Fatal diffuse pulmonary arterial thrombosis as a complication of nephrotic syndrome

A 21-year-old man was admitted to our hospital because of leg edema. Because laboratory findings revealed massive proteinuria and hypoproteinemia, he was diagnosed as having nephritic syndrome caused by minimal change disease. He was given a continuous heparin infusion and intravenous steroid therapy, at a prednisolone dose of 1 mg/kg per day, and his condition gradually improved. Five months after discharge, the patient's proteinuria relapsed. He was readmitted to our hospital and we restarted anticoagulant treatment with intravenous heparin and 60 mg prednisolone. On the third hospital day, he complained of chest pain with sudden onset and dyspnea. He quickly developed shock and died. The findings of an autopsy confirmed the presence of diffuse fibrin thrombi in bilateral pulmonary arteries, and we diagnosed the cause of death as diffuse pulmonary artery thrombosis. A coagulation test for activated partial thromboplastin time (aPTT) had already shown that aPTT was prolonged before the initiation of treatment. There may have been a deficit of antithrombin III (ATIII) – a cofactor of heparin – because of the proteinuria; thus, the continuous heparin treatment might not have been effective for the prevention of thrombosis. Alternatives to heparin treatment that do not suppress AT III, such as nafamostat mesilate or argatroban, which do not require the presence of AT III for their anticoagulant action, should be considered in cases similar to the that in the patient reported here. In patients with nephrotic syndrome who exhibit altered coagulation test results, the choice of anticoagulation therapy for treatment of the hypercoagulabilty status associated with nephrotic syndrome should be carefully considered.     

恶性血液病抗凝血酶活性的变化及其临床意义

目的探讨血液肿瘤患者抗凝血酶(AT)活性的变化及其临床意义。方法回顾性分析195例血液肿瘤患者初发、缓解、未缓解、复发时AT活性水平的差异,并具体分析了急、慢性白血病及骨髓增生异常综合征、恶性淋巴瘤、多发性骨髓瘤不同分型或分期患者AT活性水平的变化。结果初发组、缓解组、部分缓解组、复发组较对照组AT活性显著降低(P(0.01);初发、部分缓解及复发组AT活性较缓解组降低,具有显著性差异(P(0.01);非霍奇金淋巴瘤患者各分期之间及骨髓增生异常综合征不同分型之间AT活性无明显差异;多发性骨髓瘤Ⅱ、Ⅲ期患者AT活性较Ⅰ期患者降低(P(0.05);多发性骨髓瘤复发组患者与缓解组比较,AT活性显著降低,β2-微球蛋白、球蛋白及乳酸脱氢酶活性升高,差异均具有显著性(P(0.05);其中AT活性变化与β2-微球蛋白变化具有负相关性(P(0.05)。结论AT活性不仅反映血液病患者抗凝系统的功能,同时可作为判断患者病情变化及其预后的指标之一。对于多发性骨髓瘤患者AT活性水平变化与β2-微球蛋白具有相关性,AT水平变化可能具有预后评估意义。     

急性心肌梗死溶栓疗法对血浆凝血活性影响

目的 探讨溶栓疗法对血浆凝血活性的影响。方法连续监测35例急性心肌梗死患者,于确诊后定期从外周静脉采血,酶联免疫双抗体夹心法测定血浆凝血酶修饰抗凝血酶Ⅲ（antithrombin Ⅲ modified,ATM）和D-二聚体（D—D）的动态变化。结果溶栓开始2h后,血浆ATM显著内性增加（87．80μg／L±25．19μg／L,比24．48μg／L±11．62μg／L,P〈0．05）,4h达峰值（120．87μg／L±31．54μg／L）,持续3d以上;血浆D—D于2h即达到峰值（7．76mg／L±2．58mg／L,比2．7mg／L±1．36mg／L,P〈0．05）,维护8h以上,24h以后恢复正常。在溶栓组患者,不同采血时刻血浆ATM和D—D的平均值呈明显正相关。未溶栓组患者血浆ATM和D—D浓度未见显著性变。结论溶栓疗法激活凝血系统,与血栓溶解的标志物（D—D）呈明显正相关。早期应用有效抗血栓药物可能抑制凝血系统的激活,减少血栓再闭塞的发生。     

In vivo age dependency of unfractionated heparin in infants and children

INTRODUCTION: Unfractionated Heparin (UFH) is used widely in paediatrics. Paediatric specific recommendations for UFH therapy are few, with the majority of recommendations being extrapolated from adult practice. In vitro studies have shown that this practice may be suboptimal. This study aimed to improve the understanding of the impact of age upon UFH response in vivo. MATERIALS AND METHODS: This prospective, observational study, conducted in the Paediatric Intensive Care Unit (PICU), included: patients 16 years or younger; treated with UFH of at least 10 U/Kg/hr. Laboratory analysis included: Antithrombin, APTT, Anti-Xa, Anti-IIa and thrombin generation expressed as the Endogenous Thrombin Potential. Results were grouped according to patient age (i.e. <1, 1-5, 6-10 and 11-16 years). RESULTS: 85 patients received an equivalent mean UFH dose with a median duration of 3 days. Antithrombin levels were decreased compared to age-related norms in children up to 11 years of age. APTT results were comparable across the age-groups. The Anti-Xa results using two different assays showed a trend for lower values in younger children. All children less than one year old recorded Anti-Xa values outside the therapeutic range for heparin therapy, for both assays. There was a trend for decreased Anti-IIa activity in younger children. Endogenous Thrombin Potential showed a significant trend for increased inhibition in older children. In vitro Antithrombin supplementation did not change the Anti-Xa or thrombin generation. CONCLUSIONS: This study confirms that, in vivo, for the same dose of UFH, the anti Xa and anti IIa effect, as well as the inhibition of endogenous thrombin potential is age dependent and that these differences are not purely AT dependent. The implication is that the anticoagulant and antithrombotic effect of a given dose of UFH differs with age. Clinical outcome studies to determine the optimal dosing for each age group are warranted.     

Prophylaxis with AT III for thromboembolism in nephrotic syndrome: why should it be done?

Children with nephrotic syndrome (NS) are at risk for sinovenous and arterial thrombosis, uncommon but serious complications of the nephrotic syndrome. Multiple factors are involved in the hypercoagulable state of patients with NS, for instance, enhanced platelet reactivity and deficiency of antithrombin III due to urinary loss of this protein. We report the case of a 7-year-old girl with relapse of nephrotic syndrome and with a clinical risk for thromboembolic complications, identified by very low AT III and albumin serum levels and high fibrinogen and cholesterol serum levels. However, having symptoms of hypovolemia, she was treated with albumin and diuretics, known risk factors for thrombotic incidents, although these drugs were both administered after prophylactic intravenous antithrombin. There are no randomized controlled clinical trials supporting prophylactic anticoagulation in the management of nephrotic syndrome. Arterial thromboses during nephrotic syndrome has been associated with thrombophilic states and the use of diuretics. It might be advisable to do laboratory monitoring for coagulation profiling and, in children at risk, prophylactic treatment with AT III before administering albumin infusion and diuretics.     

Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives

BACKGROUND: Clinical studies suggest that the second generation antipsychotics (APs) clozapine and olanzapine and to a lesser extent the typical antipsychotics may be associated with a procoagulant and proinflammatory state that promotes venous thromboembolism. We evaluated here several blood factors associated with coagulation and inflammation in AP-treated schizophrenia patients and their first-degree relatives. METHODS: Procoagulant factors (fibrinogen and plasminogen activator inhibitor [PAI-1]), the anticoagulant factor antithrombin III [AT-III], and inflammation-related factors (C-reactive protein [CRP] and leptin) were assessed in patients chronically treated with clozapine (n=29), olanzapine (n=29), typical APs (n=30) and first degree relatives of clozapine (n=23) and olanzapine subjects (n=11). RESULTS: The typical AP group had the highest CRP level (p=0.013) in spite of having the lowest body mass index (BMI). Patients as a single group had higher CRP levels than relatives (p=0.003). The typical AP group also had the highest AT-III levels (p=0.021). Fibrinogen levels did not differ between the groups (p=0.13). Olanzapine patients displayed the highest PAI-1 and leptin levels among the drug-treated subjects, but values were similar to those observed in their relatives, and were significantly correlated with the BMI. CONCLUSIONS: A homogeneous negative profile of high inflammation and procoagulant factors along with low levels of anticoagulants was not detected in any group. While preliminary, our results suggest that the observed abnormalities were not related to a direct drug effect, but to elevated BMI (high PAI-1 and leptin in olanzapine-treated patients). We speculate that the high CRP in the typical AP group might be related to poor lifestyle habits, but this must we confirmed in future studies.     

Amyloid and Amyloidosis. The 2nd Romhányi Memorial Symposium April 24, 2004, Pécs,Hungary

Various pathogenic factors have been proposed to explain the abnormal hemostasis observed in AL amyloidosis. Since imbalance between clottingfactors and inhibitors could play a pathogenic role in both hemorrhagic and thrombotic manifestations, we investigated the thrombin-antithrombin pathway in 35 patients with AL amyloidosis. Ten patients suffered from bleeding while 3 patients experienced deep venous thrombosis. Thrombin time was prolonged in 29 subjects, the mean values of antithrombin III activity (ATIII Act) were significantly lower than those of antithrombin III antigen (ATIII Ag) with loss of relationship between these two direrent techniques of ATIII detection, normally observed in healthy controls. In 19 patients increased levels of thrombin-antithrombin (TAT) complexes were present. Crossed immunoelectrophoresis of ATIII, performed in presence of heparin, evidenced ATIII forms with reduced binding capacity to heparin and TAT complexes of various electrophoretic mobilities. In conclusion, the impairment of the thrombin-antithrombin pathway, in association with the low ATIII biological activity, mightplay a pathogenic role in the hypercoagulable state reported in AL amyloidosis, despite the higher frequency of bleeding manifestations.     

抗凝血酶基因Ala384Ser多态性与肺血栓栓塞症相关性研究

目的 探讨抗凝血酶基因Ala384Ser多态性与肺血栓栓塞症(pulmonary thromboembolism,PTE)的相关性.方法 采用病例对照研究的方法,运用聚合酶链反应扩增,产物纯化.Pvu Ⅱ限制性内切酶片段长度多态性聚合酶链反应及DNA测序技术对65例PTE患者及65名健康对照者进行抗凝血酶基因Ala384Ser分析.结果 PTE组仅3.3%患者有PTE家族史,这与西方人群报道结果存在显著差别;心血管疾病家族史、口服避孕药、吸烟、饮酒史、外伤及手术史PTE组与对照组比较差异无统计学意义.PTE组、对照组等位基因频率为1、0,符合Hardy-Weinberg平衡定律,G/G、G/T、T/T基因型频率和G、T等位基因频率在PTE组与对照组之间差异无统计学意义.结论 抗凝血酶基因Ala384Ser多态性可能不是中国人群PTE的一个危险因素,与西方调查者实验结果的差别说明基因多态性存在种族差异,且在不同种族中PTE的致病机制可能不同.     

原发性肝癌凝血及抗凝指标检测结果分析

 目的　探讨肝癌患者凝血及抗凝指标与肝癌病情及预后的关系。方法　对 4 9例肝癌患者 (其中 2 3例术后复查 )的部分凝血及抗凝指标进行检测。结果　肝癌合并肝硬化组PT、APTT、TT与正常组比较均显著延长 ;肝癌组术前FIB显著高于正常对照组 ,肝癌并肝硬化组FIB则显著降低 ;肝癌患者TF活性均显著高于正常对照组 ;各组肝癌患者AT III活性均显著降低。结论　肝癌患者明显存在凝血及抗凝血激活状态 ,TF和AT III可作为肝癌诊断和判断预后的指标     

Antithrombin and first complement protein recognize the same active heparin fraction

Antithrombin (AT) high affinity of unfractionated heparin (UFH) resides in a specific pentasaccharide sequence. Heparin also regulates complement activity on the classical and the alternative pathways. Most experimental pieces of evidence accumulated show that these important activities reside in different segments of the heparin molecule. We demonstrated in previous papers that a low ionic strength and the presence of calcium ions are essential to detect specific interactions between glycosaminoglycans and proteins. Then these very strict conditions were used, and we demonstrated that the first protein complex of the human complement cascade recognizes in the UFH a fraction with very high anticoagulant activity. After isolation from the precipitate of the interaction, this fraction of heparin also contained the pentasaccharide sequence responsible for the great affinity with AT: in fact, it was strongly bound to a resin of AT agarose, and to detach it, an ionic strength of 0.6 M sodium chloride was required. In this way, the heparin regions responsible for the anticoagulant activity and also for the effects over the complement system were identified on the same short segment of the heparin molecule, which includes the active fraction of the glycosaminoglycan. The differences with early results could be explained by our experimental conditions of low ionic strength and the presence of calcium ions used for the interaction of the protein and the glycosaminoglycan.