超声心动图和下肢静脉超声联合血浆D-二聚体对孕产妇肺栓塞的临床诊断价值

目的分析和评价超声心动图和下肢静脉超声联合血浆D-二聚体对孕产妇肺栓塞（pulmonary thromboembolism, PE）的临床诊断和预测价值。方法回顾性收集2019年5月—2021年5月同济大学附属第一妇婴保健院收治120例临床疑诊PE的孕产妇临床资料,按照肺动脉断层血管造影（computed tomographic pulmonary angiographic, CTPA）的结果分为阴性组和阳性组,比较和评价超声心动图、下肢静脉超声、血浆D-二聚体单独及联合诊断孕产妇PE的临床诊断和预测效能。结果临床特征比较： 两组间年龄、孕次、产次、受孕方式、受孕胎数、终止妊娠方式、是否早产、既往妇产科手术史、既往外科手术史、是否合并高血压、糖尿病、肥胖及BNP等指标比较差异均无统计学意义（均P>0.05）。两组间仅血浆D-二聚体比较差异有统计学意义（t=-3.598,P＜0.001）。超声心动图、下肢静脉超声和血浆D-二聚体升高单独及联合诊断孕产妇PE的灵敏度分别为45.00%、53.33%、95.00%和85.00%,特异度分别为83.33%、91.67%、21.67%和81.67%,阳性预测值分别为72.97%、86.49%、54.81%和82.26%,阴性预测值分别为60.24%、66.27%、81.25%和84.48%。与单独诊断相比较,联合诊断显著提高灵敏度（χ2=49.669,P＜0.001）、特异度（χ2=88.413,P＜0.001）、阳性预测值（χ2=20.629,P＜0.001）和阴性预测值（χ2=11.169,P=0.01）。多因素Logistic回归分析提示超声心动图阳性（OR=18.266,P＜0.001）、下肢静脉血栓（OR=45.482,P＜0.001）及D-二聚体升高（OR=6.595,P=0.019）与孕产妇PE发生显著相关,ROC曲线分析显示单独及联合诊断的曲线下面积（AUC）分别为0.642、0.725、0.583和0.833。结论超声心动图和下肢静脉超声联合血浆D-二聚体对孕产妇PE具有良好的诊断和预测价值,为临床早期预防、诊断和治疗提供可靠依据。     

Thromboresistant properties of hydrophilic gels

The thromboresistant properties of hydrophilic gels based on copolymers of nitrogen-containing heterocyclic vinyl compounds with vinyl monomers were investigated. The hydrophilic gels were shown to prevent adsorption of fibrinogen, activation of procoagulants, and adhesion of platelets. Hydrogen surfaces possess selective affinity for plasma albumin. The authors consider that the thromboresistant effect of hydrophilic gels is due to the competitive action of plasma albumin. Modification of hydrophilic gels increases their thromboresistant properties.Laboratory of Thromboresistant Materials, Institute of Transplantation of Organs and Tissues, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. M. Chernukh.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 3, pp. 296–298, March, 1980.     

Biological coagulation findings in third-generation oral contraceptives

An increased risk of venous thrombosis has been demonstrated in women receiving oral contraceptives (OCs). This risk has been primarily associated with the oestrogen content, but recent studies showed that the progestogen may also play a role. A higher risk was found with the so-called third-generation (desogestrel, gestodene) as compared with the second-generation progestogens (levonorgestrel). The risk was approximately two-fold. These unexpected results have been the subject of many debates, and bias--such as selection bias--has been suggested. The existence of bias cannot be completely excluded, but the thrombotic risk seems however to be slightly higher with the third-generation progestins. Haemostatic changes have been observed during OC intake. Both coagulation and fibrinolytic activity are increased: the beneficial profibrinolytic effect may counterbalance the deleterious procoagulant effect. This may explain that the absolute risk of venous thromboembolism is low during OC treatments. Some women who have pre-existing haemostatic abnormalities such as deficiency in antithrombin or activated protein C resistance with factor V Leiden, may be at a higher risk. The biological plausibility of the increased risk related to the third-generation progestogens has been explored. Theoretically, this could be due to an increased coagulation or to a lack of increased fibrinolysis as compared with second-generation progestogens. The only difference presently reported with third-generation OCs is a decreased sensitivity to activated protein C, possibly resulting in a hypercoagulability of greater magnitude. The selection bias suggested in epidemiological studies may also exist for the latter study, as women taking third- or second-generation OCs were not randomized. The possible increased risk related to third-generation OCs should not change the known general contra-indications. Practical guidelines are proposed for women with personal or family history of venous thromboembolism, and for those with a congenital cause of thrombophilia.     

大鼠创伤性深静脉血栓形成中纤溶、凝血相关基因表达分析

在急性、亚急性创伤性深静脉血栓形成大鼠模型中,动态检测并比较分析血管内皮纤溶、凝血相关基因的表达变化和差异,探讨其在创伤性深静脉血栓形成中的作用和意义。分别取150只SD大鼠建立急性、亚急性血栓形成模型。急性血栓模型组采用直接钳夹股静脉 双后肢石膏固定、亚急性组采用定量击打双侧大腿 双后肢石膏固定的方式造模。根据深静脉血栓形成过程中不同的生物学状态,将实验动物分为正常对照、创伤即刻、血栓形成初始期、血栓形成高峰期、血栓消退、血栓不消退和血栓不形成7组。采用Genechip Rat Genome4302.0芯片,测定股静脉RNA表达情况,运用基因芯片数据分析方法(倍数变化分析)筛选出差异性表达基因。重点分析血管内皮纤溶、凝血相关基因在两种模型中的变化和差异。结果显示:内皮细胞抗凝和纤溶功能相关基因如ThbdN、os及Plat等基因的表达变化与创伤性深静脉血栓形成关系密切。内皮细胞抗凝和纤溶功能的减弱是创伤性深静脉血栓形成的重要因素之一。这一机制在血管直接受损的急性血栓模型中更显著。     

Diagnostic performance of aPS/PT antibodies in neuropsychiatric lupus and cardiovascular complications of systemic lupus erythematosus

Abstract

Background: Systemic lupus erythematosus (SLE) is associated with a constellation of complications affecting multiple organs, including neuropsychiatric manifestations (NPSLE) and ischaemic events, leading to increased long-term morbidity. Antiphospholipid antibodies (aPL) are a major determinant of vascular inflammation and thromboembolic risk. The diagnostic role of anti-phosphatidylserine/prothrombin (aPS/PT) antibodies in this setting is incompletely defined.

Aim: To verify whether aPS/PT add to diagnostics and disease stratification in patients with SLE with or without other aPL.

Methods: 131 consecutive patients were studied, including 20 patients with SLE and secondary antiphospholipid syndrome (APS). aPS/PT IgG and IgM were assessed through ELISA and patients were stratified based on the presence of other aPL, on their clinical and laboratory features at time of blood sampling and on their clinical history. Synthetic indices of disease activity, chronic damage and cardiovascular risk were calculated at time of venipuncture.

Results: Fifty-one (38.9%) patients with SLE had aPS/PT and 15 (11.5%) patients had aPS/PT as the only aPL (aPS/PT-only). aPS/PT-only patients had a significantly higher prevalence of NPSLE than quadruple aPL-negative patients (p?=?.007). Patients with aPS/PT were more likely to have a history of ischaemia, thrombocytopenia and Libman–Sacks’ endocarditis. The presence of aPS/PT also associated with previous accrual of at least one damage item (p?=?.043), but had limited predictive values for damage progression in the short term.

Conclusion: aPS/PT antibodies provide non-redundant information that could contribute to risk assessment and stratification of patients with SLE.     

Modulation of hemostatic balance with antithrombin III replacement therapy in a case of liver cirrhosis associated with recurrent venous thrombosis

Patients with liver failure can present both thrombotic and hemorragic complications because of the deficiency in coagulation factors and inhibitors (protein C and S, antithrombin III) and impairment of fibrinolytic balance. Here we report the case of a 63-year-old man with liver cirrhosis, recurrent thrombosis, and features of low-grade consumption coagulopathy, showing severe antithrombin III deficiency (about 30% of normal values). Treatment with antithrombin III (2000 U/day) and low doses of heparin (5000 U b.i.d.) was successful in modulating the coagulation system toward an antithrombotic effect. After discharge from hospital the ambulatory treatment with antithrombin III concentrates (2000 U twice a week) allowed the attainment of antithrombin III activity of about 60% and prevented the patient from recurrence of venous thrombosis.Abbreviations AT-III Antithrombin III - DIC Disseminated intravascular coagulation - TAT complexes Thrombin-antithrombin III complexes - PAI-1 Plasminogen activator inhibitor-1     

Transformationsvorgänge in der Frühphase der Entstehung des arteriellen Thrombus

Zusammenfassung In unserer ultrastrukturell durchgeführten Studie wurden Thromben in der Arteria carotis communis von Ratten nach einer zuerst von Meng und Seuter (1977) beschriebenen Methode experimentell erzeugt. Induktion der Thrombusbildung erfolgte in vivo durch Unterkühlung eines kleinen Gefäßabschnittes unter konstantem Druck und kurzfristiger Stase. Eine Änderung des Blutflusses wurde durch einen Silberclip erzeugt. Die geschädigten Gefäßsegmente einschließlich der Thromben bzw. deren Vorstufen wurden nach 5, 10, 30 min und 1, 4 und 24 h nach der Thrombosestimulation entnommen und fixiert. Semidünnschnitte und Ultradünnschnitte wurden im Licht- und Elektronenmikroskop morphologisch untersucht.Den Transformationsvorgängen im Thrombus konnten exakte Zeitmarken zugeordnet werden. Als wichtigstes histopathologisches Merkmal für die Altersbestimmung arterieller Thromben in der Frühphase der Thrombogenese werteten wir die Querstreifung der Fibrinfasern. Diese trat bereits nach 5 min auf, erreichte nach 30 min ein Maximum und verschwand als Folge der zunehmenden Verdichtung der Fasern nach einer Stunde. Nach 4 h sahen wir eine weitgehende Retraktion der Fibrinfasern, die nach 24 h zur Bildung des Fibrinfasergerüstes mit Einmauerung korpuskulärer Elemente führte. Überdies beobachteten wir zwei Thrombocytenaggregate von differenter Struktur. Wir unterschieden ein fibrinarmes Aggregat, in dem die Thrombocyten dichtgepackt und pseudopodienreich erschienen von einem thrombocytenarmen Aggregat mit reichlich interponierten Fibrinfasern. Die nach 5 min im Zentrum des Thrombus auftretende Agglutination der Plättchen im thrombocytenreichen Aggregat führte nach 30 min zur Thrombocytorrhexis und ergab daher einen weiteren Anhalt für die Altersbestimmung des Coagulum. Der entstandene celluläre Abraum stimulierte mononucleäre Zellen und Leukocyten zur Phagocytose. Daher sahen wir nach 4 h eine massive Leukocytose als Folge der frühen Thrombocytorrhexis. Nach 24 h war die viscöse Metamorphose im fibrinreichen und fibrinararmen Aggregat weitgehend abgeschlossen. Innerhalb des beobachteten Zeitraumes entstand eine Verballung und bizarre Deformierung der Erythrocyten, die bereits nach 5 min vom Zentrum des Thrombus ausging und nach 24 h die Peripherie erreichte. Eine Hämolyse der Erythrocyten war nach dieser Zeit noch nicht erkennbar.

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Evolution in the early changes in the establishment of arterial thrombi

Summary Ultrastructural studies of thrombi were carried out on the common carotid artery of the rat using a method first described by Meng and Seuter (1977). Induction of thrombus formation in vivo was achieved by chilling of a small vessel segment under constant pressure and short-termed stasis. Disturbance of the blood flow was produced by a silver clip. The damaged vessel segments with the thrombotic deposits were removed 5, 10, 30 min, and 1, 4 and 24 h after stimulation of thrombosis. They were fixed and samples were studied as semithin and ultrathin sections morphologically using light and electronmicroscopy.In the maturation of thrombi exact time intervals could be determined. The most important histopathological characteristics for age determination of arterial thrombi in the early period of thrombogenesis were the cross stripes of fibrin fibres. They appeared after 5 min, reaching a maximum after 10 min and disappeared as a result of increasing fibre density after 1 h. After 4 h nearly complete retraction of fibrin fibres was found which led after 24 h to the formation of a corresponding frame walling in the corpuscular elements. Apart from this aggregation of thrombocytes, which were of two different types were observed, one showing a fibrin-poor aggregate in which the thrombocytes appeared densely packed with numerous pseudopods, and one showing a thrombocyte poor aggregate with abundant interposed fibrin fibres. Agglutination of platelets which occurred in the thrombocyte-rich aggregate in the centre of the thrombus after 5 min led to thrombocytorrhexis after 30 min. The resulting cellular waste stimulated phagocytosis by mononuclear cells and leucocytes. Because of this a massive leucocytosis was found as a result of the early thrombocytorrhexis after 4 h. After 24 h the viscous metamorphosis in the fibrin-rich and in the fibrin-poor aggregate was largely completed. Clumping and deformation of erythrocytes was observed in the middle of the thrombus after 5 min and at the periphery of the thrombus after 24 h. Haemolysis did not occur within this time interval.

Frau Antoni, Herrn Ing. grad. Derks und Herrn Rieger sei für ausgezeichnete technische Assistenz herzlichst gedankt.     

Pathogenesis of antiphospholipid syndrome: recent insights and emerging concepts

Introduction: Even though our understanding of the antiphospholipid syndrome (APS) has improved tremendously over the last decades, we are still not in a position to replace symptomatic anticoagulation by pathogenesis based causal treatments.

Areas covered: Recent years have provided further insights into pathogenetically relevant mechanisms. These include a differentiation of pathogenic subtypes of antiphospholipid antibodies (aPL), novel mechanisms modulating disease activity, for example, extracellular vesicles and microRNA, and novel players in pathogenesis, for example, neutrophils and neutrophil extracellular traps (NETs).

Expert commentary: It is evident that aPL induce a proinflammatory and procoagulant state and recent data suggest that different aPL species activate different signaling pathways which sometimes converge into a common cellular response. This implies that presence of more than one aPL species may disproportionally increase the risk for the major manifestations of APS, that is, thrombosis and fetal loss. Further delineation of the pathogenic mechanisms will hopefully provide clues to causal rather than symptomatic treatments of APS.     

Effect of Antiphospholipid Antibodies on β2Glycoprotein I-Phospholipid Interaction

PROBLEM: β₂ glycoprotein I (β₂GPI) physiologically binds to negatively charged phospholipids (PLs) and is a natural regulator of the coagulation cascade. Thrombotic clinical complications and recurrent fetal loss associated with autoimmune antiphospholipid (aPL) antibodies are thought to be related to their binding to β₂GPI-PL complex and interference with the physiological function of β₂GPI. METHOD OF STUDY: To investigate the effect of aPL on β₂GPI-PL interaction, we studied the binding of biotinylated β₂GPI to cardiolipin (CL) by enzyme-linked immunosorbent assay (ELISA) in the presence and absence of purified aPL immunoglobulin G (IgG) antibodies. RESULTS: Adding five different aPL IgG antibodies with different levels of aPL activity isolated from the sera of five patients with aPL-associated recurrent fetal death greatly increased the binding of biotinylated β₂GPI to CL-coated plates. The optical densities (ODs) were 0.635, 0.890, and 1.265 in the presence of three aPL IgG antibodies, compared to 0.425 in the absence of aPL IgG. In contrast, normal human IgG had no enhancing effect. The OD was 0.480 and 0.425, respectively. The enhancement of β₂GPI binding to CL by aPL IgG correlated with the titers of aPL antibodies. The use of phosphate-buffered saline with increasing salt concentrations as a washing buffer for the ELISA resulted in more stable binding of β₂GPI to PL in the presence of aPL IgG. CONCLUSIONS: These findings suggest that the binding of autoimmune aPL antibodies to β₂GPI-PL complex results in abnormally tighter interaction between β₂GPI and PLs, which may lead to physiological dysfunction of β₂GPI as a regulator of coagulation.