The International Prospective Glanzmann's Thrombasthenia Registry (GTR) Special Issues in Children

Glanzmann's thrombasthenia (GT) is a severe inherited bleeding disorder with defective platelet membrane αIIbβ3. Until now there have been only limited data regarding treatment of GT with platelets (P), NovoSeven (rFVIIa), and antifibrinolytics (AF) in children.

The GTR is an international prospective multicenter registry on the efficacy and safety of rFVIIa as well as platelets and AF for non-surgical and surgical bleedings in GT patients. From 2004 to 2011, 218 GT patients from 45 sites in 15 countries from 4 continents were enrolled in the GTR, including 106 children. In the following the terms “rFVIIa”, “P”, and “rFVIIa+P” may include use of AF. “AF” means AF only.

Of the 96 patients with surgical procedures (n=204), 27 (28%) were children (21 < 12 yrs, 6 adolescents 12–17 yrs) with 42 procedures (21%). Dental procedures were the most frequent intervention (n=26, 62%), followed by nasal procedures (n=4, 10%), and gastrointestinal surgery and excision (each n=3, 7%). The majority of surgeries were treated equally often with rFVIIa (n= 14, 33%) and P (n=12, 29%), followed by rFVIIa+P (n=9, 21%) and AF (n=7, 17%). In major surgical procedures (n=8, 19%), children were mostly treated with rFVIIa (n=3, 38%) or with rFVIIa+P (n=3, 38%), while P (n=1, 13%) or AF (n=1, 13%) was used less often. In minor procedures (n=34), P or rFVIIa were administered about twice as often as rFVIIa+P, or AF, respectively (P: n=11, 26%, rFVIIa: n=11, rFVIIa+P: n=6, 14%, AF: n=6). rFVIIa (7/26, 27%), P (8/26, 31%) and AF (7/26, 27%) were used equally often in dental procedures (rFVIIa+P 4/26, 15%). When children were treated with AF in surgery, it was always in dental procedures (7/7). The median dose was 93μg/kg. Regarding the efficacy of the different treatments, rFVIIa was 100% successful (14/14), as well as P (12/12). The efficacy of rFVIIa+P was 56% (5/9), that of AF 43% (3/7). There were no rebleedings. The numbers of minor and major procedures stratified according to the presence of antibodies and/or refractoriness are too low to allow for a separate analysis.

Out of 184 GT patients with non-surgical bleeding, 105 were < 18 years old. No history of antibodies (AB) and/or refractoriness (REF) was present in 86 of these patients (82%). AB were documented in 11 (10.5%); REF in 3 (2.9%); and REF + AB in 5 (4.8%). Bleeding (n=628) was moderate in 483 (77%) and severe in 145 (23%) episodes. Among moderate bleedings, 286/483 (59%) were spontaneous; among severe bleedings, 130/145 (90%) were spontaneous. In moderate bleedings, rFVIIa was used in 175 (36%) episodes; P in 153 (32%); AF in 130 (27%); and rFVIIa+P in 25 (5.2%). In severe bleedings, rFVIIa was used in 22 (15%) episodes; P in 62 (43%); rFVIIa+P in 22 (15%); and AF in 39 (27%). The median dose of rFVIIa was 90μg/kg. The proportion of successful treatments (bleeding stopped within 6 h of starting treatment) for rFVIIa was 78% for spontaneous and 87% for traumatic bleeding. These figures were 74% and 79%, respectively, with P; 71% and 43%, respectively, with rFVIIa+P; and 82% and 89%, respectively, with AF only. The numbers were too low to allow for a stratification for presence of AB and/or REF. Treatment failure was documented in only 13 episodes (2% of 628), 8 having received only AF. Out of 628 bleedings, 37 re-bleedings (bleedings re-starting within 6–24 h after having stopped) were registered: 6/197 after treatment with rFVIIa (3%), 20/215 with P (9.3%), 8/47 with rFVIIa+P (17%) and 3/169 with AF (1.8%). Thromboembolic events were not reported. Allergic reactions were reported following treatment with P (3/215, 1.4%).

The GTR results for children show that the efficacy of rFVIIa was as good as that of P. rFVIIa was safe. In non-surgical bleedings, P were preferred in all cases but traumatic moderate bleeding (preference for rFVIIa); surgical bleedings were treated equally often with rFVIIa and P. Overall, the efficacy was high for all treatment options. The re-bleeding rate was higher after P only than after rFVIIa only in non-surgical bleedings. The merit of the combined use of rFVIIa and platelets could not be assessed in this non-randomized study since the combined treatment is usually applicated in cases of severe bleeding with insufficient success of single treatment options.

Zotz:Novo Nordisk: Honoraria. Off Label Use: Recombinant actived FVII. di Minno:Novo Nordisk: Honoraria. d'Oiron:NovoNordisk: Honoraria. Poon:Novo Nordisk: Honoraria.