The influence of LMW heparin on the coagulation and fibrinolytic response to surgery

The response of components of the coagulation and fibrinolytic systems has been examined in patients undergoing minor and major elective surgery and receiving or not receiving subcutaneously administered prophylactic low molecular weight (LMW) heparin. Blood samples were withdrawn pre-operation (PO), post-anaesthesia (PA), during operation (DO) and 24 hours post-operation. Release of plasminogen activator occurred post anaesthesia at a time when factor VIII components were unchanged or decreased. Induction of anaesthesia decreased plasminogen (p less than 0.005) fibrinogen (p less than 0.02) ATIII (p less than 0.002) and fast a2-antiplasmin (p less than 0.005). During operation plasminogen activator release reached a peak in association with a moderate increase in factor VIII components. Heparin treatment produced a prolongation of APTT at DO (p less than 0.05) and at 24hr (p less than 0.002) stages, this prolongation being apparently unrelated to its concentration but did not prevent the rise of factor VIII components observed at 24 hr (p less than 0.02). Prekallikrein (p less than 0.05) and antithrombin III levels (p less than 0.05) were significantly higher whereas fast a2-antiplasmin (p less than 0.002) was significantly lower at 24 hours in patients undergoing major operation and treated with heparin. Protein C levels fell significantly at 24 hours in the untreated patient (p less than 0.014) and in the heparin treated group the fall was greater than the control group (p less than 0.007). At 24 hours other haemostatic and fibrinolytic components were unaffected by heparin treatment.     

脑外伤后迟发性脑梗塞患者急性期纤溶状态研究

目的初步探讨脑外伤后迟发性脑梗塞患者急性期血浆及脑脊液凝血纤溶状态变化,为临床脑外伤后迟发性脑梗塞提供诊治依据。方法脑外伤后迟发性脑梗塞患者72例,采集血浆,同时采集脑脊液,测定脑脊液及血浆部分凝血纤溶指标,并与171例脑外伤后无脑梗塞患者对照进行比较。结果脑外伤后迟发性脑梗塞组(实验组)脑脊液及血浆组织型纤溶酶原激活物(t-PA)、D-二聚体(D-D)含量明显高于非脑梗塞组(对照组)(P<0.01)而纤溶酶原(PLG)活性明显下降(P<0.01)。结论脑外伤后迟发性脑梗塞患者急性期存在明显的高凝状态和继发性纤溶活性增高。     

Influence of heparin treatment on biochemical markers of an activation of the coagulation system.

Monitoring of anticoagulant treatment is not yet satisfactory. Otherwise optimal treatment control in special situations as low dose heparin prophylaxis in hip surgery or high dose anticoagulant treatment in patients after coronary stent implantation may be desirable. Recently available thrombin markers were analyzed in 51 patients under low dose (group 1) and 30 patients under high dose therapy with unfractionated heparin (group 2a and b) as well as in controls (n = 26). Before therapy these parameters were significantly elevated in both patient groups. Elevated thrombin-antithrombin III-complexes (TAT) despite adequate prolongation of aPTT under high dose heparin in 38.2% of patients indicate that therapeutic concentrations of heparin in these cases are insufficient for depressing this parameter completely. During low dose therapy only prothrombin fragment (F1 + 2) significantly decreased. This may be explained by catalytic induction of TAT-complex formation by heparin. Decrease of D-Dimer under heparin therapy in both groups does not parallel with TAT and F1 + 2 but was more prolonged. This can be explained by dependence of the D-Dimer level on spontaneous fibrinolytic activity and by a longer plasma half-life as well as a chronic and continuous fibrinolytic process in an older thrombus. In conclusion, thrombin markers seem to be helpful in estimating anticoagulant treatment efficacy. As a consequence, anticoagulant treatment has to be intensified in high-risk patients for complete depression of these markers. Whether the benefit of higher heparin doses is worth the risk of drug-induced hemorrhage, however, remains to be clarified in clinical studies.     

Fixed-dose, body weight-independent subcutaneous LMW heparin versus adjusted dose unfractionated intravenous heparin in the initial treatment of proximal venous thrombosis. EASTERN Investigators

BACKGROUND: Body weight-adjusted subcutaneous low-molecular-weight heparin (LMWH) has been proven to be at least as effective and safe as dose-adjusted intravenous unfractionated heparin (UFH) for the treatment of patients with venous thromboembolism. However, body weight-adjusted dosage of low-molecular-weight heparin may be cumbersome and could lead possibly to incorrect dosing. Therefore a fixed LMWH dose, independent of body-weight, might rationalize initial treatment for venous thromboembolism. METHODS: Patients with proven proximal deep-vein thrombosis were randomly assigned to fixed dose subcutaneous LMWH Certoparin (8,000 anti-factor Xa U b.i.d.; 265 patients) or to adjusted dose i.v. UFH (273 patients) for 12 days. Vitamin K antagonists were started between day 3 and 7 and continued for up to 6 months. The primary outcome measure was a 30 percent or greater improvement in the Marder Score, as revealed by repeated venography on day 12 (end of the initial treatment). The secondary composite outcome measure included death, recurrent venous thromboembolism and major bleeding and was assessed at day 12 and after 6 months by a blinded adjunction committee. RESULTS: The Marder score improved by 30% or more in 30.3% and 25.0% of patients assigned to LMWH (198 paired venograms) and UFH (192 paired venograms), respectively (2p = 0.26). At the end of the initial treatment, the composite outcome was observed in 4 of the 265 patients (1.5%) randomized to LMWH, as compared with 14 of the 273 patients (5.1%) randomized to UFH (2p = 0.03). At 6 months these figures were 6.8% and 12.8%, respectively (risk reduction 0.53, confidence interval 0.31-0.90, 2p = 0.02). CONCLUSION: Fixed dose subcutaneous LMWH certoparin is at least as efficacious as UFH in resolving proximal vein thrombosis.     

Effects of two dosages of subcutaneous low molecular weight heparin (Parnaparin) and of unfractionated heparin on fibrin formation and lipolysis in acute myocardial infarction.

Although low molecular weight heparins (LMWH) have been extensively investigated for the prophylaxis and treatment of venous thromboembolism in surgical environments, few data in acute myocardial infarction are available in the literature. In this study two dosages of a new LMWH, Parnaparin, and unfractionated heparin (UF) were investigated in 50 pts with acute myocardial infarction. 20 pts received UF (15.000 units, three subcutaneous injections, Group 1), 20 pts received Parnaparin (6.400 units, single injection, Group 2) and 10 pts received a higher dose of Parnaparin (12.800 units, single injection, Group 3). Similar fibrinopeptide A (FpA) levels were observed in Group 1 and Group 2. In Group 3 the dosage of Parnaparin resulted in a significant prolongation of the APTT and in lower FpA levels. Fibrin formation was decreased by Parnaparin in a concentration-dependent way, according to both the anti-Xa activity and the APTT ratio. Parnaparin did not result in a significant increase in free fatty acid concentration, in comparison with UF. Thus, Parnaparin may offer the advantage of a single subcutaneous injection in patients with acute myocardial infarction.     

Low-dose heparin in thoracic surgery: Effect on blood coagulation and fibrinolysis system

Plasma kallikrein, antithrombin III and antiplasmin were determined with chromogenic methods in 29 patients pre-, per-and post-operativety in a controlled, randomized study. 16 patients received calcium heparin, 5000 IU s.c. every 8 hr for 7 days, the first administration given 2 hr before surgical procedure. 13 control patients received saline. A significant reduction of kallikrein and antiplasmin in per-and post-operative periods was observed in the control patients compared with the heparin-treated patients, while there was a significant reduction of anti-thrombin III in the control patients compared with the treated patients only in the per-operative period. The results obtained suggest that activation of the coagulation and fibrinolysis system occurs in patients undergoing thoracic surgery, and that it is inhibited significantly by calcium heparin prophylaxis.     

血栓通联合阿司匹林对急性脑梗死患者凝血纤溶功能及血清神经递质的影响

目的探讨血栓通联合阿司匹林对急性脑梗死患者凝血纤溶功能及血清神经递质的影响。方法将92例急性脑梗死患者随机分为联合用药组和对照组,每组46例。对照组给予阿司匹林(0. 1 g/d)口服治疗,联合用药组给予血栓通(450 mg/d)联合阿司匹林治疗。比较两组患者治疗前后临床疗效、凝血纤溶功能、血清神经递质水平。结果与治疗前比较,联合用药组及对照组治疗后NIHSS评分显著降低(均P <0. 01)。联合用药组及对照组治疗前NIHSS评分差异无统计学意义(P> 0. 05),联合用药组治疗后NIHSS评分显著低于对照组(P <0. 05)。两组间预后差异有统计学意义,联合用药组有效率显著高于对照组(P <0. 05)。与治疗前比较,联合用药组及对照组治疗后血清纤溶酶原激活物(t-PA)水平显著升高,纤溶酶原激活物抑制剂-1(PAI-1)及血小板α颗粒膜蛋白-140(GMP-140)水平显著降低(均P <0. 05)。与对照组比较,联合用药组治疗前t-PA、PAI-1、GMP-140水平差异均无统计学意义(均P> 0. 05);联合用药组治疗后t-PA水平显...     

马来酸桂哌齐特治疗急性脑梗死的疗效分析

目的 探讨马来酸桂哌齐特在辅助治疗急性脑梗死中的应用价值.方法 选择我院2011-03-2013-03收治的急性脑梗死患者80例,按不同治疗方式随机均分为对照组（常规治疗辅以血栓通）和实验组（常规治疗辅以马来酸桂哌齐特）,对2组患者的治疗效果进行比较.结果 实验组总有效率82.5%,明显高于对照组的55.0%（P＜0.05）;实验组治疗14 d后神经功能缺损评分均明显低于对照组（P＜0.05）;2组患者经治疗14 d后的血浆纤维蛋白原水平比较差异有统计学意义（P＜0.05）.结论 马来酸桂哌齐特治疗急性脑梗死效果显著,能明显改善患者神经功能,值得临床推广应用.     

急性脑梗死患者炎症因子、血凝状态的变化

目的 探讨急性脑梗死患者血小板功能、凝血与纤溶功能及炎症因子的变化情况。方法 采用血凝仪和全自动生化分析仪测定106例急性脑梗死患者APTT、FIB、D-二聚体、hs-CRP、IL-6、TNF-α、PAgT等指标水平,并与100名健康者进行对照。结果 急性脑梗死组患者凝血功能中APTT值明显缩短,FIB值和D-二聚体值明显增大,炎症因子中IL-6值、hs-CRP和TNF-α值明显升高,PAgT值增大,与对照组比较均有明显差异(P<0.01)。重度脑梗死组与中度和轻度脑梗死组比较,中度脑梗死组与轻度脑梗死组比较,各项检查值均明显改变(P<0.05)。采用多联指标分析,四项检测指标联合和五联项检测指标联合进行急性脑梗死预测与诊断,其灵敏性(100%,97%)、特异性(98%,100%)、阳性预测值(98%,100%)和阴性预测值(100%,97%)较理想。结论 检测APTT值、FIB值、D-二聚体值、IL-6值、hs-CRP、TNF-α值和PAgT值对急性脑梗死的诊断和预后判断有一定的临床意义。     

Influence of cardiopulmonary reflex on the sympathetic activity during myocardial infarction

The time-course of changes in renal sympathetic nerve activity (RSNA), arterial and cardiopulmonary baroreflexes sensitivities was evaluated in conscious rats eight hours (8 h) and ten days (10 day) after myocardial infarction (MI), induced by coronary artery ligation. RSNA was recorded by a platinum electrode implanted in left renal nerve. Arterial and cardiopulmonary baroreflexes sensitivities were evaluated by changes in blood pressure and serotonin administration, respectively. Both 8 h and 10 day groups presented hypotension (103+/-4 vs. 102+/-2 vs. 115+/-4 mm Hg), but only 8 h showed tachycardia (422+/-22 vs. 378+/-11 vs. 384+/-9 bpm) when compared to Control rats. RSNA was depressed 8 h after MI and increased in 10 day group (12+/-2 vs. 39+/-8 vs. 22+/-2 mV/cycle). Although arterial baroreflex control of heart rate was similar in all groups, the arterial baroreflex control of RSNA in 8 h group was impaired during reductions (-0.35+/-0.10 vs. -1.66+/-0.23 vs. -0.09+/-0.14 mV/cycle/mm Hg) or increases (-0.77+/-0.17 vs. -1.63+/-0.58 vs. -1.66+/-0.17 mV/cycle/mm Hg) in blood pressure when compared to Control animals. Moreover, cardiopulmonary baroreflex bradycardic response was increased in 8 h rats and normalized in 10 day group. The results suggest that the increased cardiopulmonary baroreflex sensitivity in 8 h may contribute to the reduction in the tonic level of RSNA as well as in the impairment of the baroreflex control of RSNA in the presence of hypotension.     

肝素缓释支架置入联合心肌钻孔对急性心肌梗死猪心肌细胞再生的影响

背景：课题组前期发明了一种新的心肌再血管化的方法,即肝素缓释支架置入联合心肌钻孔,可明显改善心肌灌注。 目的：观察肝素缓释支架置入联合心肌钻孔在猪急性心肌梗死后心肌细胞再生中的作用。 方法：通过结扎冠状动脉前降支制作猪急性心肌梗死模型,随机分为模型对照组、支架置入组,6只/组。支架置入组于心肌梗死区采用自制高速钻孔器由心外膜打2个直径为3.5 mm透壁孔道,每个孔道内置入1枚肝素缓释支架。置入后静脉注射BrdU用以标记DNA复制。观察治疗前后基质细胞衍生因子1 mRNA表达及心肌灌注、新生心肌、心功能等变化。 结果与结论：与模型对照组比较,置入6周后支架置入组基质细胞衍生因子1的表达明显增强(P < 0.001),灌注质量缺损百分率的差值明显降低(P < 0.001),左室射血分数明显提高(P < 0.05),新生心肌明显增加(P < 0.001),缺血区存活心肌明显增多(P < 0.001)。证实心肌钻孔与肝素缓释支架置入可以通过提高基质细胞衍生因子1表达和增加缺血区灌注,增强心肌梗死区损伤心肌细胞的修复,改善心功能。 关键词：心肌梗死;心肌细胞;再生;支架;肝素;生物材料 doi:10.3969/j.issn.1673-8225.2010.03.014     

Effects of G-CSF on systemic inflammation, coagulation and platelet activation in patients with acute myocardial infarction

Introduction

In the prospective, randomised, double-blind, placebo-controlled Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL)-2 trial patients with acute myocardial infarction (AMI) and successful mechanical reperfusion received granulocyte-colony stimulating factor (G-CSF, 10 μg/kg KG s.c.) or placebo for 5 days. Aim of this substudy was to assess the impact of G-CSF on systemic inflammatory and procoagulant responses and platelet activation.

Methods and Results

Before and five days after G-CSF (n = 56) or placebo (n = 58) circulating cytokine concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12 and Tumor-Necrosis Factor-α (TNF-α? were measured. Prothrombin fragment F1 + 2 and Tissue Factor activity served as a measure for activated coagulation. Platelet activation was characterized by cell surface expression of the activated fibrinogen receptor (PAC-1), P-selectin and CD40L by flow cytometry. Administration of G-CSF was associated with elevated TNF-α and CRP?concentrations compared to the placebo group after 5 days. Other cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12) were comparable after treatment with G-SCF or placebo. Similarly, circulating prothrombin fragments F1 + 2, TF activity and platelet activation did not differ in both groups.

Conclusion

Treatment with G-CSF in patients with AMI was associated with enhanced proinflammatory TNF-α and CRP levels but no activation of coagulation.     

Improved fibrinolysis after one year of treatment with enalapril in men and women with uncomplicated myocardial infarction

AIMS: To study long-term effects of enalapril on mass concentrations of tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), tPA/PAI-1-complex and von Willebrand factor (vWF) in both genders with uncomplicated myocardial infarction. METHODS AND RESULTS: More than three months after an uncomplicated myocardial infarction 82 survivors (46 males, 36 females) were randomised to enalapril/placebo. PAI-1, tPA, tPA/PAI-1-complex and vWF were measured after two weeks, six and 12 months following randomisation. PAI-1 decreased significantly in both genders in the enalapril-treated group after two weeks, with a maximum decrease at six months (mean reduction: 31% equal to 9.8 microg x L(-1), CI: 5.2 to 14.5 microg x L(-1), p = 0.0001) and remained significantly lower at 12 months. Mass concentration of tPA decreased significantly (mean reduction: 1.81 microg x L(-1), CI: 0.903 to 2.708 microg x L(-1), p < 0.001) after two weeks treatment in both genders but returned to baseline values at 12 months. The tPA/PAI-1-complex decreased and was significantly lower (mean reduction 0.96 microg x L(-1), CI: 0.36 to 1.56 microg x L(-1), p = 0.003) in the enalapril group after two weeks and six months (p = 0.037). No decrease of vWF was seen in the enalapril group. CONCLUSIONS: Enalapril treatment up to one year depressed mass concentrations of PAI-1 and transiently tPA and tPA/PAI-1 complex indicating an improvement of the fibrinolytic balance in both genders with uncomplicated myocardial infarction.     

Rufinamide as an adjuvant treatment in children with Lennox-Gastaut syndrome

PurposeTo evaluate the efficacy of rufinamide as an add-on treatment in children and adolescents with Lennox-Gastaut syndrome (LGS).MethodsThe study was an open-label, observational clinical trial of rufinamide as an add-on treatment in intractable LGS patients. This intent-to-treat trial included 4 weeks of scheduled titrated doses and a 12-week maintenance phase with a target dose of 20–40 mg/kg rufinamide, adjusted according to its effectiveness and tolerability after a baseline period of 4 weeks. The primary outcome was measured by the seizure-reduction rate according to individual seizure type over the 12-week maintenance period.ResultsOne hundred and twenty-eight patients with LGS who were determined to be unresponsive to one or more antiepileptic drugs or dietary therapy were enrolled. Of the 128 patients enrolled, 112 (87.5%) completed the study. After add-on rufinamide treatment, 46 patients (35.9%) achieved a more than 50% reduction in seizure frequency and 10 (7.8%) patients became seizure-free. When we identified those who responded with an at least 50% reduction in seizure frequency, 39.4% of the responders reported reductions in convulsive seizures, 36.4% in drop attacks, 33.3% in myoclonic seizures, and 20.0% in epileptic spasms. Overall, 32.8% of patients reported adverse effects, which were mostly mild and transient in nature. The most common adverse effects were fatigue (15 patients, 11.7%) and poor appetite (9 patients, 7.0%). Twenty-one (16.4%) patients experienced an increased seizure frequency.ConclusionsRufinamide appears to be a safe and effective adjuvant treatment for many cases of intractable LGS.     

L-Asparaginase and the effect of age on coagulation and fibrinolysis in childhood acute lymphoblastic leukemia

Alterations in haemostasis are frequently observed in children with acute lymphoblastic leukemia (ALL). It was the objective of this study to analyse age-related disturbances in coagulation and fibrinolysis parameters during the induction phase of the antileukemic treatment. Sixty-four children were classified by age into three groups (1-5, 6-10, 11-16 years), and studied during induction treatment of ALL including four weeks of dexamethasone, followed by two weeks tapering of dexamethasone during which 6,000 IU/m(2) native L-Asparaginase (total 4 doses) was administered intravenously twice weekly. Blood samples were collected immediately before each L-Asparaginase infusion to analyze procoagulant (fibrinogen, factor [F] II, FV, FVII, F IX, F X) and anticoagulant factors (antithrombin [AT], protein C, protein S), parameters of thrombin generation (F1+2, TAT) and fibrinolysis (alpha2-antiplasmin, plasminogen, PAP, D-dimer). Children were in a hypercoagulable state after four weeks of dexamethasone due to upregulation of coagulation parameters. Upregulation was highest in the two youngest age groups. During L-Asparaginase treatment the 11- to 16-year-olds showed lower values in procoagulant and, even more, in anticoagulant factor levels compared to the younger children. Activation markers of thrombin generation and fibrinolysis did not change over time during the study period. Decreased synthesis of alpha2-antiplasmin and plasminogen during L-Asparaginase treatment resulted in less potential of clot lysis by plasmin in children older than 11 years of age. In conclusion, a more severe decline of anticoagulant and fibrinolytic parameters in children between 11 and 16 years of age underline that these children are at higher risk of thrombosis during ALL induction treatment.     

Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases

Acute inflammatory and chronic interstitial lung diseases are characterized by excessive and persistent fibrin deposition in the lung. Intraalveolar fibrin accumulation, observed under these conditions, arises from a leakage of plasma proteins (including fibrinogen) into the alveolar space in combination with a disbalance of alveolar haemostasis. Tissue factor in association with factor VIIa and inhibition of urokinase by plasminogen activator inhibitor-1 are major factors that are responsible for the procoagulant and antifibrinolytic state. In addition, in acute respiratory distress syndrome (ARDS) patients, factor VII-activating protease and extracellular RNA, which may be released into the extracellular milieu from damaged cells during lung injury, may contribute to fibrin formation as well. Fibrin itself can increase vascular permeability, influence the expression of inflammatory mediators and alter the migration and proliferation of various cell types. Additionally, fibrin may inactivate pulmonary surfactant and provide a matrix on which fibroblasts can migrate and produce collagen. Furthermore, cellular activities of haemostatic proteases may also contribute to proinflammatory and fibrotic processes in the lung. The application of coagulation inhibitors, like tissue factor pathway inhibitor, active site-inactivated factor VIIa, activated protein C, antithrombin, heparin or hirudin turned out to be beneficial in experimental models of acute and chronic lung injury. However, the ability of anticoagulant and profibrinolytic agents to improve clinical outcome remains to be elucidated. In the current article, the role of the alveolar coagulation and fibrinolysis systems in acute inflammatory and chronic interstitial lung diseases is discussed with regard to pathomechanisms and modalities of intervention.