关于心房颤动抗凝治疗中的几个问题

心房颤动 (房颤 )是临床最常见的持续性快速心律失常 ,房颤对患者的最主要危害是增加缺血性脑卒中的发生 ,其发生率是非房颤患者的 5倍。国外大规模的临床试验显示 ,华法林抗凝治疗使房颤患者脑卒中的发生率下降 68% ,总死亡率下降33%。因此房颤患者抗凝治疗的重要性已逐渐引起临床医师的重视 ,现就抗凝治疗中存在的几个问题进行讨论如下 :1　如何选择合适的药物预防缺血性脑卒中 ?华法林抗凝治疗能有效预防房颤患者发生缺血性脑卒中 ,阿司匹林也有预防缺血性脑卒中的作用 ,但效果不如华法林。阿司匹林抗凝作用主要针对动脉粥样硬化性脑血栓…     

华法林抗凝治疗的中国专家共识

 血栓栓塞性疾病的长期抗凝治疗一直是临床中的重要问题。尽管新型抗凝药物研发取得了重要的进展,并已经或即将上市,但是华法林作为最古老的口服抗凝药物仍然是需要长期抗凝治疗患者的最常用药物,包括静脉血栓栓塞性疾病（VTE）的一级和二级预防、心房颤动（房颤）血栓栓塞的预防、瓣膜病、人工瓣膜置换术和心腔内血栓形成等^［1］。华法林在上述领域积累了大量的临床证据,目前全球有数百万患者在使用华法林。非瓣膜病房颤研究荟萃分析显示^［2］,华法林可使卒中的相对危险度降低64%,全因死亡率显著降低26%。但是,华法林在中国的使用率非常低,在房颤患者中不超过10%^［3］。导致华法林在临床中治疗率较低的原因包括：治疗窗窄、剂量变异性大、与其他药物及食物相互作用、需要实验室监测等。但是,更重要的原因是临床医生往往高估了华法林的出血危险,而对华法林抗凝作用的重要性认识不足。由于特殊的药理特性使得华法林的使用具有很多特殊性。国内临床医生对于如何应用华法林存在很多顾虑和误区,例如,如何选择适应证、平衡获益和风险、剂量的选择与调整、国际标准化比值（INR）异常升高的处理、如何处理与抗血小板药联合使用以及围手术期的处理等实际问题。为此,中华医学会心血管病学分会与中国老年学学会心脑血管病专业委员会组织制订了本共识,以推广和规范华法林的使用,降低血栓栓塞性疾病的致死率和致残率。     

基因多态性对指导华法林应用的研究进展

心房颤动是一种严重威胁人类健康的疾病,心房颤动致残或致死的主要并发症是缺血性卒中。抗凝治疗在心房颤动的卒中预防中起关键作用,近年来多种口服抗凝药物被批准用于心房颤动患者以降低卒中风险。华法林是常用的经典抗凝药物,价格低廉,可降低血栓栓塞发生率,同时也会增加相应的出血风险,华法林个体化基因检测有望平衡血栓和出血风险,使治疗结果达到最优化。现就华法林个体化基因检测的可行性及临床意义做一综述。     

华法林药物相关基因组学研究进展

临床上血栓栓塞性疾病的长期抗凝治疗是一个重要问题,目前华法林是需要长期抗凝治疗患者的最常用药物,据统计,全球有数百万患者在使用华法林,使卒中的相对危险度降低64%,全因死亡率降低26%。但是,由于华法林治疗窗窄、剂量变异性大、需要实验室频繁监测等原因使其应用率降低,华法林相关的药物基因多态性是引起剂量差异的其中因素之一,如何通过检测华法林的基因多态性来评估个体差异选择和调整合适的剂量,本文就药物华法林主要相关基因CYP2C9(cytochrome P4502C9)和VKORC1(vitamin K epoxide reductase complex 1)的检测指导临床对其合理应用做一综述。     

新型口服抗凝药物利伐沙班在老年稳定性冠心病合并心房颤动患者中的应用价值研究

背景 老年稳定性冠心病合并心房颤动(以下简称房颤)患者逐年增多,对于该类患者需要抗凝治疗,临床中常用的药物为华法林,但华法林用药期间需要长期监测不良反应发生情况,限制了其临床应用.而利伐沙班具有抗凝效果稳定、出血风险小等特点,逐渐得到临床关注.目的 探讨新型口服抗凝药物利伐沙班治疗老年稳定性冠心病合并房颤患者的临床疗效...     

心外科术后患者华法林的应用风险因素分析及护理对策

目的分析心外科术后患者华法林的应用风险因素及护理对策。方法选取2012年1月—2013年6月我院收治的心外科手术患者100例,对其术后服用华法林抗凝过程中可能存在的风险因素进行分析,并提出相应的护理对策。结果对患者术后服用华法林抗凝过程中可能存在的风险因素进行分析,发现受疾病影响68例(68.0%),受药物影响51例(51.0%),受饮食影响43例(43.0%),受个体差异(机体对药物的敏感性差异)影响21例(21.0%),受实验室(采血检测操作不规范)影响4例(4.0%),部分患者同时存在两种或以上的影响因素。结论心外科术后患者华法林的应用风险包括个体差异、饮食、疾病及药物等。加强心理护理、饮食及用药指导、自我监护等护理,可有效降低华法林应用风险,提高抗凝效果及用药安全性。     

新型口服抗凝药预防心房颤动患者的缺血性卒中

新型口服抗凝药包括直接凝血酶抑制剂和因子Xa抑制药,它们克服了华法林的多个缺点,在非瓣膜性心房颤动患者中预防卒中和体循环栓塞的疗效优于或不逊于华法林,且降低了出血(尤其是颅内出血)风险.然而,目前尚无高效逆转其抗凝作用的药物.文章对目前常用的新型口服抗凝药的药理学特点、临床疗效、并发症及其处理等进行了综述.     

短期停用华法林安全吗?

华法林能够阻止心室内、心瓣膜上或未破损的血管内血栓的形成。数以万计的人们服用华法林等抗凝药物来预防血栓引起的中风．肺栓塞或深静脉血栓的形成。     

新型Xa因子抑制剂——依度沙班在心房颤动患者抗凝治疗中的研究进展

心房颤动是最常见的心律失常,也是缺血性卒中的主要危险因素之一。一直以来华法林都是心房颤动患者预防脑卒中和系统性血栓的一线抗凝药,但由于其治疗窗窄、药物及食物之间相互作用,需频繁监测国际标准化比值等不足,限制了其在临床上的应用。新型口服抗凝药如达比加群酯、利伐沙班和阿哌沙班目前均已上市,且广泛用于非瓣膜性心房颤动患者预防脑卒中和系统性血栓的治疗中。依度沙班是最新的用于抗凝治疗的Xa因子抑制剂,实验结果显示,依度沙班在非瓣膜性心房颤动患者预防脑卒中及系统性血栓事件上效果不亚于华法林,总的出血事件及心血管死亡事件发生率更低。现对依度沙班的临床研究及临床应用进展做一综述。     

基层医院非瓣膜病房颤华法林抗凝治疗的临床问题

心房颤动(AF)是导致缺血性脑卒中的主要危险因素,近年来随着AF病因的变化,非瓣膜性AF导致的卒中比例越来越大。华法林预防卒中的效果得到肯定,而临床上以AF的华法林抗凝治疗预防脑卒中的处方率很低或量不足。临床医生要充分认识华法林抗凝治疗的必要性和重要性,自觉提高医生和患者的抗凝意识,严格遵循最新抗凝指南建议,规范抗凝治疗。     

Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy.

Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.     

Vitamin K-dependent Proteins,Warfarin, and Vascular Calcification

Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin''s effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.The most well-known vitamin K-dependent proteins (VKDPs) are the coagulant factors II,VII, IX, and X. Produced by the liver, they are converted into their biologically active forms by the carboxylation of glutamic acid residues, a process requiring vitamin K as a cofactor. By interfering with this carboxylation process, warfarin has become the mainstay of anticoagulant therapy. However, beyond these coagulant factors, there are other VKDPs with widespread physiologic activities. Recent studies have focused on two particularly important VKDPs, Matrix Gla protein (MGP) and Growth Arrest Specific gene 6 (Gas-6) protein. These proteins have many diverse biologic functions, yet with the recognition that they are produced by vascular smooth muscle cells, their roles in vascular biology are being increasingly explored. MGP functions primarily as a vascular calcification inhibitor. Gas-6 affects vascular smooth muscle cell movement and apoptosis. Together, these proteins constitute a new mechanism of local vascular regulation, where the blood vessel defends itself against injury and participates in self-repair. A failure of these local mechanisms might be an important first step in a cascade of events culminating in vascular calcification, and supports the notion that vascular calcification is an active, regulated process.To become biologically active, both MGP and Gas-6 undergo carboxylation, a process that occurs at the blood vessel level. Like hepatic carboxylation, this peripheral carboxylation is inhibited by the administration of warfarin, yet whereas warfarin''s anticoagulant effect is well known, its effect on the vasculature is less certain. Emerging in vitro and whole animal data suggest that warfarin may induce vascular calcification, a potential relationship that has not yet been well studied in humans.Given the widespread use of warfarin, understanding the full spectrum of its biologic effects is important. This article reviews the general physiology of VKDPs and explores a potential relationship between warfarin and vascular calcification in susceptible individuals.     

Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis

PURPOSE: To determine if the natural anticoagulant protein C plays a role in the pathogenesis of systemic calciphylaxis, a syndrome characterized by extensive vascular and soft tissue calcification and skin necrosis, which is similar to that seen in warfarin-induced skin necrosis. PATIENTS AND METHODS: The study population included five patients with end-stage renal disease and systemic calciphylaxis undergoing hemodialysis, 12 patients without evidence of calciphylaxis undergoing dialysis, eight patients with nephrotic syndrome, and eight normal healthy volunteers. Protein C antigen levels were measured by rocket immunoelectrophoresis, and functional activity was quantitated by a chromogenic assay and an anticoagulant assay utilizing the venom of Agkistrodon contortrix. RESULTS: Skin biopsy specimens of involved areas in three patients showed thrombotic occlusion of venules identical to that seen in warfarin-induced skin necrosis. Protein C antigen levels were normal in all groups. However, protein C activity was significantly reduced as measured by chromogenic (p less than 0.01) or anticoagulant assays (p less than 0.01) in patients with calciphylaxis compared with the other three groups. CONCLUSION: These findings suggest that hypercoagulability due to functional protein C deficiency may contribute to thrombosis, resulting in skin necrosis and digital gangrene in systemic calciphylaxis.     

利伐沙班在冠心病二级预防中的应用研究进展

抗血小板治疗在冠心病的二级预防中无可替代。早期的研究显示[1],抗血小板基础上联合华法林治疗虽可进一步降低冠心病患者未来心血管事件,但出血的危险却显著增加。与华法林相比,非维生素K拮抗口服抗凝药物利伐沙班应用安全、方便,为冠心病的抗栓策略提供了新的选择,联合非维生素K拮抗口服抗凝药及抗血小板治疗的抗栓治疗成为冠心病二级预防研究的热点,本文基于对利伐沙班作用机制的新认识,同时聚焦小剂量利伐沙班（2.5mg 每日两次）在冠心病治疗领域的最新研究进行综述。     

Warfarin-associated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud's phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis

Necrosis of the digits is a rare complication of warfarin therapy of obscure pathogenesis. We report a 61-year-old woman with a 12-month history of Raynaud's phenomenon who developed multiple digital necrosis following aortic valve replacement with mechanical prosthesis for aortic insufficiency caused by nonbacterial thrombotic endocarditis. Exacerbation of Raynaud's phenomenon occurred during the postoperative period, with daily episodes of ischemia of the fingers and toes that improved with local warming. However, coincident with the occurrence of immune heparin-induced thrombocytopenia, and while undergoing routine warfarin anticoagulation because of the mechanical valve prosthesis, the patient abruptly developed progression of digital ischemia to multiple digital necrosis on postoperative day 8, at the time the international normalized ratio reached its peak value of 4.3. All limb pulses were readily palpable, and vascular imaging studies showed thrombosis only in the superficial femoral and popliteal veins of the right leg. Coagulation studies showed greatly elevated levels of thrombin-antithrombin complexes and prothrombin fragment F1.2 levels, consistent with uncontrolled thrombin generation. After vitamin K administration, no abnormalities of the protein C anticoagulant pathway were identified, consistent with previous studies of other patients with warfarin-induced necrosis complicating heparin-induced thrombocytopenia. Subsequently, the patient was shown to have metastatic breast adenocarcinoma, which explained the patient's initial presentation with nonbacterial thrombotic endocarditis. This patient case suggests that multiple digital gangrene can result from the interaction of various localizing and systemic factors, including compromised microvascular blood flow (Raynaud's phenomenon), increased thrombin generation (heparin-induced thrombocytopenia, adenocarcinoma), and warfarin-induced failure of the protein C natural anticoagulant pathway.     

华法林引发骨质疏松症的发病机制及治疗策略

骨质疏松症是一种以骨矿物质含量低下、骨微结构损坏、骨强度降低、骨脆性增加、易发生骨折为主要特征的全身性骨代谢障碍性疾病。华法林可拮抗维生素K,使骨钙素的羧化受抑制,减少骨钙沉积,抑制骨矿化,从而干扰骨代谢,导致骨质疏松症或骨折,对于老年患者的影响尤其明显。长期服用华法林导致骨质疏松症的风险可能与用药剂量和时间相关。目前预防和治疗华法林引起的骨质疏松症主要依据原发性骨质疏松症的治疗原则,对于长期服用华法林的患者应补充钙剂和维生素D以预防骨质疏松症,对于已出现骨质疏松症的患者根据具体病情选择用双膦酸盐、降钙素、雌激素和甲状旁腺类似物治疗。本文对华法林引发骨质疏松症的发病机制、研究进展和治疗策略进行综述。     

Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a common, often catastrophic, syndrome that produces the most hypercoagulable of states. Emerging therapeutic strategies use alternative anticoagulants; warfarin's place is being reexamined. Early in the course of warfarin therapy, there may be net procoagulant effects because of the inhibition of protein C. With HIT, it has been suggested that unopposed warfarin can precipitate venous limb gangrene. There are also reports of warfarin-induced skin necrosis. We seek to confirm and increase awareness of the risks of warfarin with HIT. METHODS: We describe 6 patients with HIT seen at 3 medical centers in whom frank or impending venous limb gangrene, central skin necrosis, or both were temporally related to warfarin initiation. RESULTS: At warfarin initiation, 5 patients had recognized HIT and 1 had it recognized later. Complications emerged after 2 to 7 days, and consisted of warfarin-induced skin necrosis (n = 5) and venous limb gangrene (n = 2); 1 patient had both. This emerged with unopposed warfarin in 4 patients and as a direct thrombin inhibitor was being withdrawn in 2. All had supratherapeutic international normalized ratios. One patient required leg and breast amputations, and another one died. CONCLUSIONS: Because of the early effects on protein C, warfarin can precipitate venous limb gangrene and/or skin necrosis in the extreme hypercoagulable milieu of HIT. With HIT, unopposed warfarin should be avoided and caution is needed during transition from a direct thrombin inhibitor. Warfarin should be initiated at modest doses in patients with HIT after platelet recovery. Implications extend to warfarin initiation with other thrombotic diatheses.     

Management dilemmas in patients with mechanical heart valves and warfarin-induced major bleeding

Management of warfarin-induced major bleeding in patients with mechanical heart valves is challenging.There is vast controversy and confusion in the type of treatment required to reverse anticoagulation and stop bleeding as well as the ideal time to restart warfarin therapy safely without recurrence of bleeding and/or thromboembolism.Presently,the treatments available to reverse warfarin-induced bleeding are vitamin K,fresh frozen plasma,prothrombin complex concentrates and recombinant activated factor Ⅶa.Currently,vitamin K and fresh frozen plasma are the recommended treatments in patients with mechanical heart valves and warfarin-induced major bleeding.The safe use of prothrombin complex concentrates and recombinant activated factor Ⅶa in patients with mechanical heart valves is controversial and needs well-designed clinical studies.With regard to restarting anticoagulation in patients with warfarin-induced major bleeding and mechanical heart valves,the safe period varies from 7-14 d after the onset of bleeding for patients with intracranial bleed and 48-72 h for patients with extra-cranial bleed.In this review article,we present relevant literature about these controversies and suggest recommendations for management of patients with warfarin-induced bleeding and a mechanical heart valve.Furthermore,there is an urgent need for separate specific guidelines from major associations/professional societies with regard to mechanical heart valves and warfarin-induced bleeding.     

Oral anticoagulant therapy: efficacy, safety and the low-dose controversy

The issue of optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still unresolved. However, recent data suggest that short (6 weeks to 3 months), intermediate (3- 6 months) or indefinite-term anticoagulant therapy should be adopted on the basis of the classification of patients into low-, intermediate- and high-recurrence-risk groups, respectively. Oral anticoagulants have been shown to effectively prevent cardioembolic stroke in nonvalvular atrial fibrillation. Recent data seem to suggest that their safety can be ameliorated with adequate risk stratification on the basis of clinical and echocardiographic features. After unstable angina and non-Q-wave myocardial infarction, oral anticoagulant therapy (INR range 2-3) combined with aspirin has been shown to be advantageous over aspirin alone, although at the cost of a slight increase in bleeding. Bleeding complications are major drawbacks of oral anticoagulant therapy thus limiting their generalized adoption in recognized indications. To sharply reduce the bleeding risk and need of laboratory control, the low- or fixed-dose oral anticoagulant approach has been evaluated. In primary prevention and in low or low-to-moderate thrombotic risk, minidose warfarin treatment has been shown to be advantageous. In secondary prevention, and in patients at high risk for recurrent venous or arterial thrombotic events, standard range (INR 2-3) or higher level of anticoagulation is needed.     

Anticoagulant-induced intramural duodenal haematoma presenting with upper-gastrointestinal haemorrhage

Warfarin is an anticoagulant agent known to have a common complication, bleeding. Intramural intestinal haematoma is an uncommon incidence of warfarin-induced haemorrhage. Abdominal pain is its most frequent symptom and presentation with upper-gastrointestinal haemorrhage is rarely seen. Here, we present a 67-year-old male who was admitted to the hospital with active upper-gastrointestinal haemorrhage. In this case, the cause of bleeding has been attributed to duodenal intramural haematoma due to warfarin overuse.