Noninfectious Complications of Blood Transfusion

Issues of Concern

Classification of Non-infectious Complications of Blood Transfusion

These are broadly classified as acute and delayed reactions based on time of occurrence. These categories are further subclassified based on the etiology, whether it is immune or non-immune related. 

Acute Reaction (<24 hours)

•  Immune-mediated reactions include
  • Acute hemolytic transfusion reaction(AHTR) 
  • Febrile nonhemolytic transfusion reaction (FNHTR)
  • Allergic reactions 
  • Anaphylactic reactions 
  • Transfusion-related acute lung injury (TRALI) 
• Non-immune mediated reactions include
  • Air embolism
  • Transfusion-associated circulatory overload (TACO) 
  • Non-immune hemolysis

Delayed Reaction (>24 hours)

• Immune-mediated reactions include
  • Delayed hemolytic transfusion reaction(DHTR) 
  • Alloimmunization
    • To HLA antigens
    • To platelet antigens 
    • To red cell antigens
  • Transfusion-related immunomodulation (TRIM)
  • Transfusion-associated graft versus host disease (TA-GVHD)
  • Post-transfusion purpura (PTP)
• Non-immune reaction includes
  • Iron overload[5]

Clinical Significance

Hemolytic Transfusion Reaction (HTR)

This reaction occurs due to immune or non-immune-related RBC hemolysis. Incidence of HTR is 2.0 per 100,000 RBC transfusions. Our focus here is immune-mediated HTR, which is more clinically significant ann encountered more frequently than non-immune-related RBC hemolysis. HTR occurs due to immunologic incompatibility between the donor RBC and the recipient, i.e., the recipient has preformed antibodies against the antigen(s) on donor RBC. Immune-mediated-hemolysis can be due to ABO or non-ABO antibodies. These antibodies can be IgM (activate complement causing intravascular hemolysis), IgG (mainly causing extravascular hemolysis), or both. In most cases, ABO hemolysis is caused by the clerical error from the laboratory or the clinical service performing the transfusion; however, non-ABO hemolysis is multi-factorial. HTR are divided into Acute hemolytic transfusion reaction (AHTR) (<24hrs) or delayed hemolytic transfusion reaction(DHTR)(>24hrs). Most HTRs are due to RBC transfusion; however, less commonly, transfusion of plasma and platelets products containing high titers of isoagglutinin can also cause hemolysis of recipient RBCs.[6] 

Another important and avoidable cause of AHTR is clerical errors either at the transfusionist's end or the laboratory. ABO-incompatible transfusions are estimated to occur in 1 in 14,000 to 1 in 38,000 RBC transfusions.[2] As per data reported by SHOT, a clerical error was the most common cause of transfusion-related adverse events when defining clerical error as transfusion with a blood product that did not meet the appropriate requirements or that was intended for another patient.[6]. Delayed hemolytic transfusion reaction (DHTR) occurs due to the evanescence property of certain antibodies. It occurs in 7.3 per 100,000 RBC transfusions. The titer of these antibodies falls below the limit of detection. After the re-exposure, the transfusion antibody titer can quickly increase over a few days to up to 4 weeks (usually 3 to 14 days) and cause immune-mediated hemolysis.[7] The presentation can be an unexplained decrease in hemoglobin, low-grade fever, increased bilirubin to the full range of symptoms seen in AHTR, although rare. 

HTR can have a wide spectrum of symptoms, including fever, chills, rigors, chest/back/abdominal pain, infusion site pain, nausea/vomiting, shock, dyspnea, hemoglobinuria, oliguria/anuria, and diffuse bleeding. The severity of the reaction varies and can depend on the amount and how rapidly the incompatible blood is transfused. In severe cases, it can lead to acute kidney failure, shock, DIC, or death. Some of these symptoms are difficult to assess in certain populations, such as pediatric and unconscious patients.[2]

Laboratory findings of hemolysis are present, including decreased or absent haptoglobin, elevated bilirubin, elevated LDH, hemoglobinemia, or hemoglobinuria. In addition, the peripheral smear shows acanthocytes (intravascular hemolysis) and spherocytes (extravascular hemolysis). 

Immune-mediated HTR can be confirmed by positive direct antiglobulin test (DAT) in most cases which identifies IgG antibody or complement coating the RBC. The alloantibody, if present, can be confirmed in the plasma by indirect antiglobulin test(IAT). Rarely DAT can be negative if antibody-coated RBCs have already been cleared before the sample draw. 

Non-immune causes of HTR include improper storage of RBC or poor techniques of thawing leading to lysis, mechanical problems like small needle or malfunctioning pumps, properties of the RBC like donors having hemoglobinopathies.

• Management: Transfusion should be stopped immediately if AHTR is suspected. IV infusion with the goal to maintain urine output 70 -100ml/hr and monitor renal function. Supportive measures such as supplemental oxygen may be necessary. Monitor coagulation profile for DIC and send transfusion reaction work-up to the lab.  
• Prevention: Most common cause of AHTR is a clerical error. Practicing safe transfusion practices, including a robust patient identification process, can mitigate the incidence of these reactions. In addition, extended phenotype matched RBC transfusion can reduce the incidence of RBC alloimmunization and potential DHTR in patients who require chronic transfusion. 

Febrile Nonhemolytic Transfusion Reaction (FNHTR)

FNHTR is one of the most commonly encountered transfusion reactions occurring at a rate of 86.4 per 100,000 all components transfused.[4] It is generally mild and self-limiting; however, its symptoms overlap with other serious adverse events associated with transfusion. Therefore, FNHTR is a diagnosis of exclusion. It is defined as a fever greater than 100.4°F (38°C) and a change of at least 1.8°F (1.0°C) from the pretransfusion level during or within 4 hours of transfusion. Occasionally fever may be absent with the presence of chills and rigor only.[2] Diagnosis of FNHTR requires excluding both transfusion and non-transfusion-related possible causes of fever. It is generally associated with red blood cells and platelets transfusions but is uncommon with plasma products. 

The underlying pathophysiology is believed to be cytokines released by white blood cells in the stored blood products.[8] Implicated cytokines include interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha (TNFα). Alternate pathophysiology for FNHTR has been activating granulocytes by anti-neutrophil antibodies, suggesting it could be a mild form of transfusion-related acute lung injury (TRALI). 

• Management: Stop transfusion immediately. Send the transfusion reaction work-up to the laboratory. Acetaminophen to reduce fever. Exclude all other causes of fever. Demerol can be considered for severe rigors. As symptoms commonly overlap with other severe adverse events ruling out AHTR becomes critical.
• Prevention: leukoreduction is a key blood product modification that decreases FNHTR. Premedication with acetaminophen may be helpful in the event of repeated FNHTR. 

Allergic Transfusion Reactions (ATRs)

These are another group of common adverse events mainly caused by the transfusion of plasma and platelets. These reactions are estimated to occur in 1-3% of transfusions.[9] An allergic reaction can vary from mild skin manifestations such as hives, edema, pruritis, angioedema to serious life-threatening reactions like anaphylaxis presenting with hypotension and bronchospasm. Anaphylaxis has an incidence of 1 in 20,000 to 50,000 transfusions.[10]

Pathophysiology of these reactions is believed to be soluble antigens in the donor unit to which the recipient has been previously sensitized. Leukoreduction does not prevent this. Anaphylaxis has been reported in IgA deficient individuals with anti-IgA antibodies receiving blood products containing IgA, although other proteins can be responsible.[11]

• Management: Stop transfusion immediately. Mild allergic reaction presenting with hives and urticaria can be managed by the administration of diphenhydramine. Severe anaphylactic reactions may require administration of epinephrine, oxygen supplementation, and IV fluids.
• Prevention:  Premedication with diphenhydramine can be helpful in cases of recurrent allergic reactions. Cases with severe allergic reactions may require the washing of cellular products. In addition, products from IgA deficient donors can help to prevent anaphylaxis in recipients with IgA antibodies. 

Transfusion-related Acute Lung Injury (TRALI)

This is a life-threatening complication characterized by acute lung injury within 6 hours of transfusion and one of the leading causes of mortality associated with blood transfusion. It occurs in 1.2 per 100,000 components transfusions. The diagnosis requires ruling out all other possible causes of pulmonary findings.[12] Pathophysiology is the transfusion of plasma with anti-HLA (1&2) or anti-HNA antibodies.[13] 

Incidence correlates with high plasma volume transfusion and is 50 to 100 times more common in critically ill and surgical patients than in the general hospital population.[2] Other possible causes are antibodies in the patient reacting with transfused leukocytes (known as reverse TRALI) and pro-inflammatory (also known as non-immune TRALI) mediators that accumulate in the blood product released by RBCs and platelets during storage (soluble Lipids and CD40).[12] Clinically it presents with dyspnea, hypoxemia (O2 saturation <90% on room air), tachypnea, low-grade fever, rigors, tachycardia, hypothermia, and hypotension. New-onset bilateral pulmonary infiltrates on imaging in the absence of any other cause of acute lung injury. 

• Management: Stop transfusion immediately and notify blood bank/transfusion services. Perform chest imaging. Aggressive respiratory support with supplemental oxygen and/or positive airway ventilation, as needed. Steroids are not helpful. Diuretics are also not helpful since the underlying mechanism is not volume overload. 
• Prevention: Exclusion of plasma donation from high-risk donors such as multiparous women or screening and deferral of donors with HLA antibodies.  Leukoreduction may help prevent reverse TRALI. 

Transfusion-associated Circulatory Overload (TACO)

This s another leading cause of mortality associated with transfusion. It occurs in 9.1 per 100,000 component transfusion. TACO is related to underlying medical conditions such as heart failure and is more common in critically ill patients. Multiple blood products and the rate of transfusion is also a risk factor. Clinical presentation includes dyspnea, hypoxemia, tachycardia, hypertension. Imaging shows pulmonary edema and pleural effusion. Laboratory findings show elevation of the beta-natriuretic peptide (BNP). Symptoms and clinical presentation overlap with TRALI. However, the absence of fever, elevated BNP, hypertension (TRALI usually presents with hypotension), and symptomatic relief with diuretics favor TACO over TRALI.[14][15]

• Management: Stop transfusion immediately and notify the blood bank/transfusion services. Chest imaging and BNP. Diuretics fr symptomatic relief. 
• Prevention: Avoid unnecessary transfusion is the best measure. Transfuse blood products at a slow rate (up to 4 hours). Other options include splitting the blood products and volume depletion. 

Transfusion-associated graft versus Host Disease (TAGvHD)

This is a rare complication with very high mortality and has an incidence of 0.01 per 100,000 transfusions. The underlying mechanism is the transfusion of viable donor T lymphocytes that are present in blood products. T-lymphocytes engraft and proliferate in the host and induce an immune response characterized by fever, rash, liver dysfunction, pancytopenia, and gastrointestinal symptoms that develop over 1 to 6 wks after a transfusion. Pancytopenia due to bone marrow aplasia is usually the cause of fatality. Patients at the highest risk of this complication are the immunocompromised, such as very young patients, those receiving chemotherapy. Additionally, the patients receiving blood products from close first-degree relatives are susceptible to develop TA-GVHD due to a partial HLA match between the donor and the recipient. T-lymphocytes from donors are not recognized as foreign by the recipient immune system because of a heterozygous HLA haplotype for which the donor is homozygous. T-lymphocyte are present in cellular products, including RBC, platelets, and granulocytes but not plasma products.[16][2]

• Management: No definitive treatment. Immunosuppression with corticosteroids and cytotoxic agents can help up to some extent. A bone marrow transplant can be potentially curable; however, generally not an option due to the acute course of progression. 
• Prevention: Irradiation of blood products such as RBC, Platelets, and granulocytes. Avoiding haploidentical transfusions such as from close relatives.

Alloimmunization

Alloimmunization occurs due to the sensitization of the immune system to a particular antigen that is lacking in the host. Alloimmunization could be against RBC antigens, HLA antigens (present on WBC and Platelets), and (HPA) Human platelet antigen. There are over 30 different blood group systems based on RBC antigens, and their expression varies amongst individuals; hence there is a potential of developing antibodies on transfusion. The incidence of alloimmunization is 2 to 8% in chronic RBC transfusion recipients.[17]  Immunogenicity of the RBC antigen determines its ability to induce antibody formation, and the Rh "D" blood group is the most significant of these groups. Other important blood groups causing alloimmunization are Kell, Kidd, Duffy, and Rh groups (E > C > c). Alloimmunization leads to the risk of HTRs. 

HLA alloimmunization can occur by platelet or white blood cells exposure but not RBCs due to lack of HLA antigens on RBC. Studies have reported HLA alloimmunization rate of approximately 64% with non-leukoreduced product transfusion.[18] HLA I alloimmunization can cause platelet refractoriness. HLA alloimmunization can cause complications leading to graft rejection.[19]

HPA alloimmunization can also cause platelet refractoriness but is relatively uncommon compared to HLA alloimmunization. Its incidence is reported to be 2 to 10% in multiply transfused patients. It primarily occurs to HPA-1b and HPA-5b antigens. Patients with Bernard-Soulier syndrome and Glanzmann thrombasthenia are at risk of developing antibodies to  GPIb/IX/V and GPIIb/IIIa platelet antigens.[20]

• Management:  Platelets: HLA or HPA matched platelet products are considered in individuals with platelet refractoriness after ruling out other etiologies of refractoriness. Crossmatched products can also be considered.
  • RBC: Antigen negative units in an individual known to have alloantibody should be matched in pretransfusion testing.
• Prevention:  Leukoreduction can prevent HLA alloimmunization. Extended phenotype matching of RBC can be helpful in chronically transfused patients; however, it is difficult to implement. Platelet ABO matching and leukoreduction have been shown to reduce the requirement of HLA-matched platelet transfusions.[21]

Other Non-infectious Complications

Complications Due to Massive Transfusion: Massive transfusion is when 10 or more RBC units are transfused within 24 hours.[22] Complications can arise related to metabolic and hemostatic issues, immune hemolysis, and air embolism. Metabolic complication as acidosis and hyperkalemia can occur immediately. Following transfusion, citrate toxicity can also occur, which causes alkalosis, hypocalcemia and can lead to hypokalemia. This is more likely to occur in patients that have gone into shock or have liver impairment. These complications may not warrant a treatment unless severe and causing symptoms. Massive transfusion can also cause hypothermia. Hemostatic issues include thrombocytopenia, platelet dysfunction, elevated prothrombin time (PT), and partial thromboplastin time (PTT). The reason behind these findings is believed to be consumptive coagulopathy in addition to dilution factors.[23]

Complications related to the storage and processing of blood components are usually benign. Citrate anticoagulant in the blood products chelates calcium and can cause symptoms related to hypocalcemia. Other complications could be related to the accumulation of storage lesion-related molecules, e.g., cytokines, potassium, or depletion of important nutrients over a period of storage such as 2,3 DPG required to maintain RBC membrane integrity. Older platelets tend to lose their quality and may be less functional in-vivo.

Fresh blood products may be needed in specific patient populations. For instance, fresh RBC for newborns as their body has not yet developed to replenish depleted 2,3DPG, unlike adults.

Postransfusion Purpura (PTP): This is a rare complication to platelet transfusion with an incidence of 1 in 25,000 transfused units. It occurs due to antibodies against platelet-specific antigens, mainly HPA-1 or HPA-3a, leading to thrombocytopenia and wet purpura, usually 5-10 days from transfusion. Management includes the use of intravenous immunoglobulin (IVIG) and use of antigen-negative platelets. 

Transfusion-related immunomodulation (TRIM): This is an area still debated. Its a complication leading to immune system dysregulation, which causes increased morbidity and mortality. It is a host T-cell mediated response due to the transfusion of blood products containing leukocytes. Leukocytes in transfused products are believed to cause inhibition of cellular Th1 response while increasing cellular Th2 response, which leads to decreased immunity with increased susceptibility to infections and increased hospital stay, especially in a certain group of patients like cardiac surgery.[24]

Hypotensive Reaction: This reaction can occur as an underlying part of a transfusion reaction or patient's condition; Standalone hypotensive reaction is considered when a drop in the systolic BP of ≥30 mmHg and systolic BP ≤80 mmHg or  25% drop in the baseline systolic BP of children. Bedside leukoreduction filters and/or angiotensin-converting enzyme (ACE) inhibitors are implicated in acute hypotensive reactions.[25]

Enhancing Healthcare Team Outcomes

Blood products should be transfused based on guidelines, and clinical assessment and unnecessary transfusions should be avoided. Transfusions have become a lot safer over few decades with the advancement of component preparation practices. For example, Leukoreduction of RBC or platelets significantly reduces complications of FNHTR and HLA alloimmunization. These product modifications are implemented predominantly in developed nations but still universally lacking in the developing world. Irradiation, washed RBC/platelets and plasma depletion of platelets are the specific modification that should be put in place for patients with special blood product need. 

A thorough discussion about such procedures between the physician and blood transfusion specialist always helps benefit the patient. Close communication between blood banks and clinical services is crucial to establish safe transfusion practices. Hemovigilance keeps track of adverse events and helps develop better policies to reduce the chance of any transfusion-related complication.

With ever-changing medicine, we are bound to keep ourselves updated with the latest guidelines in transfusion. Participation in CMEs, conferences, and symposium help transfer techniques and the latest technology to improve patient care. Regular academic interaction between physicians in the blood bank and at the patient end is crucial and technical and nursing staff. Every physician undergoing residency should have a mandatory rotation in transfusion medicine to implement better transfusion practice overall.

Nursing, Allied Health, and Interprofessional Team Interventions

All team members involved in the transfusion chain play an integral role in preventing errors or early identification of transfusion complications. Therefore, proper training and regular education of interdisciplinary teams consisting of laboratories, physicians, nurses, and phlebotomists involved in the transfusion process is paramount to achieve safe transfusion.