Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease

Abstract

A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared to healthy controls, SCD patients exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with TNFα. Additionally, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, uPAR and αMβ2 integrin expression in SCD patient neutrophils compared to healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in SCD patients.

Plasma Kallikrein as a Forgotten Clotting Factor

“…Finally, a recent study by Sparkenbaugh et al explored the contribution of FXII to thrombotic complications in individuals with SCD. 46 This study demonstrated that FXIIa contributes to the activation of the intrinsic and inflammatory pathways in SCD patients. Sparkenbaugh et al reported highly significant correlations between FXIIa:C1 and FXIa: C1 with FIXa:AT complexes and also a significant correlation between plasma levels of PKa:C1 and FIXa:AT complexes.…”

“…These data reflect FXIIa activation of both FXI and PK in SCD patients, and furthermore suggest that activation of FIX is mediated by both FXIa and, in part, by PKa. 46 However, as in the previously mentioned study by Henderson et al, further work is needed to conclude that the correlation between PKa:C1 levels and FIXa:AT levels is due to activation of FIX by PKa in these patients. 45…”

Highly Efficient Hemostatic Cross-Linked Polyacrylate Polymer Dressings for Immediate Hemostasis

“…Meanwhile, negatively charged hemostatic materials can rapidly activate endogenous coagulation pathways by activating FXII [ 45 , 46 , 54 ]. The quantitative analysis of HPA-5 interactions with FXII indicated a reduced content of the FXII factor in the HPA-5 group (123.77 ng/mL) compared with the blank group (435.25 ng/mL).…”

Angiopoietin2 is associated with coagulation activation and tissue factor expression in extracellular vesicles in COVID-19

“…Of note, soluble PLAUR is also a biomarker of disease severity in other conditions associated with immunothrombosis and alveolar damage such as sepsis ( 25 , 26 ). Another pathway that could link increased PLAUR levels with coagulation activation is the association of this molecule with factor XII and neutrophil activation, which has been demonstrated in wound healing ( 27 ) and sickle cell disease ( 28 ).…”