1. Browse Program
2. Thrombosis / Basic Science
3. FXI & FXII
4. Presentation

Abstract

Role of Antiplatelet and Anticoagulant Therapy in Veno-Occlusive Crisis  

Erica M. Sparkenbaugh 

Sickle Cell Disease (SCD) is caused by a mutation in the beta-globin gene, resulting in the presence of sickle hemoglobin (HbS). The aggregation of HbS in deoxygenated red blood cells (RBCs) triggers hemolysis, sterile inflammation, and endothelial activation, culminating in vaso-occlusive crisis (VOC). The complex pathophysiology of VOC involves the adhesion of sickled RBCs, activated platelets, and leukocytes to the endothelium, resulting in vascular obstruction and ischemia. Recurrent painful episodes characterize VOC, making it a primary cause of hospitalization and mortality in SCD patients. Despite affecting approximately 8 million people worldwide, treatment options for VOC and associated pain remain limited. Standard treatments include analgesics, hydration, and blood transfusion, which provide symptomatic relief but fail to address the underlying mechanisms triggering VOC. Emerging transformative stem cell and gene therapies are likely to be applicable to a very small number of people for the foreseeable future. 

Chronic platelet activation and a hypercoagulable state are notable features of SCD, and significant research has been aimed at exploring these pathways in VOC and pain. Animal models of vaso-occlusion have revealed that targeting the ADP receptor P2Y12 to reduce platelet aggregation does not limit occlusion. Moreover, clinical trials that have employed P2Y12 antagonists such as ticagrelor and prasugrel have not been successful at reducing VOC. P-selectin, an adhesion molecule upregulated on both platelets and endothelial cells, is known to mediate VOC in mouse models. In 2019, Crizanlizumab (Adakveo), a monoclonal antibody targeting p-selectin, was approved to prevent VOC in SCD patients over the age of 16. Although initial clinical trial data were positive, real-world efficacy may not outweigh the risks associated with the treatment, which requires monthly infusions, possible infusion reactions, and modest efficacy.  

The hypercoagulable state in SCD contributes to chronic thrombin generation, elevating the risk of venous thromboembolic events, and this cascade has also been implicated in VOC. Clinical trials exploring anticoagulants have demonstrated varying degrees of success. Tinzaparin, a low molecular weight heparin, shortened the duration of pain and hospitalization in one clinical trial. Conversely, trials with rivaroxaban and apixaban, which target factor X, have not yielded positive results, potentially attributed to sample size and length of treatment. We have employed a mouse model of SCD to investigate the coagulation cascade. When targeting the tissue factor (TF)-dependent pathway, including FX and thrombin, not only was inflammation and vascular congestion reduced, but also vascular stasis in a model of VOC. In more recent studies, we found that targeting the intrinsic coagulation factor, Factor XII (FXII) also reduced inflammation and venous thrombosis, as well as vaso-occlusion. Targeting FXII can reduce VOC without carrying a bleeding risk - a critical advantage over targeting FX and thrombin.  

These data suggest that simultaneous intervention of multiple pathological processes in SCD with anticoagulants might offer superior outcomes in reducing VOC as compared to targeting platelets alone. Potential challenges such as bleeding risks and contraindications (eg stroke history), are important considerations when investigating anticoagulant therapies in SCD. Recognizing that vaso-occlusive episodes are likely to be a problem for many decades in the US and elsewhere in SCD, future research should prioritize larger and well-designed clinical trials and explore the long-term implications of these targeted interventions in shaping the landscape of SCD management.