Abstract
BackgroundThe coagulation protein von Willebrand Factor (VWF) is known to be elevated in pregnancy. However, the timing and nature of changes in VWF and associated parameters throughout pregnancy are not well understood.ObjectivesTo better understand the changes in VWF provoked by pregnancy, we studied VWF-associated parameters in samples collected over the course of healthy pregnancies.MethodsWe measured VWF antigen (VWF:Ag), VWF propeptide (VWFpp), Factor VIII (FVIII), and ADAMTS13 activity in samples collected from 46 women during pregnancy and at non-pregnant baseline. We also characterized pregnant vs. non-pregnant VWF multimer structure in 21 pregnancies, and performed isoelectric focusing (IEF) of VWF in two pregnancies which had samples from multiple trimesters.ResultsVWF:Ag and FVIII levels were significantly increased during pregnancy. ADAMTS13 activity was unchanged. VWFpp levels increased much later in pregnancy than VWF:Ag, resulting in a progressive decrease in VWFpp:Ag ratios. FVIII:VWF ratios also decreased in pregnancy. Most pregnancies exhibited a clear loss of larger VWF multimers and altered VWF triplet structure. Further evidence of acquired VWF qualitative changes in pregnancy was found in progressive, reversible shifts in VWF IEF patterns over gestation.ConclusionsThese data support a new view of pregnancy in which VWF can acquire qualitative changes associated with advancing gestational age. Modeling supports a scenario in which both increased VWF production and doubling of the VWF half-life would account for the data observed. We propose that gestation induces a prolongation in VWF survival, which likely contributes to increased total VWF levels and altered VWF structure.
Highlights
Introduction von WillebrandFactor (VWF) is an abundant plasma glycoprotein which stabilizes Factor VIII (FVIII, the protein deficient in Hemophilia A) in circulation and adheres at sites of vascular injury, where it recruits platelets
These data support a new view of pregnancy in which von Willebrand Factor (VWF) can acquire qualitative changes associated with advancing gestational age
We propose that gestation induces a prolongation in VWF survival, which likely contributes to increased total VWF levels and altered VWF structure
Summary
Factor (VWF) is an abundant plasma glycoprotein which stabilizes Factor VIII (FVIII, the protein deficient in Hemophilia A) in circulation and adheres at sites of vascular injury, where it recruits platelets. Variation in VWF levels can be clinically significant. Secreted VWF:Ag is a very large, hemostatically active multimer which is cleaved in circulation into smaller multimers by the plasma protease a disintegrin and metalloproteinase with thrombospondin motifs-13 (ADAMTS13) [6]. Deficiency in ADAMTS13 leads to an overabundance of ultra-large VWF multimers and is associated with thrombotic thrombocytopenic purpura [7]. The coagulation protein von Willebrand Factor (VWF) is known to be elevated in pregnancy. The timing and nature of changes in VWF and associated parameters throughout pregnancy are not well understood
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