Anti-Complement Therapy Decreases Endogenous Thrombin Potential in Patients with Cold Agglutinin Disease

Background

Individuals with hemolytic anemias (including cold agglutinin disease (CAD)) demonstrate an increased risk of thromboembolic events (TEs). Studies evaluating clinical predictors of TE risk such as severity of anemia or hemolysis are conflicting, and the risk factors for developing TEs in patients with CAD remain uncharacterized. TEs can lead to significant morbidity and may contribute to increased mortality. As more effective therapies for CAD become available, it is important to better understand the effect of these treatments on thrombosis risk. There are no routine laboratory tests that reliably predict thrombotic potential. Novel attempts to determine the hemostatic phenotype at the individual level have been made using the thrombin generation assay (TGA) (Binder, et al. 2021). TGAs in patients which demonstrate an elevated endogenous thrombin potential (ETP) have been shown to be associated with an increased risk of thrombosis (van Hylckama Vlieg, et al. 2015). TGAs can be performed with or without the addition of thrombomodulin (TM), which is the physiological activator of protein C. Prior studies have shown that ETP measured with TM better distinguishes patients with different risks of TEs compared to ETP measured without TM (Tripodi, et al. 2007). In this study, we compared ETPs in patients with CAD who were and were not receiving anti-complement therapy.

Methods

Collection of samples for this prospective observational study began in March 2024, at a single Hematology center. We collected a total of 8 blood samples from patients with CAD and 8 blood samples from healthy controls. Platelet-poor plasma was obtained via double centrifugation, snap-frozen at -80°C, and later thawed at 37°C for testing using the ST Genesia Machine for quantitative thrombin generation determination via a fluorogenic method. The STG® - ThromboScreen +/- TM reagents, containing phospholipids and tissue factor, initiated the coagulation system in plasma. We analyzed TGA parameters with the addition of TM, and descriptive statistics were used to present the data.

Results

Samples were obtained from 8 patients with CAD and 8 healthy controls. All 8 CAD patients were female with a mean age of 71 years. Five of the eight patients were receiving sutimlimab. Two of the CAD patients on sutimlimab were also on therapeutic anticoagulation (AC), Three of the eight CAD patients were not on sutimlimab. One was on therapeutic AC and 2 were not on AC. All patients on therapeutic AC were on rivaroxaban. The 3 patients on sutimlimab alone had a mean ETP of 861.9nM.min, lag time of 2.48min, peak of 182.33nM. The 2 patients not on AC or sutimlimab had an ETP of 1192.2nM.min, lag time of 2.42min, and peak of 230.35nM. The 2 patients on AC and sutimlimab had a mean ETP of 622.58nM.min, lag time of 6.16min, and peak of 97.23nM. The patient on AC alone had an ETP of 784.7nM.min, lag time of 3.34min, and peak of 95.3nM. The mean ETP in 8 healthy controls is 732.3nM.min, lag time of 2.87min and peak of 148.7nM.

Conclusions

These data represent an exploratory study to evaluate a tool to assess the thrombotic potential of individual patients with CAD and probe whether anti-complement therapy has any impact on the thrombotic potential. When compared with healthy controls, patients with CAD that are not on therapeutic AC show a higher thrombotic potential using TGA parameters. This data with albeit a limited patient population demonstrate an improvement in ETP, lag time, and peak height of TGA curves in patients with CAD treated with anti-complement therapy. This improvement was seen in patients plus or minus therapeutic AC. Given the limited sample size, it will be important to expand this study to a larger number of centers and patients to verify our findings. Robust knowledge of the thrombotic potential of patients with CAD as well as the effects of various therapeutic interventions for CAD will better inform clinicians regarding morbidity risks and treatment decisions for this rare disease.

Broome:Sanofi: Honoraria, Research Funding; argenx: Consultancy, Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Electra: Research Funding; Alpine: Consultancy, Honoraria, Research Funding; Novartis: Research Funding.