Background Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by IgM autoantibodies that trigger hemolysis via classical complement pathway. Increased incidence of thrombotic events (TEs) has been reported in patients with other forms of hemolysis. The incidence of TEs in patients with CAD is unknown. Objective Evaluate TE risk in patients with CAD. Patients/Methods This is a matched cohort comparison study evaluating the risk of TEs in patients with CAD and without CAD over a 10‐year period. A total of 608 patients with CAD were identified in the Optum Claims–Clinical data set by reviewing clinical notes for CAD terms and matched with up to 10 patients without CAD (N = 5873). TEs were defined as the first medical claim for a TE using International Classification of Diseases, Ninth and Tenth Revision codes. Cox regression models were used to estimate time to first TE. Sensitivity analyses were conducted to estimate TE risk among patients with primary CAD. Results At least 1 TE occurred in 29.6% of patients with CAD and 17.6% of patients without CAD. The proportion of patients experiencing venous, arterial, and cerebral TEs were each higher among CAD patients. The overall risk of having TEs was higher in patients with CAD (adjusted hazard ratio [aHR], 1.94; 95% confidence interval [CI], 1.64‐2.30). Patients with presumed primary CAD also demonstrated an increased risk of TEs (aHR, 1.80; 95% CI, 1.46‐2.22). Patients with CAD with the fewest comorbidities had 2.44‐fold higher risk of having a TE (95% CI, 1.70‐3.52). Conclusions Patients with CAD have an increased risk of TEs when compared with a matched non‐CAD population.

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Key Points This study demonstrates the severity of anemia and relapsing nature of CAD over time, even after administration of multiple therapies. The majority of CAD patients will at some point in their disease course manifest severe disease necessitating transfusion.