Racing toward a common biology of venous thromboembolism prophylaxis: the small interfering RNA fibrinogen knockdown strategy

Venous thromboembolism (VTE) remains a vexing problem in the care of postsurgical and injured patients. Although prophylaxis utilizing low-molecular-weight heparin (LMWH) is common, there is an art to the science of best practice to prevent VTE. Ideal prophylaxis strategies balance the risk of bleeding complications [1] with the incidence of VTE, which varies widely depending on surgery, injury severity, and patient comorbidities [2]. Despite prophylaxis with LMWH, VTE events remain high in certain populations [2], and traumatically injured patients may manifest resistance to LMWH due to acute antithrombin III deficiency [3]. Further, thrombotic complications vary in the timing of presentation, including hyperacute and unpreventable pulmonary thrombosis [4] and acute postsurgical and traumatic VTE in the early days of hospitalization [5]. Importantly, VTE can also be a late event, occurring well after discharge in trauma, emergency general surgery, and medically ill and oncology patients, which makes the duration of prophylaxis a persistent topic of debate [6–12]. Given the wide range of timing of events and types of patients, there may be multiple mechanistic pathways at play, leading to an elevated risk of VTE; however, the race to find a common biology among these varying clinical presentations is critical to identify therapeutic targets.

In the present issue of the Journal of Thrombosis and Haemostasis, Seadler et al. [13] present results from a novel strategy for VTE prophylaxis in a large animal model. Citing limitations of LMWH, including its short half-life, risk of hemorrhage, and narrow therapeutic window, the authors chose to target decreasing a portion of the conversion of fibrinogen to fibrin utilizing the delivery of small interfering RNA (siRNA) encapsulated in a lipid nanoparticle. The authors previously described this approach and demonstrated its efficacy against thrombosis in mice without impairment of hemostasis [14]. The present work extends these observations to a large animal model utilizing female Yorkshire/cross swine and an established model of hemorrhagic shock. The siRNA fibrinogen knockdown strategy (siFibrinogen) was found to reduce circulating fibrinogen levels for over a week without impairment of hemostasis. Importantly, this knockdown was acutely reversible with fibrinogen concentrate, which presents a major advance to present VTE prophylaxis with LMWH, which is poorly responsive to available reversal agents.

Postinjury and postsurgery hyperfibrinogenemia represents one very promising target for the common biology of VTE. Although fibrinogen levels vary widely, elevated fibrinogen is especially common in the days following acute injury and sepsis [15,16]. A VTE prophylaxis strategy targeting this late pathway mediator of thrombosis is appealing for multiple reasons. The authors nicely demonstrate in their prior work [14] that this approach is effective in reducing thrombosis, while the present large animal model further characterizes the safety of this approach. The long-duration effect, coupled with a feasible reversal strategy, creates a highly favorable profile that might provide both acute and sustained benefit for patients whose excess fibrinogen is a key mediator of VTE.

The study has several important limitations that will provide opportunities for the authors as they expand this exciting technology. This study utilizes healthy animals with normal fibrinogen levels. Postsurgical and injury patients have dynamic changes in fibrinogen, including a subset of patients presenting with hypofibrinogenemia [17]. Validation of a relevant injury or postsurgical model across a wide range of fibrinogen values is a critical next step. Not only will the presenting fibrinogen level be relevant, but the dynamic progression of patients through stages of pathologic and physiologic fibrinolysis will be critical to assess [18]. Particularly relevant and presenting one of the greatest challenges to this approach is the reported 1- to 2-day delay in the onset of action of siFibrinogen. As previously mentioned, many VTE events occur early after trauma and surgical stress, and the delayed onset may leave a vulnerable period, rendering prophylaxis insufficient. Although this delay may mitigate concerns about acute hypofibrinogenemia and prevent rebound hyperfibrinogenemia, the time to a VTE event in patients with acute hypofibrinogenemia is not known with certainty to fall within that rebound period. These patients may still be at risk of early VTE events, which may be independent of the fibrinogen level and/or may fail prevention with this approach. Much work remains to define the timing and therapeutic window of the siFibrinogen approach, and it will be fascinating to learn whether VTE persists despite fibrinogen knockdown (suggesting a fibrinogen-independent mechanism).

In sum, Seadler et al. [13] have provided an important iterative advancement and a critical safety description of their novel nanoparticle- and siRNA-focused approach to inhibiting fibrinogen. A long-acting, effective, safe, and easy-to-administer (avoiding painful subcutaneous injections) prophylaxis strategy will resonate with clinicians and patients alike. Further, although unexplored in the present or prior work, this strategy may mitigate microvascular thrombosis related to fibrin(ogen) accumulation after injury or major surgery. Microvascular thrombosis is hypothesized to be a major driver of organ injury, particularly after trauma [19], and the potential of this strategy to attenuate the consequences of microvascular injury is a potential exciting area of future investigation. Although the complexity of fibrinogen dynamics and the pharmacokinetics of this approach pose significant hurdles to advancing it, the preclinical efficacy in mice and the present convincing safety data from a large animal model are key leaps in the race toward optimal VTE prophylaxis.