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Yoo, Choi, and Park: Maintenance Therapy with Activated Prothrombin Complex Concentrate (aPCC) for Hemophilia Patients with High Levels of Responding Inhibitors
Original Article

Korean J Hematol 2009;44(4):205-211.

Published online: 20 December 2009

DOI: https://doi.org/10.5045/kjh.2009.44.4.205

Maintenance Therapy with Activated Prothrombin Complex Concentrate (aPCC) for Hemophilia Patients with High Levels of Responding Inhibitors

Ki Young Yoo, M.D.1, 2, , Yong Mook Choi, M.D.1, 2, Young Shil Park, M.D.2

1Korea Hemophilia Foundation, Kyung Hee University, Seoul, Korea

2Department of Pediatrics, College of Medicine, Kyung Hee University, Seoul, Korea

Correspondence to：Ki Young Yoo, M.D. Korea Hemophilia Foundation 1628-26, Seocho-1dong, Seocho-gu, Seoul 137-072, Korea Tel: ＋82-2-3473-6100, Fax: ＋82-2-3473-6634 E-mail: gowho@hotmail.com

Received 21 October 2009       Revised 1 December 2009       Accepted 1 December 2009

Copyright © 2009 Korean Society of Hematology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Eleven percent of severe hemophilia A patients and 5% of severe hemophilia B patients may develop inhibitors. We have conducted aPCC-based maintenance therapy for hemophilia patients with high levels of responding inhibitors and we analyzed the efficacy, safety, the factor consumption and the expense of this treatment, as compared to on-demand therapy.

Methods

Eleven hemophilia patients with high levels of responding inhibitors were eligible for the study. We tried to evaluate the longitudinal bleeding episodes, the inhibitor titers, the X-ray findings, the adverse events and the factor consumption between on-demand therapy and maintenance therapy. The bypassing agent in this study was aPCC having a longer half-life. The dosage was 30∼50 U/kg, 3 times a week.

Results

The mean follow-up period was 6.8 months for on-demand therapy and 10.6 months for maintenance therapy. The mean dosage of aPCC was 45.2 U/kg. The episodes of hemarthrosis decreased by 61.4% (P=0.003) and other significant bleedings decreased by 45.2% (P=0.109). The inhibitor titers decreased in 7 patients and these increased in 4 patients, but anamnesis took place in only 1 patient. Radiologically, 2 patients improved, 1 patient got worse and 7 patients were stable. Neither adverse signs nor symptoms were noticed. The mean factor consumption changed from 55.8×103 U for aPCC and 48.6 mg for rFVIIa on-demand therapy to 216×103 U for aPCC and 4.8 mg rFVIIa for maintenance therapy. Maintenance therapy cost 67% more than on-demand therapy monthly (P=0.041).

Conclusion

aPCC-based maintenance therapy for hemophilia patients with high responding inhibitors cost 67% more than on-demand therapy, but it reduced by 61.4% the episodes of hemarthrosis and 45.2% of the other significant bleedings. aPCC-based maintenance therapy can very effectively reduce the bleeding episodes of hemophilia patients with high levels of responding inhibitors.

Keywords: Hemophilia, Inhibitor, aPCC, Maintenance therapy

References

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Table 1.
Characteristics of patients
No. of patient (N=11) Type of hemophilia TEG Index Age (year) Follow-up duration (month) Dosage of aPCC (μ/kg)
Pre-MT Post-MT OD MT Interval
1 A NT 8 9 6 13 45.4, tiw
2 A －1.7 8 9 6 14 50.0, tiw
3 A NT 1.2 2 6 9 38.5, tiw
4 A －1.0 10 11 12 12 46.9, tiw
5 B NT 5 7 12 12 40.1, tiw
6 A NT 1.6 2 6 7 51.0, tiw
7 A NT 16 17 12 12 40.8, tiw
8 A 1.3 11 12 12 10 46.9, tiw
9 B NT 9 10 6 10 50.0, tiw
10 A －0.6 51 52 6 8 50.0, tiw
11 A －3.1 33 34 13 9 37.8, tiw
Average － －1.5 14.0 15.0 6.8 10.6 45.2, tiw

Abbreviations: MT, maintenance therapy; OD, on-demand; NT, not test; tiw, three times a week.

Table 2.
Outcomes of maintenance therapy of aPCC
No. of patient Inhibitor titer (BU/mL) Outcomes
Pre-MT On MT Post-MT X-ray findings No. of hemarthrosis (monthly) No. of other bleedings (monthly)
Pre-MT Post-MT On OD On MT On OD On MT
1 4.64 4.6 2.16 IV IV 14 (2.33) 11 (0.85) 0 0
2 6553.6 2099.2 576 IV IV 18 (3.00) 16 (1.14) 2 (0.33) 1 (0.07)
3 10.4 4.6 2.28 NT NT 3 (0.50) 1 (0.11) 5 (0.83) 3 (0.33)
4 25.6 13.2 2.56 IV IV 17 (1.41) 5 (0.42) 10 (0.83) 3 (0.25)
5 25.6 26 14 IV IV 16 (1.33) 8 (0.67) 9 (0.75) 5 (0.42)
6 210 2.11 211 I 0 5 (0.83) 4 (0.57) 1 (0.17) 5 (0.83)
7 7.6 8.2 8.2 III 0 10 (0.83) 0 7 (0.58) 0
8 30.8 11.6 4.8 III III 10 (0.83) 8 (0.80) 6 (0.50) 5 (0.50)
9 0.6 3.6 3.6 0 0 5 (0.83) 4 (0.40) 1 (0.17) 1 (0.1)
10 28 － － IV IV 15 (2.50) 5 (0.63) 1 (0.17) 0
11 86.4 90.2 91.2 IV IV 5 (0.38) 1 (0.11) 2 (0.22) 0
Average 634.84 205.76 83.25 － － 10.7 (1.35) 5.7 (0.52) 4.0 (0.42) 2.1 (0.23)

Abbreviations: MT, maintenance therapy; NT, not tested.

Table 3.
Consumption of coagulation factor concentrates through study period
No. of patients On-demand Maintenance
aPCC (×103 U) rFVIIa (mg) KRW (monthly) aPCC (×103 U) rFVIIa (mg) KRW (monthly)
1 124   176,065,120 (29,344,186) 349   495,538,120 (38,118,316)
2   355.2 351,059,583 (58,509,930) 333   472,820,040 (33,772,860)
3 40 93 56,795,200 (9,465,866) 93   132,048,840 (14,672,093)
4 67 4.8 100,590,766 (8,382,563) 285   404,665,800 (33,722,150)
5 52   73,833,760 (6,152,813) 153   217,241,640 (18,103,470)
6 7.5   10,649,100 (1,774,850) 51   72,413,880 (10,344,849)
7 51   172,515,420 (14,376,285) 318   451,521,840 (37,626,820)
8 45   63,894,600 (5,324,550) 130   184,584,400 (18,458,440)
9   81.6 81,933,328 (13,655,554) 178 52.8 305,772,874 (30,577,287)
10 151.5   215,111,820 (35,851,973) 298.5   423,834,180 (52,979,272)
11 76   107,910,880 (8,300,837) 195   276,876,600 (30,764,066)
Average 55.8 48.6 128,214,507 (17,376,310) 216.7 4.8 312,483,234 (29,012,693)

Abbreviation: KRW, Korean won.

Table 4.
Reports of aPCC-based matintenance thrapy
  Ewenstein (ref. 17) Valentino (ref. 18) Lambert (ref. 19) Cheng (ref. 20) Dimichele (ref. 21) Leissinger (ref. 22)
No. of patients 16 6 6 5 14 5
Mean age on maintenance (year) NA 9.2 Child: 5 pts Adult: 1 pt 9.2 25 8.5
aPCC dosage 69 U/kg, qod∼q3d 100 U/kg, qd tiw for 2 pts qod, qd for 4 pts 50 U/kg, tiw for 4 pts 75 U/kg qw for 1 pt 69 U/kg, qod 50∼75 U/kg, tiw for 4 pts 100 U/kg, qd for 1 pt
F/U duration 19.5 mon 4.5 yrs NA 0.5∼1.5 yrs (mean: 11 mon) 9.5 mon 15 mon
Adverse events No 1 allergy for a specific lot No No No No
Reduction rate of bleeds 53% 95% 65% 90% 53% 73%

Abbreviations: NA, not available; Yrs, years; mon, month; qod, every other day; q3d, every three day; qd, everyday; tiw, three times a week; pt(s), patient(s); qw, once a week; F/U, follow-up.

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