血友病A患者总体止血能力检测及临床应用

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李伟皓, 刘永春, 张静, 纪昕. 血友病A患者总体止血能力检测及临床应用. 2011, 26(3): 156-159
LI Weihao, LIU Yongchun, ZHANG Jing, JI Xin. Determination and clinical application of overall haemostasis potential for patients with hemophilia A. Labratory Medicine, 2011, 26(3): 156-159 复制到剪切板

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血友病A患者总体止血能力检测及临床应用

李伟皓, 刘永春, 张静, 纪昕

河北医科大学第二医院检验科,河北石家庄 050000

作者简介:李伟皓,男,1975年生,硕士,主管技师,主要从事医学检验工作。

摘要

目的

探讨血友病A患者总体止血能力(OHP)、总体凝血能力(OCP)、总体纤溶能力(OFP)的异常改变,研究血浆FⅧ∶C水平与OHP、OCP、OFP的相关性。

方法

测定不同FⅧ∶C血浆OHP、OCP及OFP,采用对数曲线回归分析及Pearson相关分析法分析血浆FⅧ∶C水平与OHP、OCP、OFP的相关性。检测38例血友病A患者及50名健康体检者血浆OHP、OCP及OFP,比较2组间3个参数的差异。

结果

FⅧ∶C与OHP、OCP及OFP相关指数( r²)分别为:0.994 2、0.997 0、0.988 4, P<0.01;回归方程分别为: Y=1.508 6 ln( X) +2 .842 5, Y=1.769 7 ln( X) +5 .793 2, Y=-3.736 4 ln( X)+43.167,表明FⅧ∶C与OHP、OCP、OFP呈对数相关。血友病患者活化部分凝血活酶时间(APTT)及OFP明显高于正常对照组( P<0.01);OCP明显低于对照组( P<0.01)。

结论

OHP、OCP及OFP可反映血友病A患者血浆FⅧ∶C水平高低,为血友病A诊断提供新的实验依据。

关键词: 血友病A; 总体止血能力; 总体凝血能力; 总体纤溶能力

中图分类号:R446.11 文献标志码:A 文章编号:1673-8640(2011)03-0156-04

Determination and clinical application of overall haemostasis potential for patients with hemophilia A

LI Weihao, LIU Yongchun, ZHANG Jing, JI Xin

Department of Laboratory Medicine, the Second Hospital of Hebei Medical University, Hebei Shijiazhuang 050000, China

Abstract

Objective

To investigate the abnormal change of overall haemostasis potential (OHP), overall coagulation potential (OCP) and overall fibrinolytic potential (OFP) in patients with hemophilia A, and observe the correlation of FⅧ∶C with OHP, OCP and OFP.

Methods

The OHP, OCP and OFP were determined in plasma with different FⅧ∶C, and the correlation of FⅧ∶C with OHP, OCP and OFP was analyzed by the statistical method of logistic regression and Pearson correlation. OHP, OCP and OFP in 38 hemophilia A patients and 50 healthy controls were determined, and the difference of OHP, OCP and OFP between the 2 groups were compared.

Results

The correlation indices ( r²) between FⅧ∶C and OHP, OCP and OFP were 0.994 2, 0.997 0 and 0.988 4 ( P<0.01). The logistic regression equations were Y=1.508 6 ln( X)+2.842 5, Y=1.769 7 ln( X)+5.793 2 and Y=-3.736 4 ln( X)+43.167. The correlation of FⅧ∶C with OHF, OCP and OFP was logarithmic. The activated partial thromboplastin time (APTT) and OFP in hemophilia A group was higher than those in healthy controls( P<0.01), and OCP was lower than that in healthy controls( P<0.01).

Conclusions

OHP, OCP and OFP are well correlated with FⅧ∶C in the patients with hemophilia A and could be new parameters for the screening of hemophilia A.

Keyword: Hemophilia A; Overall haemostasis potential; Overall coagulation potential; Overall fibrinolytic potential

Show Figures

引言

血友病是常见的X连锁隐性遗传病。是由于血浆凝血因子Ⅷ (血友病A)或凝血因子Ⅸ (血友病B)缺乏而引起的以出血为主要临床表现的一组凝血障碍性疾病, 发病率为5/1 000 000, 无明显地区和种族差异。血友病A最为常见, 发病率约为血友病B的4倍^[1]。其诊断主要根据反复出血史、家族史、临床体征和实验室检查。目前实验室检查方法主要为血浆活化部分凝血活酶时间(APTT)测定、凝血因子Ⅷ 抗原性/活性测定及基因诊断方法。1999年, He S等^[2]将总体止血能力(overall haemostasis potential, OHP)、总体凝血能力(overall coagulation potential, OCP)与总体纤溶能力(overall fibrinolysis potential, OFP)3个试验指标用于综合评价机体凝血与纤溶能力, 并研究了其在部分血栓及出血性疾病中的诊断价值^[35]。关于OHP、OCP及OFP对血友病A的诊断价值目前报道尚少, 我们进行了相关试验研究。

材料和方法

一、研究对象

选取2006年7月~2008年11月河北医科大学第二医院门诊、住院血友病A患者及门诊健康体检者。血友病A患者38例, 均为男性, 年龄3~37岁, 平均年龄16.7± 10.6岁。有明确家族史者29例, 散发家系9例。病例选择标准参照血友病A国内诊断标准^[6]。正常对照50名, 均为男性, 年龄10~48岁, 平均年龄23.4± 13.2岁。2组年龄差异无统计学意义(P> 0.05)。

二、仪器与试剂

凝血因子Ⅷ 活性(FⅧ ∶ C)测定所需标准血浆、乏因子FⅧ 血浆及APTT试剂购自美国IL公司。组织型纤溶酶原激活物(tissue plasminogen activator, t-PA)购自德国Boehringer Ingelheim公司。凝血酶购自广东庆鸿药业有限公司。ACL-9000全自动凝血分析仪购自美国IL公司。Multiskan Ascent酶标仪购自美国Thermo公司。

三、方法

1. 标本采集

空腹条件下抽取正常对照组及血友病A组患者的静脉血2.7 mL, 置于含109 mmol/L枸橼酸钠0.3 mL的一次性抗凝管中, 300 0 r/min(离心半径17.5 cm)离心20 min, 分离血浆。-70℃保存。

2. 不同FⅧ ∶ C血浆的配制

将乏FⅧ 血浆与FⅧ ∶ C为116%的标准血浆按一定比例混合, 分别配制成FⅧ ∶ C为1%、5%、10%、15%、20%、30%、50%、70%、90%的混合血浆。1h内进行OHP、OCP及OFP测定。

3. APTT测定

ACL-9000全自动凝血分析仪采用一期法测定APTT。

4. FⅧ ∶ C测定

ACL-9000全自动凝血分析仪采用一期法测定FⅧ ∶ C, 结果以百分率表示。

5. OHP、OCP及OFP测定

OHP、OCP及OFP测定参照He S等^[2]建立的方法。OCP检测液含0.019 mmol/L凝血酶及35 mmol/L CaCl₂的Tris缓冲液(66 mmol/L Tris, 130 mmol/L NaCl, pH值7.0)。OHP检测液为含660 ng/mL u-TPA的OCP检测液。60 μ L待检血浆分别与50 μ L OCP检测液及50 μ L OHP检测液置于不同微孔中, 振荡混匀。Multiskan Ascent酶标仪记录405 nm波长下吸光度值A, 每2 min记录1次, 连续记录40 min, 以时间(min)为横坐标, A为纵坐标绘制吸光度变化曲线(OCP及OHP曲线), 计算反应曲线内总A值, 即得出OCP及OHP值。OFP按下式计算:OFP=(OCP-OHP)/OCP× 100%。OHP、OCP及OFP测定如图13所示。

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	图1 OCP测定示意图

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	图2 OHP测定示意图

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	图3 OFP测定示意图

四、统计学方法

所有数据均为计量资料以 ± s表示, 试验数据采用SPSS11.0统计软件进行处理。2组间均数比较采用t检验, 以P< 0.05表示差异有统计学意义。OHP、OCP、OFP与FⅧ ∶ C相关性分析采用对数曲线回归分析及Pearson相关分析法。

结果

一、血浆FⅧ ∶ C与OHP、OCP及OFP相关性比较

FⅧ ∶ C与OHP、OCP及OFP相关指数(r²)分别为:0.994 2、0.997 0、0.988 4, P值均小于0.01; 回归方程分别为:Y=1.508 6 ln(X)+2.842 5, Y=1.769 7ln(X)+5.793 2, Y=-3.736 4 ln(X)+43.167, 表明FⅧ ∶ C与OHP、OCP、OFP呈对数相关(图4)。

	Figure Option View Download New Window
	图4 不同浓度FⅧ ∶ C血浆OHP、OCP、OFP测定结果注:(a)为不同浓度FⅧ ∶ C血浆OHP测定结果; (b)为不同浓度FⅧ ∶ C血浆OCP测定结果; (c)为不同浓度FⅧ ∶ C血浆OFP测定结果

二、血友病组及正常对照组APTT、FⅧ ∶ C、OHP、OCP及OFP测定结果

血友病患者APTT及OFP明显高于正常对照组(P< 0.01); OCP明显低于对照组(P< 0.01)。见表1。

表1 血友病组与正常对照组APTT、FⅧ ∶ C、OHP、OCP及OFP比较(

± s)

讨论

在生理情况下, 机体内凝血与抗凝系统处于动态平衡状态, 这种动态平衡一旦被破坏, 即可引起机体凝血或抗凝功能异常。目前, 凝血酶原时间(PT), APTT、凝血酶时间(TT)等实验指标被广泛用于止血及血栓性疾病的筛查。但这些指标只能反应凝血过程中某一阶段的异常, 并不能反映机体总的止血能力^[7]。1995年, Hemker 等^[8]建立了内源性凝血酶能力(endogenous thrimbin potential, EPT)测定方法, 用于评价机体凝血平衡。该实验采用组织因子(TF)和磷脂混合物来全面激活凝血过程, 可以反映机体血栓前状态和凝血障碍。但该方法以凝血酶生成为监测点, 只能反映凝血酶生成以上阶段的凝血功能, 并不能反映凝血的全过程(如纤维蛋白原转变为纤维蛋白), 也没有包括纤溶过程, 不能反映机体总体止血功能^[9]。1999年He S等建立了OHP测定方法, 该方法在低浓度凝血酶(0.04 IU/mL)及t-PA存在的情况下, 同时激活凝血及纤溶过程, 监测纤维蛋白形成和降解过程中反应物A 405nm变化, 获得OHP曲线, 计算OHP曲线内总A值, 即为OHP值。若仅以低浓度凝血酶激活凝血过程, 通过监测纤维蛋白形成过程中反应物A 405nm变化, 获得OCP曲线, 计算OCP曲线内总A值, 即为OCP值。该实验过程中, 低浓度凝血酶并不能直接激活纤维蛋白原转化为纤维蛋白, 而是通过激活FⅤ 、Ⅶ 、Ⅷ , 从而启动及加速血液凝固^[10]。本研究结果显示, OHP及OCP均与标本FⅧ ∶ C呈对数正相关(r²分别为0.994 2与0.997 0, P< 0.01)。证明低浓度凝血酶对凝血过程起启动及放大作用, 而并不直接激活纤维蛋白原。OCP与OHP随FⅧ ∶ C的规律性变化说明这2个指标有望成为评价机体FⅧ ∶ C水平的试验指标, 为血友病A的诊断提供新的试验依据。

OFP是反映机体纤溶能力的指标。本研究表明OFP水平与FⅧ :C呈对数负相关(r²=0.988 4, P< 0.01), 且血友病A患者OFP明显高于正常对照组(P< 0.01)。这是由于缺乏FⅧ 血浆中FⅧ 活性低, 低浓度凝血酶激活FⅧ 的量较正常血浆低, 在测定OHP过程中, 产生的凝血酶减少, 使纤维蛋白的产生量降低。在t-PA浓度一定的情况下, OFP反而升高^[11]。另一种学说认为, 由于OHP测定过程中乏FⅧ 血浆生成凝血酶减少, 引起凝血酶激活的纤溶抑制物(thrombin activatable fibrinolysis inhibitor, TAFI)产生量减少, 从而表现为纤溶活性增强^[12]。至于哪种学说能正确解释这一结果, 目前尚无定论。

根据出血史、家族史及实验室检查对血友病A进行诊断并不困难。目前, APTT测定及FⅧ ∶ C测定是诊断血友病最常用的实验。随着分子生物学技术的发展, 血友病A的基因诊断及产前诊断已成为可能^[13]。但目前尚无能精确反映血友病A患者出血风险的实验室指标^[14]。Hojima等^[15]发现部分血友病A患者FⅧ ∶ C降低(< 1%), APTT异常延长, 但并无出血体征出现。Aleksandra Antovic曾报道2名FⅧ ∶ C< 1%, 临床无明显症状的血友病A患者, 其OHP仅轻度降低^[6]。由于OHP除与机体FⅧ 活性有关外, 尚与其他凝血因子活性及纤溶酶原活性有关, 因而OHP可反映人总体止血能力, 从而反映机体病理情况下的出血风险。本研究显示血友病A患者OCP、OHP较正常对照组低, 说明血友病A患者由于体内FⅧ 缺乏而使凝血及止血能力减低。至于OCP、OHP、OFP是否可作为准确评估血友病A患者出血风险的试验指标, 以及在用作血友病A筛查指标时是否比APTT更为敏感, 尚需进一步研究证实。

The authors have declared that no competing interests exist.

参考文献

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2007

0.0

... 血友病A最为常见,发病率约为血友病B的4倍^[1] ...

1999

3.133

0.0

... 1999年,He S等^[2]将总体止血能力(overall haemostasis potential,OHP)、总体凝血能力(overall coagulation potential,OCP)与总体纤溶能力(overall fibrinolysis potential,OFP)3个试验指标用于综合评价机体凝血与纤溶能力,并研究了其在部分血栓及出血性疾病中的诊断价值^[35] ...

... OHP、OCP及OFP测定参照He S等^[2]建立的方法 ...

2007

6.081

0.0

. 2007, 5(3):528-534

Reduced fibrinolysis and increased fibrin generation can be detected in hypercoagulable patients using the overall hemostatic potential assay

J. L. CURNOW 1,2 ,M.-C. MOREL-KOPP 1,2 ,C. RODDIE 1 ,M. ABOUD 2,3 andC. M. WARD 1,2

1 Northern Blood Research Centre, University of Sydney, Sydney 2 Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney 3 Pacific Laboratory Medical Services, Sydney, Australia * Christopher M. Ward, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW 2065, Australia. Tel.: +61 2 9926 7118; fax: +61 2 9906 1635; e-mail: cward@med.usyd.edu.au

> Background: Routinely available coagulation assays are not capable of detecting clinically defined hypercoagulable states. A number of global coagulation assays have been developed with the potential to evaluate hypercoagulability, which predisposes to the common clinical events of arterial and venous thromboembolism (VTE). Objectives: We hypothesized that the overall hemostatic potential (OHP) assay would show abnormal fibrin generation and lysis in patients with clinically defined hypercoagulable states. Methods: We used the OHP assay as described by Blombäck and colleagues [ 1,2 ] in 161 clinically hypercoagulable patients with arterial or VTE, pregnancy complications or autoimmune disease. Eighty patients had associated antiphospholipid antibodies (APLA). Ninety-eight normal plasma donors were tested for comparison. Results: We derived three new assay parameters for correlation with hypercoagulable states: the maximum optical density, maximum slope, and delay in onset of fibrin generation. We found significantly different assay results for all patients’ parameters examined when compared with controls, indicating both increased fibrin generation and reduced fibrinolysis in hypercoagulable patients. The findings were similar whether samples were collected in association with an acute thrombotic event or not. Estimated assay sensitivity for detection of a clinically defined hypercoagulable state was 96%. Conclusions: The OHP assay is a simple, inexpensive global test that is useful for assessing patients with hypercoagulable states including APLA. OHP results are significantly abnormal in hypercoagulable groups compared with controls, indicating that both increased fibrin generation and reduced fibrinolysis contribute to hypercoagulable states. The assay may ultimately assist in tailoring clinical management to patients’ individual requirements.

2008

2.821

0.0

2005

1.248

0.0

1998

0.0

... 病例选择标准参照血友病A国内诊断标准^[6] ...

... 1%,临床无明显症状的血友病A患者,其OHP仅轻度降低^[6] ...

2004

0.0

... 但这些指标只能反应凝血过程中某一阶段的异常,并不能反映机体总的止血能力^[7] ...

1995

6.081

0.0

... 1995年,Hemker 等^[8]建立了内源性凝血酶能力(endogenous thrimbin potential,EPT)测定方法,用于评价机体凝血平衡 ...

2007

0.0

... 但该方法以凝血酶生成为监测点,只能反映凝血酶生成以上阶段的凝血功能,并不能反映凝血的全过程(如纤维蛋白原转变为纤维蛋白),也没有包括纤溶过程,不能反映机体总体止血功能^[9] ...

2001

6.081

0.0

... ,从而启动及加速血液凝固^[10] ...

2000

15.202

0.0

... 在t-PA浓度一定的情况下,OFP反而升高^[11] ...

2001

0.0

. 2001, 7(6):557-560

Total thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and pro-TAFI in patients with haemophilia A

J. Antovic 1 ,S. Schulman 2 ,A. Eelde 2 andM. Blombäck 1

1 Coagulation Research, Department of Surgical Sciences, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden, 2 Coagulation Unit, Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden * Jovan Antovic MD Coagulation Research, Clinical Chemistry L25, Karolinska Hospital, S-171 76 Stockholm, Sweden. Tel.: + 46 8517 79 653; fax: + 46 8 31 24 38; e-mail: jovan.antovic@kirurgi.ki.se

> Pro-thrombin-activatable fibrinolysis inhibitor (pro-TAFI), also known as TAFI, procarboxypeptidase U, or procarboxypeptidase B, is a relatively recently described plasma glycoprotein synthesized in the liver. It can be catalysed into its active form, TAFI (TAFIa, carboxypeptidase U or B) by a complex of thrombin/thrombomodulin. TAFI can potentially inhibit fibrinolysis by removing carboxyterminal lysine residues from partially degraded fibrin, decreasing plasminogen binding on the surface of fibrin, which thereby results in a decrease of the fibrinolytic activity. As TAFI represents a connection between coagulation and fibrinolysis, it can be expected that TAFI levels are altered in different thrombotic and haemorrhagic diseases, such as haemophilia A. Total TAFI antigen (including pro-TAFI, TAFI and the inactive form of TAFI [TAFIi]) and pro-TAFI were determined in 17 patients with haemophilia A. Thirteen healthy age-matched volunteers served as controls. No significant difference in levels of total TAFI antigen was observed between controls and patients with haemophilia, although it was slightly decreased in patients with haemophilia. Pro-TAFI was significantly reduced in haemophilia patients compared to controls ( P =0.0113). TAFI antigen levels similar to controls have already been described in different clinical conditions, including haemophilia A. Decrease of pro-TAFI in haemophilia A can be an additional factor, together with decrease in thrombin generation, which induces impaired activation of pro-TAFI to TAFI, and could cause accelerated fibrinolysis. This supports the validity of usage of antifibrinolytics in the treatment of haemophilia A. In this paper we use new nomenclature for TAFI, and we believe that this recommended terminology for different forms of TAFI can simplify further standardization in TAFI investigation.

... 血浆生成凝血酶减少,引起凝血酶激活的纤溶抑制物(thrombin activatable fibrinolysis inhibitor,TAFI)产生量减少,从而表现为纤溶活性增强^[12] ...

2003

0.0

... 随着分子生物学技术的发展,血友病A的基因诊断及产前诊断已成为可能^[13] ...

2003

0.0

. 2003, 9(4):348-352

Potential role of the dynamic properties of whole blood coagulation in assessment of dosage requirements in haemophilia

J. Ingerslev,L. H. Poulsen andB. Sørensen

Centre for Haemophilia and Thrombosis, Department of Clinical Biochemistry, University Hospital Skejby, Aarhus N, Denmark * Dr Jørgen Ingerslev, Centre for Haemophilia and Thrombosis, Department of Clinical Biochemistry, University Hospital Skejby, DK-8200 Aarhus N, Denmark. Tel.: +45-8949-5180; fax: +45-8949-5192; e-mail: j-ing@post3.tele.dk

> Summary. In the clinical setting, patients suffering from haemophilia are classified according to the residual level of the deficient coagulation factor. Patients suffering from the severe form of haemophilia (critical factor level −1 ) display some heterogeneity in their tendency to bleeding despite the uniform factor level. Utilizing a new thrombelastographic method in which coagulation is activated by very small amounts of tissue factor and where resulting data are processed with new software, we studied the whole blood coagulation profile in 11 patients with severe haemophilia A and 11 patients with moderate haemophilia. In both groups of patients, we found a considerable degree of heterogeneity in the coagulation signal. In moderate haemophilia with factor VIII (FVIII):C levels between 0.01 and 0.05 IU mL −1 , variance was expected, whereas a quite substantial diversity had not been forecasted in patterns of the whole blood coagulation profiles in patients with the severe form of haemophilia A. Ex vivo substitution to patient's blood to reach various theoretical levels of recombinant factor VIII (rFVIII) revealed that the coagulation response to FVIII supplementation varied substantially. In some severely affected patients levels of FVIII:C close to 0.05 IU mL −1 was sufficient to normalize the coagulation profile, while others required a dose giving >0.50 IU mL −1 of FVIII to achieve a normal whole blood clotting profile. In conclusion, our study revealed that severe haemophilia A seems not to be a single entity, but rather several different clinical and biochemical phenotypes, and that the response to added FVIII varies amongst patients.

... 但目前尚无能精确反映血友病A患者出血风险的实验室指标^[14] ...

1980

3.133

0.0

... Hojima等^[15]发现部分血友病A患者F#cod#x02167 ...