Elevated fibrinogen, von Willebrand factor, and Factor VIII confer resistance to dilutional coagulopathy and activated protein C in normal pregnant women

Abstract

BackgroundGestational changes in coagulation factor concentrations include elevations in fibrinogen, Factor VIII, and von Willebrand factor (vWF). We hypothesised that blood samples from term pregnant (TP) subjects are less prone to coagulation disturbances from haemodilution compared with those from non-pregnant (NP) females. MethodsBlood samples were collected from 15 NP and 15 TP subjects. In vitro haemodilution with normal saline was assessed by modified Clauss fibrinogen assay, factor activity, flow-chamber assay, and thromboelastometry. The impact of human fibrinogen concentrate (hFC), cryoprecipitate, and vWF/Factor VIII (FVIII) concentrate replacement in diluted TP and NP blood was compared. Thrombin generation and activated protein C sensitivity were assessed. ResultsTP blood contained twice the concentrations of fibrinogen, FVIII, and vWF relative to NP blood (P<0.0001). Platelet thrombus formation (PTF) under flow was reduced by 99.2% and 69.2% in diluted NP and TP blood, respectively. Platelet thrombus formation was partially restored by adding vWF/FVIII, but not hFC or cryoprecipitate. Fibrin clot firmness approached the threshold of 10 mm in diluted NP blood, and clot firmness was effectively restored by hFC, but not by vWF/FVIII. In the presence of thrombomodulin, peak thrombin generation was decreased by 86.7% in NP plasma, but by 31.8% in TP plasma (P<0.0001 vs NP plasma), indicating reduced activated protein C sensitivity in TP plasma. Both elevated FVIII and haemodilution contributed to activated protein C insensitivity. ConclusionsOur in vitro model showed relative resistance of TP blood to dilutional coagulation changes with respect to platelet adhesion, fibrin polymerisation, and thrombin generation. Careful therapeutic monitoring for different pro-haemostatic agents in pregnant women is warranted.