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Sigbjørn Berentsen,1 Alexander Röth,2 Ulla Randen,3 Bernd Jilma,4 Geir E Tjønnfjord5–71Department of Research and Innovation, Haugesund Hospital, Haugesund, Norway; 2Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 3Department of Pathology, Akershus University Hospital, Lørenskog, Norway; 4Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; 5Department of Haematology, Oslo University Hospital, Oslo, Norway; 6KG Jebsen’s Center for B-cell Malignancies, University of Oslo, Oslo, Norway; 7Institute of Clinical Medicine, University of Oslo, Oslo, NorwayAbstract: Cold agglutinin disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic disease, accounting for 15–25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.Keywords: autoimmune hemolytic anemia, cold agglutinin disease, lymphoproliferative, complement, complement inhibitors, therapy

Bleeding tendency is weakly correlated with the activity of factor VII ( FVII) in the plasma of patients with FVII deficiency. A laboratory method for predicting bleeding risk in patients with this coagulation disorder is lacking. We investigated whether global coagulation assays, specifically thromboelastography ( TEG) and thrombin generation assay ( TGA), could be used to predict bleeding risk. We also sought to identify factors that may explain the differences in bleeding phenotype observed among individuals with severe FVII deficiency. The study comprised 12 patients with severe FVII deficiency ( FVII activity <1%). Eleven patients were homozygous for the Gln100Arg mutation and one patient was compound heterozygous. Clinically, 10 patients had increased haemorrhagic diathesis, whereas two patients were asymptomatic. Blood sampling was performed at baseline for TEG and TGA analyses. The platelet aggregation assay was performed and the plasma level of anticoagulation inhibitors and thrombophilic risk factors assessed. No difference in the TEG and TGA results was observed in all FVII-deficient individuals. The level of free tissue factor pathway inhibitor was within the normal range and similar in symptomatic and asymptomatic subjects. None of the participants had the FV Leiden mutation, prothrombin gene mutation, or abnormal anticoagulant inhibitor levels. Asymptomatic subjects showed normal platelet aggregation. These data suggested that TEG and TGA were not suitable methods for predicting the clinical phenotype in FVII-deficient subjects. [ABSTRACT FROM AUTHOR]