Inhibition and reversal of platelet-rich arterial thrombus in vivo: direct vs. indirect factor Xa inhibition

BACKGROUND/OBJECTIVE: The efficacy of a direct factor (F)Xa inhibitor, ZK-807834, was compared with indirect inhibition by enoxaparin for inhibition and deaggregation of acute platelet-rich thrombi in a well-characterized porcine carotid injury model. METHODS: A crush injury was performed on a randomly chosen carotid artery and the thrombus allowed to propagate for 30 min. Pigs then received intravenous drug for 35 min: ZK-807834-Dose 1 (40 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion, n=6); ZK-807834-Dose 2 (20 microg kg(-1) bolus + 0.75 microg kg(-1) min(-1) infusion; n=6); enoxaparin (1 mg kg(-1) bolus; n=6); or saline (n=6). Five minutes after drug initiation, the contralateral artery was injured. Thrombus size was monitored by scintillation detection of autologous 111In-platelets. RESULTS: The prothrombin time ratio was 2.2 +/- 0.1; 1.4 +/- 0.3; 1.2 +/- 0.9 and 1.1 +/- 0.2, respectively. ZK-807834-Dose 1 significantly inhibited carotid platelet deposition (525 +/- 226 x 10(6) cm(-2); P = 0.008), whereas ZK-807834-Dose 2 (2325 +/- 768) and enoxaparin (1236 +/- 383) were not different from saline (2776 +/- 642). Thrombus deaggregation was greatest for animals receiving ZK-807834-Dose 1 (473 +/- 185). Neither ZK-807834-Dose 2 (1588 +/- 480) nor enoxaparin (1618 +/- 686) was different from saline control (2222 +/- 598). CONCLUSIONS: Direct FXa inhibition with ZK-807834, at a prothrombin time ratio of 2.2, effectively inhibits thrombosis and promptly deaggregates thrombi induced by arterial injury. In contrast, indirect FXa inhibition with enoxaparin was ineffective.     

Factor Xa-activated whole blood clotting time (Xa-ACT) for bedside monitoring of dalteparin anticoagulation during haemodialysis.

BACKGROUND: Low molecular weight heparins (LMWH) like dalteparin are increasingly used for anticoagulation during haemodialysis (HD). The available laboratory tests for monitoring LMWH anticoagulation are time-consuming and expensive, and the suitability of the conventional activated clotting time (ACT) is controversial. A simple and cheap bedside test would be useful. METHODS: We studied the factor Xa-activated whole blood clotting time (Xa-ACT) in vitro and in vivo in nine patients undergoing chronic HD with i.v. dalteparin bolus anticoagulation and compared it with the conventional ACT. Plasma anti-factor Xa (antiXa) activity was determined with a chromogenic assay. Thrombin-antithrombin complexes were measured to detect coagulation activation. RESULTS: Xa-ACT and ACT were prolonged with rising dalteparin concentration. In vitro, both clotting times were strongly correlated with the antiXa levels (r = 0.94 and 0.89, respectively). Nevertheless, compared with the ACT, the Xa-ACT was considerably more sensitive to the LMWH in vitro (healthy blood: Xa-ACT 90 s/U vs ACT 26 s/U; uraemic blood: Xa-ACT 96 s/U vs ACT 31 s/U) as well as in vivo (Xa-ACT 81 s/U vs ACT 22 s/U) and reflected different intensities of anticoagulation. An initial dalteparin bolus of 80+/-11 U/kg body weight was able to prevent coagulation activation for up to 4 h of HD. CONCLUSION: For monitoring LMWH anticoagulation the Xa-ACT was superior to the conventional ACT in vitro as well as in vivo during HD. The Xa-ACT can be useful as a LMWH bedside test. The ACT was not sensitive enough to serve as a LMWH monitoring tool.     

硫酸铁铵催化合成乙酰乙酸乙酯乙二醇缩酮

采用正交试验优选出最佳条件为：当乙酰乙酸乙酯为0.2moL时，硫酸铁铵0.7g，环乙烷10mL。乙酰乙酸乙酯和惭二醇摩尔比为1：1.5，反应时间为5h。所得产率为59.2%。     

Drug Induced Acute Generalized Exanthematous Pustulosis

A 62-year-old woman with diabetic triopathy developed widespread erythematous macules, numerous pustules, and a high fever after she underwent electric coagulation for vitreous hemorrhage. She was administered several drugs at that time. After discontinuation of the drugs, the eruption disappeared, and the fever returned to normal within two weeks. A positive patch test with isepamicin sulfate highly suggested that the symptoms described above were due to drug allergy. Cadralazine, which was positive in the drug lymphocyte stimulation test (DLST), could not be excluded from the causative drugs. A false-positive DLST with ofloxacin was confirmed by an accidental challenge test. To our knowledge, this is the first report of acute generalized exanthematous pustulosis due to isepamicin sulfate and/or cadralazine.     

Heparin–coated circuit during cardiopulmonary bypass

A prospective randomized study was performed to investigate the effect of surface coating with covalently endpoint–attached heparin (Carmeda Bio Active Surface) and reduced general heparinization on haematological indices and complement C5 activation. Care was taken to optimize the rheological design of the system using centrifugal pump and a closed system without venting or machine suction. Twenty patients scheduled for aortocoronary bypass grafting (EF > 0.5) participated in the study. Ten patients were randomized to be treated with heparin–coated equipment (CBAS) and reduced i.v. heparin (1.5 mg kg^-1) while 10 patients treated with identical but noncoated equipment and full heparinization (3 mg–kg^-1) served in a Control group. A vacuum suction was used to collect the blood from the operating field and it was autotransfused at weaning from extracorporeal circulation (ECC). Blood samples were obtained from the venous (precircuit) and arterial (postcircuit) side. We used a new and very specific method for detection of C5a based on monoclonal antibodies. The concentration of C5a was low in both groups during the operation but a significant increase was seen on days 1 and 2. In the Control group there was an increase from 10.2 ngml^-1±1.2 to 27.5 ng ml^-1 ± 4.8 on day 2 and in the CBAS group from 10.7 ng ml^-1 ± 1.2 to 35.6 ng ml^-1 ± 11.6 on day 2 (NS between groups). The granulocytes and total leukocyte count increased at the end of ECC and was maintained at the elevated level throughout the study period. The amount of free haemoglobin was high in the autotransfused blood in both groups. The present results confirm the feasibility of reducing general heparin when using heparin–coated systems but the study does not support the superiority of such coating with regard to biocompatibility in short procedures with a Theologically optimized circuit. The potential benefit from reduced heparin and protamine has not been fully evaluated.     

硫酸多糖对体外人脐静脉内皮细胞损伤的保护作用

研究表明,硫酸多糖体外对多聚阳离子和氧自由基损伤的人脐静脉内皮细胞有保护作用。肝素、硫酸软骨素A抗多聚阳离子损伤作用比同浓度低分子肝素和甘糖酯强。肝素、硫酸软骨素A、甘糖酯抗氧自由基损伤作用优于同浓度低分子肝素。结果显示硫酸多糖有保护血管内皮的作用,其作用可能与所带阴离子基团有关。     

Correlation between inflammatory cellular responses and chemotactic activity in bronchoalveolar lavage fluid following intratracheal instillation of nickel sulfate in rats

In a preceding study, we reported that the numbers of macrophages and polymorphonuclear leukocytes (PMN) were increased in bronchoalveolar lavage fluid (BALF) following the intratracheal instillation of nickel sulfate (NiSO₄) in rats. In the present study, BALF chemotactic activities for both macrophages and PMN were measured to investigate if the increases of these inflammatory cells in BALF depend on increases in chemotactic activities in epithelial lining fluid (ELF) of the lung. Both the number of PMN and the PMN chemotactic activity peaked at 2 days post-instillation and they were significantly correlated. However, the PMN chemotactic activity was inversely correlated with concentration of leukotriene B₄ (LTB₄), a well-known chemotaxin. Although PMN were not observed in control BALF, LTB₄ concentration in the control ELF (ca. 5×10^–7 M) was estimated to have a potential to attract PMN chemotactically through a membrane in in vitro migration assay. These results suggest that the presence of LTB₄ in ELF itself does not trigger transpulmonary PMN infiltration. The rat BALF were fractionated by high performance liquid chromatography (HPLC), and PMN chemotactic activity of each fraction was measured. The elution profiles of PMN chemotactic activity showed that there were at least two different chemotaxins in BALF obtained from the NiSO₄-exposed rats. Macrophage chemotactic activity in BALF also peaked at 2 days post-instillation. However, the number of macrophages was not significantly correlated with the chemotactic activity for macrophage in BALF. The HPLC study showed that the macrophage chemotactic substance in the BALF obtained from NiSO₄-exposed rats was different from complement fragment (C5a) and its MW was estimated to be 10 – 12 kD. Received: 1 December 1993/Accepted: 16 March 1994     

荞麦花粉抗贫血作用的实验研究

用荞麦花粉的水提取液进行了抗大白鼠缺铁性贫血的研究，结果表明：荞麦花粉具有和硫酸亚铁相似的抗缺铁性贫血作用．饮用荞麦花粉提取液３５ｄ的大白鼠，生长发育良好，主要脏器未见损害．该研究为荞麦花粉的开发利用提供了实验依据．     

The effect of oral anticoagulant therapy on aptt results from a bedside coagulation monitor

Objective. The Ciba Corning 512 coagulation monitor (CC512) can be used to monitor heparin therapy by performing an activated partial thromboplastin time (APTT) at the patient’s bedside. This study was designed to compare the CC512 results to results using the laboratory system. The relative sensitivities of both systems to the effect of oral anticoagulant therapy also was investigated.Methods. Activated partial thromboplastin times were performed with both the CC512 and laboratory system on 74 specimens from patients receiving IV heparin therapy, and on 14 specimens from patients on warfarin only. Heparin assays were performed on 43 of the specimens from the heparinized patients.Results. When a patient was receiving heparin only, the APTT results of the CC512 proved to be similar to existing laboratory methods. The CC512 APTT results of patients on warfarin only were markedly prolonged, whereas the laboratory APTTs were only slightly affected.Conclusion. The CC512 results were comparable to the laboratory system. However, the CC512 APTT was more sensitive to the effect of warfarin than the laboratory APTT system used in this study. CC512 APTT results on a patient receiving both oral and intravenous anticoagulation could be misleading. The authors wish to thank D.M. O’Brien and the nursing staff of the Coronary Care Unit for providing CC512 data and laboratory specimens, and I. Smith for the preparation of graphics. We also wish to thank Australian Diagnostics Corporation, which provided consumables.