in this issue of critical care , dempfle and colleagues   present an original double - blind study assessing the biological effect of the combination of enoxaparin and drotrecogin alpha ( activated ) ( daa ) ( recombinant human activated protein c ) for the treatment of acute submassive pulmonary embolism ( pe ) . the authors demonstrate that daa infusion accelerates the control of coagulation activation in patients with a d - dimer level higher than 4 mg / l . this phase ii exploratory study sponsored by eli lilly and company ( indianapolis , in , usa )   is of special interest because the use of thrombolytic therapy in patients with submassive pe is a matter of significant and ongoing debate . low - molecular - weight heparins ( lmwhs ) still represent the gold standard for the treatment of venous thromboembolism , as they have proven to be very effective and to have a high efficacy / safety ratio . nevertheless , evidence suggests that thrombolytic agents may rapidly dissolve blood clots and might reduce the death rate associated with pe . however , there are concerns about the possible risk of adverse effects of these agents , such as life - threatening hemorrhage . daa , a vitamin k - dependent protein , is a potent anti - coagulant agent that inhibits activated coagulation factors v and viii ( va and viiia ) . it also promotes fibrinolysis by inhibiting fibrinolytic inhibitors such as plasminogen activator inhibitor-1 and thrombin - activatable fibrinolysis inhibitor . dhainaut and colleagues   have demonstrated that this compound could be beneficial in overt and nonovert disseminated intravascular coagulation patients while partially controlling the activation of the system . moreover , daa has been used in managing acute myocardial infarction patients after thrombolysis . as an activation of the coagulation system with a high level of thrombin generation is often observed in ( nonseptic ) pe patients , combining daa with an lmwh could be understood as a very interesting hypothesis in this regard , even if the sum of the two parts is not as great as the whole . dempfle and colleagues have compared increasing doses of daa for a short duration of infusion ( 12 hours ) with placebo in enoxaparin - treated patients . up to now , little has been known about the endogenous plasma level of activated protein c in ( nonseptic ) pe patients . interestingly , the endogenous activated protein c levels were elevated in the daa - treated group but not in the control group . this unexpected finding represents the pivotal data of this study , creating the potential for further developments in the field . sometimes , physicians use shortcuts to save time , forgetting that pharmacology follows very strict rules . it seems that no animal study and no phase 1 study were performed before the start of the study by dempfle and colleagues . combining a potent anticoagulant ( lmwh ) with another one ( daa ) furthermore , if lmwhs have already been given concomitantly with therapeutic doses of daa in the past [ 9 - 11 ] , the doses were only prophylactic , and , to our knowledge , no therapeutic doses have ever been combined with daa in nonseptic patients , and this is because the bleeding risk of these patients is much different than that of hypercoagulable septic patients . as already mentioned , daa develops an anticoagulant activity . in several pivotal daa trials in sepsis , some major bleeding episodes have been reported to be related to this anticoagulant effect . moreover , in daily clinical practice , the induced - bleeding risk of daa was reported to be much higher than that of the control trials . in the study by dumpfle and colleagues , which is actually registered as a safety study , the observed results are a little bit disappointing , leaving unresolved the potentially increased bleeding risk . the authors state that daa accelerates the control of coagulation activation in a subgroup of patients with high levels of intravascular fibrin . no significant difference is observed in echocardiographic data between the treated group and the control group . finally , as one patient in the daa group developed an intracranial hemorrhage ( which is fairly uncommon in enoxaparin - treated patients ) , the question of the clinical benefit of such a combination has to be raised , notwithstanding the low power of this study to detect an increase in major bleeding . daa : drotrecogin alpha ( activated ) ; lmwh : low - molecular - weight heparin ; pe : pulmonary embolism .
combining therapeutic doses of low - molecular - weight heparins and increasing doses of recombinant activated protein c - drotrecogin alpha ( activated ) , or daa - is of theoretical interest with regard to the control of coagulation activation . 
 the study by dempfle and colleagues presents new data showing that endogenous activated protein c levels do not increase in nonseptic patients with pulmonary embolism . 
 however , the results of the addition of these two treatments are puzzling , leaving unresolved the questionable clinical relevance of this combination and the possible increase in bleeding risk .