摘要
第一部分血栓性血小板减少性紫癜(TTP)患者临床与实验室特点分析
目的:
总结分析37例TTP患者的临床表现,实验室特点及治疗反应,评价vWF裂解酶ADAMTS13活性测定对于TTP的诊断价值,以期发现对TTP诊断和鉴别诊断有用的实验室诊断指标。
方法:
1、对我院1998年1月~2009年4月期间诊断为TTP的37例患者进行临床和实验室特征以及治疗转归分析。
2、对所有病例外周血涂片进行破碎红细胞计数,计数5000个成熟红细胞中破碎红细胞数量以百分率表示。
3、应用FRET-vWF86荧光发色底物法测定其中22例患者血浆ADAMTS13活性。
4、采用流式细胞技术对其中18例患者及20例正常对照进行T淋巴细胞亚群分析。
结果:
1、37例患者中仅7例(18.92%)出现典型TTP五联征;30例(81.08%)表现为三联征(血小板减少、微血管病性溶血性贫血、神经系统症状)。病因分类主要为特发性TTP患者(56.76%)及自身免疫性疾病相关性TTP患者(35.14%)。血浆置换联合血浆输注是本组患者主要的治疗方法。26例血浆置换治疗患者21(80.77%)例获得完全缓解;11例血浆输注治疗患者缓解率仅为18.18%,死亡率高达81.82%。4例患者输注浓缩红细胞后出现一过性神经精神症状加重或恶化。
2、本组病例外周血涂片100%存在破碎红细胞,均值为4.4%,范围为0.3%~13.4%。
3、22例患者中4例特发性TTP出现重度ADAMTS13活性下降(ADAMTS13活性<10%);ADAMTS13活性中度下降(10%~40%)9例,ADAMTS13活性正常(40%~100%)9例。
4、患者组CD3+细胞计数及CD4+细胞计数明显低于对照组,存在统计学差异(P<0.05),而两组CD 8+细胞计数组间并无显著差异(P>0.05)。
结论:
TTP诊断仍依赖于临床特征及常规实验室检查,尤其是微血管病性溶血性贫血(破碎红细胞)的证据。ADAMTS13活性测定对于特发性TTP诊断具有较好的特异性,但敏感性较差。细胞免疫异常可能与TTP发病有关。
第二部分动静脉血栓形成获得性/遗传性危险因素筛查
第一章深静脉血栓形成患者获得性危险因素分析
目的:
总结分析深静脉血栓形成(DVT)患者临床表现及实验室特点,分类鉴别深静脉血栓形成的获得性危险因素。
方法:
对我院2005年~2009年期间诊断的389例深静脉血栓形成患者进行回顾性分析。
结果:
389例DVT病人男性病例204例,女性185例。男女比例1.1:1;中位年龄47岁(12~90岁)。发病有明确诱因者253例(65.04%),未发现明确诱因者136例(34.96%)。较常见的获得性危险因素包括:外科手术/外伤(26.74%);恶性肿瘤(14.91%);妊娠(8.23%);静脉曲张(8.23%);长期卧床患者(5.40%);风湿免疫性疾患(2.57%)。
结论:
手术/创伤,尤其是骨折和骨科手术占中国人种DVT获得性危险因素百分率最高,恶性肿瘤也是中国人种深静脉血栓形成重要的获得性危险因素。
第二章动静脉血栓形成遗传性危险因素筛查
目的:
筛查中国人种深静脉血栓形成及脑梗死患者血浆高同型半胱氨酸水平、抗凝血酶活性下降、蛋白C活性下降、总蛋白S浓度下降、FV Leiden突变及凝血酶原G20210A基因突变发生频率。
病例和方法:
1、120例深静脉血栓形成,130例脑梗死患者及100例正常对照均常规抽取静脉血,3.8%枸橼酸钠抗凝,室温下3000rpm离心15min分离血浆,血浆标本置于-70度冰箱冻存,取白细胞层常规酚氯仿法抽提基因组DNA。
2、血浆同型半胱氨酸测定采用循环酶法。血浆抗凝血酶活性及蛋白C活性测定采用发色底物法,分别以S-2772或S-2366作为发色底物,在日立7170A自动生化仪上进行分析。血浆总蛋白S浓度测定采用ELISA方法。高同型半胱氨酸血症定义为测定值高于对照组测定值按大小排序95百分位同型半胱氨酸测定值。抗凝因子缺陷定义为测定值低于相应的对照组测定值按大小排序95百分位抗凝因子测定值。
3、PCR分别扩增因子V 10号外显子,凝血酶原3'非翻译区。PCR扩增产物通过限制性内切酶长度多态性分析鉴定是否存在FVLeiden、凝血酶原G20210A突变。
结果:
1、DVT组血浆同型半胱氨酸水平显著高于正常对照组(P<0.05)。DVT患者组血浆抗凝血酶活性、蛋白C活性及总蛋白S浓度均显著低于正常对照组(P<0.05)。DVT组抗凝因子总缺陷率为32.5%(39/120),高同型半胱氨酸血症、抗凝血酶缺陷、蛋白C缺陷、蛋白S缺陷患者占总患者人数百分率分别为7.5%,15%,13.33%,6.67%。
2、脑梗死组血浆同型半胱氨酸水平及高同型半胱氨酸血症患者百分率均高于对照组(OR=2.85, P<0.05)脑梗死组血浆抗凝血酶活性水平与对照组无显著性差异(P>0.05)。
3、Logistic回归分析显示血浆抗凝血酶活性缺陷(OR=3.82)和蛋白C活性缺陷(OR=3.20)是静脉血栓形成重要的独立危险因素(P<0.05)。而高同型半胱氨酸血症(OR=1.40)和血浆总蛋白S浓度下降(OR=1.16)对静脉血栓发病影响无统计学意义(P>0.05)。
4、100例正常对照,120例DVT,130例脑梗死患者中均未发现FV Leiden突变及凝血酶原G20210A突变。
结论:
抗凝血酶活性缺陷、蛋白C活性缺陷是中国人种深静脉血栓形成重要的遗传性危险因素。高同型半胱氨酸血症和总蛋白S浓度下降可能并非中国人种独立的危险因素。抗凝血酶活性缺陷并非脑梗死的发病危险因素,而高同型半胱氨酸血症是脑梗死独立的危险因素。FV Leiden突变、凝血酶原G20210A突变可能并非中国人种动静脉血栓形成的危险因素。
Objective:
To analyze the clinical features, outcome and laboratory characteristics of patients with TTP, and determine diagnostic value of ADAMTS13 activity for TTP.
Method:
Thirty-seven TTP patients admitted to our hospital from 1998 to 2009 were analyzed. The number of schistocytes per 5,000 red cells was counted at 1000-power magnification. The results were expressed as number of schistocytes per 100 red cells. Plasma ADAMTS13 activity was determined in 22 patients with the FRET-vWF86 assay. T lymphocyte subpopulation was measured in 18 TTP patients and 20 healthy controls with FACS Calibur.
Results:
There were 30 patients (81.08%) with the triad of TTP, including hemolytic anemia, thrombocytopenia and neurologic abnormalities; 7 (18.92%) had the classical pentad of TTP. Major etiologic factors were acquired autoimmune disorders (35.14%) or idiopathic TTP (56.76%). The schistocytes of peripheral blood smears were present in all cases with a mean of 4.4%and a range of 0.3%-13.4%. Only 4 idiopathic TTP patients (18.18%) had severe ADAMTS 13 deficiency (activity<10%); 9 (40.91%) had moderate deficiency of ADAMTS 13 activity (activity: 10-40%); another 9.(40.91%) had normal ADAMTS 13 activity (>4.0%). CD3+cell counts and CD4+cell counts were significantly lower in TTP patients than those in controls (P<0.05), whereas there was no statistical difference between CD 8+T cell counts in TTP patents and that in normal controls (P>0.05). In this study, plasmapheresis in combination with plasma infusion is the main therapeutic method.21 of 26 patients (80.77%) accepting plasmapheresis achieved complete remission; those patients who only underwent plasma infusion had low remission rate (2/11; 18.18%) and high mortality (9/11; 81.82%).4 patients with packed RBC infusion manifested transient exacerbation of neurologic or psychiatric symptoms.
Conclusion:
The diagnosis of TTP is still based on clinical features including evidence of microangiopathic haemolysis. Plasma ADAMTS 13 activity assay is highly specific but lowly sensitive indicator in diagnosing idiopathic TTP. Cellular immune abnormality may be associated with TTP.
Chapter I Acquired risk factors analysis in deep vein thrombosis patients
Objective:
To analyze clinical features and acquired risk factors for Chinese patients with deep vein thrombosis.
Methods:
Three hundred and eighty-nine patients with deep vein thrombosis (during 2005~2009) were analyzed retrospectively.
Results:
In the serials,204 males and 185 females, male to female ratio was 1.1. Among the 389 cases with median age of 47 (range from 12 to 90), 253 (65.04%) presented acquired risk factors. There was not known risk factors in 136 (34.96%) cases. Major acquired risk factors were trauma/surgery (26.74%), malignancy (14.91%), pregnancy (8.23%), varix (8.23%), long-term immobilization in bed (5.40%) and autoimmune disorders (2.57%).
Conclusions:
The trauma/surgery, especially fracture or osteological operations, and malignancy are the main acquired risk factors of deep vein thrombosis in China.
Chapter II Screening of Inherited risk factors in patients with arterial or venous thrombosis
Objective:
To identified the incidence of Hyperhomocysteinaemia, antithrombin activity deficiency, protein C activity deficiency, decreased total protein S concentration, prothrombin 20210A allele and FV Leiden mutation in Chinese patients with arterial or venous thrombosis.
Methods:
A total of 350 subjects, including 120 patients with deep vein thrombosis,130 patients with cerebral infarction and 100 healthy controls, were consecutively entered into our study. Blood was collected in tubes containing 3.8% trisodium citrate. Plasmas were prepared by centrifugation for 15 minutes at 3000rpm at room temperature and stored at -70℃in 1.5mL aliquots until the time of analysis. Antithrombin activity and protein C activity were measured with a chromogenic method using S-2772 or S-2366 as substrate respectively on automatic analyzer (HITACHI 7170A). Total protein S concentration was determined by polyclonal enzyme-linked immunosorbent assay (ELISA). Plasma homocysteine levels were determined by enzymatic cycling assay. Hyperhomocysteinaemia was defined as a value above the 95th percentile of healthy subjects. Anticoagulation factors deficiencies were defined as a value lower than the 95th percentile of healthy subjects. Genomic DNA was extracted from whole blood in each subjects using standard method. For the identification of FV Leiden and prothrombin 20210A allele genetic mutations, we used the PCR followed by restriction fragment length polymorphism analysis. Genomic DNA was specifically amplified for exon 10 of the factorV gene and 3'-UT regions of the prothrombin gene using PCR respectively. The fragments obtained by PCR were digested by Mnll or Hindlll respectively and then examined by agarose gel electrophoresis.
Results:
Compared with the control group, The plasma level of total protein S concentration and activities of Antithrombin and protein C were significantly lower in DVT patients (P<0.05). The plasma level of homocysteine was higher in DVT patients than that in controls (P<0.05). The incidence of any anticoagulation factor deficiency in patients with DVT was 32.5% (39/120).7.5% of patients (9 out of 120) had Hyperhomocysteinaemia; 15% of patients (18 out of 120) had low AT activity; 13.33% of patients (16 out of 120) had a deficiency in PC; 6.67% of patients (8 out of 120) had a decreased total protein S concentration. The level of AT activity in cerebral infarction patients was not different from the controls with statistical significance (P>0.05). Both plasma level of homocysteine and the ratio of who shew hyperhomocysteinaemia were significantly higher in cerebral infarction patients than those in healthy controls (P<0.05). Thrombotic risk assessment by logistic regression analysis demonstrated that both antithrombin deficiency (OR=3.82) and protein C deficiency (OR=3.20) are strong independent risk factors for deep vein thrombosis (P<0.05). Neither plasma level of Total protein S concentration (OR=1.16) nor hyperhomocysteinaemia (OR=1.40) was significantly associated with venous thrombophilia (P>0.05). None of the subjects, including 100 healthy controls,120 DVT and 130 cerebral infarction patients, was found to have abnormal prothrombin 20210A allele or FV Leiden mutation.
Conclusion:
Antithrombin activity deficiency and protein C activity deficiency are strong independent risk factors of venous thrombosis in Chinese race. Both hyperhomocysteinaemia and decreased total protein S concentration are considered a relatively weak prothrombotic factors for venous thrombophilia in Chinese population. Antithrombin activity deficiency is not the independent risk fator for cerebral infarction in Chinese race. There is a strong association between hyperhomocysteinemia and cerebral infarction. Neither prothrombin 20210A allele nor FV Leiden mutation is the thrombophilic risk factor of DVT and cerebral infarction in Chinese race.
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