On hospital day 5, providers noted repeated clotting of his CRRT circuit, prompting hematology consultation. Testing included platelets 823??109/L, D-dimer 3799?ng/mL (upper limit 230), and fibrinogen greater than 1000?mg/dL. 1 A 70-year-old man presented with fevers and cough. Chest imaging demonstrated bilateral infiltrates, and he was intubated for hypoxia before transfer to our medical center. Nasopharyngeal PCR was positive for SARS-CoV-2. He received vasopressors, ceftriaxone, and hydroxychloroquine. He developed renal failure requiring continuous renal replacement therapy (CRRT). On hospital day 5, providers noted repeated clotting of his CRRT circuit, prompting hematology consultation. Testing included platelets 823??109/L, D-dimer 3799?ng/mL (upper limit 230), and fibrinogen greater than 1000?mg/dL. Protime (PT) and activated partial thromboplastin time (aPTT) were within reference ranges. Evaluation from day 2 included a negative antibody screen, but samples from days 5 and 6 demonstrated a cold-reactive autoantibody and direct antiglobulin test (DAT) positive for C3b/C3d and negative for IgG. This antibody did not react at physiological temperature but reacted with patient and donor red blood cells (RBCs) at cold temperatures. Peripheral smear demonstrated RBC agglutination. Serum protein electrophoresis (SPEP) with immunofixation was performed which showed an IgG kappa monoclonal protein, with an M-spike of 1 1.1?g/dL, against a background oligoclonal banding characteristic of multiple clonality. Serum kappa and lambda free light chains were elevated with a normal kappa/lambda ratio. Despite elevated lactate dehydrogenase (LDH) at 2151?U/L (upper limit 610), there was little active hemolysis as evidenced by normal haptoglobin and stable hemoglobin on serial measurements. However, repeated instances of clotted specimens made laboratory monitoring challenging. He was managed with warming of CRRT circuit integrated warming unit, running tubing under a Bair hugger warmer, and heparin infusion with improvement in CRRT function. His course was complicated by progressive thrombocytopenia, with nadir of 62??109/L. Testing confirmed heparin-induced Rabbit Polyclonal to Transglutaminase 2 thrombocytopenia. He was transitioned to argatroban without further CRRT failure. Case 2 A 67-year-old man developed dyspnea upon returning from New York, prompting hospital presentation. Nasopharyngeal PCR was positive for SARS-CoV-2. He was managed with azithromycin, hydroxychloroquine, and ceftriaxone. He was intubated on hospital day 5 and developed renal failure requiring CRRT on day 10. Laboratory evaluation was notable for D-dimer 3050?ng/mL, fibrinogen greater than 1000?mg/dL, with normal 20(S)-NotoginsenosideR2 PT/aPTT. In patient’s sample from day 10, a cold-reacting antibody was identified. This antibody reacted with all patient and donor RBCs at cold temperatures but did not react at physiological temperature. DAT was negative. There was no significant hemolysis, with stable blood counts, minimal hyperbilirubinemia (1.3?mg/dL), LDH 1051?U/L, and normal haptoglobin. A serum protein electrophoresis demonstrated no evidence of monoclonal protein. His course was complicated by refractory septic shock and hypoxic respiratory failure, and the patient died after his family elected for comfort-oriented care. Discussion Additional antibody testing was performed (Table 1 ). Drug-dependent 20(S)-NotoginsenosideR2 RBC antibody studies were negative for ceftriaxone and hydroxychloroquine for both patients. Both autoantibodies were found to 20(S)-NotoginsenosideR2 be anti-I. Weiner et al. described this near-universal RBC antigen in 1956 after encountering a patient with a cold agglutinin who was unable to be transfused without severe hemolysis [3]. Subsequent studies revealed that anti-I antibodies are often seen as a post-infectious complication in patients with infection. The trigger for the formation of this specific autoantibody after infection is not known, as there does not appear to be an I antigen on this organism [4]. 20(S)-NotoginsenosideR2 Interestingly, cold agglutinin syndrome with anti-I was also reported in a patient infected with the influenza A H1N1 during the 2009 pandemic [5]. However, anti-I antibodies have not been associated with coronavirus infection prior to the Covid-19 pandemic to our knowledge. Table.