Impact of cold agglutinin syndrome on clinical manifestations in COVID-19

In a recently published case report Journal of Clinical Laboratory Analysisresearchers presented two cases to highlight the impact of cold agglutinin syndrome (CAS) on the clinical manifestations of coronavirus disease 2019 (COVID-19).

Study: Cold agglutinin anti-I antibodies in two patients with COVID-19. Photo credit: Kira_Yan/Shutterstock


CAS has been identified among previously infected individuals Mycoplasma pneumoniae, measles virus, and Epstein Barr virus (EBV), increased risk of thrombosis among individuals with lymphoproliferative disorders. Abnormalities in coagulation have been reported in severe cases of COVID-19. Studies have documented thrombosis and hemolytic anemia in cases of CAS associated with COVID-19; however, the clinical significance of CA in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is unclear.

About the case report

In the current report, researchers describe two patients with SARS-CoV-2 infection who developed high CA titers without thrombosis or hemolytic anemia.

Two patients had no known risk factors for CA and were diagnosed as SARS-CoV-2-positive. Serum was obtained from the first patient and the second patient on day 11 and day 32 after admission. To detect the presence of CA, sera were applied to rabbit erythrocyte stroma, an absorber of anti-I immunoglobulin M (IgM) antibodies. Adult type O red blood cells (RBCs) were used, and newborn (infant) type O red blood cells were obtained from the remaining peripheral blood samples.

Autologous erythrocytes can only be obtained from a second patient. Later, erythrocyte agglutination analysis was performed. Erythrocyte agglutination with elevated CA titers was observed in both patients. The team retrospectively confirmed that the CAs were anti-I antibodies. None of the SARS-CoV-2 positive cases showed hemolysis or thrombosis, but elevated CA titers.

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The first case was a 64-year-old male patient who presented with fever for five days. He suffered a myocardial infarction seven years ago. Nasopharyngeal swabs collected from the patient were subjected to rRT-PCR (real-time reverse transcription polymerase chain reaction) analysis and diagnosed as SARS-CoV-2-positive. A chest x-ray revealed bilateral infiltration, and he presented clinically with hypoxia and was admitted to the hospital in January.

His peripheral blood smear (PBS) study showed elevated MCHC (mean corpuscular hemoglobin concentration) and strong adult erythrocyte agglutination at 4°C, which was disrupted by absorption of anti-IgM antibodies by rabbit erythrocyte stroma (RES) at 25°C. C. Agglutination of erythrocytes was not observed in newborns. Further laboratory studies revealed low zinc levels and macrocytic anemia without hemolytic anemia.

DAT (direct antiglobulin test) showed C3b/C3d-positive and immunoglobulin G (IgG)-negative. CA titers were elevated (1:512), well above the normal range (0 to 1:63 titers), and it was negative for the Donat-Landsteiner antibody. In addition, the results of the bone marrow biopsy showed no malignant cells in the lymphoma.

On the 6th day after hospitalization, he was put on mechanical ventilation due to worsening hypoxia. Thereafter, treatment with tocilizumab, piperacillin-tazobactam, and dexamethasone was initiated, and mechanical ventilation was gradually discontinued after therapy. Zinc supplementation and clinical treatment increased hemoglobin (Hb) levels and reduced CA titers to 10.6 mg/dL and 1:64, and he was discharged on day 38 of hospitalization.

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The second case is a 76-year-old female patient with rRT-PCR-diagnosed SARS-CoV-2 infection six days before hospitalization due to pneumonia and hypoxia in May. After treatment with remdesivir and dexamethasone, the pneumonia improved, but she developed a urinary tract infection (UTI).

His PBS was collected on day 25 after hospitalization and showed strong RBC agglutination at 4°C. However, the reduced effect of RBC agglutination on the adsorption of anti-I antibodies by RES was found to be weaker compared to that observed in the first patient. Further evaluation using ficin-treated RBCs confirmed the presence of anti-I antibodies.

His MCHC was elevated, Hb level was 15 g/dL, and DAT showed C3b/C3d-positive and IgG-negative results. An elevated CA titer of 1:2048 was observed, which decreased to 1:512 at the first outpatient follow-up after discharge.


The results of this case report show that not all cases of COVID-19 with anti-I and CAS (COVID-19/CAS) have clinical manifestations such as thrombosis and hemolysis due to elevated MCHC. Therefore, subclinical cases of COVID-19/CAS can be overlooked. Clinical manifestations may have been absent in two patients due to lack of exposure to cold stimulation; however, further studies are needed to clarify the pathophysiology of CA in SARS-CoV-2 infections.

SARS-CoV-2-positive patients may develop a hypercoagulable state because of underlying coagulation abnormalities such as endothelial damage, hypercoagulability, and stasis (Virchow’s triad). CAS may exacerbate the hypercoagulable state in SARS-CoV-2-positive patients; therefore, the diagnosis of COVID-19/CAS may be clinically relevant.


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