Strategies
Complications of Blood Transfusion
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Introduction
Medical evidence has been accumulating over recent decades associating blood transfusion with increased risk; but that knowledge has not made a proportionate impact on medical training and clinical care. Blood transfusion is still viewed by many healthcare providers as the only viable, scientifically sound and responsible option in many clinical scenarios. This strongly held conviction on the part of the provider may at times result in an adversarial stance toward the patient who chooses to decline transfusion, which may in turn bring stress to the provider and harm to the patient.
It is hoped that a heightened awareness of the risks of blood transfusion along with a better understanding of the body’s tolerance of anemia, will help providers to see that bloodless care is a reasonable, responsible choice. Such awareness and understanding has proven to eliminate unnecessary friction in the doctor-patient relationship for healthcare providers who treat Jehovah’s Witnesses.
What are the currently known complications of blood transfusion?
Early Complications:
Hemolytic reactions (immediate and delayed)
Non-hemolytic febrile reactions
Allergic reactions to proteins, IgA
Transfusion-related acute lung injury
Reactions secondary to bacterial contamination
Circulatory overload
Air embolism
Thrombophlebitis
Hyperkalemia
Citrate toxicity
Hypothermia
Clotting abnormalities (after massive transfusions)
Late complications:
Transmission of infection
Viral (hepatitis A, B, C, HIV, CMV)
Bacterial (Salmonella)
Parasites (malaria, toxoplasma)
Graft-vs-host disease
Iron overload (after chronic transfusions)
Immune sensitization (Rhesus D antigen)
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Acute hemolytic transfusion reactions
Acute hemolytic transfusion reactions occur when ABO-incompatible blood is transfused, resulting in recipient antibodies attaching to donor RBC antigens and forming an antigen-antibody complex. This antigen-antibody complex activates complement, resulting in intravascular RBC lysis with release of RBC stroma and free Hb. Immune system activation also results in bradykinin release (leading to hypotension) and mast cell activation (causing serotonin and histamine release). The net result may be shock, renal failure due to Hb precipitation in renal tubules, and DIC. Many signs and symptoms of an acute hemolytic transfusion reaction appear immediately and include fever, chest pain, anxiety, back pain, and dyspnea. Many are masked by general anesthesia, but clues to the diagnosis include fever, hypotension, hemoglobinuria, unexplained bleeding, or failure of Hct to increase after transfusion. The incidence of fatal hemolytic transfusion reaction in the US is approximately 1 of every 250,000 to 1,000,000 units transfused. Most reactions occur because of administrative errors, with most due to improper identification of the blood unit or patient. The importance of adhering to strict policies of checking blood and matching to the correct patient in the operating room cannot be overemphasized.
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Air Embolism
The incidence of air embolism has now reduced markedly with the use of plastic blood bags. Nevertheless, air can enter a central catheter while blood administration sets or blood bags are being changed or if blood in an open system is infused under pressure.
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Allergic transfusion reactions
Allergic transfusion reactions are common, occurring in 1% to 3% of transfusions. They arise from recipient antibody response to donor plasma proteins. Urticaria with pruritus and erythema is the most common manifestation, but rarely bronchospasm or anaphylaxis presents. Many patients also have a fever. Patients with IgA deficiency may be at increased risk of allergic transfusion reaction because of the presence of anti-IgA antibodies that react with transfused IgA. Treatment involves stopping the transfusion, excluding a more severe reaction, and administering antihistamines.
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Bacterial and Viral Infections
Bacterial and viral contamination of blood components is an infrequent complication of transfusion. However, if it does occur, the potential for fulminant sepsis in a recipient is associated with high mortality. It can result from contamination during venipuncture or if a symptomatic donor is bacteremic or viremic at the time of donation. Symptoms occur during or shortly after transfusion of the contaminated unit and include high fever, rigors, erythema and cardiovascular collapse.
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Coagulopathy
A massive transfusion of RBCs may lead to a dilutional coagulopathy, as plasma-reduced RBCs contain neither coagulation factors nor platelets. Secondly, hemorrhage, as a consequence of delayed or inadequate perfusion, can result in DIC. This causes consumption of platelets and coagulation factors and may account for the numerical distortion of clotting studies appearing out of proportion to the volume of blood transfused. Aggressive, expectant replacement of clotting factors with FFP, platelets and cryoprecipitate transfusions are required to prevent this coagulopathy becoming severe enough to make hemorrhage worse.
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Delayed hemolytic transfusion transfusion reactions
Delayed hemolytic transfusion reactions occur because of incompatibility of minor antigens and are characterized by extravascular hemolysis. They present 2 days to months after transfusion. Patients complain of no or minimal symptoms but may display signs of anemia and jaundice. Lab studies reveal a positive direct antiglobulin test, hyperbilirubinemia, decreased haptoglobin levels, and hemosiderin in the urine.
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Febrile nonhemolytic transfusion reactions
Febrile nonhemolytic transfusion reactions are the most common transfusion reactions, occurring in approximately 1% of RBC transfusions and up to 30% of platelet transfusions. They occur when anti-leukocyte antibodies in a recipient react with white blood cells in a transfused blood product. Signs and symptoms include fever, chills, tachycardia, discomfort, nausea, and vomiting. Approach to treatment involves first stopping the transfusion and excluding an acute hemolytic transfusion reaction or bacterial contamination of the donor unit. Acetaminophen and meperidine may diminish fever and rigors. Once the diagnosis of FNHTR has been made, future reactions may be avoided or diminished by administering leukocyte-reduced blood products, premedicating at-risk patients with acetaminophen and hydrocortisone and administering the transfusion slowly.
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Graft-Versus-Host Disease (GVHD)
Graft-Versus-Host Disease (GVHD) is a rare and almost always fatal complication of blood transfusions resulting from an attack of immunocompetent donor lymphocytes on the host’s various tissues. After the majority of transfusions, the donor lymphocytes are destroyed by the recipient’s immune system, preventing GVHD. However, if the host is immunodeficient or if there is a specific type of partial HLA matching between the donor and recipient, GVHD is more likely to occur. It can develop 4 to 30 days after transfusion, with patients typically presenting with fever and erythematous maculopapular rash that may become generalized. Other symptoms include anorexia, vomiting, abdominal pain, and cough. The diagnosis is made by a skin biopsy and confirmed by demonstrating circulating lymphocytes that have a different HLA phenotype verifying their origin from the donor. GVHD is poorly responsive to available treatments. Therefore, prevention is of utmost importance, which is achieved by irradiating all lymphocyte containing components with gamma radiation, thereby inactivating them.
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Hypothermia
Red blood cells are stored at 4 degrees Celsius. Rapid transfusion at this temperature will quickly lower the recipient’s core temperature and further impair hemostasis. Hypothermia reduces the metabolism of citrate and lactate and increases the likelihood of hypocalcemia, metabolic acidosis and cardiac arrhythmias. A decrease in core temperature shifts the oxyhemoglobin dissociation curve to the left, reducing tissue oxygen delivery at a time when it should be optimized. This reduction in temperature can be minimized by warming all I.V. fluids and by the use of forced air convection warming blankets to reduce radiant heat loss.
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Transfusion associated immunomodulation
The down-regulation of recipient’s cellular immune response caused by transfusion of allogeneic blood has traditionally been defined as transfusion associated immunomodulation (TRIM). The detrimental clinical impacts of TRIM are increased chances of post-operative infections and cancer recurrence and possibly a transfusion-related multiple organ dysfunction syndrome.
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TACO (transfusion-associated circulatory overload)
TACO (transfusion-associated circulatory overload) is a condition of circulatory congestion secondary to the fluid volumes administered as transfusions. The symptoms are similar to congestive heart failure and include dyspnea, pulmonary edema, tachycardia, and increased jugular venous distention. While TRALI also produces pulmonary edema, signs of circulatory overload are seen in TACO that helps differentiate the two. TACO often affects patients at risk for congestive heart failure and occurs in less than 1% of transfusions. If a patient is at risk for fluid overload, diuretics can be administered with transfusion as a preventative measure.
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Transfusion-Related Acute Lung Injury (TRALI)
Transfusion-Related Acute Lung Injury (TRALI) is a condition of severe pulmonary insufficiency following blood, FFP, cryoprecipitate, or platelet transfusion. Signs and symptoms include fever, dyspnea, hypoxemia, hypotension, and pulmonary edema developing within 4 hours of transfusion. TRALI happens when anti-HLA antibodies and anti-leukocyte antibodies present in donor plasma cause the recipient leukocytes to injure their own tissues. Most cases are tracked to female donors who have previously been pregnant and developed anti-HLA antibodies. Measures to prevent plasma donation by women who have been pregnant may reduce TRALI-related episodes.
In view of the number and potential severity of these complications of blood transfusion, one might expect to find improved patient outcomes when less blood is administered. This expectation is realized in an increasing number of high-quality published reports. The seminal study in this regard was the TRICC Trial published in the New England Journal of Medicine in 1999 — “A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care.” In this study 838 patients were randomized to a restrictive (Hgb target 7-9) or a liberal (Hgb target 10-12) transfusion strategy. Mortality was lower in those patients who were younger or less ill when a restrictive strategy was utilized.
Many subsequent studies of diverse patient populations have demonstrated the outcome benefits of a restrictive transfusion strategy or the lack of benefit of a liberal strategy.
A 2017 retrospective study of 605,046 patients admitted to four major adult tertiary-care hospitals in Western Australia published in Transfusion in 2017 reported “Improved outcomes and reduced costs associated with a health-system-wide patient blood management program.”
Why important?
Awareness of these risks is important because, as stated above, blood transfusion is still viewed by many healthcare providers as the only viable, scientifically sound and responsible option in many clinical scenarios. This strongly held conviction on the part of the provider may at times result in an adversarial or even overtly hostile stance toward the patient who chooses to decline transfusion, which may bring stress to the provider and harm to the patient.
The physician or nurse who is knowledgeable about the complications of blood transfusion is more likely to be motivated to expend the time and effort needed to master bloodless strategies. These strategies equip the provider to deliver optimal care not only for Jehovah’s Witnesses, but also for patients who cannot be transfused for other reasons, for example–in patients with hemolysis and antibody formation due to transfusion reactions, or those with crossmatch incompatibility–and in situations where blood is not available at all. It is also noteworthy that doctors like Dr. John Yosaitis, Medical Director for MedStarbloodless.org, who have welcomed the bloodless approach into their practice, frequently begin using bloodless strategies to treat all their patients. Many share Dr. Yosaitis view that the bloodless approach “is just better medicine.”
Application in adult care
In an article that includes a discussion of the mechanisms of transfusion and anemia, “A new perspective on best transfusion practices,” Shander et al. point out that “[d]espite widespread use, transfusion decisions are often taken in the absence of adequate training and based on limited and frequently low quality evidence alongside an often exaggerated anxiety towards any level of anaemia. Before being approved for clinical use, new therapeutics are expected to undergo rigorous randomised controlled trials to establish their safety and efficacy in the target population for the intended indication. In contrast, allogeneic blood transfusion has largely enjoyed a privileged status as a therapeutic, “grandfathered” to our era from the early twentieth century.”
Evidence-based investigations to evaluate the efficacy of blood transfusion have not yielded positive results proportionate to its almost universal acceptance and the degree to which it is entrenched in medical practice. As J. Rawn points out in his article “The silent risks of blood transfusion,” “Clinical research has identified blood transfusion as an independent risk factor for immediate and long-term adverse outcomes, including an increased risk of death, myocardial infarction, stroke, renal failure, infection and malignancy. New findings have called into question the traditional assumptions clinicians utilize in evaluating the risks and benefits of blood transfusion…Recent clinical outcomes research has examined the impact of blood transfusion on critically ill patients, trauma patients, patients undergoing cardiac surgery, patients experiencing acute coronary syndromes, oncology patients and others. These studies provide additional evidence of adverse outcomes associated with blood transfusion in a wide variety of clinical contexts…The benefits of blood transfusion have never been conclusively demonstrated, but evidence of transfusion-related harm continues to accumulate.”
Dr. Hiep Dao, Co-director of MedStar Georgetown University Hospital Program for Bloodless Medicine and Surgery, describes a “paradigm shift” taking place in some institutions where blood utilization has been significantly reduced by the application of bloodless strategies, and better outcome are achieved. Full interview
A global look at blood supplies gives even more reason to explore alternatives to blood transfusion. According to the World Health Organization’s 2017 report on blood safety and availability, for many patients, blood is simply not available. There are vast differences in the safety and availability of blood in high- versus low-income countries:
“About 112.5 million blood donations are collected worldwide. More than half of these are collected in high-income countries, home to 19% of the world’s population…There is a marked difference in the level of access to blood between low- and high-income countries. The whole blood donation rate is an indicator for the general availability of blood in a country. The median blood donation rate in high-income countries is 32.1 donations per 1000 people. This compares with … 4.6 donations per 1000 people in low-income countries…67 countries report collecting fewer than 10 donations per 1000 people…All are low- or middle-income countries.” This disparity in blood availability is paralleled by a related disparity in the rate of transfusion-transmissible infection:
Table 1. Prevalence of transfusion-transmissible infections in blood donations (Median, Interquartile range (IQR)), by income groups
| HIV | HBV | HCV | Syphilis | ||
| High-income countries | 0.003% | 0.03% | 0.02% | 0.05% | |
| (0.001% – 0.04%) | (0.008% – 0.18%) | (0.003% – 0.16%) | (0.005% –0.26%) | ||
| Upper middle-income countries | 0.08% | 0.39% | 0.21% | 0.31% | |
| (0.006% – 0.2%) | (0.16% – 0.69%) | (0.05% – 0.42%) | (0.12% –1.07%) | ||
| Lower middle-income countries | 0.20% | 1.60% | 0.40% | 0.58% | |
| (0.05% – 0.44%) | (0.94% – 4.13%) | (0.19% –1.5%) | (0.18% – 1.47%) | ||
| Low-income countries | 1.08% | 3.70% | 1.03% | 0.90% | |
| (0.56% – 2.69%) | (3.34% – 8.47%) | (0.67% – 1.80%) | (0.31% – 1.88%) |
Source: WHO report on blood safety and availability
In regions where blood supply is limited and/or risk is elevated, a skilled bloodless approach to anemia, trauma, and other conditions for which blood transfusion is often recommended offers even greater benefit to healthcare providers and their patients.
It is safe to say that any patient would prefer to avoid even the “mildest” complications of transfusion. Complications that may be considered clinically “minor” could be devastating or even lethal to a severely compromised patient, and blood transfusion has been shown to increase the probability of severe complications in certain patient populations. In an interview in our “Clinical Pearls” section, Gerald Sandler, Professor and Director of the Transfusion Service in the Department of Pathology and Laboratory Medicine at MedStar Georgetown University, candidly related his own experience when he faced cardiac surgery and was asked to sign a consent form for a blood transfusion:
“I’ve had open heart surgery, and I was faced with, do I want to get someone else’s blood if I don’t really really need it? And the surgeon didn’t know my specialty, and he came in and he said, ’You know, we’ve asked you to sign the informed consent for blood,’ and I said, ‘You know, I’m a specialist in transfusion medicine, and I’ve been there for decades’; but I came face to face with the reality that I talk about in the abstract to people. And when it really came to me—do I want to get someone else’s blood? Only unless I’m as white as my white lab coat would I want to get a transfusion; only if I was in a life-threatening situation; and that is where I come from, and where the contemporary specialization of transfusion medicine is—and of course, that’s where bloodless medicine and surgery is.”
After a 50-year career in transfusion medicine, Dr. Sandler gives this advice to his less experienced colleagues: “I’m relying on my older colleagues to convey to my younger colleagues the reality of their experience of having given a unit of blood that caused…maybe it was HIV, maybe it was Hepatitis C, and then questioning, ‘Did I really need to give Mrs. Smith that unit of blood that’s caused her to have this complication?’ And I want that message coming down from our more experienced physicians to the ones who are learning.” Full interview
Another observation that supports the legitimacy of the bloodless approach is that doctors who learn about it and practice it often come to use bloodless strategies for all their patients, as they see better outcomes. Even in settings where transfusion may still be an option, the lessons learned from the bloodless approach help the physician “treat the patient, not a number”:
Three of our MedStar specialists highlight this point in interviews:
Dr. John Yosaitis
Medical Director, MedStar SiTEL
“What got me interested in bloodless medicine is that I’m primarily interested in giving the best care to our patients. “We started coming up with techniques and allowing the hematocrits to go lower, and we started seeing better results—we started seeing our patients healthier, we started seeing them leave the hospital sooner, we started seeing their wounds heal faster, we just started seeing better outcomes…
“It’s not an alternative therapy at all, in fact, myself and a lot of other physicians started doing it for the Jehovah’s Witness patients, but now we do it for everybody; it’s mainstream medicine now; it’s just better medicine.”
Dr. Gerald Sandler
Professor and Chief of Transfusion Medicine
“I’ve learned to be comfortable with [a patient whose hemoglobin is below 6] and not to feel compelled to give her something less than optimal. Where does that come from? It comes from decades of experience and publications that have come out of the Jehovah’s Witness community globally, world wide…”
Dr. Willard Barnes
Chief of Gynecologic Oncology at MedStar Georgetown University Hospital
“[S]ince the bloodless medicine program has come to Georgetown, we’ve been able to minimize or eliminate the need for blood…any patient, if he or she could avoid the use of blood products, would prefer to do so…This works. A lot of good ideas are good; they just don’t work. This one works.”
Application in pediatric care
The implications for blood transfusion in pediatric care are the same as for adult care, except that the impact of transfusion on children may be more devastating than on adults. For example, J. Lavoie of Montreal Children’s Hospital ] provides this sobering report in her article “Blood transfusion risks and alternative strategies in pediatric patients”: “The incidence of noninfectious transfusion reactions is greater than that of infectious complications. Furthermore, the mortality associated with noninfectious risks is significantly higher. In fact, noninfectious risks account for 87-100% of fatal complications of transfusions. It is concerning to note that the majority of pediatric reports relate to human error such as overtransfusion and lack of knowledge of special requirements in the neonatal age group. The second most frequent category is acute transfusion reactions, majority of which are allergic in nature. It is estimated that the incidence of adverse outcome is 18:100,000 red blood cells issued for children aged less than 18 years and 37:100,000 for infants. The comparable adult incidence is 13:100,000.”
In low-income countries, the complications of blood transfusion in pediatrics contribute to a particularly distressing situation, described by facts from the World Health Organization Blood Safety report for the African Region: “The African Region faces a high demand for blood transfusion due to bleeding related to pregnancy and childbirth, high prevalence of malaria with the attendant complication of severe malarial anemia, high rates of road traffic accidents and other types of injury as well as other indications for blood transfusion.
“Challenges to the blood supply include: a high burden of disease transmissible through blood transfusion, including HIV, HBV, HCV and syphilis; posing difficulties in selecting donors at reduced risk of infection, unstable economies, lack of suitable infrastructure to provide blood services, inadequate human resources as well as lack of conducive career development structures for BTS staff in many member states. Reliance on family replacement donations, limited coverage and quality of testing, inappropriate blood transfusion and poorly developed quality systems pose additional challenges…In low-income countries, up to 65% of blood transfusions are given to children under 5 years of age [our emphasis]…”
The practice of administering blood transfusion to treat anemia of malaria carries an especially insidious risk in this setting. According to a study presented at the 7th Multilateral Initiative on Malaria (MIM) Pan African Malaria Conference in Dakar, Senegal (2017), there is a high prevalence of malaria parasites in banked blood. Selali Fiamanya, a co-author of the study and a research fellow at the Worldwide Antimalarial Resistance Network (WWARN), says his team assessed the presence of malaria parasites in 22,508 potential blood donors in 24 studies conducted in nine countries of Sub-Saharan Africa from 2000 to 2017. “The study assessed the presence of malaria parasites in blood bags. Prevalence ranged from 6.5 per cent to 74.1 per cent in different study sites.” Most of the studies were conducted in Central and West Africa, including more than ten studies from Nigeria.The group conducted a systematic review of the risk of transfusion-transmitted malaria from blood donors in Sub-Saharan Africa and concluded that “[w]ithout better vigilance, children receiving transfusions to address malaria’s impacts risk exposure to more malaria-causing parasites.”
According to the World Health Organization, 285,000 children died of malaria in 2016. It seems clear that treating children or adults for malaria in a manner that could potentially exponentially aggravate this already dire situation is not ideal from the standpoint of quality and safety.
The impact of the complications of blood transfusion on children is more severe than for adults, not only because they are physiologically and socially vulnerable, but also because of the number of years impacted by “life-long” harm.