Opal Steven M, Kessler Craig M, Roemisch Juergen, Knaub Sigurd
Infectious Disease Division, Brown Medical School, Providence, RI 02860, USA.
Crit Care Med. 2002 May;30(5 Suppl):S325-31. doi: 10.1097/00003246-200205001-00024.
To review the experimental and clinical evidence that antithrombin has multiple mechanisms for both its anticoagulant and anti-inflammatory properties. The interaction between antithrombin and specific polysulfated, acidic oligosaccharide moieties found on heparin and related proteoglycan molecules within the circulation and on endothelial surfaces will also be examined.
Review of the literature relating to antithrombin published during the past 25 yrs.
Antithrombin is the most abundant endogenous anticoagulant circulating in human plasma. This serine protease inhibitor participates in the regulation of clotting in both physiologic and pathologic states. Reduced antithrombin activity in the early phases of sepsis contributes to a procoagulant state with excess activation of the innate immune response. Antithrombin binds to specific pentasaccharides expressed on heparin, glycosaminoglycans, and related proteoglycans within the circulation and along endothelial surfaces. The functions of neutrophils, monocytes, and endothelial cells are altered as a result of their interaction with antithrombin. These effects are mediated by the enzyme inhibitory action of antithrombin and its ability to function as a ligand for antithrombin receptors on cell surfaces. In addition, antithrombin exerts anti-inflammatory properties by both prostacyclin-dependent and prostacyclin-independent actions; heparin interferes with these anti-inflammatory properties. The role of antithrombin in sepsis, its therapeutic utility in severe sepsis, and its combination with heparin remain the subject of considerable debate. The results of a recent phase 3 clinical trials with high-dose antithrombin in sepsis suggested a beneficial effect in patients who did not concomitantly receive heparin, thereby generating new challenges in the understanding of interactions between antithrombin and heparin or heparin-like proteoglycans.
Antithrombin has complex interactions with host coagulopathic and systemic inflammatory responses under physiologic conditions and in sepsis. The impact of these interactions in critically ill patients and the therapeutic implications of administration of antithrombin, and various doses and types of heparin in such patients, need further clarification.
回顾抗凝血酶具有抗凝和抗炎特性的多种机制的实验和临床证据。还将研究抗凝血酶与循环中和内皮表面上肝素及相关蛋白聚糖分子上发现的特定多硫酸化酸性寡糖部分之间的相互作用。
回顾过去25年发表的与抗凝血酶相关的文献。
抗凝血酶是人类血浆中循环的最丰富的内源性抗凝剂。这种丝氨酸蛋白酶抑制剂参与生理和病理状态下的凝血调节。脓毒症早期抗凝血酶活性降低导致促凝状态，伴有先天免疫反应过度激活。抗凝血酶与循环中和沿内皮表面的肝素、糖胺聚糖及相关蛋白聚糖上表达的特定五糖结合。中性粒细胞、单核细胞和内皮细胞的功能因与抗凝血酶相互作用而改变。这些作用由抗凝血酶的酶抑制作用及其作为细胞表面抗凝血酶受体配体的功能介导。此外，抗凝血酶通过前列环素依赖性和非依赖性作用发挥抗炎特性；肝素会干扰这些抗炎特性。抗凝血酶在脓毒症中的作用、其在严重脓毒症中的治疗效用以及与肝素的联合应用仍是大量争论的主题。最近一项关于高剂量抗凝血酶治疗脓毒症的3期临床试验结果表明，在未同时接受肝素治疗的患者中有有益作用，从而在理解抗凝血酶与肝素或类肝素蛋白聚糖之间的相互作用方面产生了新的挑战。
在生理条件下和脓毒症中，抗凝血酶与宿主凝血障碍和全身炎症反应存在复杂的相互作用。这些相互作用对重症患者的影响以及抗凝血酶给药的治疗意义，以及此类患者中不同剂量和类型的肝素的治疗意义，需要进一步阐明。
