Recombinant factor VIIa to treat severe bleeding in patients with liver disease: Pitfalls and possibilities

Hemostasis and thrombosis in patients with liver disease: The ups and downsJournal of HepatologyVol. 53Issue 2PreviewPatients with chronic or acute liver failure frequently show profound abnormalities in their hemostatic system. Whereas routine laboratory tests of hemostasis suggest these hemostatic alterations result in a bleeding diathesis, accumulating evidence from both clinical and laboratory studies suggest that the situation is more complex. The average patient with liver failure may be in hemostatic balance despite prolonged routine coagulation tests, since both pro- and antihemostatic factors are affected, the latter of which are not well reflected in routine coagulation testing. Full-Text PDF Patients with liver disease frequently develop substantial changes in their hemostatic system [[1]Lisman T. Caldwell S.H. Burroughs A.K. Northup P.G. Senzolo M. Stravitz R.T. et al.Hemostasis and thrombosis in patients with liver disease: the ups and downs.J Hepatol. 2010; 53: 362-371Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar]. Recent laboratory and clinical data are compatible with the concept of rebalanced hemostasis in liver disease [[2]Lisman T. Porte R.J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.Blood. 2010; 116: 878-885Crossref PubMed Scopus (421) Google Scholar]. According to this concept, the average patient with liver disease is in hemostatic balance due to a concomitant decrease in pro- and anticoagulant pathways. The hemostatic balance in patients with liver disease, however, is much more fragile as compared to the hemostatic balance in healthy individuals. Consequently, patients with liver disease are at risk for both bleeding and thrombosis when the balance is disturbed. Unfortunately, there is currently no clinical or laboratory test able to predict whether a patient with liver disease is at risk for either bleeding or thrombosis. In a recent commentary in the section “International Hepatology” of this Journal, Thabut and coworkers address the question whether administration of recombinant factor VIIa (NovoSeven, rFVIIa) to patients with liver disease poses them at an increased risk for thrombotic complications [[3]Thabut D. Rudler M. Rousseau G. Poynard T. Recombinant activated factor VII in chronic liver diseases: Should we be afraid of thromboembolic events?.J Hepatol. 2011; 55: 483-485Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. The authors conclude that the use of rFVIIa to patients with uncontrollable bleeding may be justified, and potential thrombotic events should be considered as ‘collateral damage’. Here, we aim to comment on the use of rFVIIa in patients with liver disease to better appreciate the risk-benefit ratio in different clinical scenarios. Current clinical data do not support prophylactic administration of rFVIIa to prevent excessive bleeding during surgical procedures including partial hepatectomy and liver transplantation [4Levy J.H. Fingerhut A. Brott T. Langbakke I.H. Erhardtsen E. Porte R.J. Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile.Transfusion. 2006; 46: 919-933Crossref PubMed Scopus (84) Google Scholar, 5Planinsic R.M. van der Meer J. Testa G. Grande L. Candela A. Porte R.J. et al.Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease.Liver Transpl. 2005; 11: 895-900Crossref PubMed Scopus (193) Google Scholar]. Also, administration of rFVIIa to patients with variceal bleeding is not indicated based on randomized controlled trials. Although the average patient with liver disease is in hemostatic balance, there are situations in which severe and uncontrollable bleeding does occur [[1]Lisman T. Caldwell S.H. Burroughs A.K. Northup P.G. Senzolo M. Stravitz R.T. et al.Hemostasis and thrombosis in patients with liver disease: the ups and downs.J Hepatol. 2010; 53: 362-371Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar]. If the primary cause of bleeding is not surgical and not primarily related to (excessive) portal hypertension, administration of rFVIIa may be beneficial, which is supported by anecdotal reports [6Flower O. Phillips L.E. Cameron P. Gunn K. Dunkley S. Watts A. et al.Recombinant activated factor VII in liver patients: a retrospective cohort study from Australia and New Zealand.Blood Coagul Fibrinolysis. 2010; 21: 207-215Crossref PubMed Scopus (10) Google Scholar, 7Lieberman B.L. Kennedy M.K. Lorenzo D.R. Reed L.J. Adamo A.K. Cardo Jr., V.A. et al.Control of life-threatening head and neck hemorrhage after dental extractions: a case report.J Oral Maxillofac Surg. 2010; 68: 2311-2319Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. The main advantage of rFVIIa over other hemostatic therapies, such as blood product infusion, is the low volume, which prevents fluid overload and exacerbation of portal hypertension. In addition, transfusion-related complications such as transfusion-related acute lung injury and other transfusion reactions do not occur when rFVIIa is administered. The theoretical advantages of rFVIIa when used as a “rescue agent” need to be balanced against a potentially increased risk of thrombosis. We believe that clinical studies are required to establish whether rFVIIa is truly effective in controlling bleeding complications in patients with liver disease. Furthermore, we believe it is important to realise which types of uncontrollable bleeding might benefit from rFVIIa administration, and in which cases therapy with rFVIIa is likely futile. The patients with uncontrollable bleeding that may benefit from rFVIIa are those patients in whom the bleeding complication is likely a result of an inadequate coagulation system. Examples of this are patients with massive hematomas, patients with bleeding complications after small invasive procedures including dental extraction, liver biopsy, paracenthesis and thoracenthesis, and patients with bleeding complications during or after larger invasive procedures. In the latter case, it should be excluded that there is a surgical cause for the bleeding complication. Clinically, a bleeding complication during surgery that is likely attributable to inadequate hemostatic capacity is characterized by multiple simultaneous bleeding sites, persistent oozing from a non-identifiable source, or delayed bleeding following adequate hemostasis. Patients that are theoretically unlikely to benefit from rFVIIa are patients with surgical bleeding, or bleeding complications that are primarily related to pressure effects (such as variceal bleeding). In those patients with uncontrollable bleeding related to a hemostatic defect, two factors may determine whether rFVIIa might be effective in inducing hemostasis. Firstly, both in vitro studies and clinical studies in trauma patients have established a loss of hemostatic activity of rFVIIa with decreasing pH [8Meng Z.H. Wolberg A.S. Monroe 3rd, D.M. Hoffman M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients.J Trauma. 2003; 55: 886-891Crossref PubMed Scopus (393) Google Scholar, 9Stein D.M. Dutton R.P. O’Connor J. Alexander M. Scalea T.M. Determinants of futility of administration of recombinant factor VIIa in trauma.J Trauma. 2005; 59: 609-615PubMed Google Scholar]. Patients with severe acidosis, which for example frequently occurs in patients with acetaminophen-induced acute liver failure, may not benefit from rFVIIa. Secondly, rFVIIa likely requires a certain amount of residual endogenous coagulation factors. rFVIIa is believed to exert its hemostatic effect by enhancement of thrombin and fibrin generation in either a tissue factor-dependent or -independent manner [[10]Lisman T. De Groot P.G. Mechanism of action of recombinant factor VIIa.J Thromb Haemost. 2003; 1: 1138-1139Crossref PubMed Scopus (94) Google Scholar]. For rFVIIa to enhance thrombin and fibrin generation, a certain level of procoagulant proteins (factors X, V, II, and fibrinogen) will be required. In the patient with liver disease, levels of these procoagulants are low, but generally sufficient to support hemostasis. However, severe deficiencies in procoagulants or fibrinogen may occur in patients with severe dilutional- or consumption coagulopathy (including patients with severe sepsis and disseminated intravascular coagulation and patients with uncontrolled bleeding). In such patients, administration of rFVIIa may be futile. In conclusion, there is a need for carefully designed clinical studies to assess efficacy of rFVIIa administration to patients with liver disease and uncontrollable, hemostasis-related bleeding. Only when these studies show a beneficial effect of rFVIIa, an increased risk of thrombotic events may be considered acceptable ‘collateral damage’. For now, we believe there is little evidence for a widespread use of rFVIIa as a rescue agent in patients with liver disease. T.L. – received unrestricted educational grants from Novo Nordisk, the manufacturer of recombinant factor VIIa.