Pregnancies Complicated By Severe Preeclampsia Exhibit Perturbed Von Willebrand Factor (VWF)-Associated Parameters
Authors: Drury-Stewart Danielle N. , Hoppe Kara K. , Lannert Kerry W. , Chung Dominic W. , Gammill Hilary S. , Johnsen Jill M. 
Published: October 2019

Abstract

Background
Elevated levels of the critical coagulation glycoproteins von Willebrand Factor (VWF) and Factor VIII (FVIII) are associated with thrombovascular disease. VWF and FVIII levels are elevated in healthy pregnancy compared with the nonpregnant state, and further increases have been reported in pregnancies complicated by preeclampsia, a potentially life-threatening vascular disorder of pregnancy. Aside from the quantitative increases in VWF and FVIII, data is inconsistent or little is known regarding other key VWF-associated parameters in pregnancies complicated by preeclampsia.

Hypothesis
We hypothesized that pregnancies complicated by severe preeclampsia would exhibit distinct changes in VWF-associated parameters compared to healthy pregnancies.

Methods
We assayed VWF-associated parameters in subjects newly diagnosed with severe preeclampsia, based on standard blood pressure (BP) and proteinuria criteria. Severe preeclampsia was defined on the basis of one or more of the following: severe hypertension (systolic BP >160 or diastolic BP >110) for at least 6 hours, seizures (eclampsia), hemolysis, elevated liver enzymes, thrombocytopenia, pulmonary edema, renal dysfunction, or fetal growth restriction. We compared results from preeclamptic pregnancies to gestational age-matched healthy pregnant controls. VWF antigen (VWF:Ag), VWF propeptide (VWF:pp), and FVIII antigen (FVIII:Ag) levels were determined by ELISA. Factor VIII activity (FVIII:C) was measured using a one-stage assay and ADAMTS13 activity was determined via cleavage of an enzyme-linked peptide substrate.

Results
Forty-two patients with severe preeclampsia and a cohort of thirty-nine controls of similar gestational ages met study inclusion criteria (Table 1). The results of the coagulation assays are presented in Table 2. In summary, preeclamptic pregnancies were notable for statistically significant (p<0.001) increases in VWF:Ag (1.4-fold), VWF:pp (1.5-fold), and FVIII:Ag (1.2-fold) compared to controls. FVIII:Ag and FVIII:C were similar, and FVIII:Ag was used in the calculation of the VWF:FVIII ratio. The VWF:FVIII ratio trended higher in preeclamptic pregnancies, but this did not reach statistical significance (p=0.058). The mean ADAMTS13 activity in patients with preeclampsia was also significantly lower (0.76-fold, p<0.001) than healthy pregnancy controls.

Conclusions
In pregnancies complicated by severe preeclampsia, VWF:Ag and FVIII were significantly elevated, as expected. VWF:FVIII ratios also tended to be higher in preeclamptic pregnancies compared to controls. Interestingly, activity of the VWF-cleaving protease ADAMTS13 was modestly but significantly decreased in preeclampsia pregnancies, a finding for which there is conflicted literature. Three subjects with thrombocytopenia had ADAMTS13 activities >85%, indicating the thrombocytopenia was unrelated to a relative ADAMTS13 deficiency. These findings support the hypothesis that pregnancies complicated by severe preeclampsia exhibit VWF biology that is distinct from healthy pregnancy. We speculate that preeclampsia-associated VWF differences could play a direct role in the vascular pathogenesis and end-organ damage of preeclampsia. These data offer new clues towards better understanding of the mechanisms of severe preeclampsia and represent promising future targets for diagnosis and/or treatment.

Disclosures:
No relevant conflicts of interest to declare.