clinical topic updates

Updates on the Understanding of Thrombotic Risk in Sickle Cell Disease

by Julie Kanter, MD

Overview

Thrombotic risk in sickle cell disease (SCD) is not entirely understood; however, findings from clinical trials with antithrombotic agents provide some insights. Endothelial activation is of interest, and age-based frameworks might be appropriate. Additional research is needed to better understand thrombotic risk in SCD and to identify ways to effectively intervene.

Expert Commentary

Julie Kanter, MD

Associate Professor, Division of Hematology and Oncology
Director, Adult Sickle Cell Program
Codirector, Lifespan Comprehensive Sickle Cell Center
University of Alabama at Birmingham
Birmingham, AL

“My own hypothesis is that patients accrue more thrombotic risk in general as they get older; that endothelial dysfunction increases with age in patients with SCD, as it does in those with many other conditions.”

Julie Kanter, MD

The current understanding of thrombotic risk in SCD is incomplete, as is the understanding of how to prevent the higher frequency (compared with the non–sickle cell population) of thrombotic events in patients with SCD. In addition, we do not have SCD-specific standard methods for identifying or evaluating individuals at risk for thrombosis (eg, can the Wells criteria be used to risk stratify patients with SCD for pulmonary embolism?). As it turns out, in some ways it can, but I will refrain from saying more at this juncture, as we have had a paper accepted on this very topic in the British Journal of Haematology. 

The use of antithrombotic agents (eg, rivaroxaban and apixaban) in SCD continues to be of investigational interest. Most clinical studies have explored the use of such therapies to decrease the frequency of vaso-occlusive crisis (VOC) events. I would not predict that we are going to be successful in using antithrombotic agents to moderate or reduce the frequency of VOCs, for a variety of reasons. For instance, blood clots often occur in the large vessels, whereas painful acute VOCs occur in the microcapillaries.

Additionally, platelets play a significant role in endothelial activation, and we have certainly seen with crizanlizumab that P-selectin plays a large role. Thus, I think that we need to better evaluate the use of antiplatelet agents. My own hypothesis is that patients accrue more thrombotic risk in general as they get older; that endothelial dysfunction increases with age in patients with SCD, as it does in those with many other conditions. An antiplatelet agent such as prasugrel will therefore not be effective in younger children who have not developed the endothelial disease that would respond to that type of intervention. So, how we utilize some of these agents in an age-based framework should be considered.

With respect to antipolymerization agents in thrombosis, you would have to ask whether and how the antipolymerization agents are effective in SCD to better understand that relationship. There is an abnormal interaction between sickle hemoglobin and the red cell membrane among patients with SCD. That abnormal interaction remains, even when individuals receive a drug such as voxelotor. This interaction likely adds to the endothelial damage and dysfunction in affected persons. Further, although there are different theories about the mechanism of action of a medication such as voxelotor, at some point the hemoglobin still has to release its oxygen to be an effective oxygen-delivering protein. As a result, there is always a chance of it eventually causing polymerization and leading to endothelial activation. 

References

Ataga KI, Elsherif L, Wichlan D, et al. A pilot study of the effect of rivaroxaban in sickle cell anemia. Transfusion. 2021 Mar 4. doi:10.1111/trf.16343

Biemond BJ, Tombak A, Kilinc Y, et al; TVOC01 Investigators Group. Sevuparin for the treatment of acute pain crisis in patients with sickle cell disease: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Haematol. 2021;8(5):e334-e343. doi:10.1016/S2352-3026(21)00053-3

Bray MA, Sartain SE, Gollamudi J, Rumbaut RE. Microvascular thrombosis: experimental and clinical implications. Transl Res. 2020;225:105-130. doi:10.1016/j.trsl.2020.05.006

Cappellini MD. Coagulation in the pathophysiology of hemolytic anemias. Hematology Am Soc Hematol Educ Program. 2007;74-78. doi:10.1182/asheducation-2007.1.74

Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019;133(9):906-918. doi:10.1182/blood-2018-11-882993

Shet AS, Lizarralde-Iragorri MA, Naik RP. The molecular basis for the prothrombotic state in sickle cell disease. Haematologica. 2020;105(10):2368-2379. doi:10.3324/haematol.2019.239350

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