Introduction
Glanzmann thrombasthenia (GT) is an autosomal platelet function disorder caused by
a quantitative or qualitative defect of the platelet membrane glycoprotein IIb–IIIa
(integrin αIIbβ3) complex.[1]
[2] With a prevalence of 1:1 million, GT is rare, although the prevalence is higher
in areas where marriage between relatives is common. It manifests clinically as an
increased tendency to spontaneous bleeds (e.g., epistaxis, hematoma, menorrhagia,
and bleeding complications) and also during and after surgery.[2]
[3]
The standard treatment for GT is platelet transfusion (PT), which carries the risk
of development of antibodies (AB) to αIIbβ3 and/or human leukocyte antigen (HLA).
Possible alternatives to PT include the administration of antifibrinolytics (AF),
local hemostatic agents, and bone marrow transplantation. In addition, recombinant
activated factor VII (rFVIIa) can be used for the treatment and prevention of bleeding
episodes, and for surgery, in patients with GT and AB, as well as past or present
platelet refractoriness. Nevertheless, this off-label use of rFVIIa in patients with
GT who have bleeds is increasing, mainly because of its convenience and to avoid alloimmunization
to platelets. Data from an international survey of patients with GT who have bleeding
episodes or hemorrhagic surgery complications supported a preliminary suggestion of
an optimal rFVIIa dosing regimen for the treatment of moderate or severe bleeding
episodes (≥80 μg/kg given at intervals of ≤2.5 hours for ≥3 doses).[4] Based on these survey results, rFVIIa was approved by the European Medicines Agency
(EMA) in 2004 for use in patients with GT who have AB and past or present platelet
refractoriness.
As the prevalence of GT is so low, data are not readily available for different subgroups
of patients. Particularly rare are data on the treatment of GT in children, for both
surgical and nonsurgical bleeding; though case studies are available, no large pediatric
studies have been conducted. The GT Registry (GTR) was an international, multicenter,
observational registry that focused on both adults and children. As such, it is one
of the first efforts to provide pediatricians with comprehensive information on the
effectiveness and safety of rFVIIa in children. This article summarizes new GTR data
and aims to evaluate rFVIIa effectiveness and safety as a treatment for young patients
with GT. Treatment results for all GTR patients have been published previously.[5]
[6]
Methods
The GTR was an international, multicenter, observational study on the effectiveness
and safety of rFVIIa in patients with GT (ClinicalTrials.gov identifier: NCT01476423),
prospectively collecting data on the treatment and outcomes of bleeds. Data were entered
into the GTR from 2007 until its closure in 2011, using a customized, Web-based collecting
tool. Treatment was based on local clinical practice rather than a set protocol, and
performed in accordance with general data protection laws and local country requirements
for conducting observational studies.[5]
[6] Centralized data management was overseen by Novo Nordisk and an external expert
panel comprising four hemostasis physicians from Europe and North America.
Patients
The analyses focused on patients <18 years old, and only a diagnosis of congenital
GT was included in the GTR. Patients with acquired thrombasthenic states caused by
autoimmune disorders or medications were excluded. Refractoriness and the presence
of AB were coded initially and assessed periodically as deemed necessary by the investigator.
Because tests for AB may not have been available at all centers, AB may also have
been present in patients classified as having refractoriness only. For GT definitions,
as well as key terms regarding bleeding, surgery, and definitions of effectiveness
(effective, partially effective, ineffective), see [Supplementary Table S1].
Ethics Committee Approvals
The GTR was conducted in accordance with the Declaration of Helsinki and Guidelines
for Good Pharmacoepidemiology Practices. Each participating center complied with local
regulations. Ethical and/or regulatory approval was obtained before data entry into
the registry, as required. Signed informed consent to participate was obtained from
all parents/legal guardians of the patients.
Statistical Methods
The effectiveness analysis was based on all children in the GTR and treatment-allocated
bleeds for which the efficacy endpoint was known. All children and bleeding episodes
were included in the safety analysis. The effectiveness data were summarized using
numerical variables (mean, standard deviation, median, maximum, and minimum), while
categorical variables were summarized as numbers and percentages. No formal statistical
comparisons were performed. No subdivision into age groups was performed because patient
numbers would be too low to yield meaningful results.
Results
GTR Enrollment and Composition of Datasets
Details of recruitment into the GTR and the safety and effectiveness datasets for
all surgical and nonsurgical bleeds have been reported previously for adults and children.[5]
[6] For children with GT, data were collected from 643 admissions (bleeding, 599; surgery,
44); 131 children with GT were enrolled from 45 sites in 15 countries from Africa,
Asia, Europe, and North America. The safety analysis dataset included all 643 admissions,
while effectiveness analyses were performed using data available from 590 admissions
for nonsurgical bleeding and 44 surgical admissions.
Clinical and Demographic Characteristics of the GTR Population Undergoing Surgery
or with Nonsurgical Bleeds
The clinical and demographic characteristics of children who participated in the GTR
and underwent surgery are provided in [Table 1]. Of 44 invasive procedures reported in 27 patients, 36 (in 23 patients) were minor
and 8 (in 8 patients) were major.
Table 1
Registry: clinical and demographic characteristics of the population <18 years old
at admission
|
Variable
|
Nonsurgical patients
(n = 104)
|
Nonsurgical bleeding episodes
(n = 599)
|
Surgical patients
(n = 27)
|
Surgical episodes
(n = 44)
|
|
Males, n (%)
|
48 (46.2)
|
259 (43.2)
|
19 (70.4)
|
34 (77.3)
|
|
Females, n (%)
|
56 (53.9)
|
340 (56.8)
|
8 (29.6)
|
10 (22.7)
|
|
Age (y), mean ± SD
|
6.3 ± 4.8
|
6.6 ± 4.3
|
7.5 ± 4.5
|
7.9 ± 4.4
|
|
Males, mean ± SD
|
5.2 ± 4.4
|
5.1 ± 4.3
|
6.3 ± 4.0
|
7.2 ± 4.3
|
|
Females, mean ± SD
|
7.2 ± 5.0
|
7.7 ± 4.0
|
10.3 ± 4.8
|
10.0 ± 4.4
|
|
Age category, n (%)
|
|
< 12 years
|
87 (83.7)
|
506 (84.5)
|
21 (77.8)
|
34 (77.3)
|
|
12–17 years
|
17 (16.4)
|
93 (15.5)
|
6 (22.2)
|
10 (22.7)
|
|
Body weight (kg), mean ± SD
|
21.2 ± 14.3
|
22.3 ± 13.3
|
30.3 ± 20.8
|
31.6 ± 20.8
|
|
Males, mean ± SD
|
19.3 ± 14.5
|
20.0 ± 14.1
|
26.3 ± 17.1
|
30.0 ± 19.8
|
|
Females, mean ± SD
|
22.8 ± 14.0
|
24.2 ± 12.4
|
39.9 ± 26.6
|
37.0 ± 24.2
|
|
Type of disease, n (%)
|
|
Type 1
|
26 (25.0)
|
234 (39.1)
|
9 (33.3)
|
13 (29.6)
|
|
Type 2
|
12 (11.5)
|
34 (5.7)
|
1 (3.7)
|
1 (2.3)
|
|
Variant
|
3 (2.9)
|
8 (1.3)
|
–
|
–
|
|
Unknown type
|
63 (60.6)
|
323 (53.9)
|
17 (63.0)
|
30 (68.2)
|
|
History of antiplatelet AB and/or refractoriness to platelets
|
|
AB (AB confirmed, refractoriness status unknown)
|
11 (10.6)
|
85 (14.2)
|
5 (18.5)
|
12 (27.3)
|
|
AB + refractoriness (both confirmed)
|
5 (4.8)
|
77 (12.9)
|
4 (14.8)
|
5 (11.4)
|
|
All AB[a]
|
16
|
162
|
9
|
17
|
|
Anti-αIIbβ3
|
13 (81.3)
|
64 (39.5)
|
7 (77.8)
|
13 (76.5)
|
|
Antihuman leukocyte antigen
|
2 (12.5)
|
9 (5.6)
|
1 (11.1)
|
3 (17.7)
|
|
Other
|
5 (31.3)
|
56 (34.6)
|
2 (22.2)
|
3 (17.7)
|
|
Refractoriness (refractoriness confirmed, AB not confirmed)
|
3 (2.9)
|
37 (6.2)
|
1 (3.7)
|
1 (2.3)
|
|
No confirmed history of antiplatelet AB and/or refractoriness to PT
|
85 (81.7)
|
400 (66.8)
|
17 (63.0)
|
26 (59.1)
|
Abbreviations: AB, antibodies; PT, platelet transfusions; SD, standard deviation.
a Number of types of AB may not add up to number of all AB, since type of AB was not
always registered, or more than one type of AB was registered.
Of the 599 admissions for nonsurgical bleeds in children, 145 (24.2%) were classified
as severe and 454 (75.8%) as moderate, while 423 bleeds (70.6%) were spontaneous and
176 (29.4%) were classified as being posttraumatic (see [Supplementary Table S2] for a detailed description of the bleeding episodes reported). Clinical and demographic
characteristics of the patients who experienced nonsurgical bleeds are presented in
[Table 1].
Surgical Bleeding—Minor Procedures
Treatment and Outcome
Of the 36 minor surgical procedures performed, dental procedures were most common
(25/36; 69.4%), followed by nasal procedures (4/36; 11.1%). Most minor procedures
([Table 2A]) were treated with rFVIIa, either alone (6/36; 16.7%), with AF (6/36; 16.7%), or
PTs (12/36; 33.3%). Data on the number of minor procedures rated as “effective” (see
definition in [Supplementary Table S1]) for the different treatments (overall and stratified according to the status of
platelet AB and platelet refractoriness) are provided in [Table 2A].
Table 2
Children <18 years old: treatments rated “effective” for (A) surgical bleeds and (B)
nonsurgical bleeds
|
A: Surgical bleeds
|
|
Surgical category/clinical status
|
rFVIIa
number effective/total number (%)
|
rFVIIa + AF
number effective/total number (%)
|
PT ± AF
number effective/total number (%)
|
rFVIIa + PT ± AF
number effective/total number (%)
|
AF
number effective/total number (%)
|
Overall
number effective/total number (%)
|
|
Minor procedures (n = 36)
|
|
No AB/No refractoriness (n = 18)
|
3/3 (100.0)
|
2/2 (100.0)
|
5/5 (100.0)
|
2/2 (100.0)
|
2/6 (33.3)
|
14/18 (77.8)
|
|
AB + refractoriness (n = 5)
|
1/1 (100.0)
|
2/2 (100.0)
|
–
|
2/2 (100.0)
|
–
|
5/5 (100.0)
|
|
Refractoriness only (n = 1)
|
–
|
–
|
–
|
0/1 (0.0)
|
–
|
0/1 (0.0)
|
|
AB only (n = 12)
|
2/2 (100.0)
|
2/2 (100.0)
|
6/7 (85.7)
|
1/1 (100.0)
|
–
|
11/12 (91.7)
|
|
Total (n = 36)
|
6/6 (100.0)
|
6/6 (100.0)
|
11/12 (91.7)
|
5/6 (83.3)
|
2/6 (33.3)
|
30/36 (83.3)
|
|
Major procedures (n = 8)
|
|
No AB/No refractoriness (n = 8)
|
1/1 (100.0)
|
2/2 (100.0)
|
1/1 (100.0)
|
0/3 (–)
|
1/1 (100.0)
|
5/8 (62.5)
|
|
AB + refractoriness (n = 0)
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Refractoriness only (n = 0)
|
–
|
–
|
–
|
–
|
–
|
–
|
|
AB only (n = 0)
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Total (n = 8)
|
1/1 (100.0)
|
2/2 (100.0)
|
1/1 (100.0)
|
0/3 (–)
|
1/1 (100.0)
|
5/8 (62.5)
|
|
B: Nonsurgical bleeds
|
|
Variable
|
rFVIIa
number effective/total number (%)
|
rFVIIa + AF
number effective/total number (%)
|
PT ± AF
number effective/total number (%)
|
rFVIIa + PT ± AF
number effective/total number (%)
|
AF
number effective/total number (%)
|
Overall
number effective/total number (%)[a]
|
|
Bleed type
|
|
Spontaneous bleeding (n = 420)
|
29/34 (85.3)
|
43/54 (79.6)
|
129/173 (74.6)
|
28/38 (73.7)
|
102/121 (84.3)
|
331/420 (78.8)
|
|
Posttraumatic bleeding (n = 170)
|
46/50 (92.0)
|
21/22 (95.4)
|
33/41 (80.5)
|
5/7 (71.4)
|
45/50 (90.0)
|
150/170 (88.2)
|
|
Bleed severity
|
|
Severe bleeds (n = 144)
|
–
|
16/23 (69.6)
|
50/62 (80.6)
|
11/21 (52.4)
|
33/38 (86.8)
|
110/144 (76.4)
|
|
Moderate bleeds (n = 446)
|
75/84 (89.3)
|
48/53 (90.6)
|
112/152 (73.7)
|
22/24 (91.7)
|
114/133 (85.7)
|
371/446 (83.2)
|
|
Clinical status
|
|
No AB/refractoriness (n = 395)
|
66/73 (90.4)
|
34/37 (91.9)
|
100/121 (82.6)
|
22/26 (84.6)
|
118/138 (85.5)
|
340/395 (86.1)
|
|
AB + refractoriness (n = 77)
|
3/4 (75.0)
|
4/5 (80.0)
|
30/57 (52.6)
|
5/6 (83.3)
|
5/5 (100.0)
|
47/77 (61.0)
|
|
Refractoriness only confirmed (n = 37)
|
2/3 (66.7)
|
13/15 (86.7)
|
4/5 (80.0)
|
2/5 (40.0)
|
8/9 (88.9)
|
29/37 (78.4)
|
|
AB only confirmed (n = 81)
|
4/4 (100.0)
|
13/19 (68.4)
|
28/31 (90.3)
|
4/8 (50.0)
|
16/19 (84.2)
|
65/81 (80.2)
|
Abbreviations: AB, antibodies; AF, antifibrinolytics (e.g., tranexamic acid); PT,
platelet transfusions; rFVIIa, recombinant activated factor VII.
a Effectiveness outcome was missing for nine nonsurgical bleeds. Missing data are categorized
as follows: spontaneous bleeding (n = 3), posttraumatic bleeding (n = 6); by treatment: rFVIIa (n = 2), rFVIIa + AF (n = 2), PT ± AF (n = 1), rFVIIa + PT ± AF (n = 1), AF (n = 3); by severity: severe bleeds (n = 1), moderate bleeds (n = 8).
Treatment with rFVIIa
Data on rFVIIa use were available for 18 minor procedures treated with rFVIIa, rFVIIa + AF,
or rFVIIa + PT ± AF; 100% of treatments were rated effective for rFVIIa (6/6) and
rFVIIa + AF (6/6), and 83.3% (5/6) of treatments were rated effective for rFVIIa + PT ± AF
([Table 2A]). For all minor procedures, median rFVIIa dose was 175 μg/kg (range: 3.6–300; interquartile
range [IQR]: 110 μg/kg), median number of doses was two (range: 1–20; IQR: 2) and
median interval between doses was 2 hours (range: 2–6; IQR: 1 hour) ([Table 3]).
Table 3
Children <18 years old: doses and duration of treatment with rFVIIa in the GTR stratified
according to bleeding severity and to a history of AB/refractoriness for (A) surgical
prophylaxis for bleeding (n = 24) and (B) nonsurgical bleeds (n = 210)
|
A: Surgical prophylaxis for bleeding
|
|
Surgical category/clinical status
|
Dose (μg/kg)
|
Number of doses
|
Cumulative dose (μg/kg)
|
Time interval between doses (h)
|
Duration of treatment (h)
|
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
|
All minor procedures (n = 18)
|
147.7 ± 55.5
|
175.0
110.0
3.6–300
|
4.2 ± 5.9
|
2.0
2.0
1–20
|
929.8 ± 2,166.5
|
185.0
120.0
3.6–8,544.0
|
2.6 ± 1.2
|
2.0
1.0
2.0–6.0
|
11.6 ± 16.5
|
5.0
3.0
2.0–54.0
|
|
All major procedures (n = 6)
|
105.8 ± 27.9
|
90.0
30.0
79.0–180.0
|
10.7 ± 9.1
|
9.5
16.0
1.0–22.0
|
1,154.0 ± 1,019.9
|
1,035.0
1,530.0
180.0–2,608.0
|
5.5 ± 6.0
|
3.0
4.0
1.0–30.0
|
77.0 ± 51.3
|
72.5
82.0
24.0–139.0
|
|
No AB or refractoriness to PT (n = 13)
|
118.3 ± 37.7
|
90.0
68.0
71.0–180.0
|
7.6 ± 8.1
|
3.0
13.0
1.0–22.0
|
1,300.8 ± 2,321.2
|
270.0
1,530.0
178.0–8,544.0
|
4.5 ± 5.1
|
3.0
2.0
1.0–30.0
|
38.2 ± 46.0
|
23.0
45.0
2.0–139.0
|
|
AB + refractoriness (n = 11)
|
153.4 ± 64.6
|
200.0
110.0
3.6–300.0
|
3.6 ± 5.5
|
2.0
2.0
1.0–20.0
|
614.0 ± 1,332.5
|
270.0
175.0
3.6–4,617.0
|
2.7 ± 1.0
|
2.0
1.0
2.0–6.0
|
11.0 ± 19.0
|
5.0
4.0
2.0–54.0
|
|
B: Nonsurgical bleeds
|
|
Bleeding severity/clinical status
|
Dose (μg/kg)
|
Number of doses
|
Cumulative dose (μg/kg)
|
Time interval between doses (h)
|
Duration of treatment (h)
|
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
Mean ± SD
|
Median
IQR
Range
|
|
Severe bleeding episodes (n = 44)
|
91.4 ± 21.8
|
90.0
15.2
36.0–185.0
|
8.2 ± 11.3
|
5.5
6.0
1.0–59.0
|
1,499.4 ± 2,895.0
|
532.5
741.0
40.0–15,600.0
|
8.1 ± 14.1
|
3.0
4.0
1.0–114.0
|
77.6 ± 138.3
|
26.5
44.5
3.0–578.0
|
|
Moderate bleeding episodes (n = 166)
|
96.9 ± 34.6
|
90.0
0.0
28.0–300.0
|
2.3 ± 1.9
|
2.0
2.0
1.0–10.0
|
220.2 ± 188.5
|
180.0
180.0
28.0–1,020.0
|
5.1 ± 8.6
|
3.0
1.0
1.0–70.0
|
17.7 ± 24.6
|
6.0
20.0
2.0–136.0
|
|
No AB or refractoriness to PT (n = 138)
|
93.5 ± 34.5
|
90.0
0.0
36.0–290.0
|
2.1 ± 1.8
|
1.0
2.0
1.0–10.0
|
200.9 ± 178.6
|
128.2
180.0
40.0–1,020.0
|
5.3 ± 8.2
|
3.0
2.0
1.0–57.0
|
18.8 ± 25.0
|
5.0
23.0
2.0–136.0
|
|
AB + refractoriness (n = 72)
|
94.8 ± 25.0
|
90.0
5.0
28.0–300.0
|
6.2 ± 9.3
|
3.0
5.0
1.0–59.0
|
1,049.0 ± 2,340.4
|
350.0
563.0
28.0–15,600.0
|
7.6 ± 13.6
|
3.0
3.0
1.0–114.0
|
58.0 ± 119.0
|
15.5
38.0
2.0–578.0
|
Abbreviations: AB, antibodies; GTR, Glanzmann Thrombasthenia Registry; IQR, interquartile
range; PT, platelet transfusions; rFVIIa, recombinant activated factor VII; SD, standard
deviation.
Treatment with Platelets
Treatment with PT ± AF was used in 12 minor procedures, with 91.7% of treatments overall
being rated effective ([Table 2A]). This treatment was rated effective in all five procedures in the no AB/no refractoriness
group and in six of seven procedures in the AB-only group. For the six minor procedures
treated with rFVIIa + PT ± AF, 83.3% were rated effective overall ([Table 2A]).
Ineffective Treatments
One of the 36 minor procedures was rated “ineffective” (no AB/no refractoriness; AF
only) using PT ± AF.
Surgical Bleeding—Major Procedures
Treatment and Outcome
Of the eight major surgical procedures performed, gastrointestinal and circumcision
procedures were most common (n = 3; 37.5% each). Major procedures were treated most frequently with rFVIIa + PT ± AF
(n = 3; 37.5%). All major procedures occurred in the no AB/no refractoriness group.
Effectiveness ratings for the different treatments for major procedures (overall and
stratified according to the status of platelet AB and platelet refractoriness) are
provided in [Table 2A].
Treatment with rFVIIa
Data on rFVIIa use were available for analysis in six major procedures treated with
rFVIIa, rFVIIa + AF, or rFVIIa + PT ± AF, with 100% of treatments rated effective
for rFVIIa (1/1) and rFVIIa + AF (2/2); 0% (0/3) of treatments were rated effective
for rFVIIa + PT ± AF ([Table 2A]). For all major procedures, the median rFVIIa dose was 90 μg/kg (range: 79–180);
median dose interval was 3 hours (range: 1–30 hours). The median number of doses was
9.5 (range: 1–22) and the median cumulative rFVIIa dose was 1,035 μg/kg (range: 180–2,608)
([Table 3]).
Treatment with Platelets
The effectiveness outcome for major procedures treated with platelets (PT ± AF and
rFVIIa + PT ± AF) was available for four cases ([Table 2A]). Of these, the one treated with PT ± AF was effective.
Partially Effective/Ineffective Treatments
Of the eight major procedures, three were rated as either partially effective (n = 2) or ineffective (n = 1) in patients treated with rFVIIa + PT ± AF with no AB/refractoriness. No postsurgical
bleeding was reported following rFVIIa and/or platelet treatment for major procedures
(as defined in [Supplementary Table S1]).
Safety Data
For surgery, one nonserious adverse event (AE) was reported in the GTR, which was
an incidence of pyrexia in a male child without platelet AB or refractoriness, who
was treated with rFVIIa + PT + AF (major surgery). It was considered unlikely that
this AE was related to rFVIIa, and the patient recovered completely. [Supplementary Table S3] summarizes the AEs reported in treated patients.
Nonsurgical Bleeding
Treatment Dosing and Scheduling
Regardless of bleeding severity, the PT ± AF combination was the most commonly used
treatment ([Supplementary Fig. S1]). Of the 590 bleeding episodes included in the effectiveness assessment, 214 (36.3%)
were treated with PT ± AF, 171 (29.0%) with AF only, 84 (14.2%) with rFVIIa alone,
76 (12.9%) with rFVIIa + AF, and 45 (7.6%) with rFVIIa + PT ± AF. Concomitant AF treatment
was documented in 76/160 (47.5%) bleeds treated with rFVIIa, in 60/214 (28.0%) treated
with PT, and in 36/45 (80.0%) treated with rFVIIa + PT.
Investigators reported that, for the 195/590 bleeds that occurred in patients with
a history of antiplatelet AB and platelet refractoriness, AB only, or refractoriness
only, PT ± AF was used in 93/195 (47.7%; 29 severe and 64 moderate), rFVIIa + AF in
39/195 (20.0%, 20 severe and 19 moderate), AF alone in 33/195 (16.9%, 2 severe and
31 moderate), rFVIIa + PT ± AF in 19/195 (9.7%, 15 severe and 4 moderate), and rFVIIa
alone in 11/195 (5.6%, all moderate) bleeds. The use of rFVIIa, alone (3/37; 8.1%)
or together with AF (15/37; 40.5%), to treat bleeds was most frequent in patients
with a history of refractoriness alone, while AF was mainly used to treat bleeds that
occurred in patients with no history of AB and/or platelet refractoriness (138/395;
34.9%) ([Table 2B]).
The number of rFVIIa doses, cumulative dose, and overall duration of treatment were
greater in patients with severe bleeds than in those with moderate bleeds. They were
also greater in patients with a history of AB and/or refractoriness to platelets versus
patients without such medical history ([Table 3]).
Evaluation of Treatment Effectiveness
Overall, treatment was judged as effective (see [Supplementary Table S1] for definition) in 89.3% (75/84) of bleeds treated with rFVIIa alone, 86.0% (147/171)
with AF alone, 84.2% (64/76) with rFVIIa + AF, 75.7% (162/214) with PT ± AF, and 73.3%
(33/45) with rFVIIa + PT ± AF ([Table 2B]). For 73 moderate bleeds treated with rFVIIa (either alone, with AF, or with PT)
for which information on treatment duration was available, the median total duration
of rFVIIa treatment was 6 hours. For 36 severe bleeds treated with rFVIIa (either
alone, with AF, or with PT) for which information on treatment duration was available,
the median total duration of rFVIIa treatment was 26.5 hours. In addition, the median
total duration of treatment was 4 hours for 20 bleeds with AB, 11 hours for 13 bleeds
with AB + refractoriness, 5 hours for 57 bleeds without AB or refractoriness, and
34 hours for 19 bleeds with refractoriness.
Ineffective Treatment
Ineffective treatment was documented in 13 cases (2.2% of the total number of patients),
comprising three severe bleeds and 10 moderate bleeds. Of these, seven had a history
of AB/refractoriness. Regarding the initial treatment employed, 8 of the 13 cases
were receiving AF, 3 were receiving PT ± AF, and 2 were receiving rFVIIa + AF.
Rebleeding
For 557 bleeds where data on rebleeding were available, 36 rebleeds in 17 patients
were registered, comprising 15/136 (11.0%) severe bleeds, 21/421 (5.0%) moderate bleeds,
15/380 (3.9%) bleeds in patients without AB or refractoriness, and 21/177 (11.9%)
bleeds in patients with a history of AB and/or refractoriness to platelets. Rebleeding
occurred in 20/204 (9.8%) bleeds treated with PT ± AF, 9/42 (21.4%) treated with rFVIIa + PT ± AF,
1/78 (1.3%) treated with rFVIIa alone, and 3/69 (4.3%) treated with rFVIIa + AF.
Safety Data
For the nonsurgical bleeding results presented in this article, 24 AEs were reported
(including six serious AEs; [Supplementary Table S3]). For bleeds where patients received rFVIIa, eight AEs occurred, five of which were
serious (subarachnoid bleeding, septicemia, respiratory insufficiency, cardiac decompensation,
and rebleeding/hematoma due to a fall) and three nonserious (bacterial infection,
fever, and headache). All were judged by the investigators as unlikely to be related
to rFVIIa treatment. For the subarachnoid bleed, it was not possible to confirm the
time relationship between this serious AE and rFVIIa treatment, i.e., whether rFVIIa
was used to treat the subarachnoid bleed or not, and whether this is related to a
lack of efficacy for rFVIIa or not. No thromboembolic events or unexpected laboratory
values were reported for any of the treatments for nonsurgical bleeds.
Discussion
The GTR data reported here have been taken from the largest observational study on
patients with GT and include information on the management of invasive procedures;
the shortcomings of the previous survey[4] have been addressed through consideration of the use of hemostatic agents other
than rFVIIa. For the most part, this subgroup analysis confirmed previous insights.
rFVIIa and other currently available treatments for bleeding in patients with GT were
found to have good safety and effectiveness profiles in most children, in both surgical
and nonsurgical bleeds. When compared with previous GTR analyses, overall there were
no relevant differences between children and adults regarding effectiveness and safety
of the studied treatment options (with the exception of PT for treatment of nonsurgical
bleeds in children with AB and refractoriness, which was less effective than in adults).[5]
[6] The surgical patient subgroups included in the discussion below (e.g., patients
with or without AB/refractoriness) were based on low patient numbers ([Table 2]).
Treatment with rFVIIa
In general, rFVIIa, alone or with AF, was used more frequently than platelets (PT ± AF)
in surgical patients with AB and refractoriness, in surgical patients with major procedures,
in nonsurgical patients with refractoriness only, and in nonsurgical patients with
posttraumatic bleeding. The numbers receiving rFVIIa ± AF were similar in both surgical
patients without AB/refractoriness and those with minor procedures overall. In all
other subgroups, rFVIIa, alone or with AF, was used less often than platelets. The
GTR results further indicate that rFVIIa has a good safety profile in patients with
GT.
Assessment of rFVIIa dose and dosing schedule in this registry suggests that, in patients
without AB or refractoriness, rFVIIa 90 to 120 μg/kg given at approximately 2 to 4-hour
intervals (median: 2–3 hours) for ≥3 doses (median: 1–5.5, until effective hemostasis)
could be used, with the first dose given immediately preoperatively in surgical patients.
As reported by Poon et al,[6] this is similar to the regimen previously suggested for bleeding episodes (rFVIIa
≥80 μg/kg at intervals of ≤2.5 hours for ≥3 doses),[4] and is also similar to standard rFVIIa dosing in patients who have congenital hemophilia
A or B with inhibitors.[7]
A median rFVIIa dose of 90 μg/kg was used most frequently in nonsurgical patients
with AB and/or refractoriness, and in surgical patients with neither of these (200 μg/kg
was used in surgical patients with AB and/or refractoriness). The median dose interval
was 3 hours, except in surgical patients with AB and/or refractoriness (for whom it
was 2 hours). For severe bleeds, the number of doses reported was understandably higher
than for moderate bleeds. In addition, severe bleeds were also associated with longer
treatment duration and higher cumulative doses. Based on these results, rFVIIa at
≥90 μg/kg at intervals of ≤3 hours should be used, at least at the beginning of treatment.
The subsequent number of doses required would need to be determined by the clinical
situation and dosing should be continued until hemostasis is assured.
Treatment with Platelets
PT was generally effective in covering surgical procedures and nonsurgical bleeds
in patients, both with and without historic report of platelet AB and/or refractoriness.
An exception is the much lower response rate for nonsurgical bleeds in children with
AB and refractoriness (30/57, 52.6%) when compared with adults with AB and refractoriness
(25/28, 89.3%).[5] Notably, some procedures in the AB-only group, as well as some nonsurgical bleeding
episodes in patients with AB and/or refractoriness, had a successful outcome with
PT ± AF ([Table 2]). A possible explanation for this is that, in some patients with a history of AB,
they were no longer present at the time of surgery and patients who had been refractory
before were no longer. As discussed by Di Minno et al,[5] although comprehensive data on the natural history of inhibitors in GT are lacking,
it is possible that the effectiveness of platelets in such a setting may be associated
with the long time intervals between exposure to platelets in GT and possibly also
to the transient nature of the inhibitors. Furthermore, Poon et al[6] suggested that the reason for this effectiveness may be that patients with HLA AB
were receiving only HLA-matched platelets. Nevertheless, even if HLA-unmatched platelets
are provided, prior data indicate that >50% of patients may not display refractoriness
to PT.[8]
[9]
[10] As previously noted for the GTR in surgical intervention,[6] these observations suggest that treatment with platelets may be attempted when other
agents are ineffective or not available—even in patients with a history of AB and/or
refractoriness.[4] Due to the low numbers of surgical patients available, we cannot provide information
on the effectiveness of treatment in refractory patients. Successful PT following
removal of platelet AB by plasmapheresis[11]
[12] or immunoadsorption[13] has also been reported.
Combined Treatment Using Platelets and rFVIIa
A key question is whether combined use of platelets and rFVIIa (rFVIIa + PT ± AF)
has an advantage over rFVIIa (alone or with AF) or PT ± AF.[4] This pediatric analysis correlated with prior data reported from the GTR indicating
that rFVIIa + PT ± AF was less effective than rFVIIa and rFVIIa + AF.[6] As previously suggested, based upon the observational nature of the registry,[6] rFVIIa + PT ± AF may have been used in patients with particularly difficult or challenging
clinical situations and often when platelets may have been added to rFVIIa ± AF or
rFVIIa added to PT ± AF. Further hemostatic agent(s) might have been added to the
regimen when effectiveness was in doubt while using other hemostatic agents.
Treatment with AF
The relative proportion of AF use for bleeds (both moderate and severe), as well as
for surgical prophylaxis (both minor and major), was similar in both children and
adults.[5]
[6] Nevertheless, in general, children with surgical procedures were administered AF
more often than adults (7/44 [15.9%] vs. 5/159 [3.1%], respectively); rFVIIa was administered
less often in children than adults (15/44 [34.1%] vs. 118/159 [74.2%], respectively).[6] For the treatment of bleeding episodes in particular, children with refractoriness
or with AB were treated more often with AF than adults with the same status (refractoriness:
9/37 [24.3%] children vs. 0/16 [0%] adults; AB: 19/81 [23.5%] children vs. 11/52 [21.2%]
adults).[5] AF were also used in children with spontaneous severe bleeding more often than in
adults (36/131 [27.5%] vs. 9/67 [13.4%], respectively), although both subgroups were
treated most often with PT (52/131 [39.7%] vs. 34/67 [50.7%], respectively).[5]
The successful use of AF without platelets or rFVIIa was reported in 3/7 (42.9%) surgical
procedures, and in 147/171 (86.0%) nonsurgical bleeding episodes. As noted previously
for the GTR,[6] this may be explained by AF treatment commencing with the intention of using other
systemic hemostatic agent(s), should hemostasis not be achieved. In addition, a less
controlled data collection process versus clinical trials complicates interpretation
or direct comparison of effectiveness between treatments. We do advise, however, that
AF should not be recommended as the sole therapy during surgery in pediatric patients,
particularly for major procedures, unless rFVIIa or platelet concentrates are available
as back up. As noted by Di Minno et al,[5] nonsurgical bleeds may, on the other hand, be treated with AF first (possibly in
the home setting), with the option of introducing other treatment (rFVIIa and/or platelets)
during the bleeding episode if required.
Safety
A potential concern with the use of rFVIIa in patients with GT is whether rFVIIa is
thrombogenic. The pediatric data reported here suggest that all systemic hemostatic
agents used had a good safety profile in surgical procedures for these patients. Among
the 599 nonsurgical bleeding episodes in 104 patients and 44 procedures performed
in 27 patients, no thromboembolic events were reported. Thus, rFVIIa appears to be
a valid first-line treatment option for nonsurgical bleeds in pediatric patients with
GT who are awaiting HLA-compatible platelet concentrates or for concentrates prepared
from single-donor apheresis. Indeed, rFVIIa has been licensed for use in GT when platelets
are not readily available.[14]
Limitations
As previously reported,[6] the major limitations of these GTR data are that they were not obtained using a
defined treatment protocol in a randomized manner and treatment effectiveness and
safety were not assessed at multiple, consistent, predefined time points. Furthermore,
the frequent use of multiple agents in GT and delays in obtaining platelets make it
particularly difficult to attribute effectiveness to any one or more products. Previously,
Di Minno et al[5] noted the arbitrary classification of severe and moderate bleeds in nonsurgical
bleeding as a further limitation. The use of these simple definitions, which are similar
to the definitions of “major and minor bleeds” published in April 2005 by the Subcommittee
on Control of Anticoagulation of the Scientific and Standardization Committee of the
International Society on Thrombosis and Haemostasis,[15] was at the request of the EMA. Furthermore, as the coding of history of AB or refractoriness
was performed at first admission and when the investigator considered appropriate,[6] the lack of documentation of specific antibody testing or refractoriness at the
time of a particular episode limits the analysis (particularly for use of platelet-based
regimens).
The rarity of GT also hinders the performance of formal clinical trials; pediatric
data reported here represent the largest dataset available in the literature, including
those in other databases.[16]
[17] These registry data represent real-life clinical practice and the standards of care
at participating sites. Narrative information, as provided in the GTR, often gives
additional useful insights that may differ from the coding of effectiveness at an
earlier time point after surgery.
In summary, this post hoc analysis suggests that, when managing children with GT and
surgical or nonsurgical bleeding episodes, rFVIIa, PT, and AF are valid first-line
treatment options as they appear effective and safe. Given the selection bias in choice
of treatment and adaption of treatment to clinical response, treatment strategies
cannot be compared in observational studies. For first-line treatment of nonsurgical
bleeds with AF, we suggest introducing other treatment options if AF proves insufficiently
effective. For major surgical procedures, AF should only be used as a first-line therapy
when rFVIIa or platelet concentrates are available as a backup treatment option. In
cases of severe bleeding, a combined treatment with AF, rFVIIa, and platelet concentrates
may be necessary. The available observations suggest that treatment with platelets
may be attempted when other agents are ineffective or not available—even in patients
with a history of AB and/or refractoriness. As there were no relevant differences
between children and adults regarding effectiveness and safety of the studied treatment
options (with the exception of PT in the treatment of nonsurgical bleeds in children
with both AB and refractoriness), the treatment of children should not differ notably
from that of adults.[5]
[6]
