Red blood cells modulate structure and dynamics of venous clot formation in sickle cell disease

Camille Faes, Anton Ilich, Amandine Sotiaux, Erica M. Sparkenbaugh, Michael W. Henderson, Laura Buczek, Joan D. Beckman, Patrick Ellsworth, Denis F. Noubouossie, Lantarima Bhoopat, Mark Piegore, Céline Renoux, Wolfgang Bergmeier, Yara Park, Kenneth I. Ataga, Brian Cooley, Alisa S. Wolberg, Nigel S. Key and Rafal Pawlinski

Key Points

  • SCD alters the composition of the clot in a mouse model of venous thrombosis.

  • Therapeutic RBC exchange partially normalizes retraction and resistance to fibrinolysis of whole blood sickle clots.

There is a Blood Commentary on this article in this issue.


Sickle cell disease (SCD) is associated with chronic activation of coagulation and an increased risk of venous thromboembolism. Erythrocyte sickling, the primary pathologic event in SCD, results in dramatic morphological changes in red blood cells (RBCs) because of polymerization of the abnormal hemoglobin. We used a mouse model of SCD and blood samples from sickle patients to determine if these changes affect the structure, properties, and dynamics of sickle clot formation. Sickling of RBCs and a significant increase in fibrin deposition were observed in venous thrombi formed in sickle mice. During ex vivo clot contraction, the number of RBCs extruded from sickle whole blood clots was significantly reduced compared with the number released from sickle cell trait and nonsickle clots in both mice and humans. Entrapment of sickled RBCs was largely factor XIIIa–independent and entirely mediated by the platelet-free cellular fraction of sickle blood. Inhibition of phosphatidylserine, but not administration of antisickling compounds, increased the number of RBCs released from sickle clots. Interestingly, whole blood, but not plasma clots from SCD patients, was more resistant to fibrinolysis, indicating that the cellular fraction of blood mediates resistance to tissue plasminogen activator. Sickle trait whole blood clots demonstrated an intermediate phenotype in response to tissue plasminogen activator. RBC exchange in SCD patients had a long-lasting effect on normalizing whole blood clot contraction. Furthermore, RBC exchange transiently reversed resistance of whole blood sickle clots to fibrinolysis, in part by decreasing platelet-derived PAI-1. These properties of sickle clots may explain the increased risk of venous thromboembolism observed in SCD.

  • Submitted July 9, 2018.
  • Accepted March 14, 2019.
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