Single Low Dose of rFVIIa Combined with Antifibrinolytic Agent is a Simple and Safe Treatment for Factor XI-Deficient Patients undergoing Surgery

Abstract

Background Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products.

Objectives We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity.

Patients and Methods Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration.

Results All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic.

Conclusion A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.

Keywords

factor XI - rFVIIa - thrombin generation - surgery - hemostasis

• References

• 1 Asselta R, Paraboschi EM, Rimoldi V. , et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood 2017; 130 (04) e1-e6
• 2 Pike GN, Bolton-Maggs PH. Factor XI-related thrombosis and the role of concentrate treatment in factor XI deficiency. Haemophilia 2015; 21 (04) 477-480
• 3 O'Connell NM, Riddell AF, Pascoe G, Perry DJ, Lee CA. Recombinant factor VIIa to prevent surgical bleeding in factor XI deficiency. Haemophilia 2008; 14 (04) 775-781
• 4 Kenet G, Lubetsky A, Luboshitz J. , et al. Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors. Haemophilia 2009; 15 (05) 1065-1073
• 5 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
• 6 Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013; 39 (06) 621-631
• 7 Zucker M, Seligsohn U, Salomon O, Wolberg AS. Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. J Thromb Haemost 2014; 12 (07) 1121-1130
• 8 Pike GN, Cumming AM, Hay CR, Bolton-Maggs PH, Burthem J. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood 2015; 126 (03) 397-405
• 9 Livnat T, Shenkman B, Martinowitz U. , et al. The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency. Thromb Res 2015; 136 (02) 465-473
• 10 Livnat T, Tamarin I, Mor Y. , et al. Recombinant activated factor VII and tranexamic acid are haemostatically effective during major surgery in factor XI-deficient patients with inhibitor antibodies. Thromb Haemost 2009; 102 (03) 487-492
• 11 Setty S, Reddell A, England A, Gomez K, Kadir R. The role of recombinant factor VIIa for obstetric block in women with severe factor XI deficiency. Haemophilia 2011; 17 (06) 906-909
• 12 Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363 (19) 1791-1800
• 13 Salomon O, Zivelin A, Livnat T. , et al. Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency. Blood 2003; 101 (12) 4783-4788
• 14 Hedner U. Factor VIIa in the treatment of haemophilia. Blood Coagul Fibrinolysis 1990; 1 (03) 307-317
• 15 Lawler P, White B, Pye S. , et al. Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiency. Haemophilia 2002; 8 (02) 145-148
• 16 Schulman S, Németh G. An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency. Haemophilia 2006; 12 (03) 223-227
• 17 Dempfle CE, Frietsch T, Hoffmann T, Ahmad-Nejad P, Neumaier M, Borggrefe M. Use of recombinant factor VIIa for hip replacement surgery in a patient with severe factor XI deficiency and drug-induced platelet defect. Haemophilia 2008; 14 (05) 1147-1149
• 18 Avci Z, Malbora B, Gokdemir M, Ozkan S, Ozbek N. Successful use of recombinant factor VIIa (NovoSeven) during cardiac surgery in a pediatric patient with congenital factor XI deficiency. Pediatr Cardiol 2008; 29 (01) 220-222
• 19 Riddell A, Abdul-Kadir R, Pollard D, Tuddenham E, Gomez K. Monitoring low dose recombinant factor VIIa therapy in patients with severe factor XI deficiency undergoing surgery. Thromb Haemost 2011; 106 (03) 521-527
• 20 Gay ND, Azar S, Salomon O, Taylor JA. Management of severe factor XI deficiency in cardiac surgery: a case report and review of the literature. Haemophilia 2017; 23 (06) e512-e514
• 21 Livnat T, Zivelin A, Martinowitz U, Salomon O, Seligsohn U. Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XI. J Thromb Haemost 2006; 4 (01) 192-200
• 22 Shibeko AM, Woodle SA, Lee TK, Ovanesov MV. Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids. Blood 2012; 120 (04) 891-899
• 23 Szlam F, Sreeram G, Solomon C, Levy JH, Molinaro RJ, Tanaka KA. Elevated factor VIII enhances thrombin generation in the presence of factor VIII-deficiency, factor XI-deficiency or fondaparinux. Thromb Res 2011; 127 (02) 135-140
• 24 Lorentz CU, Verbout NG, Wallisch M. , et al. Contact activation inhibitor and factor XI antibody, AB023, produces safe, dose-dependent anticoagulation in a phase 1 first-in-human trial. Arterioscler Thromb Vasc Biol 2019; 39 (04) 799-809
• 25 Koch AW, Schiering N, Melkko S. , et al. MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans. Blood 2019; 133 (13) 1507-1516
• 26 Büller HR, Bethune C, Bhanot S. , et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (03) 232-240
• 27 Minami H, Nogami K, Yada K. , et al. Emicizumab, the bispecific antibody to factors IX/IXa and X/Xa, potentiates coagulation function in factor XI-deficient plasma in vitro. J Thromb Haemost 2019; 17 (01) 126-137
• 28 Bakhtiari K, Meijers JCM. In vitro evaluation of factor IX as novel treatment for factor XI deficiency. Blood 2019; 134 (06) 573-575
• 29 Rakhe S, Patel-Hett SR, Bowley S. , et al. The tissue factor pathway inhibitor antibody, PF-06741086, increases thrombin generation in rare bleeding disorder and von Willebrand factor deficient plasmas. Blood 2018; 132: 2462