Which of the following is an indicator of acute immune hemolytic transfusion reaction?

• Case report
• Open Access
• Published: 26 April 2017

BMC Surgery volume 17, Article number: 48 [2017] Cite this article

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Abstract

Background

Hemolytic transfusion reactions and transfusion-related acute lung injury [TRALI] are life-threatening complications associated with the transfusion of blood products. Hemorrhage is one of the most common surgical complications and the risk of bleeding is particularly acute in patients with hematologic deficiencies. Management of surgical bleeding can be divided into two phases. The first phase centers on immediate control of acute bleeding and the second phase focuses on keeping the patient stable and on reducing the sequelae associated with blood transfusions and blood loss.

Case presentation

We present the case of a 53-year-old woman with long-standing immune thrombocytopenia who underwent repair of a symptomatic ventral hernia. On post-operative day one the patient developed hemoperitoneum, requiring exploratory laparotomy and massive transfusion of blood products. The patient’s recovery was complicated by consistently low hemoglobin, hematocrit and platelets, prompting frequent transfusion of additional blood products. Shortly after activation of the massive transfusion protocol, the patient developed TRALI. Compounding the situation, on post-operative day sixteen the patient’s serum started to show hemolysis: lactate dehydrogenase [LDH] levels rose to 1,845 IU/L, with haptoglobin at less than 5.8 mg/dL and with a high reticulocyte count [4.38%]. Previous testing had shown that the patient was positive for most major antigens implicated in antibody formation and was only producing anti-E and anti-K antibodies [considered for all transfusions]. Initial pre- and post-transfusion direct antiglobulin tests [DAT] were indeed negative. However, repeat DATs in the days following the noted serum changes were consistent with new allo-antibody formation. These findings prompted immediate withholding of all blood products and a thorough blood bank work up. Despite strong evidence for new allo-antibody formation, no specific known antibody could be identified. The patient recover well when blood products were withheld.

Discussion

We present the case of a 53-year-old woman with long-standing immune thrombocytopenia who underwent repair of a symptomatic ventral hernia. On post-operative day one the patient developed hemoperitoneum, requiring exploratory laparotomy and massive transfusion of blood products. The patient’s recovery was complicated by consistently low hemoglobin, hematocrit and platelets, prompting frequent transfusion of additional blood products. Shortly after activation of the massive transfusion protocol, the patient developed TRALI. Compounding the situation, on post-operative day sixteen the patient’s serum started to show hemolysis: lactate dehydrogenase [LDH] levels rose to 1,845 IU/L, with haptoglobin at less than 5.8 mg/dL and with a high reticulocyte count [4.38%]. Previous testing had shown that the patient was positive for most major antigens implicated in antibody formation and was only producing anti-E and anti-K antibodies [considered for all transfusions]. Initial pre- and post-transfusion direct antiglobulin tests [DAT] were indeed negative. However, repeat DATs in the days following the noted serum changes were consistent with new allo-antibody formation. These findings prompted immediate withholding of all blood products and a thorough blood bank work up. Despite strong evidence for new allo-antibody formation, no specific known antibody could be identified. The patient recover well when blood products were withheld. Suspicion for hemolytic transfusion reactions should be high in patients with prior allo-antibody formation; these may present as acute hemolysis or as a delayed hemolytic transfusion reaction. Withholding blood products from these patients until compatible products have been identified is recommended. Moreover, TRALI is the leading cause of transfusion-related fatalities and should always be considered in transfusion settings.

Conclusions

Suspicion for hemolytic transfusion reactions should be high in patients with prior allo-antibody formation; these may present as acute hemolysis or as a delayed hemolytic transfusion reaction. Withholding blood products from these patients until compatible products have been identified is recommended. Moreover, TRALI is the leading cause of transfusion-related fatalities and should always be considered in transfusion settings.

Peer Review reports

Background

This case report describes the management of post-operative bleeding with focus on adverse blood transfusion associated events. Figure 1 provides a timeline of events pertinent to this case. The aim of this report is to highlight some of the challenges associated with blood transfusions and propose judicious use of blood products. Transfusion associated adverse events should be considered in cases that require activation of a massive transfusion protocol [MTP], frequently defined as transfusion of 10 units of blood or more in a 24-h period [1, 2]. The transfusion of blood products is often lifesaving; however, it does carry a significant risk and care must be taken. Two particularly egregious complications associated with blood transfusions are delayed hemolytic transfusion reactions [DHTR; [3, 4]] and transfusion-related acute lung injury [TRALI; [5, 6]].

Fig. 1

Timeline of pertinent events. BP – blood pressure; HLA+ – positive anti-human leucocyte antigen; LDH - lactate dehydrogenase; Pre-op – pre-operative; Post-op – post-operative; IVIG - Intravenous immunoglobulin; red = related to TRALI; Blue = related to antibody-associated hemolytic hemolytic transfusion reaction. *Multiparous donor tested positive for HLA antibodies

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Per the US Food and Drug Administration [FDA], 14% of transfusion related fatalities between 2011 and 2015 were due to non-ABO hemolytic transfusion reactions [7]. Non-hemolytic transfusion reactions can be enormously challenging to prevent, particularly in cases when multiple or rare antibodies are involved. The risk of hemolytic transfusion reactions triggered by antibodies to low frequency antigens is relatively low, estimated to be around 1 per 650,000 [8]: the effects can nonetheless be devastating. Delayed hemolytic transfusion reactions have been studied extensively in the setting of sickle cell disease and beta-thalassemia [9–12], emphasizing the importance of understanding the risk of adverse events in patients with baseline hematologic deficiencies.

Transfusion of red blood cells may trigger production of allo-antibodies capable of lysing incompatible donor RBCs, and in some cases the patient’s own blood cells as well [10]. In the case of DHTRs, lysis of RBCs generally does not occur until a few days after the initial transfusion of blood products. These may be caused by evanescent allo-antibodies in the setting of re-exposure to foreign antigens, or by new allo-antibody development to one of many known antigens. Hemolytic transfusion reactions have been reported to be caused by antibodies with varying specificities, including anti-c, anti-E, anti-Fy3, anti-Fya, anti-Fyb, anti-Jka, anti-Jkb, anti-K, anti-Kpa, anti-M, anti-N, anti-s and anti-U antibodies [13, 14]. Intravenous immune globulin [IVIG] associated hemolysis, used for the treatment of the patient presented below, has also been reported [15]. The symptoms may be somewhat nebulous and range from fever of unknown origin, to mild jaundice, to fatigue and to other non-specific findings [14]. A positive direct antiglobulin test [DAT] is telling; however, DAT can be negative in as many as 50% of cases [11]. Absence of the expected response to transfused blood products, as was seen in this case report [Fig. 2], can be a particularly important observation and should prompt withholding additional blood products [4, 10, 11].

Fig. 2

Shown are hemoglobin [Hgb], hematocrit [Hct] and platelet counts [Platelet Ct] over time [days]. Additionally, transfusion of fresh frozen plasma [FFP – purple square], cryoprecipitate [Cryo – green circle], platelets [blue diamonds] and packed red blood cells [Red Blood Cells – red triangle] is indicated. Five administered doses of IVIG are indicated. Zero on the x-axis correlates with y-values prior to the initial hernia repair. The arrow indicates embolization of the spleen. MTP = massive transfusion protocol; IVIG = Intravenous immunoglobulin

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TRALI is the leading cause of transfusion-related fatalities and is responsible for 38% of such fatalities [7]. Clinically, TRALI resembles acute respiratory distress syndrome [ARDS] – the underlying pathogenic mechanisms are however essentially different – and is associated with diffuse pulmonary edema, hypoxemia and hypotension [16]. The pathophysiology of TRALI is complex and incompletely understood; although, mouse models have contributed to our understanding of the disease mechanism [5, 17, 18]. TRALI can be either antibody-mediated [anti-human leucocyte antigen [HLA] class I or II or anti-human neutrophil antigen [HNA] antibodies] or non-antibody mediated [19]. A two-hit model is assumed to underlie the disease, in which the first hit is a patient predisposing factor, such as inflammation, while the second hit is present in the transfused product in the form of antibodies or biological response modifiers [5, 6, 20].

No definitive diagnostic test exists for TRALI to date and its diagnosis remains clinical. The US National Heart, Lung and Blood Institute Working Group and a consensus panel have formulated a definition for TRALI based on radiological and clinical criteria [6, 21–23]:

1. 1]

   Acute onset of respiratory distress within 6 h of blood transfusion

2. 2]

   PaO 2 /FiO 2 ratio of