Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism

Abstract

Introduction: There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin.

Methods: In this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, 12, 18, or 24 μg/kg/hour of DAA or a placebo. Blood samples were drawn before starting DAA infusion, after 4, 8 and 12 hours (at the end of the infusion period), and on treatment days 2, 3, 4, 5 and 6.

Results: Initial endogenous plasma activated protein C (APC) levels were 0.36 ± 0.48 ng/ml (<0.10 to 1.72 ng/ml) and remained in the same range in the placebo group. APC levels in patients treated with DAA were 13.67 ± 3.57 ng/ml, 32.71 ± 8.76 ng/ml, 36.13 ± 7.60 ng/ml, and 51.79 ± 15.84 ng/ml in patients treated with 6, 12, 18, and 24 μg/kg/hour DAA, respectively. In patients with a D-dimer level >4 mg/L indicating a high level of acute fibrin formation and dissolution, DAA infusion resulted in a more rapid drop in soluble fibrin, D-dimer, and fibrinogen/fibrin degradation products (FDP) levels, compared to enoxaparin alone. There was a parallel decline of soluble fibrin, D-dimer, FDP, and plasmin-plasmin inhibitor complex (PPIC) in response to treatment with enoxaparin ± DAA, with no evidence of a systemic profibrinolytic effect of the treatment.

Conclusions: In patients with acute submassive PE endogenous APC levels are low. DAA infusion enhances the inhibition of fibrin formation.

Trial registration: ClinicalTrials.gov: NCT00191724.

Figure 1

APC activity at 0, 4, 8 and 12 hours (end of study drug infusion). Course of APC activity at inclusion, after 4 hours, 8 hours and after 12 hours (end of the study drug infusion). Patients receiving placebo as the study drug infusion displayed low APC activity levels. DAA infusion results in a dose-dependent increase in APC activity levels.

Figure 2

Prothrombin time (PT Quick percent) and aPTT 12 hours after start of infusion. Prothrombin time (PT Quick percent) and aPTT 12 hours after the start of the study drug infusion. DAA infusion caused a prolongation of PT (reduction in Quick percent ratio) and aPTT.

Figure 3

TINAquant D-dimer levels in sample drawn immediately before study drug infusion. Distribution of TINAquant D-dimer levels (0 h sample drawn immediately before the start of the study drug infusion).

Figure 4

Course of Sekisui soluble fibrin, Tinaquant D-dimer, and Iatron FDP-P. Sekisui soluble fibrin, Tinaquant D-dimer, and Iatron FDP-P before the study drug infusion, after 4, 8 and 12 hours, and on days 2, 3, 4, 5 and 6 days for all patients with an initial (0 h) TINAquant D-dimer level of >4 mg/L. Individual initial values were set at 100% to compensate for individual differences in levels. Initiation of anticoagulant therapy results in a drop in all fibrin-related markers, DAA infusion accelerates the decline of the fibrin-related markers.

Figure 5

Sekisui soluble fibrin, TINAquant D-dimer, and Iatron FDP-P at end of study drug infusion. Sekisui soluble fibrin, Tinaquant D-dimer, and Iatron FDP-P: comparison of the results of the 12-hour sample for all patients with an initial TINAquant D-dimer level of >4 mg/L Patients receiving DAA displayed significantly lower levels of fibrin-related markers at the end of the study drug infusion.

Figure 6

Plasmin-plasmin inhibitor complex (PPIC). Plasmin-plasmin inhibitor complex (PPIC) levels before the study drug infusion, after 4, 8 and 12 hours, and on days 2, 3, 4, 5 and 6 days. Individual initial values were set at 100% to compensate for individual differences in levels. Initiation of anticoagulant therapy results in a reduction in PPIC values, indicating a lower plasmin generation compared to initial levels.