抗凝治疗的实验室监测长城会议
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Pharmacotherapy. 2004;24:146S-155S. Arch Pathol Lab Med. 1998;122:782-798
18
How to Monitor?
aPTT
Heparin Assay
19
aPTT监测
优点
最常用 便宜 TAT时间短
缺点
治疗范围与试剂和批号有关 普通凝血检测指标，肝素检测非特异 只能用于 UFH, 不适合LMWH
Therapeutic ranges
OAT适应证及有效浓度范围
适用于需长期持续 抗凝的患者
INR 监测- OAT
INR 1,2
1
0,8
0,6
0,4
0,2
0 ABCDE
FGH
I
J
K L M INR 3,5
3
2,5
2
1,5
1
0,5
0 ABCDE FGH I J KLM
Same reagent / Different instruments
AT
Xa
Penta
<18 saccharide units ( MW < 5400 Da) anti-Xa activity
MW < 5400 Da
AT
Xa
Penta
>18 saccharide units ( MW > 5400 Da)
anti-Xa & anti-IIa activities
20
aPTT 试剂变异
Reagent
aPTT Range
Corresponding to
0.3 – 0.7 U/mL
Actin
54.6 – 87.6
IL Test
63.3 – 101.4
Thrombosi lI
56.6 – 80.2
Actin FSL 84.4 – 124.0
Actin FS 85.6 – 134.1
22
aPTT decreased sensitivity to heparin—heparin resistance
Baidu Nhomakorabea
inflammation
high VIII/Fibrinogen
AT III deficiency
pregnancy
post thrombotic acute phase reaction
3.8
3
2
1
885 4,123
433 4,549
332 4,654
0
24
48
72
Persistence within aPTT range (hours)
*CV events defined as CV death, MI, refractory angina
Circulation. 2003;107:2884-2888.
•Tube fill •Tube type
UFH
•LMWH: no relation to aPTT / drug dosage
Congenital Deficiencies
Acquired Deficiencies
•Mainly hemophilia (VIII, IX) •vWF / VIII (von Willebrand’s disease) •II, V, X •XI, XII •Fibrinogen (hypo <0.8 g/L) •Dysfibrinogenemia
28
肝素监测
优点:
增加特异性 (no FVIII / Fib interference) 直接、更准确反映肝素 可靠反映治疗范围 可以用于 LMWH 全自动，TAT短
29
aPTT vs. Heparin Assay
血栓复发/出血
• aPTT – 6.1% bleeding and 6.1% recurrence • Heparin Assay – 1.5% bleeding and 4.6%
抗凝治疗 的实验室监测
上海交通大学医学院 附属瑞金医院 王学锋
1
A Cell-Based Model of Coagulation and Potential Targets
2
抗凝药物发展史
1930s
普通肝素
1940s
华法林
1980s
低分子量肝素
1990s
静脉直接 凝血酶抑制剂
2002
静脉间接 Xa抑制剂
15
Which tests ?
UFH
LMWH
Platelet count
Platelet count
APTT
APTT
Anti-Xa activity
Anti-Xa activity
AT : in case of « heparin resistance » ; to detect any AT deficiency
Therapeutic ranges given in range or in “target INR”
1. American College of Chest Physicians 2. British Committee for Standards in Haematology 3. Groupement d’Etude Hémostase et Thrombose
•Liver disease •DIC •Vit K deficiency •Warfarin
AutoAntibodies
•Specific (factors) •Nonspecific (LA)
Potential to Under-Coagulate
Groce JB, Leumas J. Basic Skills in Interpreting Laboratory Data. 3rd ed. Am Soc Health System Pharmacists. May 2004.
CAP survey 2007 CG-2C
肝素治疗的实 验室监测问题
10
肝素与低分子量肝素 肝素诱导的血小板减少症
肝素抵抗
常见问题
11
肝素
OSO3
O
O OH O
HNSO3
COO -
OH OH
OSO3 O
O OSO3 O
HNSO3
COO O
OH
OSO3
O
O OH O
OSO3
HNSO3
AT binds through the pentasaccharide
Race种族
获得性因素
Variations in the metabolisms of vitamin K, OAT and coagulation factors 维生素K，口服抗凝药和 凝血因子的代谢差异
Pathologies (e.g. renal insufficiency)疾病（肾 功能不全等）
Anticoagulant activity of AT is then enhanced by ~1 000
AT-Heparin complex inhibits serine proteases (Xa & IIa)
12
Anti-IIa et anti-Xa activities : depend on molecular weight
Percent recurrent CV events*
Subtherapeutic (<60s)
9
Therapeutic (≥60s)
8.1
8
6.9
7
RR=1.22
RR=1.84
6
(0.87-1.22)
5
4.8 4
4
(1.25-2.70) P < 0.005
3.8
RR=2.21 (1.47-3.31) P < 0.0001
renal disease
Potential to Over-Anticoagulate
23
aPTT is the old “Gold Standard”
Br Med J. 1985;290:341-344.
24
aPTT
无法准确预测肝素水平
不同试剂间
一致性 47%
不到治疗水平的 aPTT – 68.5% 达到治疗的肝
13
AT
IIa
Penta MW > 5400 Da
UFH 监测
所有患者 WHY？
主要副作用: 抗凝效果延迟: 血栓进展或复发 过度抗凝: 增加出血风险 严重出血频率UFH : 5 %
HIT (Heparin Induced Thrombocytopenia)
14
LMWH 监测
Circulation. 2003;107:2884-2888.
27
aPTT
aPTT and Recurrent CV Events in UA / NSTEMI
Increase in Event Rates is Higher with Persistently Subtherapeutic Anticoagulation
21
Corresponding Ratio
(mean control) 1.9 – 3.4 1.9 – 3.1 2.0 – 2.8
2.6 – 3.8 2.7 – 4.3
Arch Intern Med. 2001;161:385-391.
aPTT延长原因
Blood Sampling (Pre-analytical)
素水平
Arch Intern Med. 1997;157:2475.
25
aPTT vs. Heparin Assay
持续aPTT不到治疗水平与VTE的发生或复发有关:
Clin Appl Thromb Hemost. 1997:3:S64-67.
24 h内治疗浓度达标:
87% of patients using Anti-Xa
Therapeutic ranges have been recommended in INR by different representative groups 不同的机构推荐使用INR作为治疗范围的监测指标
The most widely used come from the ACCP1, the BSCH2 or the GEHT3
recurrence
aPTT 比肝素测定组每天多用 4000 U肝素
Arch Intern Med. 1994;154:49-56.
16
UFH
常用，迅速发挥作用 无法预测剂量反应
结合血浆蛋白 结合内皮细胞，巨噬细胞和血小板
• 加强清除 清除率差异 12倍
高分子量排出快
Chest. 2004;126:188S-203S.
17
UFH
广泛使用，不正确使用出血风险大 药物相关问题 出血 HIT 需要多次剂量调整，反复实验室监测 开始每6h,稳定后每天一次 输注对侧肢体采血
2004
口服直接 凝血酶抑制剂
2008
口服直接 Xa抑制剂
Xa
IIa AT + Xa
IIa
II, VII, IX, X AT+ Xa + IIa (Protein C,S)
AT + Xa + IIa (Xa > IIa)
(1:1 ratio)
3
OAT药物个体差异性
遗传性因素:
Hereditary resistance to warfarin 遗传性华法林 抵抗(rare)
预防给药:不需要 治疗给药:首次给药48小时后的剂量调整 特殊情况:
体重过轻或过重 (<50 or >160 Kg) 肾功能损害 (creatinine clearance <30 mL/min) 妊娠(3rd quarter) 长期治疗 新生儿 (< 2 months) or儿童 出血者 效果不佳者
监测目标：维持病人PT在PT 一个狭窄的治疗范围内
100
80
PT
60
%
Risk of thrombosis
PT
40 Safety / efficacy zone
20 Risk of bleeding
0
0
1
2
3
4
5
6
7
Approximate therapeutic range
days
Therapeutic ranges 有效浓度范围
• Pharmacotherapy. 2004;24:713-719.
57% of patients using aPTT (calibrated to Anti-
Xa) • Ann Intern Med. 1993;119:874-881.
26
Weight-based aPTT Protocol
Age and weight 年龄和体重 Drugs and diet 药物和饮食
AVK 监测
PT (1935): 多种试剂 缺乏统一标准 室间差异大
INR (1984): 结果的标准化：统一使用ISI 有所改善，然而……
PT监测OAT
The goal of the monitoring is to maintain the patient within a narrow therapeutic range
18
How to Monitor?
aPTT
Heparin Assay
19
aPTT监测
优点
最常用 便宜 TAT时间短
缺点
治疗范围与试剂和批号有关 普通凝血检测指标，肝素检测非特异 只能用于 UFH, 不适合LMWH
Therapeutic ranges
OAT适应证及有效浓度范围
适用于需长期持续 抗凝的患者
INR 监测- OAT
INR 1,2
1
0,8
0,6
0,4
0,2
0 ABCDE
FGH
I
J
K L M INR 3,5
3
2,5
2
1,5
1
0,5
0 ABCDE FGH I J KLM
Same reagent / Different instruments
AT
Xa
Penta
<18 saccharide units ( MW < 5400 Da) anti-Xa activity
MW < 5400 Da
AT
Xa
Penta
>18 saccharide units ( MW > 5400 Da)
anti-Xa & anti-IIa activities
20
aPTT 试剂变异
Reagent
aPTT Range
Corresponding to
0.3 – 0.7 U/mL
Actin
54.6 – 87.6
IL Test
63.3 – 101.4
Thrombosi lI
56.6 – 80.2
Actin FSL 84.4 – 124.0
Actin FS 85.6 – 134.1
22
aPTT decreased sensitivity to heparin—heparin resistance
Baidu Nhomakorabea
inflammation
high VIII/Fibrinogen
AT III deficiency
pregnancy
post thrombotic acute phase reaction
3.8
3
2
1
885 4,123
433 4,549
332 4,654
0
24
48
72
Persistence within aPTT range (hours)
*CV events defined as CV death, MI, refractory angina
Circulation. 2003;107:2884-2888.
•Tube fill •Tube type
UFH
•LMWH: no relation to aPTT / drug dosage
Congenital Deficiencies
Acquired Deficiencies
•Mainly hemophilia (VIII, IX) •vWF / VIII (von Willebrand’s disease) •II, V, X •XI, XII •Fibrinogen (hypo <0.8 g/L) •Dysfibrinogenemia
28
肝素监测
优点:
增加特异性 (no FVIII / Fib interference) 直接、更准确反映肝素 可靠反映治疗范围 可以用于 LMWH 全自动，TAT短
29
aPTT vs. Heparin Assay
血栓复发/出血
• aPTT – 6.1% bleeding and 6.1% recurrence • Heparin Assay – 1.5% bleeding and 4.6%
抗凝治疗 的实验室监测
上海交通大学医学院 附属瑞金医院 王学锋
1
A Cell-Based Model of Coagulation and Potential Targets
2
抗凝药物发展史
1930s
普通肝素
1940s
华法林
1980s
低分子量肝素
1990s
静脉直接 凝血酶抑制剂
2002
静脉间接 Xa抑制剂
15
Which tests ?
UFH
LMWH
Platelet count
Platelet count
APTT
APTT
Anti-Xa activity
Anti-Xa activity
AT : in case of « heparin resistance » ; to detect any AT deficiency
Therapeutic ranges given in range or in “target INR”
1. American College of Chest Physicians 2. British Committee for Standards in Haematology 3. Groupement d’Etude Hémostase et Thrombose
•Liver disease •DIC •Vit K deficiency •Warfarin
AutoAntibodies
•Specific (factors) •Nonspecific (LA)
Potential to Under-Coagulate
Groce JB, Leumas J. Basic Skills in Interpreting Laboratory Data. 3rd ed. Am Soc Health System Pharmacists. May 2004.
CAP survey 2007 CG-2C
肝素治疗的实 验室监测问题
10
肝素与低分子量肝素 肝素诱导的血小板减少症
肝素抵抗
常见问题
11
肝素
OSO3
O
O OH O
HNSO3
COO -
OH OH
OSO3 O
O OSO3 O
HNSO3
COO O
OH
OSO3
O
O OH O
OSO3
HNSO3
AT binds through the pentasaccharide
Race种族
获得性因素
Variations in the metabolisms of vitamin K, OAT and coagulation factors 维生素K，口服抗凝药和 凝血因子的代谢差异
Pathologies (e.g. renal insufficiency)疾病（肾 功能不全等）
Anticoagulant activity of AT is then enhanced by ~1 000
AT-Heparin complex inhibits serine proteases (Xa & IIa)
12
Anti-IIa et anti-Xa activities : depend on molecular weight
Percent recurrent CV events*
Subtherapeutic (<60s)
9
Therapeutic (≥60s)
8.1
8
6.9
7
RR=1.22
RR=1.84
6
(0.87-1.22)
5
4.8 4
4
(1.25-2.70) P < 0.005
3.8
RR=2.21 (1.47-3.31) P < 0.0001
renal disease
Potential to Over-Anticoagulate
23
aPTT is the old “Gold Standard”
Br Med J. 1985;290:341-344.
24
aPTT
无法准确预测肝素水平
不同试剂间
一致性 47%
不到治疗水平的 aPTT – 68.5% 达到治疗的肝
13
AT
IIa
Penta MW > 5400 Da
UFH 监测
所有患者 WHY？
主要副作用: 抗凝效果延迟: 血栓进展或复发 过度抗凝: 增加出血风险 严重出血频率UFH : 5 %
HIT (Heparin Induced Thrombocytopenia)
14
LMWH 监测
Circulation. 2003;107:2884-2888.
27
aPTT
aPTT and Recurrent CV Events in UA / NSTEMI
Increase in Event Rates is Higher with Persistently Subtherapeutic Anticoagulation
21
Corresponding Ratio
(mean control) 1.9 – 3.4 1.9 – 3.1 2.0 – 2.8
2.6 – 3.8 2.7 – 4.3
Arch Intern Med. 2001;161:385-391.
aPTT延长原因
Blood Sampling (Pre-analytical)
素水平
Arch Intern Med. 1997;157:2475.
25
aPTT vs. Heparin Assay
持续aPTT不到治疗水平与VTE的发生或复发有关:
Clin Appl Thromb Hemost. 1997:3:S64-67.
24 h内治疗浓度达标:
87% of patients using Anti-Xa
Therapeutic ranges have been recommended in INR by different representative groups 不同的机构推荐使用INR作为治疗范围的监测指标
The most widely used come from the ACCP1, the BSCH2 or the GEHT3
recurrence
aPTT 比肝素测定组每天多用 4000 U肝素
Arch Intern Med. 1994;154:49-56.
16
UFH
常用，迅速发挥作用 无法预测剂量反应
结合血浆蛋白 结合内皮细胞，巨噬细胞和血小板
• 加强清除 清除率差异 12倍
高分子量排出快
Chest. 2004;126:188S-203S.
17
UFH
广泛使用，不正确使用出血风险大 药物相关问题 出血 HIT 需要多次剂量调整，反复实验室监测 开始每6h,稳定后每天一次 输注对侧肢体采血
2004
口服直接 凝血酶抑制剂
2008
口服直接 Xa抑制剂
Xa
IIa AT + Xa
IIa
II, VII, IX, X AT+ Xa + IIa (Protein C,S)
AT + Xa + IIa (Xa > IIa)
(1:1 ratio)
3
OAT药物个体差异性
遗传性因素:
Hereditary resistance to warfarin 遗传性华法林 抵抗(rare)
预防给药:不需要 治疗给药:首次给药48小时后的剂量调整 特殊情况:
体重过轻或过重 (<50 or >160 Kg) 肾功能损害 (creatinine clearance <30 mL/min) 妊娠(3rd quarter) 长期治疗 新生儿 (< 2 months) or儿童 出血者 效果不佳者
监测目标：维持病人PT在PT 一个狭窄的治疗范围内
100
80
PT
60
%
Risk of thrombosis
PT
40 Safety / efficacy zone
20 Risk of bleeding
0
0
1
2
3
4
5
6
7
Approximate therapeutic range
days
Therapeutic ranges 有效浓度范围
• Pharmacotherapy. 2004;24:713-719.
57% of patients using aPTT (calibrated to Anti-
Xa) • Ann Intern Med. 1993;119:874-881.
26
Weight-based aPTT Protocol
Age and weight 年龄和体重 Drugs and diet 药物和饮食
AVK 监测
PT (1935): 多种试剂 缺乏统一标准 室间差异大
INR (1984): 结果的标准化：统一使用ISI 有所改善，然而……
PT监测OAT
The goal of the monitoring is to maintain the patient within a narrow therapeutic range