国产四因子凝血酶原复合物在儿童血友病A免疫耐受诱导过程中旁路止血的疗效——单中心数据分析
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摘要
目的:血友病A抑制物出现后因子替代治疗无效,免疫耐受诱导(ITI)治疗中的出血须用旁路制剂止血。国产四因子凝血酶原复合物(4F-PCC)作为目前经济有效的旁路制剂在我国广泛使用,但尚缺乏相关数据。本研究旨在评价国产4F-PCC在血友病A抑制物患儿ITI治疗中控制出血的有效性和安全性,为开展规范治疗提供依据。方法:对2017-01-2018-07于我中心进行ITI治疗的抑制物患儿在抑制物滴度≥2BU时应用4F-PCC的病例资料进行回顾性分析。结果:共收集到24例患儿的80次出血事件,其中轻度出血12次(15.0%),中度出血67次(83.8%),重度出血1次(1.2%)。4F-PCC的剂量为(53.5±13.8)IU/kg×(2.3±1.8)次,总剂量(121.8±109.3)IU/kg,出血控制率达97.5%,其中出血控制评价为显效者达53.8%(43次),有效43.7%(35次),无效2.5%(2次)。接受4F-PCC预防治疗者有6例,在(35.9±8.2)IU/kg,每周2次至隔日1次的方案下,经中位2.6(1.1～6.2)个月的预防治疗,出血较前下降83.0%[(2.24±1.84)vs(0.38±0.80)次],且无严重出血事件发生。本研究亦未发生血栓栓塞事件。结论:鉴于我国现状,在伴抑制物的血友病A患儿的ITI治疗中,虽然国产4F-PCC用于旁路途径止血的按需和预防治疗的剂量偏低,但对于轻中度出血的按需治疗以及预防治疗均显示良好的有效性和安全性,仍需临床更多资料支持。
Objective:Domestic four-factor prothrombin complex concentrate(4 F-PCC)are used as hemostatic bypassing agents in treating patients with inhibitors,however,relevant data is limited in China.To evaluate the efficiency and safety of domestic 4 F-PCC in on-demand and prophylaxis in hemophilia A(HA)children with inhibitor receiving immune tolerance induction(ITI)therapy,and in order to provide basis for standardized treatment.Method:HA patients underwent ITI when inhibitor titer≥2 BU and used 4 F-PCC were retrospectively analyzed from January 2017 to July 2018.Result:Twenty-four patients were enrolled with the median age of 6(range 3,17)years,80 bleeding episodes had been recorded including mild bleeding 12 times(15.0%),moderate 67 times(83.8%),and severe 1 time(1.2%).Through the mean dose of(53.5±13.8)IU/kg×(2.3±1.8)times[totally(121.8±109.3)IU/kg],97.5% of bleeds could be controlled,of which 53.8%(43/80)were excellent,43.7%(35/80)were good to moderate,2.5%(2/80)were poor.Six cases used 4 F-PCC prophylaxis[mean(35.9±8.2)IU/kg,twice a week to every other day]during ITI,bleeds/month reduced 83.0% [(2.24±1.84)vs(0.38±0.80)times]without severe bleeding events in median 2.6(range 1.1,6.2)months prophylaxis.There was also no thromboembolic event.Conclusion:Under the current situation in China,a lower dose 4 F-PCC shows a quite satisfied efficiency and safety both in on-demand and prophylaxis as hemostatic bypassing agents in HA inhibitor patients receiving ITI therapy,however,more clinical data is still needed.
Objective:Domestic four-factor prothrombin complex concentrate(4 F-PCC)are used as hemostatic bypassing agents in treating patients with inhibitors,however,relevant data is limited in China.To evaluate the efficiency and safety of domestic 4 F-PCC in on-demand and prophylaxis in hemophilia A(HA)children with inhibitor receiving immune tolerance induction(ITI)therapy,and in order to provide basis for standardized treatment.Method:HA patients underwent ITI when inhibitor titer≥2 BU and used 4 F-PCC were retrospectively analyzed from January 2017 to July 2018.Result:Twenty-four patients were enrolled with the median age of 6(range 3,17)years,80 bleeding episodes had been recorded including mild bleeding 12 times(15.0%),moderate 67 times(83.8%),and severe 1 time(1.2%).Through the mean dose of(53.5±13.8)IU/kg×(2.3±1.8)times[totally(121.8±109.3)IU/kg],97.5% of bleeds could be controlled,of which 53.8%(43/80)were excellent,43.7%(35/80)were good to moderate,2.5%(2/80)were poor.Six cases used 4 F-PCC prophylaxis[mean(35.9±8.2)IU/kg,twice a week to every other day]during ITI,bleeds/month reduced 83.0% [(2.24±1.84)vs(0.38±0.80)times]without severe bleeding events in median 2.6(range 1.1,6.2)months prophylaxis.There was also no thromboembolic event.Conclusion:Under the current situation in China,a lower dose 4 F-PCC shows a quite satisfied efficiency and safety both in on-demand and prophylaxis as hemostatic bypassing agents in HA inhibitor patients receiving ITI therapy,however,more clinical data is still needed.
引文
[1]Oldenburg J,Young G,Santagostino E,et al.The importance of inhibitor eradication in clinically complicated hemophilia A patients[J].Expert Rev Hematol,2018,11:857-862.
[2]丁秋兰,王学锋,王鸿利,等.血友病诊断和治疗的专家共识[J].临床血液学杂志,2010,23(1):49-53.
[3]Dickneite G,Hoffman M.Reversing the new oral anticoagulants with prothrombin complex concentrates(PCCs):what is the evidence?[J].Thromb Haemost,2014,111:189-198.
[4]Kalina U,Bickhard H,Schulte S.Biochemical comparison of seven commercially available prothrombin complex concentrates[J].Int J Clin Pract,2008,62:1614-1622.
[5]Kempton CL,White GN.How we treat a hemophilia A patient with a factor VIII inhibitor[J].Blood,2009,113:11-17.
[6]Hoffman M,Dargaud Y.Mechanisms and monitoring of bypassing agent therapy[J].J Thromb Haemost,2012,10:1478-1485.
[7]Blanchette VS,Key NS,Ljung LR,et al.Definitions in hemophilia:communication from the SSC of the ISTH[J].J Thromb Haemost,2014,12:1935-1939.
[8]Berntorp E.Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors[J].Haemophilia,2009,15:3-10.
[9]Smejkal P,Brabec P,Matyskova M,et al.FEIBA in treatment of acute bleeding episodes in patients with haemophilia A and factor VIII inhibitors:a retrospective survey in regional haemophilia centre[J].Haemophilia,2009,15:743-751.
[10]Astermark J,Donfield SM,Dimichele DM,et al.Arandomized comparison of bypassing agents in hemophilia complicated by an inhibitor:the FEIBA NovoS-even Comparative(FENOC)Study[J].Blood,2007,109:546-551.
[11]Carcao MD,Avila L,Leissinger C,et al.An International Prophylaxis Study Group(IPSG)survey of prophylaxis in adults with severe haemophilia[J].Haemophilia,2017,23:e447-e450.
[12]Leissinger C,Gringeri A,Antmen B,et al.Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors[J].N Engl J Med,2011,365:1684-1692.
[13]Antunes SV,Tangada S,Stasyshyn O,et al.Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors[J].Haemophilia,2014,20:65-72.
[14]Rota M,Cortesi PA,Crea R,et al.Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex:a meta-analysis of 40-year published data[J].Blood Adv,2017,1:2637-2642.
[2]丁秋兰,王学锋,王鸿利,等.血友病诊断和治疗的专家共识[J].临床血液学杂志,2010,23(1):49-53.
[3]Dickneite G,Hoffman M.Reversing the new oral anticoagulants with prothrombin complex concentrates(PCCs):what is the evidence?[J].Thromb Haemost,2014,111:189-198.
[4]Kalina U,Bickhard H,Schulte S.Biochemical comparison of seven commercially available prothrombin complex concentrates[J].Int J Clin Pract,2008,62:1614-1622.
[5]Kempton CL,White GN.How we treat a hemophilia A patient with a factor VIII inhibitor[J].Blood,2009,113:11-17.
[6]Hoffman M,Dargaud Y.Mechanisms and monitoring of bypassing agent therapy[J].J Thromb Haemost,2012,10:1478-1485.
[7]Blanchette VS,Key NS,Ljung LR,et al.Definitions in hemophilia:communication from the SSC of the ISTH[J].J Thromb Haemost,2014,12:1935-1939.
[8]Berntorp E.Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors[J].Haemophilia,2009,15:3-10.
[9]Smejkal P,Brabec P,Matyskova M,et al.FEIBA in treatment of acute bleeding episodes in patients with haemophilia A and factor VIII inhibitors:a retrospective survey in regional haemophilia centre[J].Haemophilia,2009,15:743-751.
[10]Astermark J,Donfield SM,Dimichele DM,et al.Arandomized comparison of bypassing agents in hemophilia complicated by an inhibitor:the FEIBA NovoS-even Comparative(FENOC)Study[J].Blood,2007,109:546-551.
[11]Carcao MD,Avila L,Leissinger C,et al.An International Prophylaxis Study Group(IPSG)survey of prophylaxis in adults with severe haemophilia[J].Haemophilia,2017,23:e447-e450.
[12]Leissinger C,Gringeri A,Antmen B,et al.Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors[J].N Engl J Med,2011,365:1684-1692.
[13]Antunes SV,Tangada S,Stasyshyn O,et al.Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors[J].Haemophilia,2014,20:65-72.
[14]Rota M,Cortesi PA,Crea R,et al.Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex:a meta-analysis of 40-year published data[J].Blood Adv,2017,1:2637-2642.