red cell concentrate, crystalloid and/or colloid. In situations of massive transfusion, replacement of RBC's, FFP and platelets in a ratio of 1:1:1 is recommended.

See guidelines for irradiated blood by clicking here.

For specifications and indications click here.

Red cell exchange may be performed on those patients with malaria who have a high parasite load, and on patients in acute sickle cell crisis. Erythrocytes infected with plasmodium falciparum have been shown to have decreased 2,3 DPG activity. Because of the large volume of red cells transfused over a short period, it is recommended that, for exchange transfusion in adults, red cells that are no older than 5 days be transfused. The procedure is best managed using apheresis technology.