The most common complications of transfusion are
The most serious complications, which have very high mortality rates, are
Other complications include
Early recognition of symptoms suggestive of a transfusion reaction and prompt reporting to the blood bank are essential. The most common symptoms are chills, rigor, fever, dyspnea, light-headedness, urticaria, itching, and flank pain. If any of these symptoms (other than localized urticaria and itching) occur, the transfusion should be stopped immediately and the IV line kept open with normal saline. The remainder of the blood product and clotted and anticoagulated samples of the patient’s blood should be sent to the blood bank for investigation. NOTE: The unit in question should not be restarted, and transfusion of any previously issued unit should not be initiated. Further transfusion should be delayed until the cause of the reaction is known, unless the need is urgent, in which case type O Rh-negative red blood cells (RBCs) should be used.
Hemolysis of donor or recipient RBCs (usually the former) during or after transfusion can result from ABO/Rh incompatibility ABO and Rho typing More than 21 million units of blood components are transfused yearly in the US, from about 7 million volunteer donors (1). Although transfusion is probably safer than ever, risk (and the public’s... read more , plasma antibodies, or hemolyzed or fragile RBCs (eg, by overwarming stored blood or contact with hypotonic IV solutions). Hemolysis is most common and most severe when incompatible donor RBCs are hemolyzed by antibodies in the recipient’s plasma. Hemolytic reactions may be acute (within 24 hours) or delayed (from 1 to 14 days).
Febrile reactions may occur without hemolysis. Antibodies directed against white blood cell (WBC) human leukocyte antigen (HLA) in otherwise compatible donor blood are one possible cause. This cause is most common in multitransfused or multiparous patients. Cytokines released from WBCs during storage, particularly in platelet concentrates, are another possible cause.
Clinically, febrile reactions consist of a temperature increase of ≥ 1° C, chills, and sometimes headache and back pain. Simultaneous symptoms of allergic reaction Allergic reactions The most common complications of transfusion are Febrile nonhemolytic reactions Chill-rigor reactions The most serious complications, which have very high mortality rates, are Acute hemolytic... read more are common. Because fever and chills also herald a severe hemolytic transfusion reaction, all febrile reactions must be investigated as for acute hemolytic transfusion reaction, as with any transfusion reaction.
Most febrile reactions are treated successfully with acetaminophen and, if necessary, diphenhydramine. Patients should also be treated (eg, with acetaminophen) before future transfusions. If a recipient has experienced more than one febrile reaction, special leukoreduction filters are used during future transfusions; most hospitals use prestorage, leukoreduced blood components.
About 20 people die yearly in the US as a result of acute hemolytic transfusion reaction. AHTR usually results from recipient plasma antibodies to donor RBC antigens. ABO incompatibility is the most common cause of acute hemolytic transfusion reaction. Antibodies against blood group antigens other than ABO can also cause AHTR. Mislabeling the recipient’s pretransfusion sample at collection and failing to match the intended recipient with the blood product immediately before transfusion are the usual causes.
Hemolysis is intravascular, causing hemoglobinuria with varying degrees of acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more and possibly disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC). The severity of acute hemolytic transfusion reaction depends on the
An acute phase usually develops within 1 hour of initiation of transfusion, but it may occur late during the transfusion or immediately afterward. Onset is usually abrupt. The patient may complain of discomfort and anxiety. Dyspnea, fever, chills, facial flushing, and severe pain may occur, especially in the lumbar area. Shock may develop, causing a rapid, feeble pulse; cold, clammy skin; low blood pressure; and nausea and vomiting. Jaundice may follow acute hemolysis.
If AHTR occurs while the patient is under general anesthesia, the only symptom may be hypotension, uncontrollable bleeding from incision sites and mucous membranes caused by an associated DIC, or dark urine that reflects hemoglobinuria.
If AHTR is suspected, one of the first steps is to recheck the sample and patient identifications. Diagnosis is confirmed by a positive direct antiglobulin test Direct antiglobulin (direct Coombs) test More than 21 million units of blood components are transfused yearly in the US, from about 7 million volunteer donors (1). Although transfusion is probably safer than ever, risk (and the public’s... read more , measuring urinary hemoglobin, serum lactate dehydrogenase, bilirubin, and haptoglobin. Intravascular hemolysis produces free hemoglobin in the plasma and urine; haptoglobin levels are very low. Hyperbilirubinemia may follow.
After the acute phase, the degree of acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more determines the prognosis. Diuresis and a decreasing BUN (blood urea nitrogen) usually portend recovery. Permanent renal insufficiency is unusual. Prolonged oliguria and shock are poor prognostic signs.
If AHTR is suspected, the transfusion should be stopped and supportive treatment begun. The goal of initial therapy is to achieve and maintain adequate blood pressure and renal blood flow with IV 0.9% saline and furosemide. IV saline is given to maintain urine output of 100 mL/hour for 24 hours. The initial furosemide dose is 40 to 80 mg (1 to 2 mg/kg in children), with later doses adjusted to maintain urinary flow > 100 mL/hour during the first day.
Drug treatment of hypotension must be done cautiously. Pressor drugs that decrease renal blood flow (eg, epinephrine, norepinephrine, high-dose dopamine) are contraindicated. If a pressor drug is necessary, dopamine 2 to 5 mcg/kg/minute is usually used.
A nephrologist should be consulted as early as possible, particularly if no diuretic response occurs within about 2 to 3 hours after initiating therapy, which may indicate acute tubular necrosis Acute Tubular Necrosis (ATN) Acute tubular necrosis (ATN) is kidney injury characterized by acute tubular cell injury and dysfunction. Common causes are hypotension or sepsis that causes renal hypoperfusion and nephrotoxic... read more . Further fluid and diuretic therapy may be contraindicated, and early dialysis may be helpful.
Transfusion-associated graft-vs-host disease (see also Graft Rejection and Graft-vs-Host Disease Graft rejection and graft-vs-host disease Transplants may be The patient’s own tissue (autografts; eg, bone, bone marrow, and skin grafts) Genetically identical (syngeneic [between monozygotic twins]) donor tissue (isografts) Genetically... read more ) is usually caused by transfusion of products containing immunocompetent lymphocytes to an immunocompromised host. The donor lymphocytes attack host tissues because host immune system cannot destroy donor lymphocytes. Graft-vs-host disease can occur occasionally in immunocompetent patients if they receive blood from a donor (usually a close relative) who is homozygous for an human leukocyte antigen (HLA) haplotype for which they are heterozygous. Symptoms and signs include fever, rash (centrifugally spreading rash becoming erythroderma with bullae), vomiting, watery and bloody diarrhea, lymphadenopathy, and pancytopenia due to bone marrow aplasia. Jaundice and elevated liver enzyme levels are also common. Graft-vs-host disease occurs 4 to 30 days after transfusion and is diagnosed based on clinical suspicion and skin and bone marrow biopsies. GVHD has > 90% mortality because no specific treatment is available.
Prevention of graft-vs-host disease is with irradiation (to damage DNA of the donor lymphocytes) of all transfused blood products. It is done
Treatment with corticosteroids and other immunosuppressants, including those used for solid organ transplantation, is not an indication for blood irradiation.
Although transfusion-associated circulatory overload is underrecognized and underreported, recently it has been recognized as the most common cause of transfusion-related deaths reported to the FDA (1 General references The most common complications of transfusion are Febrile nonhemolytic reactions Chill-rigor reactions The most serious complications, which have very high mortality rates, are Acute hemolytic... read more ). The high osmotic load of blood products draws volume into the intravascular space over the course of hours, which can cause transfusion-associated circulatory overload in susceptible patients (eg, those with cardiac or renal insufficiency). RBCs should be infused slowly. The patient should be observed and, if signs of heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular failure causes shortness of breath and fatigue, and right ventricular failure causes peripheral and abdominal fluid... read more (eg, dyspnea, crackles) occur, the transfusion should be stopped and treatment for heart failure begun.
Typical treatment is with a diuretic such as furosemide 20 to 40 mg IV. Occasionally, patients requiring a higher volume of plasma infusion to reverse a warfarin overdose may be given a low dose of furosemide simultaneously; however, prothrombin complex concentrate (PCC) is the first choice for such patients. Patients at high risk of transfusion-associated circulatory overload (eg, those with heart failure or severe renal insufficiency) are treated prophylactically with a diuretic (eg, furosemide 20 to 40 mg IV).
Transfusion-related acute lung injury is an infrequent complication caused by anti-HLA and/or antigranulocyte antibodies in donor plasma that agglutinate and degranulate recipient granulocytes within the lung. Acute respiratory symptoms develop, and chest x-ray has a characteristic pattern of noncardiogenic pulmonary edema. This complication is the second most common cause of transfusion-related death . Incidence is 1 in 5,000 to 1 in 10,000, but many cases are mild. Mild to moderate transfusion-related acute lung injury probably is commonly missed. General supportive therapy typically leads to recovery without long-lasting sequelae. Diuretics should be avoided. Using blood donated by men reduces the risk of this reaction. Cases should be reported to the hospital transfusion medicine service or blood bank.
Allergic reactions to an unknown component in donor blood are common, usually due to allergens in donor plasma or, less often, to antibodies from an allergic donor. These reactions are usually mild and include urticaria, edema, occasional dizziness, and headache during or immediately after the transfusion. Simultaneous fever is common. Less frequently, dyspnea, wheezing, and incontinence may occur, indicating a generalized spasm of smooth muscle. Rarely, anaphylaxis Anaphylaxis Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more occurs, particularly in recipients with IgA-deficiency Selective IgA Deficiency Selective IgA deficiency is an IgA level 7 mg/dL ( 70 mg/L, 0.4375 micromol/liter) with normal IgG and IgM levels. It is the most common primary immunodeficiency. Many patients are asymptomatic... read more .
In a patient with a history of allergies or an allergic transfusion reaction, an antihistamine may be given prophylactically just before or at the beginning of the transfusion (eg, diphenhydramine 50 mg orally or IV). NOTE: Drugs must never be mixed with the blood.
If an allergic reaction occurs, the transfusion is stopped. An antihistamine (eg, diphenhydramine 50 mg IV) usually controls mild urticaria and itching, and transfusion may be resumed. However, a moderate allergic reaction (generalized urticaria or mild bronchospasm) also requires hydrocortisone (100 to 200 mg IV), and a severe anaphylactic reaction requires additional treatment with epinephrine 0.5 mL of 1:1000 solution subcutaneously and 0.9% saline IV along with investigation by the blood bank. Further transfusion should not occur until the investigation is completed.
Patients with severe IgA deficiency require transfusion of washed RBCs, washed platelets, and plasma from an IgA-deficient donor.
Blood stored for > 7 days has decreased RBC 2,3-diphosphoglycerate (DPG), and the 2,3-DPG is absent after >10 days. This absence results in an increased affinity for oxygen and slower release of oxygen to the tissues. There is little evidence that 2,3-DPG deficiency is clinically significant except in exchange transfusions in infants, in patients with sickle cell disease Sickle Cell Disease Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in blacks. It is caused by homozygous inheritance of genes for hemoglobin (Hb) S. Sickle-shaped... read more who present with acute chest syndrome or stroke, and in some patients with severe heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular failure causes shortness of breath and fatigue, and right ventricular failure causes peripheral and abdominal fluid... read more . After transfusion of RBCs, 2,3-DPG regenerates within 12 to 24 hours.
Occasionally, a patient who has been sensitized to an RBC antigen has very low antibody levels and negative pretransfusion tests. After transfusion with RBCs bearing this antigen, a primary or anamnestic response may result (usually in 1 to 4 weeks) and cause a delayed hemolytic transfusion reaction. A delayed hemolytic transfusion reaction usually does not manifest as dramatically as acute hemolytic transfusion reaction. Patients may be asymptomatic or have a slight fever. Rarely, severe symptoms occur. Usually, only destruction of the transfused RBCs (with the antigen) occurs, resulting in a falling hematocrit and a slight rise in lactate dehydrogenase and bilirubin and a positive direct antiglobulin test. Because delayed hemolytic transfusion reaction is usually mild and self-limited, it is often unidentified, and the clinical clue may be an unexplained drop in hemoglobin to the pretransfusion level occurring 1 to 2 weeks posttransfusion. Severe reactions are treated similarly to acute reactions.
Bacterial contamination of packed RBCs occurs rarely, possibly due to inadequate aseptic technique during collection or to transient asymptomatic donor bacteremia. Refrigeration of RBCs usually limits bacterial growth except for cryophilic organisms such as Yersinia, which may produce dangerous levels of endotoxin.
All RBC units are inspected before dispensing for bacterial growth, which is indicated by a color change. Because platelet concentrates are stored at room temperature, they have greater potential for bacterial growth and endotoxin production if contaminated. To minimize growth, storage is limited to 5 days. The risk of bacterial contamination of platelets is 1:2500. Therefore, platelets are routinely tested for bacteria.
Rarely, syphilis Syphilis Syphilis is caused by the spirochete Treponema pallidum and is characterized by 3 sequential clinical, symptomatic stages separated by periods of asymptomatic latent infection. Common manifestations... read more is transmitted in fresh blood or platelets. Storing blood for ≥ 96 hours at 4 to 10° C kills the spirochete. Although federal regulations require a serologic test for syphilis on donor blood, infective donors are seronegative early in the disease. Recipients of infected units may develop the characteristic secondary rash.
Hepatitis Causes of Hepatitis Hepatitis is an inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more may occur after transfusion of any blood product. The risk has been reduced by viral inactivation through heat treatment of serum albumin and plasma proteins and by the use of recombinant factor concentrates. Tests for hepatitis are required for all donor blood (see table Infectious Disease Transmission Testing Infectious Disease Transmission Testing More than 21 million units of blood components are transfused yearly in the US, from about 7 million volunteer donors (1). Although transfusion is probably safer than ever, risk (and the public’s... read more ). The estimated risk of hepatitis B is 1:1 million; of hepatitis C, < 1:2 million. Because its transient viremic phase and concomitant clinical illness likely preclude blood donation, hepatitis A (infectious hepatitis) is not a significant cause of transfusion-associated hepatitis.
HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more in the US is almost entirely HIV-1, although HIV-2 is also of concern. Testing for antibodies to both strains is required. Nucleic acid testing for HIV-1 antigen and HIV-1 p24 antigen testing are also required. Additionally, blood donors are asked about behaviors that may put them at high risk of HIV infection. HIV-0 has not been identified among blood donors. The estimated risk of HIV transmission due to transfusion is 1:1,500,000 to 2,000,000.
Cytomegalovirus Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more (CMV) can be transmitted by WBCs in transfused blood. It is not transmitted through fresh frozen plasma. Because CMV does not cause disease in immunocompetent recipients, routine antibody testing of donor blood is not required. However, CMV may cause serious or fatal disease in immunocompromised patients, who should receive CMV-negative blood products that have been provided by CMV antibody-negative donors or by blood depleted of WBCs by filtration.
Human T-cell lymphotropic virus 1 (HTLV-1), which can cause adult T-cell lymphoma/leukemia and HTLV-1–associated myelopathy/tropical spastic paraparesis, causes posttransfusion seroconversion in some recipients. All donor blood is tested for HTLV-1 and HTLV-2 antibodies. The estimated risk of false-negative results on testing of donor blood is 1:641,000.
Creutzfeldt-Jakob disease has never been reported to be transmitted by transfusion, but current practice precludes donation from a person who has received human-derived growth hormone or a dura mater transplant or who has a family member with Creutzfeldt-Jakob disease. Variant Creutzfeldt-Jakob disease Variant CJD (vCJD) Creutzfeldt-Jakob disease (CJD) is the most common human prion disease. It occurs worldwide and has several forms and subtypes. CJD symptoms include dementia, myoclonus, and other central nervous... read more (vCJD, or mad cow disease) has not been transmitted by blood transfusion. However, donors who have spent significant time in the United Kingdom and some other parts of Europe may be permanently deferred from donation (see table Some Reasons for Blood Donation Deferral or Denial Some Reasons for Blood Donation Deferral or Denial More than 21 million units of blood components are transfused yearly in the US, from about 7 million volunteer donors (1). Although transfusion is probably safer than ever, risk (and the public’s... read more ).
Malaria Malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion, seizures... read more is transmitted easily through infected RBCs. Many donors are unaware that they have malaria, which may be latent and transmissible for 10 to 15 years. Storage does not render blood safe. Prospective donors must be asked about malaria or whether they have been in a region where it is prevalent. Donors who have had a diagnosis of malaria or who are immigrants, refugees, or citizens from countries in which malaria is considered endemic are deferred for 3 years; travelers to endemic countries are deferred for 1 year.
Babesiosis Babesiosis Babesiosis is infection with Babesia species of protozoa. Infections can be asymptomatic or cause a malaria-like illness with fever and hemolytic anemia. Disease is most severe in asplenic patients... read more , Chagas disease Chagas Disease Chagas disease is infection with Trypanosoma cruzi, transmitted by Triatominae bug bites or, less commonly, via ingestion of sugar cane juice or foods contaminated with infected Triatominae... read more , and West Nile virus Some Arboviral Encephalitides Encephalitis is inflammation of the parenchyma of the brain, resulting from direct viral invasion. Acute disseminated encephalomyelitis is brain and spinal cord inflammation caused by a hypersensitivity... read more have rarely been transmitted by transfusion.
Zika virus infection Zika Virus (ZV) Infections The Zika virus is a mosquito-borne flavivirus that is antigenically and structurally similar to the viruses that cause dengue, yellow fever, and West Nile virus. Zika virus infection is typically... read more has been reported to be transmitted via blood products in Brazil. Therefore, the FDA has mandated testing for Zika virus in the US and its territories. In lieu of Zika testing, pathogen reduction technologies approved for platelets and plasma could also be used; however, their use is currently very limited, and this technology is still unavailable for red cells.
Post-transfusion purpura is a very rare complication in which the platelet count falls rapidly 4 to 14 days after an RBC transfusion, causing moderate to severe thrombocytopenia Thrombocytopenia Platelets are cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes,... read more . Almost all patients are multiparous women who typically received RBC transfusion during a surgical procedure. The exact etiology is unclear. However, the most accepted hypothesis is that a patient who is negative for human platelet antigen 1a (HPA1a) develops alloantibodies due to exposure to HPA1a antigen from the fetus during pregnancy. Because stored RBCs contain platelet microparticles and because most (99%) donors are HPA1a positive, platelet microparticles from the donor blood may trigger an antibody response in previously sensitized patients (anamnestic response). Because these platelet microparticles attach to the recipient's platelets (and thus coat them with HPA1a antigen), the alloantibodies destroy the recipient's platelets, causing thrombocytopenia. The disorder resolves spontaneously as the antigen-coated platelets are destroyed.
Patients develop purpura along with moderate to severe bleeding—usually from the surgical site. Platelet and red cell transfusions make the condition worse.
The differential diagnosis usually includes heparin-induced thrombocytopenia Heparin-induced thrombocytopenia Platelet destruction can develop because of immunologic causes (viral infection, drugs, connective tissue or lymphoproliferative disorders, blood transfusions) or nonimmunologic causes (sepsis... read more (HIT), although HIT is not associated with bleeding. Diagnosis is made by documenting HPA1a antibodies in the patient's plasma and absence of corresponding antigen on the patient's platelets.
Treatment is high-dose IV immunoglobulins (1 to 2 g/kg) and avoidance of further transfusion of platelets or RBCs. Plasma exchange Plasma exchange Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more may be considered in severe cases and, for patients with severe bleeding, platelets donated by HPA1a-negative donors could be transfused if available.
Massive transfusion is transfusion of a volume of blood greater than or equal to one blood volume in 24 hours (eg, 10 units in a 70-kg adult). When a patient receives standard resuscitation fluids of packed RBCs (colloid) plus crystalloid (Ringer's lactate or normal saline) in such large volume, the plasma clotting factors and platelets are diluted, causing a coagulopathy (dilutional coagulopathy). This coagulopathy worsens the consumptive coagulopathy due to major trauma itself (ie, as a result of extensive activation of the clotting cascade) and leads to a lethal triad of acidosis, hypothermia, and bleeding.
Recently, protocols for massive transfusions have been developed in which fresh frozen plasma and platelets are given earlier in resuscitation before coagulopathy develops, rather than trying to "catch up." Such protocols have been shown to decrease mortality, although the ideal ratios of RBCs, plasma, and platelets are still being developed. A recent trial showed no significant mortality difference between giving one unit of plasma and one platelet concentrate for each 2 units of RBCs (1:1:2) versus giving one unit of plasma and one platelet concentrate for every 1 unit of RBCs (1:1:1 [2 General references The most common complications of transfusion are Febrile nonhemolytic reactions Chill-rigor reactions The most serious complications, which have very high mortality rates, are Acute hemolytic... read more ]).
Hypothermia due to rapid transfusion of large amounts of cold blood can cause arrhythmias Overview of Arrhythmias The normal heart beats in a regular, coordinated way because electrical impulses generated and spread by myocytes with unique electrical properties trigger a sequence of organized myocardial... read more or cardiac arrest Cardiac Arrest Cardiac arrest is the cessation of cardiac mechanical activity resulting in the absence of circulating blood flow. Cardiac arrest stops blood from flowing to vital organs, depriving them of... read more . Hypothermia is avoided by using an IV set with a heat-exchange device that gently warms blood. Other means of warming blood (eg, microwave ovens) are contraindicated because of potential RBC damage and hemolysis.
Citrate and potassium toxicities generally are not of concern even in massive transfusion; however, toxicities of both may be amplified in the presence of hypothermia. Patients with liver failure may have difficulty metabolizing citrate. Hypocalcemia Hypocalcemia Hypocalcemia is a total serum calcium concentration 8.8 mg/dL ( 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration 4.7 mg/dL ( 1.17... read more can result but rarely necessitates treatment (which is 10 mL of a 10% solution of calcium gluconate IV diluted in 100 mL D5W, given over 10 minutes). Patients with kidney failure may have elevated potassium if transfused with blood stored for > 1 week (potassium accumulation is usually insignificant in blood stored for < 1 week). Mechanical hemolysis during transfusion may increase potassium. Hypokalemia Hypokalemia Hypokalemia is serum potassium concentration 3.5 mEq/L ( 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common cause is... read more may occur about 24 hours after transfusion of older RBCs (> 3 weeks), which take up potassium.
1. FDA: Fatalities reported to FDA following blood collection and transfusion: Annual Summary for Fiscal Year 2018. Silver Spring, MD, US Food and Drug Administration, 2018.
2. Holcomb JB, Tilley BC, Baraniuk S, et al: Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 313(5):471–482, 2015. doi:10.1001/jama.2015.12