Low Concentrations of Recombinant Factor VIIa May Improve the Impaired Thrombin Generation of Glanzmann Thrombasthenia Patients

Sarina Levy-Mendelovich; Tamara Levy; Ivan Budnik; Assaf Arie Barg; Nurit Rosenberg; Uri Seligsohn; Gili Kenet; Tami Livnat

doi:10.1055/s-0038-1676348

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2019; 119(01): 117-127
DOI: 10.1055/s-0038-1676348

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

Low Concentrations of Recombinant Factor VIIa May Improve the Impaired Thrombin Generation of Glanzmann Thrombasthenia Patients

Sarina Levy-Mendelovich

¹Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

²The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel

³The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel

,

Tamara Levy

¹Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

Ivan Budnik

⁴Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

,

Assaf Arie Barg

¹Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

²The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel

³The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel

,

Nurit Rosenberg

¹Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

²The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel

³The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel

,

Uri Seligsohn

¹Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

²The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel

³The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel

,

Gili Kenet

¹Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

²The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel

³The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel

,

Tami Livnat

¹Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

²The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel

³The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel

› Author Affiliations

Abstract

Introduction Glanzmann thrombasthenia (GT) is a rare bleeding disorder. The disease is caused by the lack or dysfunction of platelet membrane glycoprotein IIb/IIIa (integrin αIIbβ3) which is essential for platelet aggregation. Bleeding episodes are usually managed by platelet transfusions. Recombinant activated factor VII (rFVIIa) is a common adjunct or alternative treatment option.

Objective This article evaluates GT patients' response to increasing concentrations of rFVIIa using an ex vivo thrombin generation assay to elaborate the knowledge in which rFVIIa treats a platelet dysfunction for bleeding episodes and preoperative management.

Materials and Methods Twenty-four GT patients in a non-bleeding state were enrolled into the study. Thrombin generation was measured in platelet-rich plasma (PRP) in the presence of 0.7 to 7.0 µg/mL rFVIIa. Clinical data of rFVIIa used to treat GT patients' bleeding episodes was collected, and patients' follow-up course was documented.

Results Thrombin generation was significantly decreased in GT patients compared with controls. An individual response to rFVIIa spiking was noted in GT patients' PRP. In the majority of patients, a significant improvement in thrombin generation was already demonstrated with low concentrations (0.7 µg/mL) of rFVIIa.

Conclusion Thrombin generation is improved in the majority of GT patients following ex vivo spiking with rFVIIa. The magnitude of this improvement is individual and was noted at low concentrations of rFVIIa. There is a need for a prospective clinical trial to find the optimal doses or rFVIIa for treatment of GT patients.

Keywords

Glanzmann thrombasthenia - thrombin generation - rFVIIa

Full Text

References

References
1 Nurden AT, Pillois X, Nurden P. Understanding the genetic basis of Glanzmann thrombasthenia: implications for treatment. Expert Rev Hematol 2012; 5 (05) 487-503
2 Bellucci S, Caen J. Molecular basis of Glanzmann's thrombasthenia and current strategies in treatment. Blood Rev 2002; 16 (03) 193-202
3 Nurden AT, Fiore M, Nurden P, Pillois X. Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. Blood 2011; 118 (23) 5996-6005
4 Newman PJ, Seligsohn U, Lyman S, Coller BS. The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proc Natl Acad Sci U S A 1991; 88 (08) 3160-3164
5 Rosenberg N, Yatuv R, Orion Y. , et al. Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta3) is a second mutation in Iraqi Jews that stemmed from a distinct founder. Blood 1997; 89 (10) 3654-3662
6 George JN, Caen JP, Nurden AT. Glanzmann's thrombasthenia: the spectrum of clinical disease. Blood 1990; 75 (07) 1383-1395
7 Poon MC, Di Minno G, d'Oiron R, Zotz R. New insights into the treatment of Glanzmann thrombasthenia. Transfus Med Rev 2016; 30 (02) 92-99
8 Toogeh G, Sharifian R, Lak M, Safaee R, Artoni A, Peyvandi F. Presentation and pattern of symptoms in 382 patients with Glanzmann thrombasthenia in Iran. Am J Hematol 2004; 77 (02) 198-199
9 Di Minno G, Zotz RB, d'Oiron R, Bindslev N, Di Minno MN, Poon MC. ; Glanzmann Thrombasthenia Registry Investigators. The international prospective Glanzmann Thrombasthenia Registry: treatment modalities and outcomes in non-surgical bleeding episodes in patients with Glanzmann thrombasthenia. Haematologica 2015; 100: 1031-1037
10 Poon MC, d'Oiron R, Zotz RB, Bindslev N, Di Minno MN, Di Minno G. ; Glanzmann Thrombasthenia Registry Investigators. The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention. Haematologica 2015; 100 (08) 1038-1044
11 Reichert N, Seligsohn U, Ramot B. Clinical and genetic aspects of Glanzmann's thrombasthenia in Israel: report of 22 cases. Thromb Diath Haemorrh 1975; 34 (03) 806-820
12 Blajchman MA, Beckers EA, Dickmeiss E, Lin L, Moore G, Muylle L. Bacterial detection of platelets: current problems and possible resolutions. Transfus Med Rev 2005; 19 (04) 259-272
13 Poon MC, D'Oiron R, Von Depka M. , et al; International Data Collection on Recombinant Factor VIIa and Congenital Platelet Disorders Study Group. Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey. J Thromb Haemost 2004; 2 (07) 1096-1103
14 Fiore M, Firah N, Pillois X, Nurden P, Heilig R, Nurden AT. Natural history of platelet antibody formation against αIIbβ3 in a French cohort of Glanzmann thrombasthenia patients. Haemophilia 2012; 18 (03) e201-e209
15 Poon MC, Demers C, Jobin F, Wu JW. Recombinant factor VIIa is effective for bleeding and surgery in patients with Glanzmann thrombasthenia. Blood 1999; 94 (11) 3951-3953
16 Lak M, Scharling B, Blemings A. , et al. Evaluation of rFVIIa (NovoSeven) in Glanzmann patients with thromboelastogram. Haemophilia 2008; 14 (01) 103-110
17 Rajpurkar M, Chitlur M, Recht M, Cooper DL. Use of recombinant activated factor VII in patients with Glanzmann's thrombasthenia: a review of the literature. Haemophilia 2014; 20 (04) 464-471
18 Recht M, Rajpurkar M, Chitlur M. , et al. Independent adjudicator assessments of platelet refractoriness and rFVIIa efficacy in bleeding episodes and surgeries from the multinational Glanzmann's thrombasthenia registry. Am J Hematol 2017; 92 (07) 646-652
19 Poon MC. Clinical use of recombinant human activated factor VII (rFVIIa) in the prevention and treatment of bleeding episodes in patients with Glanzmann's thrombasthenia. Vasc Health Risk Manag 2007; 3 (05) 655-664
20 Levy-Mendelovich S, Barg AA, Rosenberg N. , et al. Treatment tailoring for factor V deficient patients and perioperative management using global hemostatic coagulation assays. Blood Cells Mol Dis 2018; 71: 5-10
21 Livnat T, Martinowitz U, Zivelin A, Rima D, Kenet G. A highly sensitive thrombin generation assay for assessment of recombinant activated factor VII therapy in haemophilia patients with an inhibitor. Thromb Haemost 2011; 105 (04) 688-695
22 Dargaud Y, Bordet JC, Trzeciak MC, Vinciguerra C, Negrier C. A case of Glanzmann's thrombasthenia successfully treated with recombinant factor VIIa during a surgical procedure: observations on the monitoring and the mechanism of action of this drug. Haematologica 2006; 91 (6, Suppl): ECR20
23 Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein IIb-IIIa complex. Blood 1988; 71 (04) 831-843
24 Hoffman M. Monroe DM III, Roberts HR. Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of high dose activated factor VII. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S61-S65
25 Vanschoonbeek K, Feijge MAH, Van Kampen RJ. , et al. Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogram characteristics. J Thromb Haemost 2004; 2 (03) 476-484
26 Ilveskero S, Lassila R. Abciximab inhibits procoagulant activity but not the release reaction upon collagen- or clot-adherent platelets. J Thromb Haemost 2003; 1 (04) 805-813
27 Reverter JC, Béguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and “clinical restenosis.” J Clin Invest 1996; 98 (03) 863-874
28 van der Meijden PE, Feijge MA, Swieringa F. , et al. Key role of integrin α(IIb)β (3) signaling to Syk kinase in tissue factor-induced thrombin generation. Cell Mol Life Sci 2012; 69 (20) 3481-3492
29 Wang H, Bang KW, Blanchette VS, Nurden AT, Rand ML. Phosphatidylserine exposure, microparticle formation and mitochondrial depolarisation in Glanzmann thrombasthenia platelets. Thromb Haemost 2014; 111 (06) 1184-1186
30 Gemmell CH, Sefton MV, Yeo EL. Platelet-derived microparticle formation involves glycoprotein IIb-IIIa. Inhibition by RGDS and a Glanzmann's thrombasthenia defect. J Biol Chem 1993; 268 (20) 14586-14589
31 Goto S, Tamura N, Li M. , et al. Different effects of various anti-GPIIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity. J Thromb Haemost 2003; 1 (09) 2022-2030
32 Byzova TV, Plow EF. Networking in the hemostatic system. Integrin alphaiibbeta3 binds prothrombin and influences its activation. J Biol Chem 1997; 272 (43) 27183-27188
33 Furman MI, Krueger LA, Frelinger III AL. , et al. GPIIb-IIIa antagonist-induced reduction in platelet surface factor V/Va binding and phosphatidylserine expression in whole blood. Thromb Haemost 2000; 84 (03) 492-498
34 Pedicord DL, Thomas BE, Mousa SA, Dicker IB. Glycoprotein IIb/IIIa receptor antagonists inhibit the development of platelet procoagulant activity. Thromb Res 1998; 90 (06) 247-258
35 Hedner U. Recombinant activated factor VII: 30 years of research and innovation. Blood Rev 2015; 29 (Suppl. 01) S4-S8
36 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
37 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
38 Lisman T, Moschatsis S, Adelmeijer J, Nieuwenhuis HK, De Groot PG. Recombinant factor VIIa enhances deposition of platelets with congenital or acquired alpha IIb beta 3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor-independent thrombin generation. Blood 2003; 101 (05) 1864-1870
39 Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99 (03) 542-547
40 Weeterings C, de Groot PG, Adelmeijer J, Lisman T. The glycoprotein Ib-IX-V complex contributes to tissue factor-independent thrombin generation by recombinant factor VIIa on the activated platelet surface. Blood 2008; 112 (08) 3227-3233
41 Lisman T, Adelmeijer J, Heijnen HF, de Groot PG. Recombinant factor VIIa restores aggregation of alphaIIbbeta3-deficient platelets via tissue factor-independent fibrin generation. Blood 2004; 103 (05) 1720-1727
42 Lisman T, Adelmeijer J, Cauwenberghs S, Van Pampus EC, Heemskerk JW, De Groot PG. Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count. J Thromb Haemost 2005; 3 (04) 742-751
43 Solh T, Botsford A, Solh M. Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options. J Blood Med 2015; 6: 219-227
44 Livnat T, Martinowitz U, Azar-Avivi S. , et al. Combined administration of FVIII and rFVIIa improves haemostasis in haemophilia A patients with high-responding inhibitors--a thrombin generation-guided pilot study. Haemophilia 2013; 19 (05) 782-789
45 Kuperman AA, Barg AA, Fruchtman Y. , et al. Primary prophylaxis for children with severe congenital factor VII deficiency - clinical and laboratory assessment. Blood Cells Mol Dis 2017; 67: 86-90
46 Seligsohn U. Treatment of inherited platelet disorders. Haemophilia 2012; 18 (Suppl. 04) 161-165
47 Coller BS, Cheresh DA, Asch E, Seligsohn U. Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel. Blood 1991; 77 (01) 75-83