Advances in the application of fresh frozen plasma in critically ill patients

Authors: Bi Liang, Luo Ting, Liu Xun, Wu Anshi, Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University

Fresh frozen plasma (FFP) has been used in
the clinic since 1941.
FFP is not only rich in plasma proteins, but also contains all coagulation factors except platelets, and is widely
used in perioperative patients or critically ill patients.
According to statistics, 30% to 90% of FFP has not been properly applied, such as unnecessary preventive infusion, supplementation of plasma colloidal osmolality, and arbitrary collocation with red blood cells
.
The following is a summary of the application of FFP
.

1.
The role of fresh frozen plasma

Improved coagulation: As a plasma product containing a large number of coagulation factors, FFP is often used in bleeding patients who need replacement therapy such as disseminated intravascular coagulation, liver disease, emergency warfarin reversal, and congenital or acquired coagulation factor replacement when specific coagulation factor concentrates cannot be obtained
.

Stabilization of vascular endothelial cells: FFP stabilizes endothelial cells and has important implications
in improving the integrity of vascular endothelial cells.
Studies have shown that infusion of FFP has a positive effect on vascular endothelial barrier function and may improve the prognosis
of animal models of hemorrhagic shock.
In order to assess the in vitro effects of FFP on key functions such as endothelial cell barrier function and adhesion to monocytes, Scheck et al.
pre-stimulate human lung microvascular endothelial cells with lipopolysaccharides, and then cultured with FFP to assess the permeability of fluorescein isothiocyanate-labeled dextrans and observe the formation of cell gaps, and the results show that FFP can restore
intercellular adhesion and damaged barrier function.

2.
Application of fresh frozen plasma

FFP has two main indications: (1) prevention of bleeding (prophylactic); (2) Hemostasis (therapeutic
).
Transfusion of FFP to patients with acute massive blood loss is important for saving the patient's life, while in critically ill patients with non-bleeding with coagulation disorders, the prophylactic use is limited
.

Application of FFP in patients with hemorrhagic shock: Hemorrhagic shock is a serious complication after massive blood loss, and the use of fluids and blood products for fluid resuscitation is the most extensive intervention, especially the use of blood products
.
For patients with hemorrhagic shock with transit time greater than 20 min, patients with pre-hospital FFP resuscitation had a lower
mortality rate of 28 days compared with patients using crystal resuscitation.

In addition, studies of hemorrhagic shock models have shown that resuscitation with FFP can improve the expression of proteins necessary for the integrity of the blood-brain barrier and reduce secondary brain damage
.
The above studies show that FFP can not only restore the internal volume of blood vessels and coagulation factors, but also repair vascular endothelial damage, reduce vascular permeability, and reduce organ damage
.
Endothelial glycocalyx (EGL) is a structure rich in acetoheparan sulfate that plays an important role in many physiological functions, such as participation in lipid homeostasis, permeability, inflammation, coagulation, etc.
After bleeding, EGL is impaired, fluid resuscitation may further alter the EGL after the initial bleeding leads to degeneration, FFP can partially restore the damaged EGL, but the crystal fluid can not
。 Therefore, transfusion of FFP during the fluid resuscitation phase in patients with hemorrhagic shock can improve patient outcomes, and administering FFP earlier can also reduce mortality
in patients.

Application of FFP in patients with sepsis: sepsis is an abnormal body response caused by infection that leads to organ function impairment, and the use of crystalloid fluid for fluid resuscitation
is still recommended.
Fluid resuscitation is an important part of sepsis treatment, but the amount of crystalline infusion is independently associated with the degradation of EGL, and intravenous fluids during resuscitation may exacerbate endothelial damage, worsening
the condition.

FFP is an important substance to stabilize the vascular endothelium, Chang et al.
by adult male rats by 35% cecum ligation and puncture to make an animal model of sepsis, model rats randomly received physiological saline or FFP for resuscitation, the results show that compared with the use of crystalloids, the use of plasma resuscitation improved the survival rate of sepsis model rats for 48h and reduced the incidence
of pulmonary edema.
However, whether FFP can significantly improve the prognosis of patients with sepsis in the clinic needs to be verified
by more prospective studies.

Prophylactic use of FFP in patients with coagulation dysfunction: Currently, clinical prophylactic use of FFP is usually used clinically to correct abnormal clotting status
before tracheostomy, central venous catheter insertion, or liver biopsy in critically ill patients with coagulation disorders 。 However, multiple studies have shown that prophylactic FFP has a limited effect on improving coagulation in critically ill patients, and even if laboratory tests such as prothrombin time/international standardized ratio (PT/INR) after infusion of FFP have a slight improvement, there is no significant difference in the risk of bleeding after invasive procedures, and even increases the incidence
of adverse events.

In order to evaluate the effect of using FFFP before invasive surgery in ICU patients, Biu et al.
conducted a prospective observational study on 136 critically ill patients with coagulation disorders but no active bleeding, and the results showed that compared with patients without infusion FFP (median INR 3.
5), the incidence of bleeding in the infusion group (median FFP was 12.
5ml/kg, median INR was 3.
1) did not decrease after invasive operation, but the incidence of acute lung
。

Clinical failure of FFP to effectively improve coagulation function in patients may be related
to the following two factors.
(1) FFP infusion: the recommended dose of FFP required to reverse coagulation disorder clinically is 10 to 15 ml/kg, but it should not exceed 20ml/kg, and there is no significant benefit from infusion of a large amount of FFP, for severe patients with continuous consumption of coagulation factors (such as patients with end-stage liver disease), the infusion of 2 to 4U FFP cannot significantly correct its coagulation disorder
.
(2) Standard laboratory coagulation tests (SLTs): such as PT/INR and platelet count, do not reliably guide the application
of FFP in critically ill patients.

Haas et al.
, through an analysis of 11 guidelines and 64 studies, showed that there was no reliable evidence that SLTs could diagnose coagulopathy or guide hemostasis, and questioned
the definition that SLTs prolonged by 1.
5 times to be coagulopathy.

Stettler et al.
have shown that in critically ill patients, most PT/INR and activated partial thromboplastin time (APTT) changes cannot be explained by a decrease in coagulation factor activity alone, although these patients have prolonged PT/INR and median thromboelastography (TEG) values remain within the normal range.
Coagulation factors are still functioning adequately before and after FFP transfusion in injured and surgical patients to produce normal coagulation
.

In addition, the ability of INR to predict bleeding risk is poor, and elevated INR may reflect liver dysfunction, so there are certain limitations in guiding patients to transfusion, and more reasonable experimental indicators are needed to guide the clinical application of
FFP.
Viscoelasticity tests such as TEG or rotational thromboelastometry (ROTEM) are currently more reasonable experimental indicators to guide the application of FFP, which can comprehensively test coagulation factors, fibrinogen, platelet aggregation function and fibrinolytic function, for diagnosing fibrinogen deficiency, predicting bleeding risk and mortality, and in guiding trauma, heart surgery, liver transplantation, and more Blood transfusions in critically ill patients such as postpartum haemorrhage are of great significance
.

Durila et al.
, a prospective study of 119 ICU patients with sepsis and non-sepsis, showed that tracheostomy without transfusion of FFP did not increase the risk
of bleeding in the case of elevated PT/INR and normal coagulation time detected by the exogenous coagulation pathway rotary thromboelasticity measuring instrument.
Thus, the application of thromboelastic diagrams reduces the irrational use
of FFP.
The use of viscoelasticity tests also has limitations, such as changes in platelet function caused by drugs, trauma, or sepsis that cannot be detected
by standard viscoelasticity tests such as ROTEM or TEG.
However, the current literature supports restrictive transfusion management based on thromboelastic measurement, which can avoid unnecessary FFP transfusions, reduce the incidence of transfusion-related adverse events, and reduce transfusion-related hospital costs
.

3.
Adverse reactions of infusion of fresh frozen plasma

FFP transfusion is an important intervention for critically ill patients, but as a type of allogeneic blood product, FFP transfusion is associated with the occurrence of transfusion-related adverse events, such as transfusion-related acute lung injury (TRALI), transfusion-related circulating overload (TACO), transfusion-related immunomodulation (TRIM), etc
.

Acute lung injury: Acute lung injury is an acute hypoxic respiratory insufficiency or failure in the course of severe infection, shock, trauma, and burns that cause damage to pulmonary capillary endothelial cells and alveolar epithelial cells leading to increased permeability and decreased lung compliance
.
Infusion of FFP can improve the vascular endothelium, reduce the occurrence of pulmonary edema, reduce lung inflammation, and reduce lung damage
to a certain extent.
FFP infusion is also a risk factor for the development of acute lung injury, and the mechanism of TARRI's development has not been elucidated and may be mediated by pathogenic antibodies or non-antibody-dependent factors
.

A double-strike model is proposed regarding the occurrence of TRERI: the first blow (by the patient's pre-existing risk factors such as chronic liver, heart, kidney disease, etc.
) recruits neutrophils to the lungs, and when combined with the second blow (the factor of blood products), neutrophils destroy barrier integrity, leading to pulmonary edema formation, leading to acute lung injury
associated with blood transfusion.

FFP infusion is both protective and dangerous for the development of
acute lung injury.
Therefore, there may be a risk-benefit ratio between infusion of FFP and the development of acute lung injury, which may be related to the amount of infusion or to the pathological state in which the patient is infusion of FFP
.
If patients with sepsis, hemorrhagic shock and other pathological states inducing endothelial cell apoptosis, during fluid resuscitation, infusion of FFP can avoid excessive rehydration at the same time, block the hyperpermeability of endothelial cells, improve vascular barrier function
.

Transfusion-related circulatory overload: TACO is a common pulmonary complication associated with transfusion, with an incidence of approximately 11% in critically ill patients, and is one of the leading causes of
transfusion-related death.
While infusion of FFP has an important impact on the occurrence of TACO, Clifford et al.
compared the incidence of blood product transfusion with TACO and found that the incidence of TACO was highest in a group receiving transfusions of mixed blood products (FFP, red blood cells and platelets), followed by only the FFP group (11.
8%), and the incidence of TACO decreased
with the decrease of FFP from female donor sources.

At present, the pathophysiological basis of the occurrence of TACO is not fully understood, and the occurrence of TACO has also proposed a model of double whammy: heart or kidney damage, positive fluid balance and advanced age, can be regarded as the first blow, inappropriate fluid management or other components in the blood transfusion product may trigger a second blow, and these two blows together lead to the occurrence
of TACO.

Transfusion-related immunomodulation: TRIM refers to transient immunosuppression after transfusion, and in critically ill surgical patients with FFP-infused TRIM, TRIM leads to a significant increase
in the incidence of nosocomial infections and sepsis.
This may be because FFP infusion is associated with the production of inflammatory cytokines such as TNF and IL-1β, the activation of relevant gene expression, and changes in total phagocytosis, and is driven by soluble mediators, affecting the activation of human U937 monocytes, thereby inducing immunologous adverse events
associated with blood transfusion.

Increased red blood cell requirements: FFP infusion can not only cause pulmonary complications and immunosuppression, recent studies have shown that FFP infusion is associated
with increased red blood cell demand.
Warner et al.
observed the relationship between prophylactic infusion of FFP, infusion of red blood cells (RBC), and hospital stay in an intensive care unit (ICU) and mortality rate of 30d in critically ill adults, and through multivariate propensity scores, the results showed that the prophylactic FFP group had a higher erythrocyte infusion rate compared with the non-infusion FFP group [odds ratio = 4.
3 (95% CI3.
3 to 5.
7)].

There are few similar studies at present, and further research is still needed to verify the relationship between
infusion of FFP and red blood cell infusion.

4.
Summary

At present, FFP is widely used in clinical practice, and has an important role in improving blood clotting and stabilizing vascular endothelium, which is of great significance
in patients with heavy bleeding and sepsis.
There are still some problems in the application of FFP, and the prophylactic application in critically ill patients with non-bleeding with coagulation dysfunction has not achieved the desired effect, and more reasonable tool guidance is needed, while the viscoelasticity test is more reasonable
than the standard laboratory coagulation test to guide the application of FFP.

In addition, it is necessary to be vigilant against the adverse effects caused by infusion of FFP, and further research is needed to confirm
the occurrence of acute lung injury caused by infusion of FFP and the increase in the need for red blood cells in critically ill patients.
In order to rationalize the use of FFP, prospective randomized controlled trials will still be needed in the future to evaluate patients with different diseases and different pathological states, so that the application of FFP can be individualized among patients and guidelines
for FFP transfusion in critically ill patients will be developed.

Source: Bi Liang,Luo Ting,Liu Xun,Wu Anshi.
Progress in the application of fresh frozen plasma in critically ill patients[J].
Journal of Clinical Anesthesiology,2022,38(03):313-317.