非婴儿获得性维生素K依赖性凝血因子缺乏症的临床和实验研究
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摘要
非婴儿获得性维生素K依赖性凝血因子缺乏症（acquired deficiency of vitamin Kdependent coagulation factors, ADVKDCF）是并不少见的进行性、系统性出血性疾病，实验室表现为凝血功能异常，与常见的新生儿性维生素K依赖性凝血因子缺乏症的病因、临床特征完全不同，本病易误诊、误治，尚无统一的诊疗方法，且病因不明确。我们总结了国际上最大宗的“不明原因”本病临床特征，诊断及治疗方法，尤其对并发颅内出血的患者探讨了其救治措施和危险因素分析，最后对“不明原因”的患者进行了病因的研究。
第一部分102例非婴儿获得性维生素K依赖性凝血因子缺乏症的临床特征及序贯治疗
目的探讨非婴儿获得性依赖维生素K凝血因子缺乏症患者的临床特征及治疗方法。方法分析了在我院诊治的获得性依赖维生素K凝血因子缺乏症102例患者的病因、临床表现、治疗以及随访情况。以2009年12月为限，将长期需维生素K治疗的患者分为序贯治疗组与非序贯组，比较两组的复发率。结果85例患者病因不明（A组），14例为杀鼠药中毒（B组），3例为华法令过量(C组)。所有患者均同时或先后出现皮肤、黏膜、皮下及内脏出血，首发最常见出血部位（症状）为血尿；28例患者因失血致Hb＜100g/L，最低仅为36g/L，各组Hb水平无统计学差异（P=0.11）。患者自出血症状始至明确诊断中位时间为8（2～1920）d，其中32例患者1～62个月才确诊，杀鼠药中毒组与“原因不明”组患者在血尿、致残、复发等差异均无统计学意义，但误诊率两组差异有显著统计学意义（P＝0.00）。此外，两组在凝血指标、Hb、Plt水平上以及序贯治疗疗程上亦无统计学差异（P＞0.05）。全组患者中位随访22个月，接受长疗程维生素K治疗后的患者无1例复发，亦未发现明显不良反应，序贯治疗与非序贯治疗相比，其复发率差异有统计学意义（P=0.001）。治疗后患者APTT、PT及INR值与治疗前相比均有统计学差异（P＝0.00），静脉使用维生素K1时间为1～22个月。序贯治疗的患者无一例出血复发。结论1、非婴儿ADVKDCF患者绝大多数“原因不明”，容易误诊、延误治疗。2、其实验室检查以获得性APTT、PT延长为主要的诊断线索，部分患者血小板数可低于正常。患者出血程度、出血部位不一，最常见的出血症状为血尿。3、临床诊断本病的患者其“不明原因”和杀鼠药中毒者其临床表现、治疗反应及预后基本一致，本病预后良好。4、大剂量维生素K的序贯治疗是本病既经济又高效的根治方法，可有效防止出血复发。
第二部分非婴儿获得性维生素K依赖性凝血因子缺乏症的病因及实验研究
目的探索非婴儿获得性维生素K依赖性凝血因子缺乏症（acquired deficiency ofvitamin K-dependent coagulation factors，ADVKDCF）的病因及实验室特征。方法对临床确诊的85例“病因不明”的ADVKDCF患者采用高压液相－串联质谱法检测其血液、尿液的抗凝血杀鼠药，对其中的50例患者采用ELISA法检测治疗0、3、7天的患者血浆中维生素K缺乏或拮抗剂诱导的蛋白（PIVKAⅡ）水平，采用自动血凝分析仪检测凝血常规，并以20例健康体检者作为对照。结果85例患者血液均可检出抗凝血杀鼠药，尤以溴敌隆多见。患者的PIVKAⅡ平均水平在3.83ng/ml，健康对照组为1.30ng/ml，两组相比差异有统计学意义（P<0.05），患者接受维生素K治疗3d后其值与治疗前相比差异无统计学意义（3.83ng/ml对3.64ng/ml，7d后其值降低但仍高于对照组水平。近期输注了血浆组其PIVKAⅡ水平为3.78ng/ml，同未输注组相比差异无统计学意义。治疗前患者凝血因子Ⅱ、Ⅶ、Ⅸ及Ⅹ活性明显降低（3.68～12.68%），而部分活化的凝血酶原时间（APTT）、凝血酶原时间（PT）明显延长（＞100S），与对照组相比差异有统计学意义（P<0.05），治疗后均恢复正常。所有患者的出血控制，仅一例患者再次误食杀鼠药后复发，其余患者均治愈。结论1、ADVKDCF患者凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ及PC、PS活性明显降低，但Ⅸ因子活性未达到重型血友病乙的程度，APTT、PT明显延长。2、“不明原因”非婴儿ADVKDCF的病因均由杀鼠药中毒引起，应尽快行抗凝血杀鼠药分析明确病因，慎防再次或多次误食杀鼠药。社会各级需加强对抗凝血杀鼠药的监管。3、PIVKAⅡ较凝血检测更敏感，具有早期辅助诊断ADVKDCF的价值，且不受血浆输注的影响。
第三部分非婴儿获得性维生素K依赖性凝血因子缺乏症合并颅内出血患者的救治及高危因素分析
目的探讨“不明原因”非婴儿获得性维生素K依赖性凝血因子缺乏症(ADVKDCF)合并颅内出血患者的临床救治及探讨其高危因素。方法对疑诊颅内出血的ADVKDCF患者采用头颅螺旋CT检查明确其出血部位，对4例合并颅内出血患者进行了早期血浆制品及维生素K序贯治疗的救治，比较了颅内出血组与无颅内出血组患者的PIVKA-Ⅱ水平,无有效的治疗时间,杀鼠药浓度、APTT、PT、PLT及凝血因子Ⅱ、Ⅶ、Ⅸ和Ⅹ的水平,采用Logistic方法分析了患者并发颅内出血的高危因素。结果1、本病颅内出血部位不一，可有脑内血肿、硬膜下血肿、蛛网膜下腔出血、硬膜外出血，甚至表现为多部位出血。头痛、颅内高压的表现是最主要的临床症状，4例患者均未予创伤性的检查及手术，仅给予药物治疗后1周，神经系统表现明显好转，复查头颅CT亦均显示明显好转甚至完全吸收，所有患者均康复，未遗留后遗症。2、4例患者的PIVKA-Ⅱ水平均明显高于无颅内出血组，分别为16.1ng/ml和4.16ng/ml，两组PIVKA-Ⅱ水平有统计学意义（P=0.001）。3、颅内出血组患者平均延迟治疗6.50d，而对照组为3.36d，两组延误治疗的时间差异有统计学意义（P=0.000）（表3）。而患者年龄、杀鼠药浓度、APTT、PT、PLT及凝血因子Ⅱ、Ⅶ、Ⅸ和Ⅹ的水平差异无统计学意义。4、应用Logistic回归分析纳入了年龄、杀鼠药浓度、APTT、PT、PLT、PIVKA-Ⅱ、无有效的治疗时间、凝血因子Ⅱ、Ⅶ、Ⅸ和Ⅹ、伴随的出血部位如口腔血泡、泌尿生殖道出血、消化道出血等因素，单因素分析结果示：除了PIVKA-Ⅱ＞10ng/ml、无有效的治疗时间＞6d是颅内出血的危险因素（P=0.000），而其它因素均未达到统计学差异。多因素分析仍然显示上述两因素是ADVKDC并发颅内出血的危险因素。结论1、伴头痛、颅内高压的ADVKDCF患者尽早行头颅CT检查以明确颅内出血的诊断，部分患者可行MRI以排除合并的血管源性疾病。2、合并颅内出血的ADVKDCF患者早期输注血浆制品以尽快其纠正凝血功能，同时给予维生素K序贯治疗防治复发。尽可能避免有创性检查及治疗。3、本病并发颅内出血的高危因素是PIVKA-Ⅱ（＞10ng/ml）和无有效的治疗时间（＞6d）。
The first section Clinical analysis of102non-infant patients withacquired deficiency of vitamin K-dependent coagulation factors
Objective To explore the clinical features and treatment of non-infant patients withacquired deficiency of vitamin K-dependent coagulation factors (ADVKDCF). MethodsAnalysis was performed on the data of the etiological factors, clinical manifestations,laboratory examinations, diagnoses and treatments of102non-infant patients with acquireddeficiency of vitamin K-dependent coagulation factors. Results There were85patientswith unknown cause (A subgroup),17patients with clear histories of anticoagulantrodenticide poisoning (B subgroup) and three with warfarin overdosage(C subgroup). Thepresentations of hemorrhage of the patients were various.The most common hemorrhagewas hematuria(52/102), followed by mucocutaneous bleeding(44/102).In28patients,hemoglobin (Hb) level was less than100g/L due to blood loss. And there were nodifference in Hb and the delayed time from hemorrhage manifestation to definite diagnosisamong the three subgroups. Eighty seven of102patients were misdiagnosed and themedian time from hemorrhage manifestation to definite diagnosis was8days (range,2daysto62months). Laboratory examinations showed normal platelet count,thrombin time andnormal fibrinogen concentration,but prolonged plasma prothrombin time(PT), activatedpartial prothrombin time (APTT) and international normalized ratio (INR)．Patients of Csubgroup only discontinued warfarin, while the rest patients had received intravenousvitamin K1with a dose of20to240mg/d.The bleeding symptoms disappeared in1to2days after treatment and the Hb level increased dramatically. There were significantdifferences in PT, APTT and INR in the patients before and after treatment (P <0.01).There was significant difference recurrence rate between the vitamin K sequential therapygroup and the non-sequential group (P=0.001). Conclusions The presentations of hemorrhage of the non-infant patients with ADVKDCF were various. The most commonhemorrhage symptom was hematuria, and the cause of major patients was unknown.Vitamin K sequential therapy is promptly effective and economic treatment to preventrecurrence. The anticoagulant rodenticide poisoning patients share same clinical featuresand favourable prognosis with those whose etiology is unknown.
The second section Laboratory study on85patients of non-infant withacquired deficiency of vitamin K-dependent coagulation factors
Objective To investigate non-infant patients with acquired deficiency of the vitaminK-dependent coagulation factors (ADVKDCF) in etiology and laboratory examinations.Methods In85patients, anticoagulant rodenticides in blood and urine were tested by highperformance liquid chromatography tandem mass spectmmeny(LC-MS/MS).There were50patients whose PIVKA-Ⅱlevel assayed by ELISA, and PT and APTT measured withautomatic blood coagulation analyzer on day0,3,7after vitamin K treatment, and Ⅱ，Ⅶ，IX and X factor activities were measured before and after7days of medication. Twentyhealthy persons were used as a control group. Results Anticoagulant rodenticides werepositive in total85patients’ blood samples and in3urine samples, mostly werebromadiolone. The average level of PIVKA Ⅱof patients3.83ng/ml, and control group is1.30ng/ml. There was significant difference between two groups (P <0.05). ThePIVKA-Ⅱ level on0and3days of medication is no statistically significant (3.83ng/ml vs3.64ng/ml, P＞0.05). After7days treatment with vitamin K, PIVKA-Ⅱ level decreasedsignificantly compared to the control group(P <0.05).The PIVKA-Ⅱlevel in plasmatransfusion patients was3.78ng/ml, which was no statistically different compared to the notransfusion group(P＞0.05). Coagulation factor II, Ⅶ, IX, Ⅹ, PC and PS activitydecreased significantly before treatment, while APTT and PT was significantly prolonged(>100seconds). They were returned to normal after vitamin K treatment. All bleeding wascontrolled after vitamin K sequential thrapy. Only one patient relapsed due to ingestion ofrodenticides again, and the others were cured. Conclusions In ADVKDCF patients,coagulation factors II, VII, Ⅸ, Ⅹ,PC and PS activity decreased, but APTT, PT wasprolonged significantly. Anticoagulant rodenticides poisoning is the only causative inpatients with unknown ADVKDCF in China and related assays are needed as soon aspossible. The PIVKA-Ⅱ level in patients is significantly higher than normal within3days of vitamin K treatment. It has the value of early diagnosis to ADVKDCF, and theconcentration is not interfered by plasma transfusion. Patients with unknown ADVKDCFhas good prognosis, however, all patients must be aware of rodenticides poisoning again.
The third section Study on diagnosis and treatment of non-infantpatients’ intracranial hemorrhage due to acquired deficiency of vitaminK-dependent coagulation factors
Objective Vitamin K is required for γ-carboxylation of glutamic acid residues of theprocoagulant factors II (prothrombin), VII, IX, and X and the anticoagulant factors proteinC and protein S. Acquired deficiency of vitamin K dependent coagulation factors (VKDCF)results from absolute vitamin K deficiency and/or abnormal cycling utilization. Thegreatest threat to life is the hemorrhage of central nervous system, which is rare but fatal.The clinical features and prognosis of4patients with intracranial hemorrhage (ICH) due toacquired deficiency of VKDCF were analyzed. Methods Initial prothrombin tim(PT),activated partial thromboplastin time (APTT) and coagulation factors analysis wasperformed on STA Compact analyazer. Factor’s activities were determined using standardtechniques of deficient plasma as substrate in PT or activated PPT testing. Anticoagulantrodenticide concentration was determined by high-performance liquidchromatography-tandem mass spectrometry (HPLC-MS/MS) with fluorescence detectionwith minimal detection capabilities of0.2ng/mL.The PIVKAⅡconcentration was assayedby ELISA. All patients received fresh frozen plasma (FFP) and venous high dose ofvitamin K1at the first3days and then were given oral vitamin K44mg.kg-1.d-1. Logisticregression was used to assess the high risk factors what was composed of APTT, PT, FC: II,FC: VII, FC:IX, FC:X activities, blood platelet counters and other bleeding sites.ResultsAll patients had various episodes of bleeding and manifestation with intracranialhypertension. Cranial CT and/or MRI demonstrated ICH.The coagulation tests showedthat the average activities of VKDCFs were decreased with markedly prolonged PT andAPTT that were corrected with normal plasma. Blood platelet count, fibrinogen, thrombintime (TT) and hepatic function were normal. Serum high bromadiolone levels were foundin total4patients. The plasma PIVKA-II concentration was significantly increased in ICHpatients than that of the no ICH patients (16.1ng/ml vs4.16ng/ml, P=0.001) All patientsimproved quickly and had no sequelae and adverse reaction after high dose and long time of vitamin K treatment. Multiple factors analysis showed that plasma PIVKA-IIconcentrations>10ng/ml and no effective treatment time for bleeding manifestation>6dayswere the independent factor in ICH.
Conclusions Spontaneous and systemic hemorrhages are the main clinicalpresentation of acquired deficiency of VKDCF, whereas intracranial bleeding is rarely seen.The diagnosis depends on the history, laboratory examinations and response to high doseof vitamin K. Early diagnosis and rapid correcting dyscoagulatoin are the key measures ofmanagement of acquired deficiency of VKDCF complicated with ICHs. Invasiveexamination and/or treatment shoule be avoided in the patients. The prognosis of acquireddeficiency of VKDCF is favorable，even complicated with ICH, and the plasma PIVKA-IIconcentrations>10ng/ml and no effective time from bleeding manifestation>6days werethe independent factor in ICH.
第一部分102例非婴儿获得性维生素K依赖性凝血因子缺乏症的临床特征及序贯治疗
目的探讨非婴儿获得性依赖维生素K凝血因子缺乏症患者的临床特征及治疗方法。方法分析了在我院诊治的获得性依赖维生素K凝血因子缺乏症102例患者的病因、临床表现、治疗以及随访情况。以2009年12月为限，将长期需维生素K治疗的患者分为序贯治疗组与非序贯组，比较两组的复发率。结果85例患者病因不明（A组），14例为杀鼠药中毒（B组），3例为华法令过量(C组)。所有患者均同时或先后出现皮肤、黏膜、皮下及内脏出血，首发最常见出血部位（症状）为血尿；28例患者因失血致Hb＜100g/L，最低仅为36g/L，各组Hb水平无统计学差异（P=0.11）。患者自出血症状始至明确诊断中位时间为8（2～1920）d，其中32例患者1～62个月才确诊，杀鼠药中毒组与“原因不明”组患者在血尿、致残、复发等差异均无统计学意义，但误诊率两组差异有显著统计学意义（P＝0.00）。此外，两组在凝血指标、Hb、Plt水平上以及序贯治疗疗程上亦无统计学差异（P＞0.05）。全组患者中位随访22个月，接受长疗程维生素K治疗后的患者无1例复发，亦未发现明显不良反应，序贯治疗与非序贯治疗相比，其复发率差异有统计学意义（P=0.001）。治疗后患者APTT、PT及INR值与治疗前相比均有统计学差异（P＝0.00），静脉使用维生素K1时间为1～22个月。序贯治疗的患者无一例出血复发。结论1、非婴儿ADVKDCF患者绝大多数“原因不明”，容易误诊、延误治疗。2、其实验室检查以获得性APTT、PT延长为主要的诊断线索，部分患者血小板数可低于正常。患者出血程度、出血部位不一，最常见的出血症状为血尿。3、临床诊断本病的患者其“不明原因”和杀鼠药中毒者其临床表现、治疗反应及预后基本一致，本病预后良好。4、大剂量维生素K的序贯治疗是本病既经济又高效的根治方法，可有效防止出血复发。
第二部分非婴儿获得性维生素K依赖性凝血因子缺乏症的病因及实验研究
目的探索非婴儿获得性维生素K依赖性凝血因子缺乏症（acquired deficiency ofvitamin K-dependent coagulation factors，ADVKDCF）的病因及实验室特征。方法对临床确诊的85例“病因不明”的ADVKDCF患者采用高压液相－串联质谱法检测其血液、尿液的抗凝血杀鼠药，对其中的50例患者采用ELISA法检测治疗0、3、7天的患者血浆中维生素K缺乏或拮抗剂诱导的蛋白（PIVKAⅡ）水平，采用自动血凝分析仪检测凝血常规，并以20例健康体检者作为对照。结果85例患者血液均可检出抗凝血杀鼠药，尤以溴敌隆多见。患者的PIVKAⅡ平均水平在3.83ng/ml，健康对照组为1.30ng/ml，两组相比差异有统计学意义（P<0.05），患者接受维生素K治疗3d后其值与治疗前相比差异无统计学意义（3.83ng/ml对3.64ng/ml，7d后其值降低但仍高于对照组水平。近期输注了血浆组其PIVKAⅡ水平为3.78ng/ml，同未输注组相比差异无统计学意义。治疗前患者凝血因子Ⅱ、Ⅶ、Ⅸ及Ⅹ活性明显降低（3.68～12.68%），而部分活化的凝血酶原时间（APTT）、凝血酶原时间（PT）明显延长（＞100S），与对照组相比差异有统计学意义（P<0.05），治疗后均恢复正常。所有患者的出血控制，仅一例患者再次误食杀鼠药后复发，其余患者均治愈。结论1、ADVKDCF患者凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ及PC、PS活性明显降低，但Ⅸ因子活性未达到重型血友病乙的程度，APTT、PT明显延长。2、“不明原因”非婴儿ADVKDCF的病因均由杀鼠药中毒引起，应尽快行抗凝血杀鼠药分析明确病因，慎防再次或多次误食杀鼠药。社会各级需加强对抗凝血杀鼠药的监管。3、PIVKAⅡ较凝血检测更敏感，具有早期辅助诊断ADVKDCF的价值，且不受血浆输注的影响。
第三部分非婴儿获得性维生素K依赖性凝血因子缺乏症合并颅内出血患者的救治及高危因素分析
目的探讨“不明原因”非婴儿获得性维生素K依赖性凝血因子缺乏症(ADVKDCF)合并颅内出血患者的临床救治及探讨其高危因素。方法对疑诊颅内出血的ADVKDCF患者采用头颅螺旋CT检查明确其出血部位，对4例合并颅内出血患者进行了早期血浆制品及维生素K序贯治疗的救治，比较了颅内出血组与无颅内出血组患者的PIVKA-Ⅱ水平,无有效的治疗时间,杀鼠药浓度、APTT、PT、PLT及凝血因子Ⅱ、Ⅶ、Ⅸ和Ⅹ的水平,采用Logistic方法分析了患者并发颅内出血的高危因素。结果1、本病颅内出血部位不一，可有脑内血肿、硬膜下血肿、蛛网膜下腔出血、硬膜外出血，甚至表现为多部位出血。头痛、颅内高压的表现是最主要的临床症状，4例患者均未予创伤性的检查及手术，仅给予药物治疗后1周，神经系统表现明显好转，复查头颅CT亦均显示明显好转甚至完全吸收，所有患者均康复，未遗留后遗症。2、4例患者的PIVKA-Ⅱ水平均明显高于无颅内出血组，分别为16.1ng/ml和4.16ng/ml，两组PIVKA-Ⅱ水平有统计学意义（P=0.001）。3、颅内出血组患者平均延迟治疗6.50d，而对照组为3.36d，两组延误治疗的时间差异有统计学意义（P=0.000）（表3）。而患者年龄、杀鼠药浓度、APTT、PT、PLT及凝血因子Ⅱ、Ⅶ、Ⅸ和Ⅹ的水平差异无统计学意义。4、应用Logistic回归分析纳入了年龄、杀鼠药浓度、APTT、PT、PLT、PIVKA-Ⅱ、无有效的治疗时间、凝血因子Ⅱ、Ⅶ、Ⅸ和Ⅹ、伴随的出血部位如口腔血泡、泌尿生殖道出血、消化道出血等因素，单因素分析结果示：除了PIVKA-Ⅱ＞10ng/ml、无有效的治疗时间＞6d是颅内出血的危险因素（P=0.000），而其它因素均未达到统计学差异。多因素分析仍然显示上述两因素是ADVKDC并发颅内出血的危险因素。结论1、伴头痛、颅内高压的ADVKDCF患者尽早行头颅CT检查以明确颅内出血的诊断，部分患者可行MRI以排除合并的血管源性疾病。2、合并颅内出血的ADVKDCF患者早期输注血浆制品以尽快其纠正凝血功能，同时给予维生素K序贯治疗防治复发。尽可能避免有创性检查及治疗。3、本病并发颅内出血的高危因素是PIVKA-Ⅱ（＞10ng/ml）和无有效的治疗时间（＞6d）。
The first section Clinical analysis of102non-infant patients withacquired deficiency of vitamin K-dependent coagulation factors
Objective To explore the clinical features and treatment of non-infant patients withacquired deficiency of vitamin K-dependent coagulation factors (ADVKDCF). MethodsAnalysis was performed on the data of the etiological factors, clinical manifestations,laboratory examinations, diagnoses and treatments of102non-infant patients with acquireddeficiency of vitamin K-dependent coagulation factors. Results There were85patientswith unknown cause (A subgroup),17patients with clear histories of anticoagulantrodenticide poisoning (B subgroup) and three with warfarin overdosage(C subgroup). Thepresentations of hemorrhage of the patients were various.The most common hemorrhagewas hematuria(52/102), followed by mucocutaneous bleeding(44/102).In28patients,hemoglobin (Hb) level was less than100g/L due to blood loss. And there were nodifference in Hb and the delayed time from hemorrhage manifestation to definite diagnosisamong the three subgroups. Eighty seven of102patients were misdiagnosed and themedian time from hemorrhage manifestation to definite diagnosis was8days (range,2daysto62months). Laboratory examinations showed normal platelet count,thrombin time andnormal fibrinogen concentration,but prolonged plasma prothrombin time(PT), activatedpartial prothrombin time (APTT) and international normalized ratio (INR)．Patients of Csubgroup only discontinued warfarin, while the rest patients had received intravenousvitamin K1with a dose of20to240mg/d.The bleeding symptoms disappeared in1to2days after treatment and the Hb level increased dramatically. There were significantdifferences in PT, APTT and INR in the patients before and after treatment (P <0.01).There was significant difference recurrence rate between the vitamin K sequential therapygroup and the non-sequential group (P=0.001). Conclusions The presentations of hemorrhage of the non-infant patients with ADVKDCF were various. The most commonhemorrhage symptom was hematuria, and the cause of major patients was unknown.Vitamin K sequential therapy is promptly effective and economic treatment to preventrecurrence. The anticoagulant rodenticide poisoning patients share same clinical featuresand favourable prognosis with those whose etiology is unknown.
The second section Laboratory study on85patients of non-infant withacquired deficiency of vitamin K-dependent coagulation factors
Objective To investigate non-infant patients with acquired deficiency of the vitaminK-dependent coagulation factors (ADVKDCF) in etiology and laboratory examinations.Methods In85patients, anticoagulant rodenticides in blood and urine were tested by highperformance liquid chromatography tandem mass spectmmeny(LC-MS/MS).There were50patients whose PIVKA-Ⅱlevel assayed by ELISA, and PT and APTT measured withautomatic blood coagulation analyzer on day0,3,7after vitamin K treatment, and Ⅱ，Ⅶ，IX and X factor activities were measured before and after7days of medication. Twentyhealthy persons were used as a control group. Results Anticoagulant rodenticides werepositive in total85patients’ blood samples and in3urine samples, mostly werebromadiolone. The average level of PIVKA Ⅱof patients3.83ng/ml, and control group is1.30ng/ml. There was significant difference between two groups (P <0.05). ThePIVKA-Ⅱ level on0and3days of medication is no statistically significant (3.83ng/ml vs3.64ng/ml, P＞0.05). After7days treatment with vitamin K, PIVKA-Ⅱ level decreasedsignificantly compared to the control group(P <0.05).The PIVKA-Ⅱlevel in plasmatransfusion patients was3.78ng/ml, which was no statistically different compared to the notransfusion group(P＞0.05). Coagulation factor II, Ⅶ, IX, Ⅹ, PC and PS activitydecreased significantly before treatment, while APTT and PT was significantly prolonged(>100seconds). They were returned to normal after vitamin K treatment. All bleeding wascontrolled after vitamin K sequential thrapy. Only one patient relapsed due to ingestion ofrodenticides again, and the others were cured. Conclusions In ADVKDCF patients,coagulation factors II, VII, Ⅸ, Ⅹ,PC and PS activity decreased, but APTT, PT wasprolonged significantly. Anticoagulant rodenticides poisoning is the only causative inpatients with unknown ADVKDCF in China and related assays are needed as soon aspossible. The PIVKA-Ⅱ level in patients is significantly higher than normal within3days of vitamin K treatment. It has the value of early diagnosis to ADVKDCF, and theconcentration is not interfered by plasma transfusion. Patients with unknown ADVKDCFhas good prognosis, however, all patients must be aware of rodenticides poisoning again.
The third section Study on diagnosis and treatment of non-infantpatients’ intracranial hemorrhage due to acquired deficiency of vitaminK-dependent coagulation factors
Objective Vitamin K is required for γ-carboxylation of glutamic acid residues of theprocoagulant factors II (prothrombin), VII, IX, and X and the anticoagulant factors proteinC and protein S. Acquired deficiency of vitamin K dependent coagulation factors (VKDCF)results from absolute vitamin K deficiency and/or abnormal cycling utilization. Thegreatest threat to life is the hemorrhage of central nervous system, which is rare but fatal.The clinical features and prognosis of4patients with intracranial hemorrhage (ICH) due toacquired deficiency of VKDCF were analyzed. Methods Initial prothrombin tim(PT),activated partial thromboplastin time (APTT) and coagulation factors analysis wasperformed on STA Compact analyazer. Factor’s activities were determined using standardtechniques of deficient plasma as substrate in PT or activated PPT testing. Anticoagulantrodenticide concentration was determined by high-performance liquidchromatography-tandem mass spectrometry (HPLC-MS/MS) with fluorescence detectionwith minimal detection capabilities of0.2ng/mL.The PIVKAⅡconcentration was assayedby ELISA. All patients received fresh frozen plasma (FFP) and venous high dose ofvitamin K1at the first3days and then were given oral vitamin K44mg.kg-1.d-1. Logisticregression was used to assess the high risk factors what was composed of APTT, PT, FC: II,FC: VII, FC:IX, FC:X activities, blood platelet counters and other bleeding sites.ResultsAll patients had various episodes of bleeding and manifestation with intracranialhypertension. Cranial CT and/or MRI demonstrated ICH.The coagulation tests showedthat the average activities of VKDCFs were decreased with markedly prolonged PT andAPTT that were corrected with normal plasma. Blood platelet count, fibrinogen, thrombintime (TT) and hepatic function were normal. Serum high bromadiolone levels were foundin total4patients. The plasma PIVKA-II concentration was significantly increased in ICHpatients than that of the no ICH patients (16.1ng/ml vs4.16ng/ml, P=0.001) All patientsimproved quickly and had no sequelae and adverse reaction after high dose and long time of vitamin K treatment. Multiple factors analysis showed that plasma PIVKA-IIconcentrations>10ng/ml and no effective treatment time for bleeding manifestation>6dayswere the independent factor in ICH.
Conclusions Spontaneous and systemic hemorrhages are the main clinicalpresentation of acquired deficiency of VKDCF, whereas intracranial bleeding is rarely seen.The diagnosis depends on the history, laboratory examinations and response to high doseof vitamin K. Early diagnosis and rapid correcting dyscoagulatoin are the key measures ofmanagement of acquired deficiency of VKDCF complicated with ICHs. Invasiveexamination and/or treatment shoule be avoided in the patients. The prognosis of acquireddeficiency of VKDCF is favorable，even complicated with ICH, and the plasma PIVKA-IIconcentrations>10ng/ml and no effective time from bleeding manifestation>6days werethe independent factor in ICH.
引文
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