A quest for the relief of atherosclerosis: potential role of intrapulmonary heparin--a hypothesis.

Recent progress in the treatment of coronary artery disease is reviewed from the standpoint of changes in lifestyle, surgical techniques to revascularize the myocardium and a variety of medical interventions. Among the medical modalities, heparin appears to have a greater potential than any other agent tested to neutralize the atherogenic process at most of its stages. This potential is supported by success in clinical trials of heparin administered by intravenous, subcutaneous, pulmonary, sublingual and topical routes. The suggested self-administration of low-dose heparin by inhalation appears to be well justified and easily adaptable to home therapy. The summarized evidence suggests the need for further clinical trials to test the use of heparin in the prophylaxis of atherosclerotic disease.     

Prevention of venous thromboembolism in the cancer surgery patient

Cancer patients, especially those undergoing surgery for cancer, are at extremely high risk for developing venous thromboembolism (VTE), even with appropriate thromboprophylaxis. Anticoagulant prophylaxis in cancer surgery patients has reduced the incidence of VTE events by approximately one-half in placebo-controlled trials, and extended prophylaxis (for up to 1 month) has also significantly reduced out-of-hospital VTE events in clinical trials in this population. Clinical trials show no difference between low-molecular-weight heparin (LMWH) and unfractionated heparin in VTE prophylaxis efficacy or bleeding risk in this population, although the incidence of heparin-induced thrombocytopenia is lower with LMWH. The risk-benefit profile of low-dose anticoagulant prophylaxis appears to be favorable even in many cancer patients undergoing neurosurgery, for whom pharmacologic VTE prophylaxis has been controversial because of bleeding risks.     

Differentiation of parenteral anticoagulants in the prevention and treatment of venous thromboembolism

Background

The prevention of venous thromboembolism has been identified as a leading priority in hospital safety. Recommended parenteral anticoagulant agents with different indications for the prevention and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and fondaparinux. Prescribing decisions in venous thromboembolism management may seem complex due to the large range of clinical indications and patient types, and the range of anticoagulants available.

Methods

MEDLINE and EMBASE databases were searched to identify relevant original articles.

Results

Low-molecular-weight heparins have nearly replaced unfractionated heparin as the gold standard antithrombotic agent. Low-molecular-weight heparins currently available in the US are enoxaparin, dalteparin, and tinzaparin. Each low-molecular-weight heparin is a distinct pharmacological entity with different licensed indications and available clinical evidence. Enoxaparin is the only low-molecular-weight heparin that is licensed for both venous thromboembolism prophylaxis and treatment. Enoxaparin also has the largest body of clinical evidence supporting its use across the spectrum of venous thromboembolism management and has been used as the reference standard comparator anticoagulant in trials of new anticoagulants. As well as novel oral anticoagulant agents, biosimilar and/or generic low-molecular-weight heparins are now commercially available. Despite similar anticoagulant properties, studies report differences between the branded and biosimilar and/or generic agents and further clinical studies are required to support the use of biosimilar low-molecular-weight heparins. The newer parenteral anticoagulant, fondaparinux, is now also licensed for venous thromboembolism prophylaxis in surgical patients and the treatment of acute deep-vein thrombosis; clinical experience with this anticoagulant is expanding.

Conclusions

Parenteral anticoagulants should be prescribed in accordance with recommended dose regimens for each clinical indication, based on the available clinical evidence for each agent to assure optimal safety and efficacy.     

Crosslinking of dialdehyde heparin: a new strategy for improving the anticoagulant properties of porcine acellular dermal matrix

The anticoagulant properties of valve materials are essential to maintain blood patency after artificial valve implantation. Porcine acellular dermal matrix (pADM) has low immunogenicity, good biocompatibility, and can reduce calcification by eliminating heterogeneous cells. However, its main component is collagen, which has strong coagulation function and poor anticoagulant activity. When used in heart valve materials, it can easily coagulate and form a life-threatening thrombus. Therefore, it is necessary to improve its anticoagulant performance. The glutaraldehyde (GA) cross-linked valves widely used clinically are easy to calcify with poor anticoagulant performance and cytotoxicity. In this study, dialdehyde heparin containing cross-linking active aldehyde groups was prepared by sodium periodate oxidation, then it was used for crosslinking with pADM to chemically modify its anticoagulant performance. Compared with GA cross-linked pADM (GA-pA), dialdehyde heparin cross-linked pADM (OL-pA) has better thermal stability and biocompatibility, especially its anticoagulant and antiplatelet adhesion were significantly improved, which can reduce the incidence of coagulation, thrombocytopenia and bleeding. In summary, dialdehyde heparin is expected to be applied to modify the anticoagulant properties of pADM and has great potential for the preparation and clinical application of anticoagulant materials such as heart valves and artificial blood vessels.

Dialdehyde heparin containing cross-linking active aldehyde groups was prepared by sodium periodate oxidation. It was used as a cross-linking agent and the anticoagulant performance of modified porcine acellular dermal matrix was much improved.     

Recent advances in search of oral heparin therapeutics

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are first choices of clinicians among available anticoagulants. Currently, these agents are administered either parenterally or subcutaneously, which reduces patient compliance and acceptability. Oral heparin may serve as an alternative to both parenteral heparin as well as presently available oral anticoagulants such as warfarin. This review focuses mainly upon recent perspectives in the development of heparin as an oral anticoagulant. The possibility of its success with special emphasis to nanotechnological approaches has been elaborated. Important strategies such as the use of penetration enhancers, the development of lipid conjugates of heparin, and the incorporation of heparin in polymeric matrix systems have been discussed. Additionally, introductory information on biological activities, physiochemical aspects, and pharmacokinetic and pharmacodynamic parameters of heparin is summarized. A brief comparison of UFH and LMWH is also included for reader's benefit. Informative discussion on clinical trials with the successes and limitations of oral heparin formulations is also presented. Overall, the present review provides complete insight to the research that has been carried out for the development of heparin as oral anticoagulant.     

Heparin mimetics with anticoagulant activity

Heparin, a sulfated polysaccharide belonging to the glycosaminoglycan family, has been widely used as an anticoagulant drug for decades and remains the most commonly used parenteral anticoagulant in adults and children. However, heparin has important clinical limitations and is derived from animal sources which pose significant safety and supply problems. The ever growing shortage of the raw material for heparin manufacturing may become a very significant issue in the future. These global limitations have prompted much research, especially following the recent well‐publicized contamination scandal, into the development of alternative anticoagulants derived from non‐animal and/or totally synthetic sources that mimic the structural features and properties of heparin. Such compounds, termed heparin mimetics, are also needed as anticoagulant materials for use in biomedical applications (e.g., stents, grafts, implants etc.). This review encompasses the development of heparin mimetics of various structural classes, including synthetic polymers and non‐carbohydrate small molecules as well as sulfated oligo‐ and polysaccharides, and fondaparinux derivatives and conjugates, with a focus on developments in the past 10 years.     

Clinical applications of bivalirudin in the cardiac catheterization laboratory

Heparin has been used in the catheterization laboratory to prevent ischemic complications of percutaneous coronary intervention (PCI). Bivalirudin, a direct thrombin inhibitor, is an anticoagulant that has several pharmacologic advantages over heparin, and it has been proposed that bivalirudin is superior to heparin in its ability to prevent bleeding complications of PCI. As such, there have been a variety of large prospective clinical trials comparing bivalirudin and heparin over the past 13 years. The results of these trials have prompted the general acceptance of bivalirudin as a safe alternative to heparin use during PCI, and bivalirudin has been given a class 1 recommendation by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for a variety of clinical indications. This article will review the data supporting the use of bivalirudin in the cardiac catheterization laboratory and describe several advantages of bivalirudin over traditional heparin use. We also include a discussion of the use of bivalirudin in conjunction with other medications that are frequently used in the catheterization laboratory. We end with an analysis of the economic differences between bivalirudin and heparin and the impact that financial factors may have on the choice of anticoagulant.     

From heparin to heparins: toward new therapeutic perspectives?

Heparin is mainly known for its anticoagulant action, but today other biological effects are investigated. With the low molecular weight heparin fractions (LMWH), more homogenous, a more detailed study of the mechanism of action of heparins can be made. The anticoagulant action of heparin is mainly antithrombin III (AT III) dependent and the binding site of AT III on the heparin molecule has been recently identified. LMWH have a lower anticoagulant (anti-IIa) activity, and a relatively higher anti-Xa activity (ratio anti-Xa/anti-IIa = 5 to 10 for LMWH and 1 for standard heparin). The antithrombotic action of heparins is not strictly correlated to their anticoagulant activity. Other mechanisms of action, such as interactions with vascular endothelial cells and the fibrinolytic system may contribute to the antithrombotic action of heparins. New therapeutical possibilities are currently under investigation. Inhibition of vascular smooth muscle cells growth by heparin suggest a possible control of the atherosclerotic process by heparin. Moreover, heparin and its derivatives might be involved in the regulation of the cellular growth process.     

Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial

BACKGROUND: Soluble thrombomodulin is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. OBJECTIVES: We conducted a multicenter, double-blind, randomized, parallel-group trial to compare the efficacy and safety of recombinant human soluble thrombomodulin (ART-123) to those of low-dose heparin for the treatment of disseminated intravascular coagulation (DIC) associated with hematologic malignancy or infection. METHODS: DIC patients (n = 234) were assigned to receive ART-123 (0.06 mg kg(-1) for 30 min, once daily) or heparin sodium (8 U kg(-1) h(-1) for 24 h) for 6 days, using a double-dummy method. The primary efficacy endpoint was DIC resolution rate. The secondary endpoints included clinical course of bleeding symptoms and mortality rate at 28 days. RESULTS: DIC was resolved in 66.1% of the ART-123 group, as compared with 49.9% of the heparin group [difference 16.2%; 95% confidence interval (CI) 3.3-29.1]. Patients in the ART-123 group also showed more marked improvement in clinical course of bleeding symptoms (P = 0.0271). The incidence of bleeding-related adverse events up to 7 days after the start of infusion was lower in the ART-123 group than in the heparin group (43.1% vs. 56.5%, P = 0.0487). CONCLUSIONS: When compared with heparin therapy, ART-123 therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients.     

Therapeutic Concentrations of Heparin Augment Platelet Activation at the Time of Coronary Angiography

Background: Besides its anticoagulant effects, heparin is known to alter platelet (PLT) function. We examined the effects of unfractionated heparin on PLT function in patients with stable coronary artery disease (CAD). Methods and Results: PLT function was evaluated by whole-blood flow cytometry to detect PLT CD62 expression and by impedance aggregometry to assess the platelet aggregation (PA) before and after bolus intravenous administration of low-dose heparin (2713 +/- 1231 U) in 16 patients undergoing coronary angiography (group 1) and high-dose heparin (7937 +/- 2414 U) in 16 patients undergoing coronary angioplasty (group 2). Activated clotting time (ACT) and plasma antifactor-Xa heparin levels also were measured. Heparin increased PLT CD62 expression, which was significantly more pronounced in group 1 patients with plasma heparin levels less than 0.7 U/mL and ACT of 222 +/- 52 seconds compared with group 2 patients with heparin levels greater than 0.7 U/mL and ACT of 365 +/- 86 seconds (8 +/- 9 v -1 +/- 4% change in resulting PLTs, P =.01, and 11 +/- 12 v 1 +/- 6% increase in adenosine diphosphate (ADP) [5 μM]-stimulated PLTs, P =.02). Heparin produced a slight increase in PA in group 1 patients (1.4 +/- 5.3 ohms) as compared with the group 2 patients, where it significantly suppressed PA (-3.0 +/- 5.3 ohms, P.05 v group 1). A strong and statistically significant negative correlation between change in platelet CD62 expression and heparin concentration was observed in group 1 patients (r = -.5, P =.05, -ADP; r = -.65, P =.006, +ADP), whereas this relationship was weak and did not reach statistical significance in group 2 patients (r = -0.4, P =.2, -ADP; r =.11, P = 0.9; +ADP). Conclusion: Bolus administration of intravenous heparin augmented PLT activation in patients at clinically relevant anticoagulant concentrations (<0.7 U/mL). These findings may have implications for optimal dosing strategy for heparin as an antithrombotic agent in clinical situations characterized by platelet-dependent thrombotic events.     

抗凝剂治疗非抗磷脂综合征妇女复发性流产

目的评价采用抗凝剂(如阿司匹林和肝素)治疗有两次自然流产史或一次近期不明原因(非遗传性血栓形成倾向)宫内胎死妇女的有效性和安全性.方法我们检索了Cochrane妊娠和分娩组临床试验注册库(2004年3月),Cochrane临床对照试验中心注册库(Cochrane图书馆2004年第1期), MEDLINE(1966.1～2004.3)及EMBASE(1980～2004.3). 我们查阅了所有检索到研究的参考文献以避免漏检.纳入对有两次自然流产史或一次近期不明原因(非遗传性血栓形成倾向)宫内胎死妇女,评估抗凝制剂治疗提高活产率效果的随机或半随机临床对照试验.干预措施包括用于预防流产的阿司匹林、未分馏肝素及低分子肝素,与安慰剂比较或互相比较.由两名作者进行文献质量评价和数据提取,数据录入RevMan并交叉核对.结果共纳入两个试验(242例患者)并均对符合评价纳入标准的妇女亚组进行了数据提取.1个试验中,54例抗心肌磷脂抗体阴性的复发性自然流产妊娠妇女随机分入低剂量阿司匹林治疗组和安慰剂组,两组活产率相似[RR=1.00, 95%CI (0.78,1.29)].另一个试验中,一个之前曾有孕20周后流产史的血栓缺陷妇女亚组共20例,随机分入依诺肝素组和阿司匹林组.与低剂量阿司匹林治疗比较,依诺肝素治疗能提高活产率[RR=10.00, 95%CI (1.56,64.20)].结论现有关于使用阿司匹林和肝素治疗该类妇女流产的有效性和安全性证据不足,现有条件下不推荐使用抗凝剂治疗.急需进行大样本安慰剂对照的随机试验.     

Study on anti-metastasis of heparin derivatives as ligand antagonist of p-selectin

Heparin has a potential value as therapeutic agents that block P-selectin-mediated cell adhesion and prevent tumor metastasis. However, the strong anticoagulant potency limits its applicability for the anti-metastasis activity. Carboxyl and sulfate groups of heparin are closely related to its anticoagulant activity, so seven kinds of heparin derivatives related to carboxyl and sulfate groups were prepared, and their effects on anti-metastasis as ligand antagonist of p-selectin were studied. The results showed that heparin, carboxyl reduction heparin, 2-O-desulfated heparin and N-desulfated- N-acetylated heparin could inhibit the adhesion of tumor cells to endothelial cells and platelets effectively as ligand antagonist of P-selectin.     

Anticoagulation in CRRT: agents and strategies in Australian ICUs.

BACKGROUND: Continuous Renal Replacement Therapy (CRRT) should ideally operate with as little interruption as possible. The majority of circuit terminations occur due to clotting. The Longevity of CRRT is able to be improved when the extracorporeal circuit is anticoagulated. AIMS: This article willt focus attention on anticoagulant agents used in Australian intensive care units (ICU) to prevent clotting in the CRRT circuit. DISCUSSION: Anticoagulants reviewed include unfractionated or standard heparin, regional heparinisation, low-molecular weight heparins and heparinoids, regional citrate, platelet-inhibiting agents (prostacyclin), thrombin antagonists (recombinant hirudin) and therapy with no anticoagulant use. Each type of anticoagulant was reviewed for mode of action, the method of delivery and how the effect is monitored. Circuit life and the incidence of bleeding were considered as the principle end points in selecting therapy, as well as side-effects with administration such as metabolic disturbances, contraindications to use including allergy and ease of use in the clinical environment. CONCLUSION: No approach to anticoagulation has yet been reported to be as successful in extending circuit life, whilst remaining inexpensive, easy to manage and easy to reverse, as unfractionated heparin. Certain patient conditions may preclude the use of heparin, such as heparin-induced thrombocytopenia (HIT); then heparinoids, thrombin antagonists and sodium citrate are suggested as alternatives. Regional citrate reduces haemorrhagic complications in patients who have coagulation disorders or are at risk of bleeding. Clinical experience with various agents and strategies should also influence choice. The option of no anticoagulant may be appropriate in selected patients rather than more expensive and less familiar drugs.     

Monitoring of anticoagulant therapy in cancer patients with thrombosis and the usefulness of blood activation markers

Thrombotic diseases caused by cancer progression have been reported as one of the major causes of cancer associated morbidity and mortality along with cancer invasiveness and infectious complications. Moreover, anticoagulant therapy with heparin and heparin-like drugs, or vitamin K antagonists, or the Direct Oral Anticoagulants, is seeing an extended application in cancer patients and offers prolonged life expectancy to oncology patients for whom blood activation and thrombotic events have a variable incidence, depending on cancer type. Laboratory tools are highly useful for identifying patients at thrombotic risk through the measurement of blood activation markers and selecting those appropriate for anticoagulant therapy. Among the pathological markers, DDimer or Extracellular Vesicles have the highest diagnostic value in these pathological conditions. Global assays are useful for dosage adjustment, such as assessing either an induced anticoagulant effect or the measurement of drug activity. Various assays are also developed such as platelet aggregometry techniques for evaluating drug induced- aggregates or methods allowing measurement of the drug activity to its targeted coagulation factors such as: heparin to thrombin or Factor Xa; DOACs to Thrombin or Factor Xa (Dabigatran to thrombin and DiXaIs, Rivaroxaban, Apixaban, and Edoxaban, to Factor Xa). Such explorative techniques help to find the right dosage adjustment to protect patients from developing thrombosis without exposing them bleeding. It also permits exploration of unexpected drug behavior in treated patients, to check the right adherence to therapy in long-term anticoagulant protocols, and prevention of bleeding in patients with impaired renal or hepatic function. Complementary use of blood activation markers brings additional information on the curative effects of the anticoagulant therapy, and allows identification of pro-thrombotic activity in the clinically silent state. These issues are concisely addressed below.     

Lepirudin for therapeutic use in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) type II is an antibody mediated severe adverse event to heparin with a paradoxical decrease of platelet count and an increased risk for thromboembolic complications. The antibodies are directed against a neoepitop of platelet factor 4 after its binding to heparin. The incidence of HIT type II is lower with low-molecular-weight heparin compared to unfractionated heparin and lower in not operated patients compared to those after major surgery. In patients with HIT type II alternative anticoagulation has to be performed immediately due to the high thrombogenicity of the antibodies. The recombinant hirudin lepirudin (Refludan) is the anticoagulant drug of choice. A long-term anticoagulation has to be performed depending on the concomitant risk factors, intravenous administration followed by subcutaneous lepirudin overlapping with vitamin K antagonists.     

Anticoagulation with prostaglandins during extracorporeal circulation

This paper reviews pathophysiological processes occurring after contact of blood with artificial surfaces and the predominant role of platelets in the genesis of extracorporeal thrombosis. Bleeding complications are common during conventional heparin anticoagulation, and both clinical and experimental evidence suggests that the efficacy of heparin as an anticoagulant is compromised by its relative ineffectiveness towards platelets. Consequently, drugs that inhibit interaction between platelets and artificial membranes have been introduced as an alternative anticoagulant strategy. This paper reviews studies on the use of short-acting antiplatelet prostaglandins such as prostacyclin and prostaglandin E1 alone or in combination with heparin during various forms of extracorporeal circulation such as cardiopulmonary bypass, haemodialysis, continuous haemofiltration, membrane oxygenation, ventricular assist devices, and haemoperfusion. Temporary paralysis of platelet function with antiplatelet prostaglandins has been effective in controlling platelet-surface interaction and reducing bleeding complications and morbidity during and after extracorporeal circulation. By inhibiting the formation of fibrin, leukocyte and platelet-based microaggregates and cytoprotective actions, prostaglandins have been shown to prevent renal, neurologic, and pulmonary dysfunction after extracorporeal circulation. Prostaglandins were most effective in increasing the biocompatibility of extracorporeal systems when they were administered as a supplement to but not as a substitute for heparin. The use of prostaglandins alone should be reserved for patients who are resistant to heparin or heparin-induced thrombocytopenia.     

两种不同抗凝药物在组合型人工肾治疗中的对照

背景：组合型人工肾可以全面清除尿毒症患者体内的各种毒素,预防和治疗透析长期并发症,但透析器和/灌流器凝血是困扰医生和患者的一大问题。目的：观察两种不同抗凝方案在组合型人工肾（血液灌流＋血液透析）治疗慢性肾衰竭患者中的抗凝效果及安全性。方法：分别应用肝素钠和低分子肝素钠对35例行组合型人工肾治疗的慢性肾衰竭患者按原抗凝方案的1.5~2.0倍进行抗凝各4周,观察并比较两种不同抗凝药物的抗凝效果及出血情况,对比治疗前、治疗4周、治疗8周的凝血酶原时间、活化部分促凝血酶原激酶时间、凝血酶时间、血小板及血红蛋白的变化。结果与结论：应用肝素时发生滤器及灌流器凝血1级2例、2级1例,应用低分子肝素时发生滤器及灌流器凝血1级3例、2级2例,两组均未发生3级滤器及灌流器凝血;应用肝素时出现出血1级12例、2级3例,应用低分子肝素时出现出血1级2例、2级1例;应用肝素后血小板减少,活化部分促凝血酶原时间延长,与治疗前比差异有显著性意义;应用低分子肝素后各检验指标变化不大,差异均无显著性意义（P〉0.05）。结果显示慢性肾衰竭患者行组合型人工肾治疗时,低分子肝素和肝素抗凝效果接近,低分子肝素出血并发症少。     

抗Ⅹa活性检测在抗凝治疗中的临床应用现状与前景

随着检测技术的进步,临床中各种疾病伴随血栓的检出率越来越高.普通肝素和低分子量肝素是目前临床应用较多的注射用抗凝剂,其中普通肝素的半衰期短、无肾毒性、有拮抗剂;低分子量肝素半衰期较长,需在一些特殊人群如儿童、孕妇、老人中进行监测.口服抗凝剂中,除华法林等传统药物外,靶向活化凝血因子Ⅹa的抗凝药物如利伐沙班亦越来越多地应...     

白树花多糖硫酸酯的抗凝血活性研究

目的研究白树花多糖硫酸酯的抗凝血效果及抗凝血机理,为制备合成高效、安全的多糖硫酸酯抗凝剂提供实验依据。方法将可食用的白树花真菌进行发酵,提取水溶性多糖,采用氯磺酸-吡啶法进行硫酸酯化修饰,获得水溶性的白树花多糖硫酸酯。通过测定APTT、TT、凝血因子活性对白树花硫酸酯的抗凝血效果及抗凝血机理进行评估和探讨。结果对正常人血浆进行的抗凝血实验表明,白树花多糖硫酸酯具有明显的抗凝血活性,在5 mg/L的浓度下即可发挥效果,在10 mg/L浓度时,相当于150 U肝素的抗凝血效果;抗凝血机理研究结果表明,白树花多糖硫酸酯作用于内源凝血系统,主要通过抗凝血酶Ⅲ抑制凝血因子Ⅱa和Xa的活性发挥抗凝血作用,抗凝血机理与肝素完全相同。结论通过上述研究结果,我们认为白树花多糖硫酸酯具备肝素的抗凝血特性。同时由于是可食用真菌多糖的制备产物,在防生物污染方面具备一定优势。因此,白树花多糖硫酸酯可作为理想的肝素替代品进行开发及临床应用。     

两种不同抗凝药物在组合型人工肾治疗中的对照

背景:组合型人工肾可以全面清除尿毒症患者体内的各种毒素,预防和治疗透析长期并发症,但透析器和/灌流器凝血是困扰医生和患者的一大问题.目的:观察两种不同抗凝方案在组合型人工肾(血液灌流+血液透析)治疗慢性肾衰竭患者中的抗凝效果及安全性.方法:分别应用肝素钠和低分子肝素钠对35例行组合型人工肾治疗的慢性肾衰竭患者按原抗凝方案的1.5~2.0倍进行抗凝各4周,观察并比较两种不同抗凝药物的抗凝效果及出血情况,对比治疗前、治疗4周、治疗8周的凝血酶原时间、活化部分促凝血酶原激酶时间、凝血酶时间、血小板及血红蛋白的变化.结果与结论:应用肝素时发生滤器及灌流器凝血1级2例、2级1例,应用低分子肝素时发生滤器及灌流器凝血1级3例、2级2例,两组均未发生3级滤器及灌流器凝血;应用肝素时出现出血1级12例、2级3例,应用低分子肝素时出现出血1级2例、2级1例;应用肝素后血小板减少,活化部分促凝血酶原时间延长,与治疗前比差异有显著性意义;应用低分子肝素后各检验指标变化不大,差异均无显著性意义(P > 0.05).结果显示慢性肾衰竭患者行组合型人工肾治疗时,低分子肝素和肝素抗凝效果接近,低分子肝素出血并发症少.