A new study involving patients with sickle cell disease (SCD) indicated an elevated level of factor XII (FXII)-mediated contact pathway activation was present in these patients and may have a role in complications, including thrombosis. Study results were presented in the journal Blood.

“Using genetic and pharmacologic approaches coupled with clinical samples and murine models, we demonstrated a role for FXII in several vascular complications associated with SCD,” the study investigators wrote in their report.

The investigators had an aim of examining whether the coagulation factor FXII and its activated protease form (FXIIa) may be involved with thrombotic complications and vaso-occlusive crises seen in SCD. The study included 53 patients with SCD who were compared with 23 race-matched control individuals without SCD for evaluations of in vivo contact pathway activation.

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Blood samples obtained from participants were used for analyses, in addition to a murine model of SCD (HbSS) that was also utilized to investigate relevant patterns in comparison with HbAA control mice.

Overall, the patients with SCD showed lower hematocrit and hemoglobin levels than control individuals did. They also had higher levels of thrombin-antithrombin complexes, D-dimer, white blood cells, and platelets than control individuals did.

In patients with SCD, markers of contact and intrinsic pathway activation were elevated relative to those of control individuals. In these patients, researchers identified higher plasma concentrations of complexes containing factors such as FXIIa, prekallikrein activator (PKa), activated factor XI (FXIa), or activated factor IX (FIXa) and their respective inhibitors (C1 esterase inhibitor [C1INH] or antithrombin [AT]), compared with control individuals. These included complexes of FXIIa:C1INH (P <.05), FXIa:C1INH (P <.01), PKa:C1INH (P <.05), and FIXa:AT (P <.05).

Plasma levels of PKa:C1INH and FIXa:AT also appeared significantly correlated with each other (P<.0001). The investigators suggested FXIIa may be involved with activation of FXI and prekallikrein in patients with SCD. Levels of FIXa:AT were also correlated with levels of FXIIa:C1INH and FX1a:C1INH in patients with SCD.

In the SCD murine model, FXIIa levels were higher than in control mice. Among other findings, in tumor necrosis factor a-challenged HbSS mice, FXII appeared to contribute to thromboinflammation, whereas tissue factor did not. FXII also appeared to be a contributor to vascular stasis and vascular congestion in HbSS mice.

Inhibition of FXII was associated with a lower degree of accumulation of fibrin and platelets in venous clots, and smaller clot volume, in both HbSS and control mice. Additionally, in HbSS mice, FXII inhibition was associated with reduced stroke severity after brain ischemia/reperfusion injury.

The study investigators noted “the unique features of SCD-related thrombosis and the evidence presented in this communication suggest that FXII(a) inhibition may be a rational and safe antithrombotic and antiadhesive strategy in SCD.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.


Sparkenbaugh EM, Henderson MW, Miller-Awe M, et al. Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease. Blood. 2023;141(15):1871-1883. doi:10.1182/blood.2022017074