Plasma transfusion is recommended in patients with active bleeding and an International Normalized Ratio INR greater than 1. Supportive care can decrease high-normal to slightly elevated INRs 1. Table 1 gives indications for plasma transfusion.
Inherited deficiency of single clotting factors with no virus-safe or recombinant factor available—anticoagulant factors II, V, X, or XI. When C1 esterase inhibitor is unavailable 9. Information from references 7 through 9. Platelet transfusion may be indicated to prevent hemorrhage in patients with thrombocytopenia or platelet function defects.
Contraindications to platelet transfusion include thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia. Transfusion of platelets in these conditions can result in further thrombosis. Patients in the lower trigger group received Gastrointestinal bleeding was more common in the lower trigger group; however, there was no difference in blood transfusions between groups.
Tables 2 9 and 3 9 — 12 give indications for platelet transfusion in adults and neonates, respectively. Information from reference 9. Consider transfusion; transfuse for clinical reasons e. Transfuse if any of the following indications exist:. Intraventricular or intraparenchymal cerebral hemorrhage.
Coagulation disorder. Sepsis or fluctuating arterial venous pressures. Invasive procedure. If the mother's platelets are used, unit must be washed, irradiated, and resuspended in plasma that is ABO compatible with the neonate.
Information from references 9 through Cryoprecipitate is prepared by thawing fresh frozen plasma and collecting the precipitate. Cryoprecipitate contains high concentrations of factor VIII and fibrinogen. Indications for cryoprecipitate transfusion are listed in Table 4. Congenital dysfibrinogenemia Information from references 12 and Transfusion-related complications can be categorized as acute or delayed, which can be divided further into the categories of noninfectious Table 5 16 and infectious Table 6 16 , Therefore, patients are far more likely to experience a noninfectious serious hazard of transfusion than an infectious complication.
Mistransfusion transfusion of the incorrect product to the incorrect recipient. Noninfectious serious hazards of transfusion. Anesth Analg. I nformation from references 16 and Hemolytic transfusion reactions are caused by immune destruction of transfused RBCs, which are attacked by the recipient's antibodies. The antibodies to the antigens of the ABO blood group or alloantibodies to other RBC antigens are produced after immunization through a previous transfusion or pregnancy.
There are two categories of hemolytic transfusion reactions: acute and delayed. Nonimmune causes of acute reactions include bacterial overgrowth, improper storing, infusion with incompatible medications, and infusion of blood through lines containing hypotonic solutions or small-bore intravenous tubes.
In acute hemolytic transfusion reactions, there is a destruction of the donor's RBCs within 24 hours of transfusion. Hemolysis may be intravascular or extravascular. The most common type is extravascular hemolysis, which occurs when donor RBCs coated with immunoglobulin G IgG or complement are attacked in the liver or spleen.
Symptoms of acute hemolytic transfusion reactions include fever, chills, rigors, nausea, vomiting, dyspnea, hypotension, diffuse bleeding, hemoglobinuria, oliguria, anuria, pain at the infusion site; and chest, back, and abdominal pain. The incidence of acute hemolytic reactions is approximately one to five per 50, transfusions. Allergic reactions range from mild urticarial to life threatening anaphylactic.
Urticarial allergic reactions are defined by hives or pruritus. These antigens are soluble, and the associated reaction is dose-dependent. Allergic transfusion reactions occur in 1 to 3 percent of transfusions. Patients with anaphylactic transfusion reactions, like those with urticarial reactions, may present with hives, but they are distinct in that they also develop hypotension, bronchospasm, stridor, and gastrointestinal symptoms.
For example, anaphylaxis occurs because of donor IgA being infused into a recipient who is IgA deficient and has preexisting circulating anti-IgA. Prevention of anaphylactic transfusion reactions includes avoiding plasma transfusions with IgA in patients known to be IgA deficient. Cellular products e. Transfusion-related acute lung injury TRALI is noncardiogenic pulmonary edema causing acute hypoxemia that occurs within six hours of a transfusion and has a clear temporal relationship to the transfusion.
Antineutrophil cytoplasmic antibodies or anti-HLA antibodies activate the recipient's immune system, resulting in massive pulmonary edema.
Donor products that contain large amounts of plasma from multiparous women are associated with TRALI. Mortality in the United Kingdom decreased significantly after donor plasma from men was used exclusively. Two mechanisms have been proposed to explain FNHTRs: a release of antibody-mediated endogenous pyrogen, and a release of cytokines.
Common cytokines that may be associated with FNHTRs include interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor. Transfusion-associated circulatory overload is the result of a rapid transfusion of a blood volume that is more than what the recipient's circulatory system can handle.
It is not associated with an antibody-mediated reaction. Those at highest risk are recipients with underlying cardiopulmonary compromise, renal failure, or chronic anemia, and infants or older patients.
Cardiomegaly and pulmonary edema are often seen on chest radiography. The diagnosis is made clinically, but may be assisted by measuring brain natriuretic peptide levels, which are elevated in response to an increase in filling pressure. Transfusion-associated graft-versus-host disease is a consequence of a donor's lymphocytes proliferating and causing an immune attack against the recipient's tissues and organs.
It is fatal in more than 90 percent of cases. Risk factors include a history of fludarabine Oforta treatment, Hodgkin disease, stem cell transplant, intensive chemotherapy, intrauterine transfusion, or erythroblastosis fetalis. Other probable risk factors include a history of solid tumors treated with cytotoxic drugs, transfusion in premature infants, and recipient-donor pairs from homogenous populations. Already a member or subscriber? Log in. Interested in AAFP membership?
Learn more. LISA N. Reprints are not available from the authors. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. Transfusion strategies for patients in pediatric intensive care units.
King KE, Bandarenko N. Bethesda, Md. Nevertheless, this strategy requires immediate access to large volumes of thawed universal donor FFP, which is challenging to implement. Despite conflict with existing guidelines, early formula-driven haemostatic resuscitation use is expanding and is gradually being used in nontraumatic bleedings in critical care [ 20 ].
Both the existing guidelines and early formula-driven haemostatic resuscitation are supported by limited evidence, generating controversies and challeng ing clinical decisions in critical care Table 1.
The objective of the present article is to review the evidence on FFP in the management of massive traumatic haemorrhage and to critically appraise early formula-driven haemostatic resuscitation, providing the reader with resources to develop an informed opinion on the current controversy.
Fresh refers to timing from collection to freezing, and frozen refers to the long-term storage condition. FFP is prepared from either single units of whole blood a whole blood-derived unit is approximately ml or plasma collected by apheresis usually ml [ 1 , 2 , 22 ].
PF24 is common in countries using the buffy-coat method, in which RBC and plasma are extracted after hard spin from whole blood and platelets recovered after a second soft spin within 24 hours of collection. PF24 has similar clinical indications as FFP [ 2 , 23 , 24 ]. FFP is commonly thawed in a water bath over 20 to 30 minutes, but US Food and Drug Administration-approved microwaves can thaw 2 units of plasma in 2 to 3 minutes [ 1 ]. After thawing, the activity of labile clotting factors such as factor V and factor VIII decline gradually, and most countries recommend FFP use within 24 hours [ 25 , 26 ].
In some countries, FFP is used up to 5 days after thawing. Photochemically treated FFP and solvent detergent FFP are approved methods of inactivating pathogens in some jurisdictions. Both methods cause loss of clotting factors, particularly factor VIII.
These solvent detergent preparations are extensively used in some European countries, while solvent detergent FFP was withdrawn in North America due to concerns of Parvovirus transmission [ 1 ]. FFP can transmit infectious diseases, albeit rarely. Screen ing and pathogen inactivation reduced transmission rates of HIV to In the UK, concerns over Creutzfeldt-Jakob disease - a rare but rapidly progressive spongiform encephalopathy - led to leukocyte depletion in all blood products and recommendations to use FFP from areas of low epidemicity [ 31 , 32 ].
Other important complications relate to blood immunogenicity, increasingly recognized over the past two decades, particularly transfusion-related acute lung injury TRALI and transfusion-associated circulatory overload [ 33 , 34 ]. TRALI is the commonest cause of transfusion-related death [ 33 , 34 ].
Donor plasma antibodies react with human leukocyte antigens, causing complement activation, endothelial damage, neutrophil activation and lung capillary leak.
Anti-human leukocyte antigens and anti-neutrophil antibodies are commonly found in plasma from multiparous female donors, and the TRALI frequency is higher in recipients from female donors [ 35 — 37 ].
Another potential mechanism involves interactions of biologically active mediators in stored plasma and lung endothelial cells. Other important transfusion-related complications include acute haemolytic reaction from anti-A and anti-B antibodies, and anaphylaxis [ 22 ]. The physiological derangements and complications are proportional to the blood loss and to the time to correct shock.
Lower levels significantly prolong the prothrombin time and the activated partial thromboplastin time above 1. FFP transfusion to replace clotting factors is often recommended for these patients but no studies exist supporting this practice [ 4 ].
Replacing one blood volume or more without FFP results in dilutional coagulopathy, diffuse microvascular bleeding and increased mortality [ 40 , 41 ]. The principles of managing massive haemorrhage include rapid control of bleeding; replenishing the intravascular volume with crystalloid followed by RBC and, once coagulopathy is present or suspected, then adding FFP, platelets and cryoprecipitate; along with correction of acidosis and hypothermia.
Most current guidelines [ 1 , 39 , 42 — 44 ], including the European and US guidelines, recommend transfusing FFP, platelets and cryoprecipitate only when laboratory assays detect a deficit. Where a laboratory is not available, these products are recommended after large infusions of crystalloid and RBC. Current crystalloid-based resuscitation guidelines initiate FFP transfusion late, often after more than one blood volume is lost and the patients have clinically overt coagulopathy [ 40 , 41 ].
Most recommendations are based on observations and expert opinion, often lacking high-level evidence. Many recommendations originated in studies conducted in nontrauma settings and when RBC units had to ml plasma [ 1 ]. Despite worldwide acceptance of similar resuscitation principles, bleeding remains the second overall cause of death in trauma - becoming the first cause of death following hospital admission [ 45 — 47 ].
Current resuscitation strategies invariably fail to prevent coagulopathy in massive bleedings. Multiple causes have traditionally been implicated in trauma coagulopathy, including clotting factor consumption and dilution, hypothermia and acidosis - all linked to large-volume crystalloid infusion and late replacement of clotting elements [ 40 , 41 ].
Further studies suggest that early coagulopathy is initiated by shock and the amount of tissue destruction, independent of clotting factor consumption or dilution Figure 1 , and is associated with a threefold mortality increase [ 48 , 49 ]. Recently proposed mechanism for coagulopathy in trauma. Early coagulopathy develops when there is an imbalance in this process, with excessive anticoagulation, hyperfibrinolysis and consumption of clotting factors. PAI-1, plasminogen activator inhibitor 1.
A unique coagulopathy in traumatic brain injury has long been suspected, where the release of brain tissue factor causes systemic activation of coagulation dissemi-nated intravascular coagulation , exhaustion of clotting elements and hyperfibrinolysis [ 50 , 51 ].
While coagulo-pathy is common and critically important in traumatic brain injury, the controversial existing evidence suggests it may not differ from trauma coagulopathy in general [ 51 ]. The early trauma coagulopathy concept has challenged the current crystalloid-based resuscitation that ignores coagulopathy until it becomes overt. Over the past 2 years, a haemostatic blood-based resuscitation - commonly termed damage control resuscitation - proposes a series of early and aggressive strategies to treat or prevent early trauma-associated coagulopathy [ 52 , 53 ].
This resuscitation entails the use of thawed plasma as the primary resuscitation fluid, limited use of crystalloid, targeted systolic blood pressure at approximately 90 mmHg to prevent renewed bleeding, early activation of a massive transfusion protocol with fixed ratios of FFP:platelets:cryoprecipitate:RBC approximately , liberal use of recombinant activated factor VII rFVIIa and the use of fresh whole blood for the most severely injured combat casualties [ 52 , 53 ].
The first reports suggesting aggressive FFP transfusions were computer simulation models. In , Hirshberg and colleagues published a haemodilution model of exsanguination, calculated the changes in coagulation and predicted an optimal FFP:RBC ratio of to adequately replenish clotting factors [ 54 ].
Ho and colleagues predicted 1 to 1. Since , growing numbers of retrospective military and civilian papers have studied early formula-driven haemostatic resuscitation with different FFP:RBC ratios mostly near and mortality [ 11 — 20 , 56 , 57 ]. These figures surpass any predictions of potentially preventable deaths in trauma [ 47 ].
While the survival advantage of early and aggressive FFP transfusion in early formula-driven resuscitation cannot be ignored, the evidence behind it has limitations that are discussed next. These data suggest that lower ratio patients may not have lived long enough to receive FFP. Another study by the same group on civilian trauma patients reported a similarly impressive survival advantage for higher ratios than lower ratios, but also a markedly dissimilar time to death 35 hours versus 4 hours [ 58 ].
Both studies disclose survivorship bias, where arguably patients had to survive long enough to receive FFP, thus questioning their conclusions. Scalea and colleagues used stepwise logistic regression analysis on patients, demonstrating no survival benefit for higher ratios when early deaths were excluded [ 56 ]. These two studies dispute the survival advantage suggested by the previous studies with such bias.
Early formula-driven resusci-tation proposes that FFP should be initiated early, ideally with the first RBC unit at the start of resuscitation [ 52 , 53 ]. Considering that even laboratory-guided resuscitation eventually results in a high FFP:RBC ratio, a critical difference in formula-driven resuscitation is the early implementation of a high ratio.
No studies to date have reported on transfusing pre-thawed FFP along with the first RBC units or on the time to reach the ratio. Snyder and colleagues stated that the median time to the first RBC was 18 minutes from arrival, while the first FFP was transfused more than 1 hour later [ 57 ].
Despite limitations, including significant differences in the baseline Glasgow coma scale and therefore the severity of head injuries between groups, the study provides better evidence that reaching high FFP:platelet:RBC ratios within the first hours of admission is associated with mortality reduction. Data on timing to initiate FFP transfusions, on timing to reach the ratio and on transfusions during the first 6 hours are equally missing in the studies supporting early formula-driven haemostatic resuscitation and in existing guidelines, limiting comparisons between the different strategies.
Missing data on the International Normalized Ratio, not measured in one-half of the patients, and heterogeneity with nonsurviving patients being significantly more coagulopathic than that for surviving patients, International Normalized Ratio 2.
Aggressive and early FFP transfusion is part of damage control resuscitation, which also proposes crystalloid restriction, rFVIIa and other interventions.
A small study on 40 combat casualties resuscitated with a package containing whole blood, rFVIIa, crystalloid restriction and a high FFP:RBC ratio illustrates the complexity of analysing multiple co-interventions [ 52 ]. Combatants receiving the package had better survival compared with historical controls managed with similar FFP:RBC ratios but not rFVIIa, whole blood and significantly less blood transfusion [ 60 ].
In this study, multiple co-interventions make it impossible to establish the contribution of any of them. PRBCs are used to replace red cell mass when tissue oxygenation is impaired by acute or chronic anemia. Cryoprecipitate is used for hypofibrinogenemia, vonWillebrand disease, and in situations calling for a "fibrin glue. A single platelet unit is derived from one whole blood unit collected. They must be used in 5 days. Pooled platelets from multiple donors from whole blood collections are cheaper to produce but the exposure to the recipient increases.
A "six pack" of platelets can be obtained by apheresis from a single donor at one time. Thus, apheresis platelets give just "one donor" exposure to the recipient, but the cost is high. The recipient's HLA type can be "matched" to a platelet donor with a similar HLA type to deal with problems of HLA alloimmunization in patients with prior transfusions or pregnancies.
The expected incremental increase in platelet count for adults is 30 - 60 K for each "six pack" of platelets Normal saline is used when providing vascular access and fluid volume when transfusing other products and pharmacologic agents. Normal saline is more readily accessible than albumin or FFP, it is relatively inexpensive, and it does not have the risk of viral transmission.
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