Chan A, Berry L, O'Brodovich H, Klement P, Mitchell L, Baranowski B, Monagle P, Andrew M
Research Institute of the Hospital for Sick Children, Toronto, Ontario M5G 1X8.
J Biol Chem. 1997 Aug 29;272(35):22111-7. doi: 10.1074/jbc.272.35.22111.
Although heparin has been used clinically for prophylaxis and treatment of thrombosis, it has suffered from problems such as short duration within compartments in vivo that require long term anticoagulation. A covalent antithrombin-heparin complex has been produced with high anticoagulant activity and a long half-life relative to heparin. The product had high anti-factor Xa and antithrombin activities compared with noncovalent mixtures of antithrombin and heparin (861 and 753 units/mg versus 209 and 198 units/mg, respectively). Reaction with thrombin was rapid with bimolecular and second order rate constants of 1.3 x 10(9) M-1 s-1 and 3.1 x 10(9) M-1 s-1, respectively. The intravenous half-life of the complex in rabbits was 2.6 h as compared with 0.32 h for similar loads of heparin. Subcutaneous injection of antithrombin-heparin resulted in plasma levels (peaking at 24-30 h) that were still detectable 96 h post-injection. Given the increased lifetime in these vascular and intravascular spaces, use of the covalent complex in the lung was investigated. Activity of antithrombin-heparin instilled into rabbit lungs remained for 48 h with no detection of any complex systemically. Thus, this highly active agent has features required for pulmonary sequestration as a possible treatment for thrombotic diseases such as respiratory distress syndrome.
尽管肝素已被临床用于血栓形成的预防和治疗，但它存在一些问题，比如在体内各腔室的作用持续时间短，而这需要长期抗凝。已经制备出一种具有高抗凝活性且相对于肝素具有较长半衰期的共价抗凝血酶-肝素复合物。与抗凝血酶和肝素的非共价混合物相比，该产品具有较高的抗Xa因子和抗凝血酶活性（分别为861和753单位/毫克，而后者分别为209和198单位/毫克）。与凝血酶的反应迅速，双分子反应速率常数和二级反应速率常数分别为1.3×10⁹ M⁻¹ s⁻¹和3.1×10⁹ M⁻¹ s⁻¹。该复合物在兔体内的静脉半衰期为2.6小时，而相同剂量的肝素的半衰期为0.32小时。皮下注射抗凝血酶-肝素后血浆水平（在24 - 30小时达到峰值）在注射后96小时仍可检测到。鉴于在这些血管和血管内空间的作用时间延长，对共价复合物在肺部的应用进行了研究。注入兔肺的抗凝血酶-肝素的活性持续48小时，且未在全身检测到任何复合物。因此，这种高活性药物具有作为呼吸窘迫综合征等血栓性疾病的一种可能治疗方法而在肺部潴留所需的特性。
