LAUSR

We read with interest the recently published manuscript entitled “Pathologically stiff erythrocytes impede contraction of blood clots” by Tutwiler et al.1 In this study, the authors investigated the kinetics of clot contraction formed from the blood of patients with sickle cell disease (SCD). Using optical tracking, the authors found that contraction was delayed, occurred at a slower velocity, and the extent of contraction was reduced in sickle clots compared with those from heathy controls. Scanning electron microscopy revealed fewer polyhedrocytes, more fibrin, and more space between the red blood cells (RBCs) of sickle clots compared with control clots, as was preliminarily reported by the Weisel group at the American Society of Hematology conference in 2015.2 To determine if the stiffness of sickle RBCs contributes to impaired clot contraction, RBCs isolated from healthy control blood were exposed to glutaraldehyde and centrifugation force. This experimental condition increased erythrocyte rigidity while mimicking the clot contraction kinetics and resulted in reduced deformability of the red cells and impaired polyhedrocytes formation. These results were confirmed with llama erythrocytes, which are inherently stiffer than human RBCs, and it was observed that increasing platelet numbers restored clot contraction and (llama) erythrocyte deformation to normal human levels. A final confirmation of this observation was performed in healthy erythrocytes treated with Wrb antibody to increase rigidity. We found these results of interest because they confirm data previously published by our group.3 We first reported abnormal clot retraction in SCD at the 2016 American Society of Hematology conference,4 with an update presented at the 2017 International Society on Thrombosis and Haematology meeting,5 and discussed the phenomenon in a 2018 review article.6 In the complete study published in 2019, we described the inability of SCD RBCs to form polyhedrocytes within a clot, thereby affecting clot structure.3 Furthermore, we demonstrated that sickle RBC rigidity not only increased intercellular spaces within the clot, but also affected their ability to be extruded from the clot. In our study, we also demonstrated that this effect could be mimicked by glutaraldehyde treatment of normal RBCs,3 which was confirmed in the study by Tutweiler et al. Tutweiler and colleagues suggested that the impairments in clot retraction might also affect susceptibility fibrinolysis in SCD. Indeed, we demonstrated that whole blood clots in SCD patients were less likely to lyse with the addition of tissue plasminogen activator.3 Moreover, we also demonstrated that therapeutic RBC exchange partially reversed the abnormal clot retraction and fibrinolysis susceptibility phenotypes in SCD. Finally, we hypothesized that the altered structure of sickle clots, which we observed both ex vivo and in vivo (in Townes SCD mice), could make clots more prone to embolism.3 We admire the work of Dr. Tutwiler and colleagues because their expertise in clot contraction and biomechanics is an important contribution to the understanding of the kinetics and structure of clots in SCD. We were also pleased to learn that an independent group using different methods was able to confirm our observations and reach similar conclusions. However, we were surprised that the authors neglected to discuss our previously published work in the context of their observations.