Recombinant activated factor VII (rFVIIa) was initially developed for treating patients with hemophilia. Its application has since extended “off-label” to achieve hemostasis in patients with uncontrollable bleeding, such as polytrauma cases or postoperative bleeding following certain surgeries. 

Two coagulation factors are available: rFVIIa (recombinant activated factor VII, NovoSeven®) and factor 8 inhibitor (FEIBA®). This study focuses on the first, which binds to activated platelets, releases thrombin, and subsequently converts fibrinogen into fibrin to form a stable clot. 

Postoperative bleeding is a common complication in surgical treatment of type A aortic dissection and thoracic aortic surgery, often resulting in significant morbidity and mortality. Although there is no consensus definition, refractory bleeding is considered present when bleeding persists despite conventional medical management and after ruling out surgically repairable causes. Coagulopathy in these patients is multifactorial, arising from cardiopulmonary bypass (CPB) usage, hypothermia, acid-base imbalance during circulatory arrest, and preoperative administration of antiplatelet and/or anticoagulant drugs. Moreover, several independent bleeding predictors exist, including advanced age, extreme body mass index, emergency surgery, low hemoglobin levels, and elevated fibrin degradation products. 

International guidelines (The European Association for Cardio-Thoracic Surgery and European Association of Cardiothoracic Anaesthesiology) recommend considering rFVIIa for achieving hemostasis in refractory bleeding cases not amenable to surgical intervention, though not as a routine prophylactic measure for bleeding. Potential thromboembolic complications from its use include acute myocardial infarction (AMI), cerebrovascular accidents (CVA), deep venous thrombosis (DVT), and pulmonary embolism (PE).

This article reviews the currently available literature on the use of rFVIIa in treating refractory bleeding after thoracic aortic surgery. A search was conducted in major scientific databases, ultimately selecting 10 publications (n = 649 patients; 319 received rFVIIa, and 330 served as controls). The included patients underwent surgical repair for aneurysms or dissections of the ascending and/or descending thoracic aorta. The selected publications comprised 3 case series, 6 retrospective studies, and 1 non-randomized clinical trial.

The usual rFVIIa doses for hemophilia patients are 90-120 mcg/kg administered intravenously every 2-3 hours until bleeding ceases. However, there are no standardized dosing recommendations for off-label use, with a wide range observed across studies, from 23 to 100 mcg/kg. Additionally, the minimum effective dose to correct coagulopathy without increasing thromboembolic risk has not been defined.

Evaluated outcomes included:

• Changes in International Normalized Ratio (INR): Six studies demonstrated improvement in INR/prothrombin time following rFVIIa administration. Of these, two studies reported significant reductions.

• Postoperative Blood Loss (including drainage output and need for blood product transfusion): Three studies reported a significant reduction in drainage output after rFVIIa administration; one study noted a decreased need for intraoperative blood transfusion, and two studies found this effect in the postoperative period. One study showed no significant differences in postoperative drainage output; two studies reported increased drainage output in the rFVIIa group, though without reaching statistical significance. This latter outcome could be justified, as rFVIIa was administered solely to patients with uncontrollable refractory bleeding.

• Incidence of Thromboembolic Complications (DVT, AMI, PE, CVA, mesenteric ischemia): Seven studies found no significant differences between the two groups.

• Duration of CPB and Aortic Cross-Clamp: One study reported longer aortic cross-clamp time in the rFVIIa group. In studies evaluating CPB duration, no significant differences were found.

• Need for Surgical Reexploration: Five studies found no significant differences; one study noted less need for reoperation in the rFVIIa group, though with limited statistical power due to small sample size; one study reported a higher reoperation rate in the rFVIIa group. The studies did not specify the reason for reexploration (persistent bleeding vs. cardiac tamponade) or intraoperative findings (diffuse coagulopathy vs. bleeding from a specific site related to the initial intervention).

• Postoperative Mortality: Among seven studies including both rFVIIa and control groups, rFVIIa use was not significantly associated with increased mortality.

Due to the heterogeneity of the included studies (in both design and population), not all measured variables could be compared to achieve statistical significance.

rFVIIa was administered both intraoperatively after CPB weaning and postoperatively in the intensive care unit. In one study, it was given prophylactically with platelets immediately after CPB weaning, regardless of postoperative bleeding status.

All studies concluded that there is a potential role for rFVIIa use in this context. However, sufficient evidence to indicate that its use is associated with higher thromboembolic complication rates or mortality was not reached, contrary to findings in previous meta-analyses, likely due to the small sample size. Other limitations of the study include variability in local protocols among different populations and brief and varied follow-up periods, complicating comparisons, and possibly underestimating long-term mortality. Cost-effectiveness of rFVIIa in comparison with other agents was not analyzed, nor were viscoelastic tests such as thromboelastography (TEG) or rotational thromboelastometry (ROTEM) employed. 

The authors of this review conclude that the currently available scientific evidence, although limited, suggests that rFVIIa may be useful in managing refractory bleeding in the postoperative period of thoracic aortic surgery. However, its impact on thromboembolic complication rates and mortality remains unclear. 

COMMENTARY: 

Cardiac surgery is associated with potential perioperative bleeding and a high likelihood of requiring blood product transfusion (with potential side effects) due to invasive procedures, exposure to CPB, and the need for high doses of anticoagulation. The need for surgical reintervention due to bleeding or cardiac tamponade also increases postoperative morbidity and mortality. 

Perioperative management can help maintain adequate hemostasis and minimize bleeding risk, reducing transfusion requirements. Multiple factors increase bleeding risk, such as advanced age, prior dual antiplatelet therapy, preoperative anemia, low body mass index, unscheduled surgery, complex/multiple procedures, non-coronary surgery, or reoperations due to prior cardiac surgery. Identifying patients at higher risk of bleeding is important for pre-, intra-, and postoperative management. Multidisciplinary management among cardiac surgeons, anesthesiologists, perfusionists, and intensivists contributes to minimizing perioperative bleeding, improving outcomes, and reducing costs. 

In the postoperative period of cardiac surgery, it is essential to assess the patient’s hemostatic status to guide treatment of coagulopathy through blood product transfusion. Current recommendations from international guidelines in this context include: 

• Antifibrinolytics like tranexamic acid reduce bleeding, transfusion needs, and reoperation for bleeding. 

• Use of fresh frozen plasma (FFP) or prothrombin complex (PCC) to reverse the action of vitamin K antagonists. 

• Administration of fibrinogen at low plasma levels (< 1.5 g/L). 

• If there is a deficiency in coagulation factors, administer FFP or PCC. 

• Consider desmopressin for platelet dysfunction. 

• In refractory bleeding not amenable to surgical intervention, consider off-label use of rFVIIa. Prophylactic use is not recommended. 

However, adherence to these guidelines remains low, with significant variability in transfusion practices. Beyond re-establishing hemostasis, physiological disturbances that may exacerbate coagulopathy, such as hypothermia and acidosis, should also be corrected. 

rFVIIa is considered the final treatment step for refractory bleeding. Although its action is theoretically localized to the vascular injury site, it may induce systemic activation of the coagulation cascade. Its half-life is approximately 2.5 hours. 

Off-label use of rFVIIa appears to be associated with an increased risk of thromboembolic complications, although this has not been clearly demonstrated. Additionally, dosage seems to influence complication rates, being more frequent at higher doses. Advanced age and the coagulopathic state/type of bleeding are independent risk factors for thromboembolic events. The bleeding cause also seems relevant, with higher event rates observed in cases of severe traumatic brain injury and cerebral hemorrhage. Notably, in many studies analyzing this issue, patients who developed thromboembolic complications also received other blood products besides rFVIIa, which may increase thrombotic risk. Current studies suggest that rFVIIa use increases arterial thromboembolic event risk more than venous events. 

In recent years, bedside coagulation monitors, such as ROTEM or TEG, have become more widespread, offering qualitative coagulation assessments as an advantage over conventional tests. This is particularly useful in scenarios where patients may have received prior antiplatelet or anticoagulant therapy. Their use has demonstrated reduced transfusion requirements and should be progressively integrated into local perioperative bleeding management protocols. 

Large, randomized controlled studies with larger sample sizes are necessary to expand knowledge on the potential benefits and complications associated with rFVIIa use in this context. Furthermore, research should focus on dosing, timing/administration criteria, and cost-effectiveness. Until such studies are conducted, individualization based on patient characteristics and clinical context is essential to assess the risk-benefit in each situation before administration. Currently, “off-label” doses most commonly used to minimize thromboembolic risk are 20-40 mcg/kg. 

REFERENCE: 

Navarro R, Bojic S, Fatima R, El-Tahan M, El-Diasty M. Recombinant Activated Factor VII (rFVIIa) for Bleeding After Thoracic Aortic Surgery: A Scoping Review of Current Literature. J Cardiothorac Vasc Anesth. 2024 Jan;38(1):275-284.