Skip to main content

Cold agglutinin-induced hemolytic anemia during room temperature fluid resuscitation: a case report

Abstract

Background

Cold agglutinin disease can cause the agglutination of red blood cells and hemolytic anemia due to cold temperature. Herein, we report a case of progressive hemolytic anemia due to cold agglutinin disease during fluid resuscitation and in the absence of exposure to cold.

Case presentation

A 71-year-old Japanese man was admitted to the emergency department with signs of hypotension and disturbed consciousness. He was diagnosed with diabetic ketoacidosis, and treatment with fluid resuscitation and insulin infusion was initiated. Laboratory test results obtained the following day indicated hemolytic anemia. On day 5 after admission, red blood cell agglutination was detected, and the patient was diagnosed with cold agglutinin disease.

Conclusions

Cold agglutinin disease should be considered in the differential diagnosis of progressive hemolytic anemia during fluid resuscitation, even if the solution is at room temperature.

Peer Review reports

Background

Anemia in patients admitted to intensive care is a common and significant problem, with 90% of patients developing anemia by the third day after admission, and 97% by the eighth day [1]. The most common causes of anemia in intensive care unit (ICU) patients are chronic diseases (32.4%) and blood loss (11.8%), with hemolysis being the cause in only 2.9% of cases [2].

Cold agglutinin disease (CAD) can cause red blood cell (RBC) agglutination and extravascular hemolysis in patients exposed to cold temperatures, resulting in anemia. CAD is caused by high levels of circulating cold agglutinins (CAs). To avoid exposure to cold temperatures, maintenance of room temperature, protection of the extremities and acral areas of the face with warm clothing, and avoidance of cold food or liquid consumption are recommended. Cold intravenous solutions and transfusions should be avoided in hospitalized patients.

In this study, we present a case of a patient with diabetic ketoacidosis (DKA) and progressive anemia due to CAD during fluid resuscitation, despite the intravenous infusion being administered using a solution at room temperature.

Case presentation

A 71-year-old Japanese man was admitted to our hospital with signs of hypotension and disturbed consciousness. The patient had a history of type 2 diabetes, but due to treatment default he was not receiving any regular medication. There was no other specific medical, social, family, or surgical history. On examination, the patient appeared pale and ill, and he had livedo reticularis. The patient’s blood pressure was 85/47 mmHg, pulse rate was 125 bpm, respiratory rate was 20 breaths/min with O2 saturation of 99% in room air, and rectal temperature was 33 ℃. The neck was supple. Results of the cardiovascular examination were normal, lungs were clear to auscultation, and the results of the abdominal examination were unremarkable. On neurological examination, his pupils were dilated to approximately 5 mm and were nonreactive to light; the Glasgow Coma Scale score was 6 (E4V1M1). Results from the initial laboratory tests revealed signs of macrocytic anemia (hemoglobin level 9.1 g/L, mean cell volume 112 fL), increased number of white blood cells (25,800 cells/μL), and elevated C-reactive protein level (40.4 mg/L). The patient had hyperglycemia (710 mg/dL). The arterial blood gas test showed metabolic acidosis (pH 6.723, base excess − 32.1 mmol/L) with an anion gap of 30.8. The urine test showed the presence of acetone bodies. Computed tomography without contrast of the whole body (head, chest-pelvis) showed bilateral pulmonary consolidation and mild pancreatic enlargement.

Based on hyperglycemia, presence of urinary acetone bodies, and metabolic acidosis with increased anion gap, the patient was diagnosed with DKA (Table 1). Initial treatment with fluid resuscitation (2000 mL per 1.5 h, lactated Ringer’s solution), insulin intravenous bolus of 5 U followed by intravenous continuous infusion (3 U/h), and active external rewarming with warm blankets was initiated in the emergency department. After the initial treatment, the patient was admitted to the ICU. Despite fluid resuscitation (400 mL/h), hypotension persisted, and treatment with norepinephrine and vasopressin was initiated. Twelve hours after admission to the ICU, his glucose level had decreased to 385 mg/dL, and 7600 mL of crystalloid fluid was administered. Complete blood count showed the progression of anemia. Biochemical analysis revealed elevated bilirubin levels, and he received a non-warmed blood transfusion. On day 3, his hemodynamic parameters improved. Thus, therapy with norepinephrine and vasopressin was discontinued, and the infusion rate was reduced (Table 2).

Table 1 Laboratory data on admission
Table 2 Laboratory findings during patient’s stay in the intensive care unit

On day 5 of the patient’s ICU stay, RBC agglutination was observed (Fig. 1). Based on RBC agglutination and elevated bilirubin levels, CAD was suspected. The result of the direct Coombs test was positive, and the CA titer test revealed an elevated autoantibody titer (1:8192 at 4 ℃). The patient was therefore diagnosed with CAD. No bacterial or viral infections causing CAD or DKA were detected (Table 3). He was discharged from the ICU on day 6. As a preventive measure, the patient was recommended to avoid cold exposure. During the hospital stay, there was no recurrence of anemia. On day 32 following presentation, he was discharged from the hospital.

Fig. 1
figure1

Peripheral blood smear showing red blood cell agglutination (arrow)

Table 3 Results of laboratory tests performed to diagnose cold agglutinin disease and determine background infections

Discussion

A case of cold agglutinin disease is extremely uncommon in the emergency department. As our patient was not exposed to cold temperatures in the ICU, there was no suspicion of CAD at presentation. We therefore decided to investigate the mechanism of CAD hemolytic anemia during room temperature fluid resuscitation.

Previous studies have demonstrated that CAs bind to antigens on the surface of RBCs in the acral areas where the blood temperature is lower than the body temperature and that they recruit components of the complement pathways. Upon warming of the central circulation to body temperature, CAs detach from the RBCs, but C3b remains bound. Some of the C3b-coated RBCs are trapped by macrophages mainly in the liver, resulting in extravascular hemolysis [3].

According to the pathophysiology described above, we considered two possible mechanisms of hemolytic anemia in this case. The first is that the rapid room temperature infusion decreased peripheral intravascular temperature, resulting in the activation of CAs. Although CAs usually agglutinate RBCs at 4 °C, most clinically important CAs act at temperatures exceeding 28–30 °C [4]. A previous study showed that during a 30-min infusion of 30 mL/kg room temperature saline solution into healthy subjects, the core temperature decreased by 0.5 °C [5]. In light of this study, it is reasonable to suggest that rapid intravenous room temperature infusion also reduces peripheral intravascular temperature.

The second possible mechanism is that rewarming and subsequent improvement in hemodynamics by fluid resuscitation affect the delayed identification of hemolytic anemia. On admission, the patient had livedo reticularis, which is a manifestation of blood flow disturbance and vessel dilation. In CAD patients, agglutinated RBCs in the cooler peripheral areas cause a hyperviscosity of blood flow and blood stasis in the capillary venules, which in turn leads to livedo reticularis [6]. There is a possibility that our patient was exposed to cold temperatures before hospitalization. As active external rewarming was performed in the hospital, CAs then detached from RBCs, and capillary stasis was eliminated; at the same time, fluid resuscitation increased blood return to the central circulation, resulting in hemolysis of C3b-coated RBCs in the liver.

There are some reports of incidental diagnosis of CAD in medical practice where the clinical symptoms presented intraoperatively during hypothermic cardiopulmonary bypass [7, 8]. Barbara et al. recommend that patients with a history or evidence of hemolysis and agglutinations should undergo CA and thermal amplitude tests in conjunction with a hematologic consultation before cardiac surgery [9].

In addition, CAD should be a differential diagnosis of progressive hemolytic anemia during rapid intravenous infusion, even if the solution used is at room temperature. In emergency care, fluid resuscitation is often administered. In patients with hemolytic anemia, peripheral blood smear, Coombs test, and CA test should be performed, and infusion or transfusion should be changed to a warmed one.

Conclusions

In this report, we present a case of hemolytic anemia during fluid resuscitation of a patient with DKA. CAD should be considered as a differential diagnosis in patients developing hemolytic anemia during fluid resuscitation, even if the solution used for resuscitation is at room temperature.

Availability of data and materials

Not applicable.

Abbreviations

CAD:

Cold agglutinin disease

CA:

Cold agglutinin

DKA:

Diabetic ketoacidosis

ICU:

Intensive care unit

RBCs:

Red blood cells

References

  1. 1.

    McEvoy MT, Shander A. Anemia, bleeding, and blood transfusion in the intensive care unit: Causes, risks, costs, and new strategies. Am J Crit Care. 2013;22:eS1–13.

    Article  Google Scholar 

  2. 2.

    Tosiri P, Kanitsap N, Kanitsap A. Approximate iatrogenic blood loss in medical intensive care patients and the causes of anemia. J Med Assoc Thail. 2010;93(Suppl 7):S271–6.

    Google Scholar 

  3. 3.

    Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122:1114–21.

    CAS  Article  Google Scholar 

  4. 4.

    Baines AC, Brodsky RA. Complementopathies. Blood Rev. 2017;31:213–23.

    CAS  Article  Google Scholar 

  5. 5.

    Moore TM, Callaway CW, Hostler D. Core temperature cooling in healthy volunteers after rapid intravenous infusion of cold and room temperature saline solution. Ann Emerg Med. 2008;51:153–9.

    Article  Google Scholar 

  6. 6.

    Copeman PW. Livedo reticularis. Signs in the skin of disturbance of blood viscosity and of blood flow. Br J Dermatol. 1975;93:519–29.

    CAS  Article  Google Scholar 

  7. 7.

    Patel PA, Ghadimi K, Coetzee E, Myburgh A, Swanevelder J, Gutsche JT, et al. Incidental cold agglutinins in cardiac surgery: intraoperative surprises and team-based problem-solving strategies during cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2017;31:1109–18.

    Article  Google Scholar 

  8. 8.

    Kanemitsu S, Onoda K, Yamamoto K, Shimpo H. Simple preoperative management for cold agglutinins before cardiac surgery. J Thorac Cardiovasc Surg. 2010;140:e73–4.

    Article  Google Scholar 

  9. 9.

    Barbara DW, Mauermann WJ, Neal JR, Abel MD, Schaff HV, Winters JL. Cold agglutinins in patients undergoing cardiac surgery requiring cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2013;146:668–80.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

No funding was obtained from any agencies.

Author information

Affiliations

Authors

Contributions

All authors participated in patient care. YK and YH prepared the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yosuke Kawai.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Copies of the written consent are available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kawai, Y., Deguchi, M., Mizouchi, N. et al. Cold agglutinin-induced hemolytic anemia during room temperature fluid resuscitation: a case report. J Med Case Reports 15, 169 (2021). https://doi.org/10.1186/s13256-021-02784-8

Download citation

Keywords

  • Cold agglutinin disease
  • Hemolytic anemia
  • Fluid resuscitation
  • Diabetic ketoacidosis
  • Intensive care
\