Antithrombin, heparin, and heparan sulfate.
OBJECTIVE
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.


METHODS
Review of the literature relating to antithrombin published during the past 25 yrs.


METHODS
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.


CONCLUSIONS
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.
Opal
Steven M
SM
Infectious Disease Division, Brown Medical School, Providence, RI 02860, USA. Steven_Opal@brown.edu
Kessler
Craig M
CM
Roemisch
Juergen
J
Knaub
Sigurd
S
D000925:Anticoagulants / Q000627:therapeutic use*; D000991:Antithrombins / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D011464:Epoprostenol / Q000096:biosynthesis / Q000502:physiology; D006493:Heparin / Q000627:therapeutic use*; D006497:Heparan Sulfate / Q000627:therapeutic use*; D006801:Humans; D012772:Shock, Septic / Q000188:drug therapy*
D000925:Anticoagulants; D000991:Antithrombins; D011464:Epoprostenol; D006493:Heparin; D006497:Heparan Sulfate