Watt Barbara E, Proudfoot Alex T, Bradberry Sally M, Vale J Allister
National Poisons Information Service (Birmingham Centre), City Hospital, Birmingham, UK.
Toxicol Rev. 2005;24(4):259-69. doi: 10.2165/00139709-200524040-00005.
Anticoagulant pesticides are used widely in agricultural and urban rodent control. The emergence of warfarin-resistant strains of rats led to the introduction of a new group of anticoagulant rodenticides variously referred to as 'superwarfarins', 'single dose' or 'long-acting'. This group includes the second generation 4-hydroxycoumarins brodifacoum, bromadiolone, difenacoum, flocoumafen and the indanedione derivatives chlorophacinone and diphacinone. Most cases of anticoagulant rodenticide exposure involve young children and, as a consequence, the amounts ingested are almost invariably small. In contrast, intentional ingestion of large quantities of long-acting anticoagulant rodenticides may cause anticoagulation for several weeks or months. Occupational exposure has also been reported. Anticoagulant rodenticides inhibit vitamin K(1)-2,3 epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX and X. The greater potency and duration of action of long-acting anticoagulant rodenticides is attributed to their: (i) greater affinity for vitamin K(1)-2,3-epoxide reductase; (ii) ability to disrupt the vitamin K(1)-epoxide cycle at more than one point; (iii) hepatic accumulation; and (iv) unusually long biological half-lives due to high lipid solubility and enterohepatic circulation. Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result. Spontaneous haemoperitoneum has been described. Severe blood loss may result in hypovolaemic shock, coma and death. The first clinical signs of bleeding may be delayed and patients may remain anticoagulated for several days (warfarin) or days, weeks or months (long-acting anticoagulants) after ingestion of large amounts. There are now sufficient data in young children exposed to anticoagulant rodenticides to conclude that routine measurement of the international normalised ratio (INR) is unnecessary. In all other cases, the INR should be measured 36-48 hours post exposure. If the INR is normal at this time, even in the case of long-acting formulations, no further action is required. If active bleeding occurs, prothrombin complex concentrate (which contains factors II, VII, IX and X) 50 units/kg, or recombinant activated factor VII 1.2-4.8 mg or fresh frozen plasma 15 mL/kg (if no concentrate is available) and phytomenadione 10mg intravenously (100 microg/kg bodyweight for a child) should be given. If there is no active bleeding and the INR is < or =4.0, no treatment is required; if the INR is > or =4.0 phytomenadione 10mg should be administered intravenously.
抗凝血剂农药广泛用于农业和城市灭鼠。抗华法林大鼠品系的出现促使了一组新的抗凝血灭鼠剂的引入，这些灭鼠剂有多种称呼，如“超级华法林”、“单剂量”或“长效”。这一组包括第二代4-羟基香豆素类的溴敌隆、溴鼠灵、敌鼠、氟鼠灵以及茚满二酮衍生物氯鼠酮和敌鼠酮。大多数抗凝血灭鼠剂中毒病例涉及幼儿，因此摄入的量几乎总是很少。相比之下，故意大量摄入长效抗凝血灭鼠剂可能导致数周或数月的抗凝状态。职业接触也有报道。抗凝血灭鼠剂抑制维生素K(1)-2,3环氧化物还原酶，从而抑制维生素K的合成以及随后凝血因子II、VII、IX和X的合成。长效抗凝血灭鼠剂更强的效力和更长的作用时间归因于它们：(i) 对维生素K(1)-2,3-环氧化物还原酶有更高的亲和力；(ii) 能够在多个点破坏维生素K(1)-环氧化物循环；(iii) 在肝脏蓄积；以及(iv) 由于高脂溶性和肠肝循环而具有异常长的生物半衰期。大量摄入会导致鼻出血、牙龈出血、广泛瘀斑、血肿、伴有侧腹痛的血尿、月经过多、胃肠道出血、直肠出血以及任何内脏器官出血；可能会导致贫血。已有自发性血腹的描述。严重失血可能导致低血容量性休克、昏迷和死亡。出血的最初临床症状可能会延迟出现，大量摄入后患者可能会在数天（华法林）或数天、数周或数月（长效抗凝血剂）内一直处于抗凝状态。现在有足够的数据表明，对于接触抗凝血灭鼠剂的幼儿，常规测量国际标准化比值（INR）是不必要的。在所有其他情况下，应在接触后36 - 48小时测量INR。如果此时INR正常，即使是长效制剂的情况，也无需进一步处理。如果发生活动性出血，应静脉给予凝血酶原复合物浓缩剂（含因子II、VII、IX和X）50单位/千克，或重组活化因子VII 1.2 - 4.8毫克，或新鲜冰冻血浆15毫升/千克（如果没有浓缩剂）以及静脉注射维生素K1 10毫克（儿童为100微克/千克体重）。如果没有活动性出血且INR≤4.0，则无需治疗；如果INR≥4.0，应静脉注射维生素K1 10毫克。
