DIC 135-627 12
CONTENTS 34 32 33 1 2 K 34 3 4 5 12 12 18 24 3 31 31 31 33 KVKA K K VKA VKA K - PT-INR KC S 1996VKA VKA 3 KK CS 33 34 35 35 35 36 36 K 32 33 213 4VKA 12VKAFDA Kcentra 42 217 1 in vitro 1 2 3 4 36 37 38 38 38 38 38 38 39 4 4 41 41 41 42 42 212 4VKA PT-INR CSL214 VKA PT-INRVKA PT-INR 3431 32 33 K 217 3 2 3
IU 1. K CS PCC Prothrombin Complex Concentrate p5 217 9 2 p7 2. 3. 4. 5. K 4 4-Factor PCC p12 29 HBsHCVHIV-1HIV-2 HIV-1 HBV HCV HAVNAT B19 NAT p7 23428.5% PT-INR 2.9% 11218.2% 1 DIC p8 3 DIC 1 1 4 1 5 5IU 2 4 3IU 4 8mg 8 4IU 6 12mg 45 92mg 2mL 1 1 1,IU 2 8 6IU 8 16mg 16 8IU 12 24mg 91 183mg 4mL 3 3 3 1 C S 2 3p9 3 5
2 ph 6.5 7.5.6 K 1 1 2 HIT heparin-induced thrombocytopenia p7 3 B19 4 B19 2 PT-INR 2 4 4 6 6 1kg 25IU/kg 35IU/kg 5IU/kg 1kg 25IU 35IU 5IU 1HBsHCVHIV-1 HIV-2 HIV-1 HBV HCVHAV NAT B19 NAT K 6 1 B19 2 vcjd vcjd 3 4 5 6 HIT heparin-induced thrombocytopenia 6 7
3 23428.5% PT-INR 2.9% 11218.2% 1 1 3.8% 2 3DIC DIC 2.5% 7 DIC 8 1 1 2 3 4 5/1 p1 11 2 13IU/kg/21IU/ 2 3 4 / 4 1991 5 B19 6 8 9
5/1 1 6 2 3 7 4 8 5 9 1 1 11
p5 11 34 1 1 34 -PT-INR1.3 KVKA VKA PT-INR VKA 11 6 5 PT-INR Day45 K PT-INR IU/kg 2 4 25 4 6 35 6 5 1kg1kg 5,IU 3 PT-INR 1 2 PT-INR 31 3 6 12 24 PT-INR 24 modified Rankin Scale mrs Day45 predicted blood loss PBL actual blood loss ABL Day14 Day45 FAS PT-INR 31 1 3 / Kaplan-MeierPT-INR 1 2 1 1 1 24 2 24 CT2% 3 24 1 / 2 1% packed red blood cells PRBC 8 1g/dL 8 1g/dLPRBC / PRBC / 14 1 14 24 2 24 CT2%35% 3 24 1 / 2 1%2PRBC8 1g/dL 8 1g/dLPRBC 2 / PRBC 4 / 1 4 / 24 2 24 CT35% 3 24 1 / 2 2% PRBC8 1g/dL 8 1g/dLPRBC 2 / PRBC 1 24 /PRBC 11g/dL 3% 24/ 2 /% 12 13
3 PT-INR 11PT-INR 2. 3 981.8%1.3 21.381.92PT-INR3.13 3 1.15 PT-INR Mean SD 3PT-INR Mean SD n=6 n=5 n=11 5.33 3.36 4.76 2.26 1.56 1.15.15 1.11 1.1 1.38 3.46 1.52 3.13 2.11 5.82 1.33.34 1.25 1.7 1.92 4.48 2.74 3.13 2.11 1.56 1.23.26 1.15 1.1 1.92 65 53 21 3 2 1 3 3PT-INR 1.3 21 3PT-INR 1.3 1 2 3 PT 1 PT-INR 2 3 1 3PT-INR1 54 1 4 5 6 1 PT Preferred term 23PT-INR 1.3PT-INR 3 7 8 9 1 11 3PT-INR 1.3PT-INR PT-INR PT-INR 3PT-INR 1.365 54 3PT-INR 1.3224 PT-INR 1.3 1 7.824 1.38 3.93 1 5.8224 1.92 2.46 13PT-INR 1 PT-INR 1.3 24.94 1.7 14 15
31 3 6 12 24 PT-INR PT-INR 1.311654.5% 24PT-INR 1.3 52 1.3 2 241.5 1 24 1.3 PT-INR 1.3PT-INR 31.3 PT-INR 3 1 3 6 12 24 n=6 4.76 2.26 1.56 1.11 1.1 1.38 1.11 1.1 1.44 1.14 1.3 1.66 1.18.99 2.6 1.15.95 2.68 1.18.96 3.93 24 11654.5 2 4 2 Day43 n=5 3.13 2.11 5.82 1.26 1.15 1.92 1.28 1.7 2.8 1.33 1.7 2.35 1.27 1.6 2.33 1.22.94 2.34 1.22.94 2.46 n=11 3.13 2.11 1.56 1.15 1.1 1.92 n=4 1 3PT-INR 1 PBL ABL ABLPBL 7 8 9 1 11 1 PBL Predicted blood loss 2 ABL Actual blood loss 1 216 52mL 83.3% 5/6 1% 5/5 18.2% 2/111 2 PBL 1 mln=5 2 1 5 ABL 2 mln=5 5 5 2 mrsday45 2 1 mrs5 Day454 1 mrs2 Day455 16 17
32 2 2 32 KVKAK CS VKA CS Intention-to-treatITT-E22 98 14 Intention-to-treatITT-S212 13 19 -PT-INR Day9K K PT-INR 1 IU/kg 1 ml/kg 24 25 1 4 6 35 12 6 5 15 1mL 25IU 24 PT-INR 2 3 6 PT-INR packed red blood cells PRBC PRBC1 24 /PRBC Day45 PT-INR 95% Farrington and Manning 1% 95% 1% 3/ Cochran-Mantel-Haenszel PT-INR 3 ITT-E 1 1kg1kg 2 3PT-INR 1.3 33PT-INRPT-INR / 1 1 1 24 2 3 24 CT2% 3/ 1 24 2 1% PRBC 8 1g/dL 8 1g/dLPRBC / 3 14 1 14 24 2 24 CT2%35% 3/ 1 24 2 1%2PRBC8 1g/dL 8 1g/dLPRBC 2 / 3 4 / 1 4 / 24 2 24 CT35% 3/ 1 24 2 2% PRBC8 1g/dL 8 1g/dLPRBC 2 / 3 CT 1% / 2 24 /PRBC 11g/dL 3% 3PRBC PRBC 11g/dL 3% 24 / 18 19
24 72.4% 65.4%7.1% 95%5.8,19.9 95%1% 3 6 3 6 73.5%67.3%6.2% 95% 6.5,18.8 95%1% % 1 8 6 4 2 72.4 65.4 n=98 7.1 95 5.8,19.9 n=14 95 % 1 8 6 4 2 73.5 67.3 n=98 95Farrington and Manning 6.2 95 6.5,18.8 n=14 95 95Farrington and Manning PT-INR PT-INR 3PT-INR 1.3 62.2%9.6% 52.6% 95% 39.4,65.9 95% 1% PT-INR / 6.47 95% 3.52,11.9 % 1 8 PT-INR6 4 2 62.2 n=98 95Farrington and Manning 52.6 9539.4,65.9 9.6 n=14 95 PT-INR PT-INR PT-INR 1.3 1 69% PT-INR PT-INR 3 6 1224 PT-INR 88%58% 1..9.8 PT-INR.7.6.5.4.3.2.1 n=98 n=14 Kaplan-Meier. 2 4 6 8 1 12 14 16 18 2 22 24 26 28 2 21
PT-INR 3 12 PT-INR 5 n=98 n=14 4 p<.5 Wilcoxon 3 2 PT-INR 1 PRBC PRBC1 PRBCMean SD1.4 1.77 1.2 1.57 Wilcoxon PRBC149% 48/9845% 47/14 PRBC 1 1g/dL3% 24 /PRBC BL.5 1 3 6 12 24 24 PRBC/ Mean SD.3 1.36.3.87 Wilcoxon Day45 Day45 95 Day45 / 1.91 95%.66,5.5 ITT-S13 19 112%96% 7.28.2 ITT-S n=13 n=19 PT-INR 24 4 6 6 IU/kg 25 35 5 1.mL/kg 1.4mL/kg 2.mL/kg n % 48 46.6 26 25.2 29 28.2 1mL25IU ITT-S n=13 23.6 31.65 ml 15.2 37.36 IU/ 149.3 58.77 ml/ IU/kg 1.97.812 ml/kg ml/kg n % 1 58 53.2 12 2 18.3 15 31 28.4 n=19 169.1 142.54 864.8 268.86 8.2 6.1.11.86 Mean SD 64.1% 66/13 65.1% 71/19 9.7% 1/13 21.1% 23/19 PT-INR21.9% 3 2.8% 1.9% 2/13 3.7% 4/19 1 1 21 1 1 3 1 22 23
33 3 3 33 KVKAK CS VKA CS Intention-to-treatITT-E168 87 81 Intention-to-treatITT-S176 88 88 -PT-INR Day9K K PT-INR 24 4 6 6 1mL 25IU 1 IU/kg 25 35 5 1 ml/kg 1 12 15 2 PT-INR 3 PT-INR 24packed red blood cells PRBC 24 PRBC PT-INR 12 95% Newcombe-Wilson 1% 95% 1% PT-INR 4 ITT-E 1actual blood loss:ablpredicted blood loss:pbl5ml / PRBC ABLPBL 2% PRBC ABLPBL 2%3% / ABL PBL 3% PRBC PRBC / ABL PBL 3% ABL PBL/ 2 ABLPBL5mL / ABL PBL/ PRBC ABL PBL 2 PRBC ABLPBL 2% / PRBC PRBC / 1 1kg1kg 2 157 FDA 33PT-INR 1.3 43PT-INRPT-INR 24 25
89.7% 75.3%14.3% 95% 2.8,25.8 95% 1% PT-INR PT-INR PT-INR1.3 1 54% PT-INR PT-INR 3 6 12 24 24PT-INR 87%48% 95Newcombe-Wilson% 1 8 6 4 2 89.7 n=87 14.3 952.8,25.8 75.3 n=81 95 1..9.8 PT-INR.7.6.5.4.3.2.1 n=87 n=81. 2 4 6 8 1 12 14 16 18 2 22 24 26 28 Kaplan-Meier PT-INR PT-INR 3PT-INR 1.3 55.2%9.9% 45.3% 95% 31.9,56.4 95% 1% PT-INR 3 24 PT-INR % 1 8 PT-INR6 4 2 55.2 45.3 9531.9,56.4 95 PT-INR 5 4 3 2 1 n=87 n=81 p<.5 Wilcoxon n=87 95Newcombe-Wilson 9.9 n=81 BL.5 1 3 6 24 26 27
55.749/88 6.253/88 9.1% 8/88 17.% 15/88 1 2 3.4% 3/88 2 1 12.5% 11/88 6 3 3.4% 3/88 3.4% 3/88 1 1 41Day48 8 24 PRBC PRBC 16.1% 14/8714.8% 12/81 Fisher ITT-S88 88 19%98% 6.99.1 24PRBC PRBC PRBC.3.9.4 1.2 Wilcoxon ITT-S 1mL25IU Mean SD n=88 PT-INR 24 4 6 6 IU/kg 25 35 5 1.mL/kg 1.4mL/kg 2.mL/kg ml/kg 1 12 15 n % 65 73.9 15 17. 8 9.1 n % 69 78.4 1 11.4 9 1.2 n=88 ITT-S ml IU/ ml/ IU/kg ml/kg n=88 21.2 14.3 9.3 32.3 139.3 66.4 1.8.9 147. 116.5 82.8 24.9 9.2 6.5.12.1 n=88 28 29
23428.5% PT-INR 2.9% 11218.2% PT-INR PT-INR 32 n=13 1 9.7% 3 2.9% 1 1.% 1 1.% 1 1.% 5 4.9% 2 1.9% 1 1.% 1 1.% 1 1.% 1 1.% 1 1.% 2 1.9% 1 1.% 1 1.% 1 1.% 1 1.% 1 1.% 1 1.% 8 9.1% 2 2.3% 2 2.3% 2 2.3% 3 3.4% 33 n=88 2 4.7 1 2.3 1 2.3 1 2.3 1 2.3 31 n=43 2 8.5 5 2.1 2.9 1.4 2.9 1.4 1.4 2.9 1.4 1.4 2.9 1.4 1.4 6 2.6 2.9 1.4 1.4 1.4 1.4 2.9 1.4 1.4 5 2.1 2.9 1.4 1.4 2.9 2.9 1.4 1.4 1.4 1.4 2.9 1.4 1.4 3 n=234 32 33 31 2 3 4 MedDRA Ver.12. 32 33 / MedDRA Ver.9.1 31 / MedDRA / J Ver.18. n=43 1 5 1518 6287 5IU/kg 5 Cmax Cmax 162%S 278%Ct1/2 4.2 59.7 144CS Mean SD % C S 3 3 6 12 24 48 144 1 97. 1.3 9.9 13.8 83.4 13. 92.3 12.3 11.4 17.3 89.2 15. 225.1 17.2 155. 24.2 158.2 24.6 26.5 3.4 265.5 26.5 167.3 27.1 224.8 17.9 149.7 26.4 152.8 28. 259.3 4. 26.3 3.8 145.1 18.2 216.4 22.5 129.1 21.1 136.7 21.4 244.7 27.4 246.7 27.9 152.5 26.9 197. 2.6 115.6 19. 139.1 31.5 234.7 26.7 22.6 21.6 135.3 23.7 176.5 19.9 13.6 18.6 118.5 17.2 212.8 16. 188.2 2. 136.3 2.9 165.3 18.3 92.1 14.8 96.5 12.6 191.1 23.5 168.6 22.9 114.7 18.2 144.8 18.2 89.7 17.1 9.8 15.1 159.9 25.6 147.8 24.4 119. 16.3 113.3 9. 86.5 15.3 83.8 13.4 116.9 14.2 126.3 19.9 86.7 16.1 3 31
C S 1 2.17 6.2 59.7 238 12.8 1. 81.7 71. 2.47 4.2 17 14.2 7.1 6.1 41.8 1.64 7. 16.7 17 27.5 3.6 21.6 92.4 2.16 3.7 263 8.2 1.25 44.3 56.1 2.82 6.7 47.2 278 91. 1.1 57. 62.9 1.99 4.7 49.1 162 9. 1.1 69.2 76.6 2.5, 2.3 25. 195 59.9.5 36.1 47.5 2.28, 2.1 118 5.7 2.9 3. 29.2 1.46, 2.9 9.5 123 14.7 1.3 13.3 56.5 1.99, 16.9 228 57.1.9 24.3 39.3 2.67, 4.7 9.3 225 3.6.6 13.4 43.9 1.84,.9 33.1 138 54.7.7 45.3 61.9 2.28 11.4 135.3 265 211.3 1.7 185.8 11. 2.67 9.2 23 34.7 17.6 13.3 68.8 1.83 14.2 127.1 213 76.4 6.8 161.2 21.9 2.32 43.8 38 117. 1.8 63.2 65.2 2.97 8.7 121.7 32 18.5 3.3 161.4 19.3 2.15 7. 83.3 218 144.1 1.8 113.5 15. 1 1 IVR9% 2 IVR3 IU/kg IVRt1/2 CmaxAUC CLMRTVss IVRIU/dL / IU/kg 2 t1/2 hn=14 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 hn=12 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 hn=12 t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg IVRIU/dL / IU/kg 2 t1/2 h t1/2 h Cmax % AUC kg h/dl CL ml/ kg h MRT h Vss ml/kg 2 K34 1 K 3IVR 1.136 IU/dL / IU/kg 2.554 IU/dL / IU/kg.868 IU/dL / IU/kg 2.262 IU/dL / IU/kg 3 CS n=6 n=5 C S %normal 3 %normal %normal 3 %normal 2.2. 34.9 16.2 8.4 39. 31.1 9.9 49. 1. 5.6 22. 38.4 23.5 52.5 37.1 21.8 46.5 87.2 54.7 18.3 51.9 38.9 84.2 79.2 49.7 92.7 13.4 55.8 138.2 116. 68.4 139. 91.6 45.9 11.7 32.5 18.3 39.5 28.2 9. 41.9 5.5 24.2 63.9 21.3 8. 24.9 44.2 19.6 55.6 39.4 23.2 54.5 71.1 56. 114.1 44.8 24.8 87.8 78.2 42.2 14.4 76.9 58.9 129.1 99.3 59.7 144.2 77.8 62.6 19.2 CS IVRIVR 1 IVRIU/dL / IU/kg= IU/dL/ IU/kg 2IVR % = 1 / IVR n=6 n=5 C S IVR 1 [IU/dL]/[IU/kg] IVR 2 % IVR 1 [IU/dL]/[IU/kg] IVR 2 % 1.961 1.51 2.38 1.136.735 1.58 1.478 1.4 1.976 2.554 2.12 3.1 2.199 1.899 2.556 1.53 1.452 1.88 8.7 63.6 121.1 44.6 31.1 84.3 6.5 42.6 92.6 12.2 91.2 148.2 9.7 81.8 123.1 65.7 6.3 84.6 1.554.94 2.963.868.451 1.823 1.22.514 1.946 2.262 1.454 4.138 1.759 1.146 3.769 1.41.923 2.772 85.6 48. 124.7 54.1 23. 78.7 67.1 26. 83.8 13.7 74.2 159.9 15.5 58.5 139.3 84.3 47.1 12.5 32 33
3 KK CS 33 3 K CS 3 5% p.5 Wilcoxon36 24 CS BL 3 6 9 12 15 18 21 24 1 8 6 4 2 n=87 n=81 BL 3 6 9 12 15 18 21 24 1 8 6 4 2 n=87 n=81 BL 3 6 9 12 15 18 21 24 12 1 8 6 4 C 12 12 12 1 8 6 4 2 12 1 8 6 4 n=87 n=81 2 n=87 n=81 BL 3 6 9 12 15 18 21 24 2 n=87 2 n=87 n=81 n=81 BL 3 6 9 12 15 18 21 24 BL 3 6 9 12 15 18 21 24 12 1 8 6 4 S C S C S 34 35
K K in vitro 6 PCC rf a PT PCC PT PT in vitro PT-INR PCC U/mL rf a nm.2.4.72 6 2.1 3.6 4.7 5.3 6.7 22.6 3. 36.6 39.2 42.9 18.4 19.1 2.3 23.7 21.3 17.5 18.5 18.2 23.7 18.1 16.9 16.3 17.2 22. 17. 12.7 14.8 23.7 16.4 2.3 7 Marcumar 2.5mg/kg 224 116 48 PCC 5U/kg rf a 1 g/kg 15 PTaPTT PT PCCrF a p.5 Wilcoxon PT PCCrF apcc appt p.1 Wilcoxon PT aptt aptt aptt 1 8 6 4 2 1 16 vs F a vs PCC F a vs PCC aptt p 3 2 2.8-1.8, 12.2-2.7-1.5, 6.8-5.5-12.1, 2.3.11.56.1 aptt 48 aptt 25 2 15 1 5 1 vs F a vs PCC F a vs PCC aptt p 3 2 4.3 -.3, 91.4 131. 124.1, 191.1 99.6 72.3, 131.3.6.1.1 PT-INR3.6in vitro nm 4 35 3 25 2 15 1 5 PT-INR3.6 PCC.72U/mL PT-INR3.6 PCC.4U/mL PT-INR3.6 PCC.2U/mL PT-INR3.6 rf a 6nM PT-INR3.6 PT PT 8 6 4 2 2 15 L1 1 vs F a vs PCC F a vs PCC PT p 3 2 36.6 25.4, 55.1.5 35.3 25.7, 54.6.5. -3.1, 2.1 1. p 3 2 vs F a 378. -229.4, 113.24 vs PCC 29.2-143.1, 192.24 F a vs PCC 58.8-731.5, 18 1. PT PT 8 6 4 2 1 25 2 L 15 1 vs F a vs PCC F a vs PCC vs F a vs PCC F a vs PCC PT p 3 2 469.5 292.2, 716.9 524. 346.9, 771.3 54.5 47.7, 69..1.1.1 p 3 2 261. -628.9, 1758.5 95.7 662.5, 2487.1 728.9 363.1, 1535.1 1 2 3 4 5 5 1 5 1 n=5 rf a (n=5) PCC (n=5) n=5 rf a (n=5) PCC (n=5) 1 PT aptt 2 95Hodges-Lehmann 3 Wilcoxon 36 37
8 35IU/kg 4 125 IU/animal 9 1 IU/kg 2 6 2 6IU/kg 2IU/kg 1 2 5 1 1IU/kg 5 1 5 5IU/kg 2646 g/kg 3 NOAEL1IU/kg 2 3 38 39
/ / 1 25 2 6% 5%RH 4 2 C 75 5%RH 25 6%RH 36 6 12 lux 2W hr/m 2 C S 25 3 2 5 1 2mL 1 1 1 4mL 1 5 229AMX536 1 229AMX537 217 3 1996 2 217 8 217 9 227 31 1. 2. 4 41
/ 1 34 2 32 3 33 4 31 5 11 6 Tanaka K.A., et al.: Thromb Res. 122, 117, 28 7 Dickneite, G: Thromb Res. 119, 643, 27 8 9 1 CSL 135-62 7 12 CSL 135-62 7 12 12-534-587 42 43