Guideline for the Use of Fresh Frozen Plasma & Cryoprecipitate in Transfusion (Adults, Children and Neonates)

1. Introduction
   1.1 Rationale for guideline
   1.2 About Fresh Frozen Plasma
   1.3 Solvent Detergent FFP
   1.4 Thresholds and Targets of FFP
   1.5 Cryoprecipitate
2. Storage and Shelf life
   2.1 FFP & Cryoprecipitate
3. Compatibility recommendations
   3.1 Compatibility table for adults
4. Clinical Indications for the use of FFP and cryoprecipitate
   4.1 Single Factor Deficiencies
   4.2 Multiple Factor Deficiencies / Disseminated Intravascular Coagulation
   4.3 Massive Transfusion
   4.4 Liver Disease
   4.5 Thrombotic Thrombocytopenic Purpura
5. Dosage
6. Administration of FFP and Cryoprecipitate
7. Children and Neonatal use of FFP and cryoprecipitate
   7.1 Compatibility table for Paediatrics and Neonates
   7.2 Neonatal and children < 1 year – indications for use
8. Risks associated with the use of FFP
   8.1 Transfusion Transmitted Infections
   8.2 Transfusion Associated Graft versus Host Disease
   8.3 Transfusion Related Acute Lung Injury (TRALI)
   8.4 Allergic reaction and anaphylaxis
9. Written Informed Consent for Transfusion of FFP
10. Requesting & Documentation

1. Introduction

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1.1 Rationale for guideline

The purpose of this document is:

• To give general guidance to clinical staff about the appropriate and safe use of FFP and cryoprecipitate transfusion.
• To give guidance on the correct procedures for prescribing, requesting, ordering and administering FFP and cryoprecipitate.

NB: FFP is not indicated for the reversal of warfarin therapy – prothrombin complex is safer and more effective.

For information on the management of Warfarin Reversal go to:

LTHT Guidelines for Warfarin Reversal
British Society for Haematology (2011).
Guidelines on oral anticoagulation (warfarin): 4th edition
British Journal of Haematology, 154, 311-324
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2011.08753.x

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1.2 Fresh Frozen Plasma (FFP)

FFP is donor plasma that has been frozen rapidly to <-25oC to maintain the activity of labile coagulation factors. FFP contains fibrinogen, Factor VIII and other clotting factors – but only in the concentrations present in the original donor plasma. FFP unit volume varies between 180 - 400ml (usually approximately 274ml) and is available as single unit packs containing 1 donation per pack.2

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1.3. Solvent-detergent FFP

Solvent detergent treated FFP (SD-FFP) is available as a licensed medicinal product OctaplasLG®). OctaplasLG® is prepared from over 1500 plasma donations. The pooling process allows the clotting factors concentrations to be of a standardised concentration.
The solvent detergent (SD) process inactivates the bacteria and a number of encapsulated viruses3. SD FFP is recommended for high volume plasma exchange in patients with Thrombotic Thrombocytopenic Purpura (TTP) because of its increased efficacy compared to standard FFP in this setting.
The decision to transfuse OctaplasLG® is a clinical decision. The clinical team must communicate with the Blood Bank staff if OctaplasLG® is required.

Based on evaluation of the risk of transmission of vCJD, SaBTO recommends that the current risk reduction measures of the provision of imported plasma and apheresis platelets for individuals born on or after 1st January 1996 can be removed.

Please refer to SaBTO-Paediatric Components Working Group report for further advice:
https://www.gov.uk/government/publications/risk-reduction-measures-for-variant-creutzfeldt-jakob-disease-pcwg-report

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1.4 Thresholds and Targets

1.4.1 Only consider fresh frozen plasma transfusion for patients with clinically significant bleeding but without major haemorrhage if they have abnormal coagulation test results (for example, prothrombin time ratio or activated partial thromboplastin time ratio above 1.5).

1.4.2 Do not offer fresh frozen plasma transfusions to correct abnormal coagulation in patients who:

• Are not bleeding (unless they are having invasive procedures or surgery with a risk of clinically significant bleeding)
• need reversal of a vitamin K antagonist

1.4.3 Consider prophylactic fresh frozen plasma transfusions for patients with abnormal coagulation who are having invasive procedures or surgery with a risk of clinically significant bleeding.

Doses

1.4.4 Reassess the patient’s clinical condition and repeat the coagulation tests after fresh frozen plasma transfusion. The coagulation results will guide if the patient has received an adequate dose of FFP or require further doses.

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1.5 Cryoprecipitate

Cryoprecipitate is obtained by thawing FFP at 4°C. The cryoprecipitate remains the supernatant plasma as a gel like precipitate; this is then rapidly frozen to -25°C. It consists of the cryoglobulin fraction of plasma containing the major portion of Factor VIII and fibrinogen. It is issued by National Heath Service Blood & Transplant (NHSBT) and primarily used as a concentrated source of fibrinogen.

Thresholds and targets.

1.5.1 Consider cryoprecipitate transfusions for patients without major haemorrhage who have:

• clinically significant bleeding and
• a fibrinogen level below 1.5g/litre.

1.5.2 Do not offer cryoprecipitate transfusions to correct the fibrinogen level in patients who:

• are not bleeding and
• are not having invasive procedures or surgery with a risk of clinically significant bleeding.

1.5.3 Consider prophylactic cryoprecipitate transfusions for patients with a fibrinogen level below 1.0g/litre who are having invasive procedures or surgery with a risk of clinically significant bleeding.

Doses

1.5.4 Use and adult dose of 2 pools when giving cryoprecipitate transfusions (for children, use 5-10ml/kg up to maximum of 2 pools)

1.5.5 Reassess the patient’s clinical condition, repeat the fibrinogen level measurement and give further doses if needed.

2. Storage and shelf life

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2.1 FFP & Cryoprecipitate

FFP and Cryoprecipitate have a shelf life of 36 months if kept at -25°C or colder. Thawing takes approximately 30 minutes. Once thawed the component must not be refrozen and should be transfused as soon as possible but at least within 4 hours.

3. Compatibility recommendations

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3.1 FFP and Cryoprecipitate compatibility table for adults
(see Section 7.1 for Paediatric compatibility table)

*only suitable for emergency use.

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4. Clinical indications for the use of FFP and cryoprecipitate

The indications covered under this section are relevant for adults and children.

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4.1 Single Clotting Factor Deficiencies

FFP should only be used for single clotting factor deficiencies for which no virus safe fractionated concentrated product is available (currently mainly Factor V). Pathogen reduced plasma should be considered for these patients as well as vaccination against Hepatitis A and B to safeguard against transmission of viral infection in a high use group.

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4.2 Multiple Factor Deficiencies / Disseminated Intravascular Coagulation (DIC)

FFP is indicated for the treatment of bleeding associated with multiple clotting factor deficiencies, for example in DIC, liver failure, massive haemorrhage and transfusion. FFP is not indicated for “prophylaxis” in patients with abnormal coagulation results or DIC with no evidence of bleeding. There is no evidence that prophylactic replacement regimens prevent DIC or reduce transfusion requirements.

Cryoprecipitate may be indicated if the plasma fibrinogen is <1g/l although there is no clear threshold for clinically significant hypofibrinogenaemia. Use of Cryoprecipitate should be guided by clinical picture and / or Thromboelastogram (TEG) results. Remember that each unit of FFP contains more fibrinogen than a unit of cryoprecipitate, albeit in a higher transfusion volume.

For further information on the management of DIC go to:
Guidelines for the diagnosis and management of disseminated intravascular coagulation
https://b-s-h.org.uk/guidelines/guidelines/diagnosis-and-management-of-disseminated-intravascular-coagulation-1/

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4.3 Massive Transfusion

In post-surgical haemorrhage, coagulation factor deficiency is the primary cause of coagulopathy during massive transfusion because of dilution of coagulation factors following volume replacement with crystalloid or colloid and transfusion of plasma-poor red cells. Administration of blood components should be guided by coagulation test results or Thromboelastogram (TEG) where possible.
Major haemorrhage due to trauma is often accompanied by early “traumatic coagulopathy” with consumption of clotting factors, later complicated by dilution after transfusion of plasma expanders and plasma-poor components.

Traditional guidelines suggest that FFP should be considered after one blood volume is replaced by transfusion and then guided by regular measurement of coagulation tests.

Non-randomised studies have shown significant improvement in trauma patient survival when early intensive replacement of FFP (and platelets) is administered in a 1:1 ratio to red cells6, 11. Four units of pre-thawed group A FFP are available upon request from Blood Bank during the event of a Massive Haemorrhage. Guidelines incorporating this into the management plan for massive haemorrhage are available at:

LTHT Guideline for the Generic Transfusion Management of Adult Massive Haemorrhage
LTHT Guideline for the management of Massive Transfusion during Major Obstetric Haemorrhage
LTHT Guideline for Massive Transfusion Management (Paediatric Patients Birth to 16 years)

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4.4 Liver disease

There is now very good evidence that routine laboratory tests of coagulation do not reliably predict the risk of haemorrhage in liver disease and that many patients are “prothrombotic” despite prolongation of PT and APTT⁷. There is no evidence to support the use of FFP to treat prolonged clotting times in non-bleeding patients. Global tests of coagulation, such as TEG or ROTEM are likely to be of more benefit in stratifying bleeding risk and guiding management.

Routine use of FFP prior to a liver biopsy to prevent bleeding in patients with a prolonged PT is also controversial and practice varies widely between clinical units. Again, global coagulation assays such as thrombin generation and thrombelastography (TEG) may provide a more accurate estimate of underlying coagulopathy and bleeding risk⁷.

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4.5 Thrombotic Thrombocytopenic Purpura (TTP)

SDFFP (Octaplas) is now advocated for use in plasma exchange for the treatment of TTP.

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5. Dosage

The recommended therapeutic dose of FFP is 12 - 15 ml/kg² for adults and children. Each unit contains approximately 274 ml. In most adult patients this corresponds to at least 4 donor units (calculated on basis of approximately 300ml per unit). Subtherapeutic dosing is common and exposes the patient to the significant risks of FFP administration without clinical benefit. This dose may have to be exceeded in massive bleeding and is dependent on the clinical situation and coagulation results. Response should be monitored by repeat coagulation tests.

In Thrombotic Thrombocytopenic Purpura (TTP), at least 1 plasma volume (2.5-3 litres) should be transfused daily in conjunction with plasma exchange.

Cryoprecipitate is issued in bags containing 5 pooled donations. The usual adult dose is two bags (equivalent to 10 single donor units)

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6. Administration of FFP and cryoprecipitate

FFP and Cryoprecipitate must be administered using an administration set with a 200 micron filter.

For full administration guidance go to:
LTHT Policy for Safer Transfusion Procedures: Administering Blood and Blood Components

7. Children and neonatal use of FFP

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7.1 Compatibility table for the use of FFP in Paediatrics and Neonates12

*only suitable for emergency use.

7.1.2 Neonatal and children < 1 year - indications for use:

• Treatment of disseminated vascular coagulation with bleeding (DIC)
• Vitamin K dependent bleeding
• Inherent deficiencies of clotting factors where no specific concentrate is available
• Pre-procedure in well babies with abnormal clotting – discuss individual cases with senior clinician.

There is NO evidence to support to use of FFP for:

• Volume replacement or corrective hypotension
• Prevention of intraventricular haemorrhage
• Routine correction of abnormal coagulation tests if clinically fit

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8. Risks associated with FFP and cryoprecipitate and management of adverse events

For Management Guidelines of Adverse Effects go to:
LTHT Policy for Safer Transfusion Procedures: Reactions to Transfusions

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8.1 Transfusion Transmitted Infections

Bacterial contamination is unlikely because the freezing process inactivates bacteria. The removal of cellular components also removes cell associated bacteria and cell associated viruses.

There is a small risk of transmission of Hepatitis E Virus (HEV) infection to immunosuppressed patients from FFP and cryoprecipitate. Current guidelines recommend transfusion of HEV negative blood and blood components for these patients. All blood and blood components provided from the NHSBT are HEV negative.
For further information please refer to the LTHT guideline
http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=3157
http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=3834

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8.2 Transfusion Associated Graft versus Host Disease (TaGvHD)

This is not applicable; FFP does not need to be irradiated as there have been no case reports of FFP associated GvHD.

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8.3 Transfusion Related Acute Lung Injury (TRALI)

TRALI is most strongly associated with the transfusion of FFP. It usually occurs within 6 hours of transfusion and presents clinically as acute respiratory distress with hypoxia, pulmonary oedema and infiltrates or ‘white out’ on chest X-ray. It is caused by antibodies in the donor plasma (mainly HLA antibodies) reacting with the recipient’s leucocytes leading to their sequestration in the lungs and breakdown of the intravascular/alveolar barrier. TRALI has a mortality of up to 40%, but appropriate management, usually with temporary ventilatory support leads to high survival rates. Since 2003, the Blood Services have sourced FFP predominantly from male donors, with a marked fall in the incidence of TRALI.
If Transfusion Related Lung Injury is suspected stop the transfusion immediately and manage the acute respiratory distress, inform Blood Transfusion Laboratory, take chest x-ray and all necessary bloods as requested by the Transfusion Laboratory. Recovery is usual within 48 hours.

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8.4 Allergic reaction and anaphylaxis

FFP has the highest association with severe allergic reactions of any blood component12. Urticaria and/or itching may occur. For patients sensitive to Immunoglobulin A (IgA), plasma deficient in IgA is available on request. If an allergic or anaphylactic reaction is suspected stop the transfusion and inform the Transfusion Laboratory.

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9. Written informed consent for transfusion of FFP

In LTH NHS Trust ALL patients are required to give their written informed consent before transfusion of any blood or blood component (wherever clinically possible). This consent and the discussion of the risks explained to the patient must be recorded on consent form 1 (adults) and consent form 2 (paediatrics - to be signed by the parent) either on the pre-printed ‘blood/blood components’ version or on the consent form being used for the patient’s surgery / invasive procedure. This consent process should be backed up with the offer of a Patient Information Leaflet on transfusion (available in
all clinical areas or from the Hospital Transfusion Team) where appropriate.
In emergency situations where the patient requires blood component therapy, information regarding the risks and benefits may be given retrospectively.

For further information on written informed consent for transfusion go to:

LTHT policy on obtaining written informed consent for blood / blood components:
http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=1217

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10. Requesting and documentation

As with all blood components the clinical reason for transfusion should be documented in the case notes.

All FFP and Cryoprecipitate must be prescribed on a LTHT Transfusion Prescription form (order code WPG602). Requests for FFP and Cryoprecipitate must be made via a telephone call to the Transfusion Laboratory LGI – 23398, SJUH - 65559).

The Transfusion Laboratory requires a confirmed ABO group and Rh D blood group on the Blood Bank system to order to issue FFP or Cryoprecipitate.
Please send a correctly labelled sample for Group and Save to the lab as soon as possible to prevent any delays- please liaise with the Blood Bank laboratory. Be aware that any FFP or Cryoprecipitate need to be thawed before being issued to a patient and this process can take up to 30 minutes plus transport time to the clinical area.

Transfusion observations must be recorded for each unit transfused.

Following transfusion all FFP and Cryoprecipitate must be positively confirmed as transfused in line with the Blood Safety and Quality Regulations 2005. Full “traceability” of all blood component transfusions is a legal requirement and the Transfusion Laboratory has to retain this information for 30 years. This can be done by using the Blood Track ‘Autofate’ system or by returning the manila tag to the transfusion laboratory.