The main indication for the transfusion of plasma is to correct deficiencies of clotting factors, for which a specific concentrate is not available, in patients with active bleeding. The products available are: fresh-frozen plasma (FFP), plasma that has undergone viral inactivation with solvent/detergent treatment (S/D FFP), with methylene blue (MB FFP) or with psoralens, in particular amotosalen (S59) and light1; inactivation technology using riboflavin will soon be available2.
A blood component prepared from whole blood or collected by apheresis, frozen within time limits and at a temperature such as to preserve the labile clotting factors adequately3–5.
FFP prepared from units of whole blood and that derived from apheresis are therapeutically equivalent in terms of haemostasis and side effects (Grade of recommendation: 1A)4.
FFP contains normal levels of the stable clotting factors, albumin and immunoglobulins. It contains at least 70% of the original coagulant factor VIII and at least similar quantities of the other labile clotting factors and natural inhibitors of coagulation1,3–5.
FFP for clinical use must not contain clinically significant irregular anti-erythrocyte antibodies. In order to increase its safety, FFP can be quarantined for a minimum period of 4 months.
Physiological individual differences in the concentrations of plasma proteins mean that the generic definition of FFP is applied to products that differ notably in quality.
S/D FFP is a pharmaceutical product, obtained from a pool of about 1,000 units of FFP, with the following characteristics2,6–34:
- - high batch per batch standardisation;
- - declared concentration/activity of the biologically active proteins;
- - reduced immunological risks related to the presence of antibodies, cells (or their fragments);
- - inactivation of the majority of potentially transmissible pathogens;
- - selective elimination of units contaminated by hepatitis A virus or parvovirus B19.
Methylene blue-treated plasma
Methylene blue (MB) is a phenothiazine dye with a virucidal effect2,35–40. MB FFP is not a pharmaceutical product, but is derived from the use of an inactivation method applied to single units of plasma.
The content of the biologically active proteins of this product cannot be standardised, so the biological variability of the units remains high.
The potential decrease in the residual infective risk is the same as that for S/D FFP.
The transfusion of FFP is indicated in the following situations (Table I):
- Correction of congenital deficiencies of clotting factors, for which there is not a specific concentrate, or acquired deficiencies of multiple clotting factors, when the PT or aPTT, expressed as a ratio, is > 1.5, in the circumstances listed below1,3,4,41–67:
- Ongoing bleeding in patients with liver disease (Grade of recommendation: 1C+)41–51,56–58,67.
- Prevention of bleeding, in the case of surgery or invasive procedures, in patients with liver disease (Grade of recommendation: 2C)41–51,56–58,67–70.
- Patients being treated with vitamin K antagonists, in the presence of major haemorrhage or intracranial bleeding or in preparation for surgery that cannot be postponed (Grade of recommendation: 1C+)42–51,56–58,67, if prothrombin complex concentrate, the treatment of first choice, is not available55,59–65.
- Patients with acute disseminated intravascular coagulation (DIC) and active bleeding, in association with the correction of the underlying cause (Grade of recommendation: 1C+)41–51,53,54,56–58,67.
- Correction of microvascular bleeding in patients undergoing massive transfusion. If the PT and aPTT cannot be obtained within a reasonable period, FFP can be transfused in any case in an attempt to stop the bleeding (Grade of recommendation: 1C+)41–51,56–58,66,67.
- Deficiencies of single clotting factors, in the absence of the specific concentrate (for example, factor V deficiency), in the presence of active bleeding or in order to prevent bleeding, in the case of surgery or invasive procedures (Grade of recommendation: 1C+)41–51,56–58,67.
- Apheretic treatment of thrombotic microangiopathies (thrombotic thrombocytopenic purpura, haemolyticuraemic syndrome, haemolytic anaemia elevated liver enzymes and low platelet count [HELLP] syndrome), as a replacement fluid (Grade of recommendation: 1A)41–52,56–58,67.
- Reconstitution of whole blood for exchange transfusion (Grade of recommendation: 2C)71,72.
- Hereditary angioedema due to deficiency of the esterase, in the absence of the inactivator of C1 specific plasma derivative (Grade of recommendation: 2C+)50.
Indications in neonates
Coagulation times in the neonate, which, on average, are longer than those in the adult, are not necessarily related to the risk of bleeding71–74. This is even more the case in premature neonates; thus, abnormal coagulation test results, in the absence of symptoms or haemorrhagic risk, are not an indication for the transfusion of FFP.
FFP is indicated for bleeding caused by vitamin K deficiency and bleeding (or high risk of bleeding) due to DIC. It is also indicated for the treatment of congenital deficiencies of single clotting factors, when the specific concentrate is not available (Grade of recommendation: 2C)4,71–74.
FFP should preferably be ‘safe’, in the sense of having undergone viral inactivation or been quarantined.
For further details, refer to the joint recommendations from the Italian Society of Neonatology and SIMTI72.
Methods of use
FFP must be thawed between 30 °C and 37 °C in a water bath under continuous agitation or with another system able to ensure a controlled temperature. The plasma must be transfused as soon as possible after thawing, but in any case within 24 hours, if stored at 4 ± 2 °C 4,5.
Refer to the product summary sheet for information on the maximum time between the completion of thawing of S/D FFP and starting its transfusion.
FFP must not be refrozen once it has been thawed (Grade of recommendation: 1C+)4.
The recommended therapeutic dose of FFP is 10–15 mL/kg of body weight1,4,43,44,47. The dose of FFP does, however, depend on the clinical situation and laboratory parameters (Grade of recommendation: 1C+)1,4,43,44,47,50, which may justify the administration of higher doses75–77.
- - Expansion of circulatory volume;
- - hypoproteinaemia;
- - correction of immune deficiencies;
- - for nutritional purposes;
- - correction of congenital or acquired deficiencies of clotting factors in the absence of haemorrhage, or correction of disorders of haemostasis in patients with chronic liver disease who are not bleeding (Grade of recommendation: 1C+)4,42–51,56–58,68,69,71–73,77–80.
Absolute contraindications to the use of FFP are documented intolerance to plasma or its components and congenital deficiency of immunoglobulin A (IgA) in the presence of anti-IgA antibodies4.
Relative contraindications are heart failure and pulmonary oedema.
Monitoring indices for clinical auditing
- - The use of transfusion therapy with FFP in the following situations:
- expansion of circulatory volume;
- correction of immune deficiencies;
- for nutritional purposes;
- correction of congenital or acquired deficiencies of clotting factors in the absence of haemorrhage, or correction of disorders of haemostasis in patients with chronic liver disease who are not bleeding.
- - Evaluation of the appropriateness of the dose of FFP.
Adverse reactions to the transfusion of FFP
- - Allergic reactions3,4,42–51,56–58,71–73:
- mild (urticaria): occur in 1% of patients;
- severe and anaphylactic: occur with a frequency of less than 1 case per 100,000 transfusions.
- - Transfusion-related acute lung injury (TRALI)81–85: non-cardiogenic pulmonary oedema developing within 4–6 hours of the transfusion of FFP. This complication can be avoided by using plasma from male donors who have never been transfused and from nulliparous female donors who have never been transfused, or by using S/D FFP.
- - Febrile reactions3,4,42–51,56–58,71–73: these occur in less than 1% of patients transfused with FFP and in up to 10% of patients undergoing plasma exchange.
- - Citrate toxicity3,4,42–51,56–58,71–73: this can occur after the rapid transfusion of large volumes of plasma and is particularly important in neonates and in patients with liver disease.
- - Transmission of infections3,4,42–51,56–58,71–73: the process of freezing inactivates bacteria; bacterial contamination and growth, with release of endotoxins, before freezing is extremely improbable. There is, however, still the risk, albeit minimal, of transmission of viral infections or infections due to other unknown or untested pathogens.
- - Graft-versus-host disease (GvHD)4: no cases of FFP-associated GvHD have ever been reported. Freezing causes the lysis of lymphocytes, so irradiation of the plasma is not necessary.
- - Circulatory overload3,4,42–51,56–58,71–73: this can occur, particularly in patients with renal or cardiorespiratory failure.
- - Inhibitors against deficient proteins86: these can develop after the transfusion of plasma in patients with severe deficiencies of clotting factors.
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