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 Table of Contents  
Year : 2022  |  Volume : 13  |  Issue : 3  |  Page : 154-156

Cold agglutinin disease in COVID-19 causing severe intravascular hemolysis

1 Department of Pathology, Vijaya Medical and Educational Trust, Chennai, Tamil Nadu, India
2 Department of Medicine, Vijaya Medical and Educational Trust, Chennai, Tamil Nadu, India

Date of Submission11-Jun-2021
Date of Decision04-Dec-2021
Date of Acceptance22-Dec-2021
Date of Web Publication15-Sep-2022

Correspondence Address:
Dr. Sarah Grace Priyadarshini
27 Vinayakar Koil Street, Little Mount, Chennai - 600 015, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_75_21

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Cold agglutinin disease (CAD) is a distinct type of acquired immune hemolytic anemia. It can be idiopathic (primary) or secondary to infections, neoplasms and autoimmune diseases. Mycoplasma pneumonia and EBV are the infections commonly associated with secondary CAD. In the current COVID-19 pandemic, there are very few case reports showing an association between CAD and COVID-19.

Keywords: Cold agglutinin disease, COVID-19, Hemolysis

How to cite this article:
Priyadarshini SG, Pasupulati S. Cold agglutinin disease in COVID-19 causing severe intravascular hemolysis. J Appl Hematol 2022;13:154-6

How to cite this URL:
Priyadarshini SG, Pasupulati S. Cold agglutinin disease in COVID-19 causing severe intravascular hemolysis. J Appl Hematol [serial online] 2022 [cited 2023 Sep 30];13:154-6. Available from: https://www.jahjournal.org/text.asp?2022/13/3/154/356095

  Introduction Top

Cold agglutinin disease (CAD) is caused by IgM antibodies against I antigen of the red blood cells (RBCs). They are referred to as “cold antibodies” as they have higher titers and increased RBC binding activity as the temperature drops toward 0°C.[1] The thermal amplitude is the temperature range over which the antibodies are reactive. The naturally occurring cold antibodies have a thermal amplitude of <4°C, whereas the pathologic cold agglutinins, which are clinically significant, have a thermal amplitude above 30°C.[2] Here we present a case of CAD associated with COVID-19 presenting with massive intravascular hemolysis.

  Case Report Top

A 43-year-old male presented to the emergency room with fever, cough for 7 days and breathlessness for 3 days. On examination, the patient was febrile and tachypneic with a sPO2 of 80. The patient was given high flow O2 (15 L/min) to maintain target sPO2 of 94. Reverse transcriptase-polymerase chain reaction was positive for COVID-19. Chest computed tomography revealed bilateral ground-glass opacity involving 45% of lung fields. Initial blood investigations revealed a hemoglobin of 11.9 g/dl, total WBC count of 14310/cumm, with neutrophilic leukocytosis, platelet count of 4,56,000/cumm and reticulocyte count of 1%. The automated analyzers gave a false high Rbc indices with a low hematocrit (MCV 103.3fl, MCH317.3 pg, MCHC 307.3 g/dl, and HCT 4.1%). The peripheral smear showed a marked agglutination of RBCs and a possibility of CAD was suggested [Figure 1]. A direct Coombs test was done, which was positive for C3 (3+). On the 1st day of admission the patient had serum bilirubin of 1.5 mg/dl, ALT of 85 IU/L, AST of 52 IU/L, LDH of 882U/L, CRP of 11 mg/dl, ferritin of 3704 ng/ml, urea of 20 mg/dl, creatinine of 0.5 mg/dl, fibrinogen of 473 mg/dl, and D-Dimer of 8539 ng/ml. The patient was started on remdesivir and steroids. The patient did not have a history suggestive of hemolytic anemia. On the secondday, patient developed hemoglobinuria [Figure 2]. There was a sharp drop of hemoglobin from 11.9 to 8.3 g/dl, (MCV 132.0fl, MCH 372.1 pg, MCHC 281.9 g/dl and HCT 2.5%), reticulocyte count increased from 1% to 3.5%, LDH also increased from 882U/L to 5661U/L and there was an increase in bilirubin from 1.5 to 5.17 mg/dl with unconjugated hyperbilirubinemia (Indirect-4.43 mg/dl). There was also an increase in total WBC count (31,000/cumm), platelet count (10,98,000/cumm), and D-Dimer (19,385 ng/ml). On the third, the patient was intubated and was put on mechanical ventilation. There was persistent hemoglobinuria and a further drop of hemoglobin to 5.3 g/dl (MCV 130.5fl, MCH 236.7 pg, MCHC 181,3 g/dl and HCT 4.4%). Blood transfusion with washed, warmed, packed red cells was given. Washed RBCs were given as there was minor crossmatch incompatibility. The patient developed severe acrocyanosis and complete renal shutdown. He developed a cardiac arrest and could not be resuscitated.
Figure 1: The peripheral blood smear of the patient showing marked agglutination (Leishman, ×400)

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Figure 2: Macroscopic appearance of hemoglobinuria

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  Discussion Top

CAD is characterized by the presence of cold active agglutinins IgM directed against “I” antigen in 90% of cases and “I” antigen in 10% of cases. In primary CAD, the etiology is a monoclonal IgMk antibody directed against the “I” antigen. Monoclonal antibodies can also be seen in monoclonal gammopathy of undetermined significance and Waldenstorm macroglobulinemia. In secondary CAD due to Mycoplasma, the culprit is a polyclonal IgM anti “I” antibodies. The underlying reason for the production of anti-I in mycoplasma can be due to the fact that “I” antigen act as receptors for mycoplasma and any modification can elicit an autoantibody response. It can also be attributed to the fact that the “I” like antigen on mycoplasma induces a cross-reacting antibody that causes RBC lysis. In infectious mononucleosis associated CAD polyclonal IgM and IgG directed against both “I” and “I” have been implicated. Despite the presence of cold agglutinins, clinically significant hemolysis is seen in few cases. Anemia in CAD is mild to moderate with chronic extravascular hemolysis by the Kupffer cells in the liver via its C3 receptor which results in phagocytosis of C3b coated RBCs. The remaining IgM coated RBCs fix complements on its surface, but the complement inhibitors CD55 and CD59 inhibit the formation of membrane attack complex, thereby preventing hemolysis. However, with higher titers of IgM, higher thermal amplitude, and in the presence of a pro-inflammatory state there is a more robust complement activation overwhelming the inhibitory effect of CD55 and CD59, resulting in intravascular hemolysis and hemoglobinuria.[3]

The pathogenesis of COVID-19 is characterized by hyperinflammatory state resulting in cytokine storm and procoagulant state. Various autoimmune disorders have been reported as a complications in COVID including autoimmune thrombocytopenia, antiphospholipid syndrome, and Guillain-Barre syndrome.[4] Few case reports of COVID-19-associated CAD have been reported, which includes both cases without significant hemolysis as well as cases with severe hemolysis. Kaur et al. reported two cases of transient cold agglutinins without significant hemolysis.[5] Jensen et al. also reported two cases of CAD in COVID-19 with only minimal hemolysis.[6] However, Zagorski et al. reported a case of COVID-19 associated CAD with massive intravascular hemolysis resulting in hemoglobinuria.[7] The largest series of seven cases of autoimmune hemolytic anemia (AIHA) associated with COVID-19 was reported by Lazarian et al. This study included 3 CAD and 4 warm AIHA developed during the course of COVID-19 infection.[8] This review of the literature suggests a possible association between COVID-19 and CAD. The hyperinflammatory state that is triggered in COVID-19 possibly results in autoimmune dysregulation and production of autoantibodies against the RBC antigens resulting in hemolytic anemia.

The role of drugs in the development of immune hemolytic anemia was also analyzed. This patient has been treated remdesivir and steroids. Remedesivir has been known to cause elevation of liver enzymes, renal injury, hypotension, arrhythmia, and rash.[9] As there is no documented association of remdesivir with immune hemolytic anemia, a possibility of COVID-19 association can be suggested in this patient.

  Conclusion Top

The present case shows the possible association of COVID-19 with CAD, resulting in massive intravascular hemolysis and an adverse patient outcome. Therefore, in patients presenting with CAD and atypical pneumonia a possibility of COVID-19 should also be excluded.


We would like to thank our laboratory technical staff and nursing staff for their cooperation.

Ethics approval

Ethics approval was obtained.


The authors certify that they have obtained all appropriate patient consent forms. Patient's privacy has been maintained.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Berentsen S. Cold agglutinin disease. Hematology Am Soc Hematol Educ Program 2016;2016:226-31.  Back to cited text no. 1
Hopkins C, Walters TK. Thermal amplitude test. Immunohematology 2013;29:49-50.  Back to cited text no. 2
Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood 2013;122:1114-21.  Back to cited text no. 3
Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, et al. COVID-19 and autoimmunity. Autoimmun Rev 2020;19:102597.  Back to cited text no. 4
Kaur J, Mogulla S, Khan R, Krishnamoorthy G, Garg S. Transient cold agglutinins in a patient with COVID-19. Cureus 2021;13:e12751.  Back to cited text no. 5
Jensen CE, Wilson S, Thombare A, Weiss S, Ma A. Cold agglutinin syndrome as a complication of COVID-19 in two cases. Clin Infect Pract 2020;7:100041.  Back to cited text no. 6
Zagorski E, Pawar T, Rahimian S, Forman D. Cold agglutinin autoimmune haemolytic anaemia associated with novel coronavirus (COVID-19). Br J Haematol 2020;190:e183-4.  Back to cited text no. 7
Lazarian G, Quinquenel A, Bellal M, Siavellis J, Jacquy C, Re D, et al. Autoimmune haemolytic anaemia associated with COVID-19 infection. Br J Haematol 2020;190:29-31.  Back to cited text no. 8
Charan J, Kaur RJ, Bhardwaj P, Haque M, Sharma P, Misra S, et al. Rapid review of suspected adverse drug events due to remdesivir in the WHO database; findings and implications. Expert Rev Clin Pharmacol 2021;14:95-103.  Back to cited text no. 9


  [Figure 1], [Figure 2]


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