Anticoagulants are unique compared with most pharmacologic agents because even small deviations from therapeutic levels

place patients at risk for life-threatening complications. Whereas critically ill patients are particularly susceptible to thrombosis, they also have higher risks of bleeding than the general medical or surgical patients. Although the choices for anticoagulant therapy are expanding with the development of new parenteral and oral agents, rigorous clinical trials of their use in the intensive care unit (ICU) population are lacking.

Low-molecular-weight heparins (LMWHs) exert their anticoagulant effects by binding to antithrombin, thereby enhancing its capacity to inhibit thrombin and factor Xa. This inhibition of factor Xa is mediated by a unique pentasaccharide sequence found on about one-fifth of LMWH chains. most of the LMWH chains are insufficient in length to bridge antithrombin to thrombin. Thus, LMWH catalyzes the inhibition of factor Xa to a greater extent than thrombin. LMWH has a more predictable anticoagulant effect than heparin because of less plasma protein binding. The half-life of LMWH ranges from 2 to 5 hours depending on the specific LMWH used. Bioavailability after subcutaneous (SQ) injection is approximately 90%, and peak concentrations are reached at 1 to 5 hours. LMWH does not reliably alter the activated partial thromboplastin time (aPTT) or prothrombin time (PT) at therapeutic concentrations. Because the clearance of LMWHs is primarily through the kidney, Protamine sulfate only partially reverses the anticoagulant effect of LMWH. Because longer chains bind protamine with higher affinity, protamine reverses all of the antiIIa (antithrombin) activity of LMWH but only 60% of LMWHs anti-Xa activity. The dose of protamine varies based on LMWH subtype (1 mg protamine per 100 mg enoxaparin or 1 mg protamine per 100 U of dalteparin or tinzaparin) a decreased incidence of heparin-induced thrombocytopenia (HIT) due to less binding to platelet factor 4. Furthermore, the risk of osteoporosis with long-term LMWH use is thought to be less than UFH because of reduced binding to osteoblasts. the use of LMWHs in the ICU setting may be more problematic, because these patients often have comorbidities (obesity, renal insufficiency/failure, anasarca, or hypotension requiring inotrope therapy), which can lead to unpredictable dose effects. If levels fall outside the usual therapeutic range as a result of these abnormalities, patients may be placed at risk for underdosing (causing avoidable thrombosis) or overdosing (causing avoidable bleeding). Because of their long half-lives compared with UFH, especially in patients with renal impairment, LMWH to produce therapeutic anticoagulation PROTECT study, which compared 5000 units of dalteparin once daily to UFH 5000 units twice daily for VTE prophylaxis in critically ill patients, there was no difference in the rates of major bleeding (5.5% vs 5.6 %, respectively) despite the inclusion of patients with a range of renal insufficiency, including patients with end-stage renal disease requiring hemodialysis. Metaanalysis of12 studies involving approximately 5000 patients revealed that therapeutic enoxa- parin dosing was associated with increase in major bleeding in patients with a CrCl of 30 mL/min or less compared with UFH. with renal failure, the authors suggest clinicians consider monitoring the anticoagulant effect with anti-Xa heparin levels 4 hours after the third dose (when steady state has been achieved) to assess for potential increased drug accumulation. Furthermore, repeat anti-Xa levels are warranted after any dose adjustments or changes in renal

function. The target therapeutic range (in anti-Xa units) is .5 to 1.0 U/mL for patients on twice-daily LMWH and 1.0 to 2.0 U/mL for patients on once-daily LMWH. clinical trials have generally excluded ICU patients. Therefore, the efficacy and safety of LMWHs in the treatment of acute VTE in critically ill patients remains unclear.