A Sardinian Family with Factor XI Deficiency

Abstract

Introduction Factor XI (FXI) deficiency is a bleeding disorder which causes a bleeding tendency after trauma or surgery. An inhibitor may be acquired secondary to replacement therapy.

Aim To study on genetical and functional grounds a family admitted to our Haemostasis and Thrombosis Centre for an incidental finding of a prolonged activated partial thromboplastin time (aPTT) in three members.

Methods aPTT mixing test, dosage of FXI activity and antigen, FXI inhibitor titration, DNA analysis and clot waveform analysis (CWA) were performed.

Results Patients II.1, II.3 and II.4 showed a severe FXI deficiency (0.7, 0.7 and 1.8%, respectively) and low antigen level. Since the proposita was already treated with plasma, the dosage of the inhibitor was determined to be 6.4 Bethesda units. They were homozygous for the p.Glu117Stop mutation. The other family members were heterozygous. The velocity and the maximum acceleration of the clot formation were lower than those of the other family members and the normal subjects but higher than those of patients with acquired haemophilia A.

Conclusion A mixing test of a prolonged aPTT should be performed because it will be present both in patients with or without the inhibitor. A molecular analysis in severe FXI deficiency is warranted as it may have prognostic significance. CWA may be helpful for better understanding the pathophysiology of this kind of defect.

Keywords

factor XI deficiency - FXI inhibitor - bleeding - clot waveform analysis - aPTT

• References

• 1 Rosenthal RL, Dreskin OH, Rosenthal N. New hemophilia-like disease caused by deficiency of a third plasma thromboplastin factor. Proc Soc Exp Biol Med 1953; 82 (01) 171-174
• 2 Wheeler AP, Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol 2016; 9 (07) 629-637
• 3 Mumford AD, Ackroyd S, Alikhan R. , et al; BCSH Committee. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (03) 304-326
• 4 Peretz H, Mulai A, Usher S. , et al. The two common mutations causing factor XI deficiency in Jews stem from distinct founders: one of ancient Middle Eastern origin and another of more recent European origin. Blood 1997; 90 (07) 2654-2659
• 5 Asakai R, Chung DW, Ratnoff OD, Davie EW. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Acad Sci U S A 1989; 86 (20) 7667-7671
• 6 Peretz H, Zivelin A, Usher S, Seligsohn U. A 14-bp deletion (codon 554 del AAGgtaacagagtg) at exon 14/intron N junction of the coagulation factor XI gene disrupts splicing and causes severe factor XI deficiency. Hum Mutat 1996; 8 (01) 77-78
• 7 Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013; 39 (06) 621-631
• 8 Hentze MW, Kulozik AE. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 1999; 96 (03) 307-310
• 9 Soldà G, Asselta R, Ghiotto R, Tenchini ML, Castaman G, Duga S. A type II mutation (Glu117stop), induction of allele-specific mRNA degradation and factor XI deficiency. Haematologica 2005; 90 (12) 1716-1718
• 10 Salomon O, Steinberg DM, Seligshon U. Variable bleeding manifestations characterize different types of surgery in patients with severe factor XI deficiency enabling parsimonious use of replacement therapy. Haemophilia 2006; 12 (05) 490-493
• 11 Quélin F, Trossaërt M, Sigaud M, Mazancourt PD, Fressinaud E. Molecular basis of severe factor XI deficiency in seven families from the west of France. Seven novel mutations, including an ancient Q88X mutation. J Thromb Haemost 2004; 2 (01) 71-76
• 12 Kasper CK, Aledort L, Aronson D. , et al. Proceedings: a more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34 (02) 612
• 13 Braun PJ, Givens TB, Stead AG. , et al. Properties of optical data from activated partial thromboplastin time and prothrombin time assays. Thromb Haemost 1997; 78 (03) 1079-1087
• 14 Shima M, Thachil J, Nair SC, Srivastava A. ; Scientific and Standardization Committee. Towards standardization of clot waveform analysis and recommendations for its clinical applications. J Thromb Haemost 2013; 11 (07) 1417-1420
• 15 Solano C, Zerafa P, Bird R. A study of atypical APTT derivative curves on the ACL TOP coagulation analyser. Int J Lab Hematol 2011; 33 (01) 67-78
• 16 Margaglione M, Brancaccio V, Giuliani N. , et al. Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant. Ann Intern Med 1998; 129 (02) 89-93
• 17 Tomaiuolo M, Favuzzi G, Cappucci F. , et al. Factor XI deficiency: two novel mutations in asymptomatic Italian patients. Haemophilia 2010; 16 (05) 767-770
• 18 Perani M. Gli ebrei in Sardegna fino al secolo VI: testimonianze storiche e archeologiche. La Rassegna Mensile Israel 1991; 57 (03) 305-344
• 19 Castaman G, Giacomelli SH, Caccia S. , et al. The spectrum of factor XI deficiency in Italy. Haemophilia 2014; 20 (01) 106-113
• 20 Teruya J, Styler M. Management of factor XI inhibitor for cardiac intervention: successful treatment with immunosuppressive therapy and plasma exchange. Haemophilia 2000; 6 (03) 158-161
• 21 Musclow CE, Amato D, Ofosu F, Armstrong AL, Abbott D. Transfusion-induced specific anti-factor XI inhibitor in a patient with previously unrecognized factor XI deficiency. Am J Clin Pathol 1988; 89 (03) 418-422
• 22 Schnall SF, Duffy TP, Clyne LP. Acquired factor XI inhibitors in congenitally deficient patients. Am J Hematol 1987; 26 (04) 323-328
• 23 Franchini M, Marano G, Mengoli C. , et al. Inhibitors in patients with congenital bleeding disorders other than hemophilia. Semin Thromb Hemost 2018; 44 (06) 595-603
• 24 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
• 25 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
• 26 Margaglione M, Castaman G, Morfini M. , et al; AICE-Genetics Study Group. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica 2008; 93 (05) 722-728
• 27 Branchini A, Ferrarese M, Campioni M. , et al. Specific factor IX mRNA and protein features favor drug-induced readthrough over recurrent nonsense mutations. Blood 2017; 129 (16) 2303-2307
• 28 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
• 29 Alsammak MS, Ashrani AA, Winters JL, Pruthi RK. Therapeutic plasma exchange for perioperative management of patients with congenital factor XI deficiency. J Clin Apher 2017; 32 (06) 429-436
• 30 Ruberto MF, Sorbello O, Civolani A, Barcellona D, Demelia L, Marongiu F. Clot wave analysis and thromboembolic score in liver cirrhosis: two opposing phenomena. Int J Lab Hematol 2017; 39 (04) 369-374
• 31 Ruberto MF, Marongiu F, Mandas A. , et al. The venous thromboembolic risk and the clot wave analysis: a useful relationship?. Clin Chem Lab Med 8; 56 (03) 448-453
• 32 Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg 2009; 108 (05) 1447-1452
• 33 Jankowski M, Undas A, Kaczmarek P, Butenas S. Activated factor XI and tissue factor in chronic obstructive pulmonary disease: links with inflammation and thrombin generation. Thromb Res 2011; 127 (03) 242-246