FXII and sickle cell: the clot thickens

In this issue of Blood, Sparkenbaugh et al¹ propose that FXIIa activates inflammation and coagulation, thereby contributing to vascular stasis and thrombosis in sickle cell disease (SCD), suggesting that contact-pathway inhibitors should be explored to prevent these complications.

Pressing concerns for patients with SCD include acute painful vaso-occlusive crises (VOC) that frequently require hospitalization, along with stroke and venous thrombosis. Although much progress has been made, these problems still cause significant morbidity and mortality. Activation of coagulation is a hallmark of SCD, and studies that selectively inhibit clotting factors have shown that tissue factor (TF)-initiated blood coagulation directly contributes to ongoing adhesion, VOC, and vascular end-organ damage in SCD.^2,3 Building on several years of exploration of the role played by the coagulation system in SCD, Sparkenbaugh et al now elegantly demonstrate how human coagulation factor XIIa (FXIIa) influences thromboinflammation, vascular stasis, and thrombosis.

The TF pathway and contact-factor pathway, composed of the zymogen FXII, high–molecular weight kininogen (HMWK), and pre-kallikrein (PK), result in activation of plasma coagulation. However, coagulation in vivo appears to be orchestrated solely by TF, whereas contact activation of FXII in vitro culminates in thrombin formation and is widely used to assess plasma coagulation time. The role of FXII in coagulation was not completely elucidated, until the discovery was made that FXII plays an essential role in the propagation phase of pathological clot formation but is not required for normal hemostasis.⁴ The current study elucidates how FXIIa possibly via signaling through neutrophils, promotes adhesion, thromboinflammation, and vascular stasis, thereby contributing to the vascular pathobiology of SCD (see figure).

Sparkenbaugh et al observed increased levels of active factors (FXIIa, human coagulation factor XIa [FXIa], and PK activator [PKa]) complexed with their endogenous plasmatic inhibitors, providing direct evidence that the intrinsic and contact pathways contribute to thrombin generation in patients with steady-state SCD. In Townes sickle mice, at baseline and after tumor necrosis factor alpha (TNFα) challenge, they found that FXII contributed to thrombin generation and inflammation, independently of TF. Using FXII-deficient mice transplanted with sickle bone marrow to recapitulate SCD (HbSS/FXII^–/–), thrombin generation was significantly reduced, as was hepatic sinusoidal and renal congestion (see Figure 3 in Sparkenbaugh et al). Strikingly, in sickle mice, an anti-FXII antibody (15D10) effectively reduced heme-induced microvascular stasis and diminished blood clot size induced in the femoral vein. The anti-FXII antibody also attenuated neutrophil adhesion and brain damage after ischemia/reperfusion of cerebral artery. What makes the article by Sparkenbaugh et al timely and relevant is that it not only identifies new players but also empirically confirms the dysregulation of the finely tuned interplay between inflammation and coagulation that is evident in patients with SCD.⁵ 

As more is becoming understood about the causal link between FXII activation and thromboinflammatory vascular pathology in patients with SCD, several questions remain. How is FXII activated in steady-state SCD, and what disease determinants trigger FXII-mediated thromboinflammatory complications? Adhesive interactions between neutrophils and endothelial cells, and signaling via the neutrophil αMβ2 integrin, are critical drivers of sickle cell vaso-occlusive pathology.^6,7 Elucidation of the mechanism(s) by which neutrophils activate FXII is needed to inform future development of clinically efficacious strategies to inhibit FXII activation. Because steady-state SCD patients have elevated contact-pathway complexes, performing these measurements in patients experiencing VOC or stroke and venous thromboses would help guide future studies that use FXII inhibitors. Studies of FXII inhibitors demonstrate potent anticoagulant efficacy, with minimal bleeding compared to traditional anticoagulants, but less explored is the role of FXIIa inhibition in inflammation.⁸ For instance, FXIIa activity leads to bradykinin release, and can activate complement, which is already overactive via P-selectin activity in SCD.⁹ Ultimately, answers to these and other questions will be needed to inform future development of FXIIa-based therapeutics for SCD.

Treating venous thrombosis with systemic anticoagulation alters the delicate hemostatic balance between procoagulant and anticoagulant processes, which can potentially cause life-threatening bleeding. Unsurprisingly, anticoagulation in SCD patients with venous thrombosis is associated with a 21% cumulative incidence of bleeding by age 40 years and a 2-fold increased risk of death.¹⁰ Moreover, use of vascular-access devices in patients with SCD is associated with venous thrombosis, likely due to contact-pathway activation. FXII inhibition, by posing no additional bleeding risk, represents a potential paradigm shift in the management of thrombotic vascular complications in SCD. Within this context is where the study by Sparkenbaugh et al has its greatest clinical relevance. Despite the many challenges on the road ahead, the future appears exciting, owing to the availability of FXIIa inhibitors with antithrombotic and anti-inflammatory efficacy for evaluation in SCD patients who may be at risk of thrombosis because of elevated FXIIa levels.

Conflict-of-interest disclosure: The author declares no competing financial interests.