Blood transfusion in children with haematological / oncological disease and following haemopoietic stem cell transplant

2. 1 The procedure and guidance for transfusion of all blood components is available within the GG&C Clinical Transfusion Policy and Special Requirement Guideline for Blood Products. [Staffnet link]

2.2 Information for Clinicians involved in Prescribing Granulocytes (RHC-HSCT-FORM-0033)

All staff involved in any part of the transfusion process must have undertaken and successfully completed the e-learning “Safe Transfusion Practice - Paediatrics” training within a two year period. (Via LearnPro)

It is the responsibility of the practitioner ordering the blood or blood product to be familiar with the specific requirements for any individual patient and to make sure that the blood or blood product ordered meets these requirements.

4.1 As indicated in the Greater Glasgow & Clyde Blood Transfusion Special Requirements Guidelines [Staffnet link].

4.2 BLOOD WARMERS

Occasional patients require blood to be warmed before infusion. This is most commonly required in large volume rapid transfusions (greater than 50 mL/kg/hr for adults or 15 mL/kg/hr for children - ie: major haemorrhage protocols -, in exchange transfusion in infants and for patients with a cold antibody). This will be indicated on the comments section of the transfusion compatibility report form and must be noted on the prescription form.

Blood should only be warmed using a commercial blood warmer according to the manufacturer’s guidelines. Blood must not be warmed in any other way, for example a water bath or on a radiator etc.

5.1.1  Blood Group:

Haemopoietic Stem Cell Transplant (HSCT) Patients

Recipients of haemopoietic stem cell transplants may be of a different blood group to their donor and this can lead to an ABO major or minor mismatch. The patient’s transplant schedule will clearly state the blood group(s) of red cells, platelets and Octaplas (fresh frozen plasma) that should be transfused. The transplant schedule should always be checked and the instructions followed. See also section 5.4 below.

Haemoglobinopathy and Bone Marrow Failure Syndrome Patients

These patients may be regularly transfused throughout life and, because of this, are extensively red cell phenotyped to minimise the risk of allo-immunisation. Their red cell phenotype should be documented in their casenotes. The Blood Bank will require advanced warning to provide appropriate blood.

5.1.2  Irradiated Blood and Blood Products:

Please see the GG&C Blood Transfusion Special Requirements Guideline [Staffnet link] for further information and the notification form [Staffnet link], which must be completed for every patient with special transfusion requirements.

All blood is now leucodepleted by the Scottish National Blood Transfusion Service (SNBTS) immediately after donation to prevent the transmission of variant CJD. However, even the very small number of white cells that remain after leucodepletion can engraft in severely immunocompromised recipients and cause Transfusion Associated Graft Versus Host Disease (TA-GVHD), which is usually fatal. 

In normal immunocompetent recipients these white cells are cleared by the immune system and cause no clinical problems.

Irradiation of blood and blood products prevents the proliferation of transfused white cells in the recipient and is completely effective in preventing TA-GVHD. Irradiated blood must also be available for the donor during the stem cell collection procedure, in the unlikely event that this is required.

Table 1 below lists the patient categories that require irradiated blood products and these include:

• All transplant patients (allogeneic and autologous), all patients receiving purine analogues (including fludarabine and clofarabine) containing regimens, all patients with Hodgkin’s disease, all patients with or suspected of having congenital immunodeficiency and all patients with Di George syndrome or those undergoing cardiac surgery who may have Di George syndrome
• All platelet and granulocyte transfusions are routinely irradiated by the SNBTS.
• All cellular blood products donated by relatives
• All patients with congenital immunodeficiencies
• Blood components that do NOT require irradiation: fresh frozen plasma (Octaplas), cryoprecipitate or fractionated plasma (BSH Guidelines, 2020).

Table 1: Duration of provision of irradiated products

* Immune reconstitution may be greatly delayed following allogeneic HSCT and it is difficult to be sure when it has taken place, particularly if HSCT is from an unrelated or haplo-identical donor, and therefore cellular blood products are usually irradiated life-long after allo-HSCT.

5.1.3  CMV Negative Blood and Blood Products:

Leucodepletion significantly reduces the risk of transfusion related CMV transmission and therefore the majority of HSCT patients do not need CMV screened blood products. Appendix 1 lists the current recommendations for the transfusion of CMV negative and irradiated blood and blood products in the GG&C Special requirements guideline.

5.1.4  Hepatitis E (HEV) Seronegative Components:

In 2017 SNBTS commenced universal screening of blood products as HEV, as transmission of HEV can occur from blood transfusion, particularly in immunocompromised individuals. All platelet components and red cell components are now HEV negative. Frozen components (Octaplas (fresh frozen plasma) and cryoprecipitate) have a longer shelf life, though SNBTS indicate that all products requested are now HEV negative. As a consequence of this change the list of requirements for HEV selected components is less relevant, though is included in Appendix 1.

5.2.1  Anaemia – Red Cells:

When ordering red cells from Blood Bank, order in mls and not units.

The transfusion threshold for red cell transfusion in patients receiving chemotherapy or post HSCT is Hb <80g/l g/l except in patients receiving radiotherapy or patients who are oxygen dependent.  The transfusion trigger for these patients should be <100 g/l.

The haemoglobin should be kept between 130-150g/l in patients undergoing HSCT for thalassaemia major, throughout conditioning and until engraftment.

Other patients with non-malignant haematological conditions such as sickle cell anaemia may tolerate a lower haemoglobin. Transfusion thresholds should be determined on a case by case basis in discussion with the patient’s Consultant where appropriate.

• 10ml/kg
• Blood should be prescribed in mls and not in units and with a specified rate.
• If irradiated blood products are required this should be clearly marked on the prescription chart.
• Patients should not be routinely transfused after 8pm except in exceptional circumstances. Patients with a haemoglobin level below the transfusion threshold who are asymptomatic should be transfused the following day.

5.2.2  Thrombocytopenia – Platelets:

Transfusion threshold for platelet transfusion in children with thrombocytopenia due to reduced production:

• In stable afebrile thrombocytopenic patients spontaneous bleeding from mucous membranes (eg into gut, skin, renal tract, brain) may occur when the platelet count falls below 10 x10 ⁹/L.
• If the platelet count is greater than 10 x 10⁹/L then the decision to transfuse should be based on the clinical situation. Active bleeding (eg rapidly appearing multiple petechiae, epistaxis, macroscopic haematuria, GI bleeding), or possible bleeding (eg severe headache, seizure activity, retinal haemorrhage, evolving focal neurology) are indications for platelet transfusion in thrombocytopenic children.

Note:  Platelet transfusion is often ineffective in children with immune destruction of platelets such as ITP (although they can still be used in selected cases with significant bleeding), and may worsen thrombotic microangiopathic conditions such as HUS/TTP.  In these patients platelets should generally be avoided and other treatment modalities considered.  If in doubt discuss with the consultant haematologist on-call

Volume of Platelets to be Transfused

• Children <15 kg – 15 mls/kg
• Children >15 kg - 1 Apheresis Unit 

ABO and Rh(D) compatibility

• Platelets should be ABO and Rh(D) compatible wherever possible.
• ABO incompatibility may reduce the expected count increment by 10-30%.

Rh(D) positive platelets SHOULD NOT be transfused to Rh(D) negative females of child bearing age, which includes all female children, except in an emergency situation or where this cannot be avoided. If Rh(D) positive platelets are given to a Rh(D) negative female patient, consideration may be given to the administration of 250 IU polyclonal anti-D immunuglobulin.

Refractoriness to platelet transfusion is defined as a failure to obtain a significant elevation of platelet count (increment < 5 x 10^9/L) from a sample taken between 10min and 1 hour after transfusion of a therapeutic dose (BSH guidelines, 2017).

Ordering Platelets

• A clinical alert stating the patient’s special requirement should be placed on Trakcare.
• If a patient requires a platelet transfusion the clinician should check with Blood Bank whether or not there are platelets in stock.
• The Blood Bank will normally be responsible for ordering platelets from SNBTS. The exception is for patients requiring HLA matched platelets, which requires a doctor to discuss and request these from SNBTS (tel: 0131-242-7528 / 7512). The ordering clinician will be asked to provide the patient’s name, blood group and Rhesus status, and any special requirements (eg irradiated). A Trakcare request is required for all blood products, including platelets. Currently, every platelet request made on Trakcare is automatically printed in the Blood Bank; once requested, the ordering clinician should call the Blood Bank to confirm that they have the request in the Laboratory and to discuss any further issues that may arise. Platelets are delivered in the morning and at 13:30hrs in the afternoon therefore platelets should be ordered no later than 13:00hrs.
• If it can be anticipated that a patient will require platelets (e.g. platelets prior to surgery the following day) these should be ordered so that they are available at the time of surgery. It is important to tell SNBTS when the platelets will be transfused to avoid a unit being dispatched that will expire before use.
• Ideally the platelet requirements for all of the patients on the ward should be ordered from Blood Bank as soon as the ward blood counts are available. It is useful to check with the other team before ordering platelets to prevent numerous calls and platelet deliveries. Taxi costs are routinely monitored.

5.2.3  Abnormal Coagulation – Octaplas(fresh frozen plasma) :

• Octaplas(fresh frozen plasma) should not be used indiscriminately. It should only be used to correct an abnormal coagulation screen and not used for volume replacement.
• Children under the age of 16 yrs should receive Octaplas.
• Volume of Octaplas to be transfused: 10-15 mls/kg.

5.2.4  Low Fibrinogen – Cryoprecipitate:

• Cryoprecipitate may be used to correct a low fibrinogen.
• Children under the age of 16 yrs should receive viral – inactivated methylene blue cryoprecipitate.  This is supplied as single units or pools.  Each single unit has a volume of approximately 40mls.  Each pool consists of 6 donor units (therefore approximate volume 230-280mls).
• Usual dose is 5-10mls/kg using single units or pools. However, 1-2 pools may be used for larger children depending on weight (maximum volume 2 pools).
• Transfusion rate 10-20ml/kg/hr

5.2.5  Albumin:

• 4% albumin contains 4g of albumin in 100ml.
• 20% albumin contains 20g of albumin in 100 ml.
• While a typical albumin infusion is 2-5ml/kg of 20% albumin, the following formula can provide a precise volume of albumin to infuse

Example:

25 kg patient with an albumin of 15g/L with a desired albumin of 20g/L

See page 24-26 of the GG&C clinical transfusion policy [Staffnet link].

Management of a Suspected Severe Haemolytic Transfusion Reaction:

1. Stop the transfusion
2. Resuscitate the patient
3. Investigate the cause of the reaction.

• Check patient and blood product identity is correct
• Inspect the bag for any signs of discolouration, which might suggest bacterial contamination.
• Inform laboratory, who will repeat the blood group and cross match on pre-transfusion sample.
• Send samples from patient and blood product for investigation of suspected antibody.
• Send blood cultures from both patient and blood product.
• Check the patients FBC count, coagulation screen with D-dimers, direct antiglobulin test, U&E and creatinine, bilirubin and free haemoglobin immediately and after an interval of several hours.
• Repeat at 24 hours or sooner if reaction is severe.
• At 1 week, perform screen for red or white cell antibodies.

4. Notify Consultant Haematologist and refer to GG&C Blood Transfusion Reaction information on Staffnet for reporting requirements.

The following investigations must be performed on all HSCT recipients and related donors who are children:

• Blood group and Rhesus status, direct antiglobulin test (DAGT) and irregular antibodies.
• ABO isoagglutinins, if appropriate
• Red-cell phenotype for patients undergoing HSCT for a haemoglobinopathy.
• Consider checking HLA antibodies in heavily pre-transfused, or platelet refractory patients.

For adult related or unrelated donors, the information on ABO and Rh(D) status will be provided in writing from the agency carrying out the pre-transplant donor assessment.

Stem cells do not express ABO antigens and therefore HSCT is possible across ABO barriers. ABO incompatibility is conventionally divided into major and minor. ABO incompatibility is associated with an increased risk of haemolysis, delayed red cell engraftment, pure red cell aplasia and increased transfusion requirements.

5.5.1 Major ABO incompatibility (i.e. recipient has antibodies to donor cells, e.g. A group donor and O group recipient)

• A major ABO incompatible HSCT may require depletion of the red cells from the infused graft, dependent on the anti-A or anti-B titre of the recipient. In case of major ABO mismatch and a recipient anti-donor isoagglutinin titre ≥1:32, the red cell contamination in PBSC grafts should be kept <20mL and RBC depletion of BM grafts must be done. If recipient anti-donor isoagglutinin titers are low (≤1:16), no manipulation of the PBSC graft is required, and RBC depletion of a BM graft might be considered but is not mandatory (EBMT handbook, 2019).
• ABO incompatible cord stem cell donation should be red cell depleted prior to cryopreservation.
• Following a major ABO incompatible transplant, the direct antiglobulin test (DAGT) may become positive when donor red cells are produced (after a few weeks) because of residual anti-A or anti-B in the recipient. The persistence of high levels of these antibodies may delay red cell engraftment.

5.5.2   Minor ABO incompatibility (i.e. donor has antibodies to recipient cells, e.g. O group donor and A group recipient)

• Donor derived anti-A, anti-B, or even anti-D, may react with residual recipient red blood cells and result in a positive DAGT at 1-2 weeks post-HSCT.
• Haemolysis may occur, but it is rarely severe.
• In case of minor ABO incompatibility and a high donor anti-recipient isoagglutinin titer (≥1:256), plasma depletion of both PBSC and BM grafts should be performed. If the donor anti-recipient isoagglutinin titer is low (≤1:128), no manipulation of the PBSC graft is required, and plasma depletion of a BM graft might be considered but is not mandatory (EBMT handbook, 2019).

5.5.3   Major and minor incompatibility – ‘bidirectional’ (i.e. both donor and recipient have antibodies against recipient and donor cells respectively e.g. donor group A and recipient group B)

• In cases of bidirectional ABO incompatibility and high titers of anti-recipient isoagglutinins, both RBC and plasma depletion are required (EBMT handbook, 2019).

5.5.4   Blood Product Requirements Pre and Post Transplant (see Appendix 2)

• Pre-transplant – recipient group red cells, LG Octaplas (new FFP equivalent) and platelets should be given.
• Post-transplant – The ABO type of blood components to be transfused early post-transplant (before engraftment), when the recipient has received an ABO incompatible transplant, is indicated in Appendix 2. Regular monitoring of the recipient’s blood group, antibody screen and DAGT is essential and this should be done weekly.
• Group O platelets should only be given to Group A or B individuals, if group specific platelets are not available and then only platelets tested and known to have a low antibody titre.

5.5.5   Full ABO conversion (i.e. the ABO antibodies to the donor ABO group are undetectable and the DAGT is negative) – usually occurs well after initial discharge and thereafter all patients should receive products of their new ABO group.

5.5.6   The ABO group of blood for transfusion should change to that of the donor after 28 days, or later when cells of the donor ABO group are detected on testing and there are no recipient ABO isoagglutinin against the donor’s group present.

5.5.7   Pre-transfusion cross match tests must be compatible and recipient red cells DAGT negative.

5.5.8  Any change to the new (donor) ABO group must be authorised by the consultant in charge and documented in blood bank records. A copy of the change of grouping should be filed in the patients electronic records.

5.6.1 HSCT recipients should receive RhD negative RBC and platelets, except when both HSC donor and recipient are RhD positive.

5.6.2. If the HSC donor is RhD positive and the recipient is RhD negative, platelet transfusion can be switched to RhD positive products after erythroid engraftment (ie: appearance of RhD positive red cells).

This SOP will be reviewed every two years.

For further information contact:

• Haematopoietic Stem Cell Transplant Consultant on-call (via Switchboard)
• Hospital Blood Bank
• Transfusion Practitioner page (80440)

Key:

*        Top up transfusions in infants aged <6 months do not require irradiation unless there has been a previous IUT or if the donation is from a first or second-degree relative

**      The requirement for irradiation after IUT remains until 6 months after 40 weeks gestation

***     Products for neonatal ET must be irradiated when there has been a previous IUT or if the donation is from a first or second-degree relative.  For other neonatal ET, irradiation is recommended if irradiation will not delay transfusion

†        Whilst a diagnosis of severe T lymphocyte immunodeficiency is considered all components transfused should be irradiated and CMV seronegative whilst further tests are being undertaken

||       more detailed requirements for transplant recipients are as follows:

allografts - irradiated components should be given indefinitely
autografts - irradiated components should be given until 3 months post SCT if no TBI and until 6 months post SCT if TBI.  Updated recommendations from the expert advisor committee on measures to protect patients from acquiring HEV via transfusion.

Patients considered at risk of persistent HEV infection and therefore requiring HEV negative selected components (note all components after 5 April 2017 will be HEV negative).

1. Patients with evidence of severe primary immunodeficiency
2. Patients currently being treated for malignant disease with immunosuppressive chemotherapy or radiotherapy, or who have terminated such treatment within at least the last six months.
3. Patients who have received a solid organ transplant and are currently on immunosuppressive treatment.
4. Patients who have received a haematopoietic stem and progenitor cell transplant for at least 12 months after finishing all immunosuppressive treatment or longer where the patient has developed graft versus host disease.
5. Patients receiving systemic high dose steroids until at least three months after treatment has stopped.
6. Patients receiving other types of immunosuppressive drugs, either alone or in combination with lower doses of steroids, until at least six months after terminating such treatment.
7. Patients who are immunocompromised due to Human Immunodeficiency Virus (HIV) infection with a CD4 count of <200/mm3.
8. Foetuses and neonates.
9. Patients who are within three months of a planned elective organ transplant and patients who may otherwise receive a solid organ transplant within three months due to being on the UK national transplant waiting list or are within three months of being placed on the waiting list.

N/A indicates not applicable

*  Time period from diagnosis to transplantation

†  Time period from transplantation to RBC engraftment

‡  Engraftment established, as indicated by direct antiglobulin testing being negative, along with 2 consecutive independent samples with the forward and reverse typing showing donor ABO status

Donor / Recipient RhD compatibility (EBMT handbook, 2019).  HSCT recipients should receive RhD negative RBC and platelets, except when both HSC donor and recipient are RhD positive.  If the HSC donor is RhD positive and the recipient is RhD negative, platelet transfusion can be switched to RhD positive products after erythroid engraftment (ie: appearance of RhD positive red cells).