Pregnancy In Type 1 Von Willebrand Disease: A Prospective Study of VWF Levels and Risk Factors for Bleeding
Authors: Sood Suman L. , James Andra H. , Bolgiano Doug , Ragni Margaret V. , Shapiro Amy D. , Shihong Iris , Vega Rolando , Witmer Char , Konkle Barbara A. 
Published: October 2019

Abstract
Abstract 1410
Women with Type 1 von Willebrand disease (VWD) experience menorrhagia and postpartum hemorrhage (PPH) more than twice as often as women without VWD. VWF levels in women without VWD increase during pregnancy in an exponential manner, and fall postpartum. In type 1 VWD, limited data exist. The goal of this study is to model changes in VWF levels during and after pregnancy in women with Type 1 VWD, and correlate findings with blood loss.
Women with Type 1 VWD, defined as at least 1 value of VWF:Antigen (Ag) or VWF:Ristocetin Cofactor (RCo) < 50%, VWF Ag/RCo > 0.7, and compatible history of mucosal bleeding pre-pregnancy, were recruited prior to 36 weeks gestation. Twin gestation, additional bleeding disorder, and anti-coagulant or -platelet therapy were excluded. Baseline demographic and bleeding scores were recorded. FVIII, VWF:Ag, and VWF:RCo were obtained monthly after enrollment, at labor, and postpartum (PP; 12, 24, 48 hours and 1, 2, and 6 weeks) and assayed centrally. Change in VWF:Ag levels during gestation and postpartum were modeled using longitudinal regression analysis.
Twelve women were recruited from 4 HTCs with median (range) age 31.3 years (19-43), BMI 24.3 kg/m2 (18.1-40.5). All were Caucasian and of non-Hispanic ethnicity. One patient dropped out at 21 weeks gestation. 67% were blood type O; 25% A; 8% B; and 5/12 (42%) were primigravidae. Four patients reported prior PPH. Mean (SD) baseline bleeding score was 8 (7). Mean weeks gestation at delivery was 39 (1), with 2 Cesarean sections (18%). Seven women (64%) used epidural anesthesia, and 1 woman each used spinal, general, local, or no anesthesia. Seven women (64%) suffered genital laceration. Estimated blood loss (EBL) was mean 643 cc (309). One woman experienced immediate PPH, likely due to uterine atony, requiring 2 U PRBC. Three women experienced bleeding at 24–48h PP, and 1 at 1–2 weeks PP. One woman received DDAVP; 3 treated with VWF concentrate peri- and postpartum. Mean length of stay was 2 days (1). None required readmission, ICU stay, or procedures to stop bleeding.
Mean (SD) VWF:Ag, VWF:RCo, and FVIII levels (%), respectively, at baseline were (n=11, 41.1 (7.1), 34.4 (8.4), 76.4 (70.8)), labor (n=11, 136.4 (50.8), 128.9 (47.8), 134.2 (42.7)), and 6 weeks PP (n=10, 57.8 (22.8), 52.1 (25.4), 80.9 (32.2)). VWF:Ag and VWF:RCo levels correlated well throughout for each woman (r 0.91–1, p <0.01). The rate of change of VWF levels was heterogeneous and varied individually, with differences between VWF:Ag value at baseline vs. labor ranging from 43–164% and from labor vs. 6 weeks PP 21–128%.
During the gestational period, an exponential growth model best fit the rise in VWF:Ag level at labor relative to pre-pregnancy, VWF:Ag=exp(0.029 × gestational age in weeks), SD 0.0077. VWF:Ag is predicted to double from 17 weeks upwards. Postpartum, an exponential decay model predicted VWF:Ag levels should return to baseline by mean 3.6 weeks (SD 1.9) PP. 59 data points were available for the gestational, and 61 for the PP analyses.
Variables associated with increased EBL include higher BMI (r, p; 0.88, 0.01), C-section (0.79, 0.03), genital laceration (0.79, 0.01), and manual placenta delivery (0.79, 0.01). Variables correlating with increased hemoglobin loss from 36 weeks to 24 h PP include episiotomy (0.75, 0.03) and degree of tear (0.99, 0.01). Cord blood obtained on 9 infants revealed a mean (SD) VWF:Ag, VWF:RCo, and FVIII level (%) 97.9 (35.8), 96.2 (34.8), 67.7 (22.6) at birth. None of 3 infants bled with procedures (1 circumcision, 2 blood draws). Infant VWD levels did not significantly correlate with respective maternal VWD levels at either baseline or labor.
In conclusion, subjects with Type 1 VWD appear to have highly individual and heterogeneous rates of rise and decline of VWF levels during gestation and postpartum. Only one of 12 women in this study experienced PPH, attributed to atonic uterus. An exponential growth and decay model best fit the VWF:Ag peripartum levels. Variables correlating with blood loss include higher BMI, C-section, genital laceration, episiotomy, and degree tear. Although this study is small and the population homogenous, it demonstrates the importance of monitoring factor levels in women with Type 1 VWD, as the rise and fall in VWF levels are variable. Mutation analysis may help further explain the heterogeneity of individual responses. Additional studies are needed to better define risk factors associated with PPH in this population.

Disclosures:
James: CSL Behring: Consultancy, Research Funding. Shapiro:Baxter BioScience: Consultancy. Konkle:CSL Behring: Consultancy, Research Funding.