A sixty-one-year-old gentleman with hypertension, diabetes mellitus, and end-stage renal disease presented with shortness of breath, cough, and lethargy for five days. COVID-19 RNA qualitative real-time- polymerase-chain-reaction (PCR) assay tested positive. During the hospital stay, he had progressive dyspnea requiring intubation and mechanical ventilation. During the second week of hospital stay, an acute drop in the hemoglobin (Hb) level to 4.5 g/dl (baseline Hb 9 g/dl).

Work-up for acute anemia revealed serum iron levels of 59 mcg/dL (normal range, 35.5-44.9), ferritin level was 1250 ng/mL (normal range, 24-336), and iron saturation was 22 % (normal 20-55 %).  The absolute reticulocyte counts were 0.1200 M/µL (normal range, 0.01600-0.1000 M/µL), and the reticulocyte index was 1.84 % (normal range, 0.5-2.5 %). Total bilirubin was 3.1 mg/dL (normal range, 0.0 to 1.6 mg/dL) and direct bilirubin was 0.6 mg/dL, LDH was 500 U/L, D-Dimer of 3890 ng/ml. Peripheral blood film showed extensive agglutination of red blood cells (RBCs) at a low temperature of 7° C (Figure 1) but no agglutination on rewarming the blood sample to 37° C (Figure 2). His direct antibody testing was positive (2+) for anti-complement (C3d) direct antiglobulin. Cold agglutinin titers were elevated at 1:160.Further testing for his hemoglobin free plasma level was elevated; 192 mg/dL (normal range, <8.0mg/dL) repeat value 2 weeks later was low; 10.5mg/dL. Urine analysis was positive for 3+ blood. Urine hemosiderin was negative. Retroperitoneal and complete abdominal ultrasound showed no active bleeding or hematoma. The fecal occult blood test was negative.

Although in our patient acute drop of hemoglobin is not related to cold agglutination syndrome, an incidental finding of elevated cold agglutinins has been noted. Not all individuals with these infections who develop cold agglutinins will have clinically significant hemolysis.