MDT-based Comprehensive Management of Type 3 Von Willebrand Disease in Pregnancy: From Preimplantation Genetic Testing to Antenatal Care, Delivery and Postpartum Period

MDT-based Comprehensive Management of Type 3 Von Willebrand Disease in Pregnancy: From Preimplantation Genetic Testing to Antenatal Care, Delivery and Postpartum Period | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report MDT-based Comprehensive Management of Type 3 Von Willebrand Disease in Pregnancy: From Preimplantation Genetic Testing to Antenatal Care, Delivery and Postpartum Period Xiaoxia Liu, Man Xiao, Yang Zhang, Lijuan Chen, Defeng Shu, Huafang Wang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9485137/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background: Type 3 von Willebrand disease is a rare and severe inherited bleeding disorder characterised by an almost complete deficiency of von Willebrand factor and markedly reduced factor VIII levels. During pregnancy, the physiological increase in coagulation factors seen in healthy women is absent, placing affected patients at high risk of maternal and neonatal haemorrhage. Management of invasive obstetric procedures and delivery therefore remains clinically challenging. This case highlights the use of a target-guided strategy with multidisciplinary collaboration and recombinant von Willebrand factor in a Chinese patient. Case presentation: A 36 years old woman with type 3 von Willebrand disease conceived via in vitro fertilisation. She was managed throughout pregnancy and the peripartum period using a target-guided strategy with recombinant von Willebrand factor, coordinated through serial multidisciplinary team evaluations. To our knowledge, this is the first reported peripartum application of this agent in China. Recombinant von Willebrand factor was administered before amniocentesis to achieve a pre-procedural von Willebrand factor activity target of ≥30% (actual 31.9%) and before elective caesarean section to achieve a surgical target of ≥50% (actual 51.2%), with adjunct factor VIII supplementation as required. Caesarean delivery was completed with an estimated blood loss of 400 millilitres, and no postpartum or neonatal haemorrhagic complications occurred. Conclusions: This case demonstrates that pregnancy complicated by type 3 von Willebrand disease can be managed safely through anticipatory planning, multidisciplinary collaboration and dynamic laboratory monitoring with target-guided recombinant von Willebrand factor replacement, providing practical guidance for obstetricians managing high-risk pregnancies with severe inherited bleeding disorders. Type 3 von Willebrand disease Pregnancy Multidisciplinary collaboration Recombinant von Willebrand factor Maternal-fetal safety Background Von Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative abnormalities of von Willebrand factor (VWF) [1]. VWF plays a central role in hemostasis by mediating platelet adhesion to sites of vascular injury and by stabilizing coagulation factor VIII (FVIII) as its carrier protein. Based on the nature of the VWF abnormality, VWD is classified into three main types. Type 1, a partial quantitative deficiency, accounts for approximately 70–80% of cases. Type 2 comprises qualitative defects and is further divided into subtypes 2A, 2B, 2N, and 2M. Type 3, characterized by severe reduction or complete absence of VWF, represents approximately 1–5% of cases [2]. The severity of bleeding correlates with the extent of VWF deficiency or dysfunction [3]. Type 3 VWD, associated with undetectable VWF and markedly reduced FVIII, carries the most severe bleeding phenotype. Affected individuals often present in childhood with mucocutaneous bleeding and menorrhagia; bleeding may also involve muscles, joints, and internal organs, and life-threatening hemorrhage—including intracranial bleeding—may occur [4]. In healthy pregnancy, estrogen-driven increases in VWF and FVIII begin in the first trimester, peak at delivery, remain elevated for two to three days postpartum, and then decline to baseline over one to three weeks. In type 1 VWD, levels typically rise as well, albeit from a lower baseline. In type 3 VWD, however, this physiological response is generally absent, leaving patients in a persistently hypocoagulable state throughout gestation and the peripartum period [5]. Consequently, the risks of spontaneous abortion, antepartum hemorrhage,d and postpartum hemorrhage are substantially elevated [6]. A carefully individualized approach to pregnancy and peripartum management is therefore essential. Here we describe the successful pregnancy and delivery of a patient with type 3 VWD, highlighting a multidisciplinary, target-guided peripartum management strategy supported by recombinant VWF replacement. Case Presentation 1. General Information The patient was a 36-year-old woman (gravida 2, para 0) admitted at 36 weeks and 1 day of gestation with occasional lower abdominal tightness for one day. Her admission weight was 60kg, and her blood type was O, RH+. She reported easy bruising and mucocutaneous bleeding since childhood. Routine blood counts and initial coagulation screening had previously been normal, and no specific treatment was given. During adolescence, her menstrual cycles were 30 days with seven days of bleeding, and menstrual volume was markedly increased, exceeding 200 mL per cycle. In March 2023, she underwent right salpingectomy for ectopic pregnancy at another institution, complicated by hemorrhagic shock; two days postoperatively, she developed recurrent intra-abdominal bleeding that required stabilization with multiple plasma transfusions. In April 2023, she was evaluated at our hematology department, where disseminated intravascular coagulation testing and VWF gene sequencing led to a diagnosis of type 3 VWD. Whole-exome sequencing revealed a heterozygous VWF mutation (chr12:5952480-5952480, exon 49; missense mutation, NM_000552.5: c.8026T>C: p.C2676R); her husband was wild-type. She reported no history of joint bleeding, deep hematoma, or transfusion-related allergic reactions. Family history was unremarkable for bleeding disorders, and neither parent reported a bleeding tendency. Overall, these features indicated a severe bleeding phenotype and informed high‑risk planning for invasive procedures and delivery. 2. Key Laboratory Findings Diagnostic laboratory testing in April 2023 showed normal complete blood counts. Coagulation profile revealed prothrombin time (PT) 12.9 s (reference range 11–16 s), international normalized ratio (INR) 0.99 (0.9–1.22), activated partial thromboplastin time (APTT) 54.8 s (20–47 s), fibrinogen 2.91 g/L (2–4 g/L), thrombin time (TT) 16.6 s (14–21 s), and factor VIII procoagulant activity (FVIII:C) 14.0% (70–150%). Plasma VWF antigen was 4.0% (50–160%, VWF:Ag), VWF activity (platelet-binding activity，VWF:GPⅠbM) was undetectable at 0.0% (40–163%), and the VWF activity-to-antigen ratio was 0.0 (≥0.5) [7]. Additional testing for hemophilia excluded inherited FVIII deficiency (hemophilia A carrier). Collectively, these findings indicated severe VWF deficiency with markedly reduced FVIII activity, consistent with type 3 VWD. 3. Pregnancy Course 3.1 Assisted Reproduction via In Vitro Fertilization In November 2024, the patient sought care at our reproductive medicine department for infertility and planned to undergo in vitro fertilization (IVF). An initial multidisciplinary team (MDT) consultation was convened by the reproductive medicine team, with participation from hematology, transfusion medicine, genetics, and laboratory medicine. The MDT concluded that the patient’s heterozygous VWF mutation warranted counseling regarding the risk of VWD in offspring, and that preimplantation genetic testing could reduce the risk of hereditary transmission. Given the high bleeding risk associated with type 3 VWD, the team recommended prophylactic hemostatic support for oocyte retrieval, with cryoprecipitate or plasma prepared in advance. The patient underwent oocyte retrieval in December 2024 and received six units of cryoprecipitate plus 600 units of recombinant human FVIII daily on the day of the procedure and for two days before and after. The procedure was uneventful, with no abnormal bleeding or intra-abdominal hemorrhage. 3.2 Amniocentesis Embryo transfer was performed on January 27, 2025. Ultrasonography at approximately seven weeks confirmed an intrauterine singleton viable pregnancy. Routine antenatal care was provided, and no abnormal bleeding occurred during pregnancy. Owing to the patient’s heterozygous VWF mutation and the use of preimplantation genetic testing, amniocentesis for prenatal diagnosis was scheduled at 18 weeks of gestation (May 23, 2025). A second MDT consultation, led by obstetrics and including hematology, transfusion medicine, ultrasound, and genetics, recommended that replacement therapy be prepared, given the substantially increased risks of bleeding and miscarriage after amniocentesis compared with healthy pregnant women. The team considered amniocentesis a minor surgical procedure and set a pre‑procedural target VWF activity of ≥30%. Pre-procedure testing on May 19, 2025, showed PT 11.9 s, INR 0.90, APTT 49.2 s, fibrinogen 4.04 g/L, TT 15.8 s, FVIII:C 6.7%, VWF antigen 6.7%, and VWF activity undetectable at 0.0%. Recombinant VWF (rVWF, vonicog alfa for injection) was selected for precise replacement. Following infusion of 1300 IU of rVWF at 9:00 AM, VWF activity measured at 11:00 AM had risen to 31.9%, meeting the predefined target. Subsequently, 400 IU of recombinant human FVIII was administered. Amniocentesis was then performed under ultrasound guidance, yielding 40 mL of clear amniotic fluid. Hemostasis was achieved after 20 seconds of compression at the puncture site. Post-procedure fetal heart rate was normal, and the patient reported no discomfort. Coagulation testing at 5:10 PM showed PT 13.0 s, INR 1.00, APTT 39.8 s, fibrinogen 3.44 g/L, FVIII:C 45.8%, VWF antigen 35.6%, and VWF activity 25.8%. Four days after the procedure, VWF activity remained measurable at 10.0% and FVIII:C at 40.0%. Amniocentesis results revealed no fetal chromosomal copy number variations, and whole-exome sequencing identified no pathogenic variants. Routine antenatal assessments, including nuchal translucency (1.4 mm), oral glucose tolerance testing, and fetal systematic ultrasound, were unremarkable, and fetal growth was appropriate for gestational age. 3.3 Peripartum Management At 36 weeks of gestation, the patient began experiencing occasional uterine contractions, raising concern for imminent labor. A third MDT consultation, led by obstetrics and including hematology, anesthesiology, intensive care, neonatology, and transfusion medicine, was convened to establish a delivery plan. The team opted for elective cesarean section at 37 weeks to avoid the unpredictable risks of precipitous labor, cervical lacerations, and perineal hematoma associated with vaginal delivery, and to enable precise timing of replacement therapy. Cesarean section was classified as major surgery, and a preoperative target VWF activity of ≥50% was established [8]. General anesthesia was chosen to eliminate the bleeding risk associated with neuraxial techniques. Postoperative intensive care unit observation was planned, along with coagulation testing of the neonate. On September 23, 2025 (37 weeks of gestation), 2600 IU of rVWF was infused at 6:00 AM. Coagulation testing at 10:00 AM showed VWF antigen 72.3%, VWF activity 51.2%, FVIII:C 55.2%, PT 12.8 s, INR 0.98, and APTT 40.3 s, meeting the target hemostatic levels for surgery. The patient was transferred to the operating room at 12:10 PM, and an additional 600 IU of recombinant human FVIII was administered preoperatively. General anesthesia was induced. A live female infant weighing 2850 g was delivered, with Apgar scores of 9 and 10. Umbilical cord blood was obtained for coagulation testing. Intraoperatively, uterine atony was managed with intravenous tranexamic acid 1 g, intravenous carbetocin 100μg, intramuscular carboprost tromethamine 250μg, and bilateral ascending uterine artery ligation to prevent postpartum hemorrhage. The subcutaneous tissue and skin were closed with interrupted 2-0 silk sutures to reduce the risk of subcutaneous hematoma. Meticulous surgical technique was employed to ensure adequate hemostasis. Total operative time was 40 minutes, with an estimated blood loss of 400mL. The neonate received routine vitamin K1 supplementation and did not develop cephalohematoma or intracranial hemorrhage. Coagulation testing 2.5 hours postoperatively demonstrated VWF activity 55.2% and FVIII:C 82.3%. On postoperative day 1, VWF activity had decreased to 33.5%, while FVIII:C was 113.7%. On postoperative day 2, VWF activity was 14.6% and FVIII:C 73.1%; an additional 2600 IU of rVWF was infused. Intravenous tranexamic acid (1 g daily) was continued until postoperative day 10, with coagulation function monitored every other day. The patient had no abnormal vaginal bleeding postoperatively, lochia volume was normal, and the abdominal incision healed well. She was discharged on postoperative day 10. No adverse events, infusion reactions, thrombotic events, or treatment‑related complications were observed during hospitalization or within the postpartum period Discussion Patients with type 3 VWD have complete VWF deficiency, resulting in impaired platelet adhesion and aggregation [9]. In addition, the absence of VWF-mediated protection of FVIII leads to a shortened FVIII half-life. Affected individuals often exhibit a severe bleeding tendency from childhood, including menorrhagia; the patient described here had a history of perioperative hemorrhagic shock and an International Society on Thrombosis and Haemostasis Bleeding Assessment Tool score of 8 [10-11]. The key challenge in managing pregnancy complicated by type 3 VWD lies in the persistent absence of physiological increases in VWF and FVIII throughout gestation, which confers a high bleeding risk [12]. Ensuring maternal and fetal safety therefore requires coordinated multidisciplinary care and proactive prophylactic replacement therapy [13]. Preconception Counseling Women with bleeding disorders should receive preconception counseling at a comprehensive center, with close follow-up by a multidisciplinary team including specialists in hematology, maternal‑fetal medicine, clinical genetics, neonatology, pediatric hematology, and anesthesiology [14]. While VWF gene mutations are identified in only 62% of patients with type 1 VWD, detection rates exceed 90% in types 2 and 3[11, 15-16]. Genetic testing is therefore advisable for patients with type 2 or type 3 disease [17]. Type 3 VWD is typically inherited in an autosomal recessive manner, resulting from homozygous or compound heterozygous VWF mutations [18]. In the present case, the patient had a heterozygous VWF mutation but presented with a type 3 phenotype (undetectable VWF); her partner was wild-type, conferring a 50% risk of inheritance in offspring. For at-risk couples, preimplantation genetic testing can prevent up to 99% of hereditary transmission [19]. Antenatal Management Invasive procedures during pregnancy—such as cervical cerclage or amniocentesis—carry increased hemostatic risks in women with VWD and require careful planning, active monitoring, and availability of replacement therapy [5]. In this case, serial coagulation testing before pregnancy and at 18, 24, and 32 weeks of gestation consistently showed VWF antigen below 10%, VWF activity undetectable, and FVIII:C between 3% and 10%, with no evidence of the physiological increase expected in pregnancy. Regarding mode of delivery, VWD is not an absolute indication for cesarean section [20]. However, for type 3 VWD, elective cesarean section is often preferred because it reduces the unpredictability associated with labor and allows precise timing of replacement therapy. The planned cesarean delivery in this case illustrates the advantages of such an approach. Postpartum Hemorrhage Postpartum hemorrhage represents one of the most significant threats in - women with VWD [21]. Even with treatment, the reported incidence of PPH ranges from 20% to 51%. Hemorrhage may occur at delivery or during the puerperium, necessitating close monitoring of VWF and FVIII levels [5]. Operative vaginal deliveries (forceps or vacuum extraction) should be avoided to minimize traumatic bleeding for both mother and infant. In addition to ensuring appropriate VWD management, specific obstetric causes of PPH—such as uterine atony and retained placenta—must be addressed [22]. In this case, uterine atony was managed with uterotonic agents and bilateral ascending uterine artery ligation. Antifibrinolytic agents are effective for both PPH treatment and VWD management [22-24]. Guidelines from the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia recommend tranexamic acid for PPH prophylaxis in all patients with VWD, administered orally or intravenously for 10–14 days postpartum [25]. In our patient, postoperative tranexamic acid was continued for 10 consecutive days, effectively covering the peak risk period for PPH. Anesthesia Considerations Epidural or combined spinal-epidural anesthesia is generally contraindicated in patients with coagulation disorders [26]. Current guidelines suggest that neuraxial techniques may be considered when VWF activity is maintained above 50 IU/dL, with these levels sustained for at least six hours after catheter placement and removal [25, 27]. In the present case, although preoperative VWF activity reached 51.2% following rVWF replacement, the multidisciplinary team opted for general anesthesia. This decision was made based on the limited institutional experience with neuraxial anesthesia in patients with complete VWF deficiency, as well as the desire to eliminate any potential bleeding risk associated with epidural catheter insertion and removal. General anesthesia offers a well-established safety profile, excellent controllability, and the absence of procedure-related bleeding risk in this high-risk population [28]. This decision reflected institutional practice and experience rather than a universal contraindication to neuraxial anesthesia in all patients with VWD. Timing and Targets of Peripartum rVWF Replacement Unlike healthy pregnant women or those with type 1 VWD, patients with type 3 VWD do not exhibit a physiological increase in VWF, and FVIII:C remains persistently low. Maintaining effective VWF activity throughout pregnancy is therefore essential [5-6,8]. Current guidelines recommend that perioperative VWF activity and FVIII:C levels be maintained above 50% in patients with VWD, and for major surgeries such as cesarean section, these levels should be sustained for at least three days postoperatively. For type 3 VWD, replacement therapy is advised for at least five days after uncomplicated vaginal delivery and for seven to ten days following cesarean section [25]. Cesarean section involves greater surgical trauma than amniocentesis, and complications such as uterine atony further increase bleeding risk, necessitating higher VWF activity targets. In this case, a 1300 IU rVWF infusion before amniocentesis raised VWF activity sufficiently to allow the procedure without bleeding complications. Prior to cesarean section, administration of 2600 IU of rVWF achieved the predefined hemostatic target. On postoperative day 2, when VWF activity declined to 14.6%, an additional 2600 IU rVWF was administered, effectively preventing PPH. These observations suggest that replacement doses can be tailored to procedural risk and individual patient characteristics, avoiding overtreatment [29]. The strategy of preoperative rVWF infusion followed by postoperative monitoring used here avoided the fluctuations in VWF levels associated with traditional replacement regimens and highlights the advantage of precision therapy with rVWF [30]. When rVWF is used for replacement, concurrent FVIII supplementation is required before surgery or invasive procedures. The combination of rVWF and FVIII may act synergistically: VWF supports platelet adhesion and stabilizes FVIII, while FVIII directly participates in the coagulation cascade [31]. Their combined use may contribute to effective control of surgical and postpartum bleeding in selected clinical settings. In this patient, postoperative tranexamic acid was also administered, providing additional synergy with rVWF to further reduce PPH risk [23]. Notably, tranexamic acid does not affect breastfeeding, aligning with perinatal medication safety considerations. Type 3 VWD is the most severe subtype. Traditional replacement options include cryoprecipitate, fresh frozen plasma, and plasma-derived FVIII concentrates containing VWF, each with limitations such as viral transmission risk and incomplete VWF multimer integrity [32]. Recombinant VWF, produced using genetic engineering technology, offers high purity and an intact multimer structure [33]. It specifically replenishes VWF while also raising FVIII:C levels, making it an attractive option for replacement therapy in type 3 VWD. Neonatal Considerations In the neonatal period, VWF and FVIII levels may be falsely elevated owing to stress; umbilical cord blood testing is therefore important to establish baseline values [34]. In this case, cord blood showed VWF activity 58.0% and FVIII:C 67.2%, with no bleeding manifestations and normal coagulation function. Because amniocentesis had confirmed that the neonate did not carry the pathogenic variant, long-term coagulation follow-up was not required. Value of Multidisciplinary Management Managing VWD in pregnancy requires a multidisciplinary team comprising specialists in adult hematology, maternal-fetal medicine, obstetrics, anesthesiology, and neonatology, with input from genetic counselors, specialized pharmacists, coagulation laboratories, and transfusion medicine services [25, 35]. The patient is also a key member of the team and should be actively involved in treatment decisions. In this case, three MDT consultations enabled individualized care from the preconception period through delivery, ultimately achieving favorable maternal and neonatal outcomes consistent with international consensus on peripartum VWD management. Conclusion Pregnancy complicated by type 3 von Willebrand disease is a rare and high-risk obstetric condition. Successful maternal and neonatal outcomes depend on early diagnosis, preconception counseling, and sustained multidisciplinary collaboration. Recombinant von Willebrand factor provides a precise, safe, and effective option for peripartum replacement therapy in pregnant women with type 3 VWD, substantially reducing bleeding risk associated with invasive procedures and the peripartum period itself. With careful monitoring of coagulation parameters and targeted rVWF replacement, life-threatening hemorrhage can be effectively prevented or managed, enabling favorable pregnancy outcomes. Declarations Acknowledgement We would like to acknowledge the whole team members involved in the management. Author contribution Xiaoxia Liu, Man Xiao，and Yang Zhang were involved in drafting the manuscript. Lijuan Chen, Defeng Shu, Huafang Wang and Jing Wu were the members of the MDT team and had given very professional opinions on patients' assisted reproduction, genetic counseling, hematology management and anesthesia management. Yin Zhao and Li Zou were the MDT leaders of this case and core members of obstetrics, and the manuscript was reviewed and edited by them. All authors read and approved the final manuscript. Funding This work was supported by Hubei Provincial Health and Well-ness Science and Technology Project (WJ2025M069). Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent has been obtained from the patient to publish this paper. Competing interests The authors declare no competing interests. References Seidizadeh O, Eickenboom JCJ, Denis CV, et al. von Willebrand disease. 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An evaluation of von Willebrand factor (recombinant) therapy for adult patients living with severe type 3 von Willebrand disease. Expert Rev Hematol. 2023 Mar;16(3):157-161. https://pubmed.ncbi.nlm.nih.gov/36861445/ Singal M, Kouides PA. Recombinant von Willebrand factor: a first-of-its-kind product for von Willebrand disease. Drugs Today (Barc). 2016 Dec;52(12):653-664. https://pubmed.ncbi.nlm.nih.gov/28116368/ Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–. Von Willebrand Factor. 2018 Dec 3. https://www.ncbi.nlm.nih.gov/books/NBK501387/ Winikoff R, Scully MF, Robinson KS. Women and inherited bleeding disorders - A review with a focus on key challenges for 2019. Transfus Apher Sci. 2019 Oct;58(5):613-622. https://pubmed.ncbi.nlm.nih.gov/31582329/ Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9485137","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":632963107,"identity":"1f2e64b4-943f-4f85-bcc6-4f7a5339753c","order_by":0,"name":"Xiaoxia Liu","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoxia","middleName":"","lastName":"Liu","suffix":""},{"id":632963108,"identity":"2680d5ca-83f1-4cb9-a9fa-3696839ebbf4","order_by":1,"name":"Man Xiao","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Xiao","suffix":""},{"id":632963109,"identity":"283d9115-2822-4ed2-b2f8-1c52187d7949","order_by":2,"name":"Yang Zhang","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Zhang","suffix":""},{"id":632963110,"identity":"d8d93a62-d3be-40b2-9206-4ec9802681e7","order_by":3,"name":"Lijuan Chen","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lijuan","middleName":"","lastName":"Chen","suffix":""},{"id":632963111,"identity":"614f5889-a7eb-42e1-9b11-dccb7d02a2da","order_by":4,"name":"Defeng Shu","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Defeng","middleName":"","lastName":"Shu","suffix":""},{"id":632963112,"identity":"40e65c1b-4e33-4e34-bb2b-5d6f8f5a9221","order_by":5,"name":"Huafang Wang","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huafang","middleName":"","lastName":"Wang","suffix":""},{"id":632963113,"identity":"5698d0c9-3721-4eee-9924-e312153c09c0","order_by":6,"name":"Jing Wu","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Wu","suffix":""},{"id":632963114,"identity":"44310948-bd78-43dd-83aa-ede266d80d13","order_by":7,"name":"Yin Zhao","email":"","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yin","middleName":"","lastName":"Zhao","suffix":""},{"id":632963115,"identity":"20a183a5-c4c3-47b2-80f5-5eff570b4f02","order_by":8,"name":"Li Zou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYDACZgY2MM3HzHwMKpRApBY2ZrY0IGVAhBYGmBYGHjPitBgcZz724MMfm8Q2dp5vj3n+/GHgZ88xYPi5A7cWyWa2dMMZPGmJbcy824152wwYJHveGDD2nsGthZ+Zx0yaR+IwSMs2ad4GAwaDGzkGzIxteDzCzP9N+o8BSAvPM2mePwYM9oS0AG1hk2ZIAGthk+ZhA9oiQUAL0C9mkj0H0ozbmIGMuW3GPBJnnhUc7MWjxeD84WcSP/7YyPbzAxlv/sjJ8bcnb3zwE48WDMADIg6QoGEUjIJRMApGARYAACi6QXSBK7+VAAAAAElFTkSuQmCC","orcid":"","institution":"Wuhan Union Hospital","correspondingAuthor":true,"prefix":"","firstName":"Li","middleName":"","lastName":"Zou","suffix":""}],"badges":[],"createdAt":"2026-04-21 13:39:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9485137/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9485137/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108948589,"identity":"fe3ca2a2-a84a-4099-876e-32d10f0537f5","added_by":"auto","created_at":"2026-05-11 06:45:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":166349,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9485137/v1/5c4987ba-f865-460e-b148-a118ad11af63.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"MDT-based Comprehensive Management of Type 3 Von Willebrand Disease in Pregnancy: From Preimplantation Genetic Testing to Antenatal Care, Delivery and Postpartum Period","fulltext":[{"header":"Background","content":"\u003cp\u003eVon Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative abnormalities of von Willebrand factor (VWF) [1]. VWF plays a central role in hemostasis by mediating platelet adhesion to sites of vascular injury and by stabilizing coagulation factor VIII (FVIII) as its carrier protein. Based on the nature of the VWF abnormality, VWD is classified into three main types. Type 1, a partial quantitative deficiency, accounts for approximately 70–80% of cases. Type 2 comprises qualitative defects and is further divided into subtypes 2A, 2B, 2N, and 2M. Type 3, characterized by severe reduction or complete absence of VWF, represents approximately 1–5% of cases [2].\u003c/p\u003e\n\u003cp\u003eThe severity of bleeding correlates with the extent of VWF deficiency or dysfunction [3]. Type 3 VWD, associated with undetectable VWF and markedly reduced FVIII, carries the most severe bleeding phenotype. Affected individuals often present in childhood with mucocutaneous bleeding and menorrhagia; bleeding may also involve muscles, joints, and internal organs, and life-threatening hemorrhage—including intracranial bleeding—may occur [4]. In healthy pregnancy, estrogen-driven increases in VWF and FVIII begin in the first trimester, peak at delivery, remain elevated for two to three days postpartum, and then decline to baseline over one to three weeks. In type 1 VWD, levels typically rise as well, albeit from a lower baseline. In type 3 VWD, however, this physiological response is generally absent, leaving patients in a persistently hypocoagulable state throughout gestation and the peripartum period [5]. Consequently, the risks of spontaneous abortion, antepartum hemorrhage,d and postpartum hemorrhage are substantially elevated [6]. A carefully individualized approach to pregnancy and peripartum management is therefore essential. Here we describe the successful pregnancy and delivery of a patient with type 3 VWD, highlighting a multidisciplinary, target-guided peripartum management strategy supported by recombinant VWF replacement.\u0026nbsp;\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003e\u003cstrong\u003e1. General Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient was a 36-year-old woman (gravida 2, para 0) admitted at 36 weeks and 1 day of gestation with occasional lower abdominal tightness for one day. Her admission weight was 60kg, and her blood type was O, RH+. She reported easy bruising and mucocutaneous bleeding since childhood. Routine blood counts and initial coagulation screening had previously been normal, and no specific treatment was given. During adolescence, her menstrual cycles were 30 days with seven days of bleeding, and menstrual volume was markedly increased, exceeding 200 mL per cycle. In March 2023, she underwent right salpingectomy for ectopic pregnancy at another institution, complicated by hemorrhagic shock; two days postoperatively, she developed recurrent intra-abdominal bleeding that required stabilization with multiple plasma transfusions. In April 2023, she was evaluated at our hematology department, where disseminated intravascular coagulation testing and VWF gene sequencing led to a diagnosis of type 3 VWD. Whole-exome sequencing revealed a heterozygous VWF mutation (chr12:5952480-5952480, exon 49; missense mutation, NM_000552.5: c.8026T\u0026gt;C: p.C2676R); her husband was wild-type.\u003c/p\u003e\n\u003cp\u003eShe reported no history of joint bleeding, deep hematoma, or transfusion-related allergic reactions. Family history was unremarkable for bleeding disorders, and neither parent reported a bleeding tendency. Overall, these features indicated a severe bleeding phenotype and informed high‑risk planning for invasive procedures and delivery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Key Laboratory Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiagnostic laboratory testing in April 2023 showed normal complete blood counts. Coagulation profile revealed prothrombin time (PT) 12.9 s (reference range 11–16 s), international normalized ratio (INR) 0.99 (0.9–1.22), activated partial thromboplastin time (APTT) 54.8 s (20–47 s), fibrinogen 2.91 g/L (2–4 g/L), thrombin time (TT) 16.6 s (14–21 s), and factor VIII procoagulant activity (FVIII:C) 14.0% (70–150%). Plasma VWF antigen was 4.0% (50–160%, VWF:Ag), VWF activity (platelet-binding activity，VWF:GPⅠbM) was undetectable at 0.0% (40–163%), and the VWF activity-to-antigen ratio was 0.0 (≥0.5) [7]. Additional testing for hemophilia excluded inherited FVIII deficiency (hemophilia A carrier). Collectively, these findings indicated severe VWF deficiency with markedly reduced FVIII activity, consistent with type 3 VWD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Pregnancy Course\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1 Assisted Reproduction via In Vitro Fertilization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn November 2024, the patient sought care at our reproductive medicine department for infertility and planned to undergo in vitro fertilization (IVF). An initial multidisciplinary team (MDT) consultation was convened by the reproductive medicine team, with participation from hematology, transfusion medicine, genetics, and laboratory medicine. The MDT concluded that the patient’s heterozygous VWF mutation warranted counseling regarding the risk of VWD in offspring, and that preimplantation genetic testing could reduce the risk of hereditary transmission. Given the high bleeding risk associated with type 3 VWD, the team recommended prophylactic hemostatic support for oocyte retrieval, with cryoprecipitate or plasma prepared in advance. The patient underwent oocyte retrieval in December 2024 and received six units of cryoprecipitate plus 600 units of recombinant human FVIII daily on the day of the procedure and for two days before and after. The procedure was uneventful, with no abnormal bleeding or intra-abdominal hemorrhage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Amniocentesis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEmbryo transfer was performed on January 27, 2025. Ultrasonography at approximately seven weeks confirmed an intrauterine singleton viable pregnancy. Routine antenatal care was provided, and no abnormal bleeding occurred during pregnancy. Owing to the patient’s heterozygous VWF mutation and the use of preimplantation genetic testing, amniocentesis for prenatal diagnosis was scheduled at 18 weeks of gestation (May 23, 2025). A second MDT consultation, led by obstetrics and including hematology, transfusion medicine, ultrasound, and genetics, recommended that replacement therapy be prepared, given the substantially increased risks of bleeding and miscarriage after amniocentesis compared with healthy pregnant women. The team considered amniocentesis a minor surgical procedure and set a pre‑procedural target VWF activity of\u0026nbsp;≥30%. Pre-procedure testing on May 19, 2025, showed PT 11.9 s, INR 0.90, APTT 49.2 s, fibrinogen 4.04 g/L, TT 15.8 s, FVIII:C 6.7%, VWF antigen 6.7%, and VWF activity undetectable at 0.0%.\u003c/p\u003e\n\u003cp\u003eRecombinant VWF (rVWF, vonicog alfa for injection) was selected for precise replacement. Following infusion of 1300 IU of rVWF at 9:00 AM, VWF activity measured at 11:00 AM had risen to 31.9%, meeting the predefined target. Subsequently, 400 IU of recombinant human FVIII was administered. Amniocentesis was then performed under ultrasound guidance, yielding 40 mL of clear amniotic fluid. Hemostasis was achieved after 20 seconds of compression at the puncture site. Post-procedure fetal heart rate was normal, and the patient reported no discomfort. Coagulation testing at 5:10 PM showed PT 13.0 s, INR 1.00, APTT 39.8 s, fibrinogen 3.44 g/L, FVIII:C 45.8%, VWF antigen 35.6%, and VWF activity 25.8%. Four days after the procedure, VWF activity remained measurable at 10.0% and FVIII:C at 40.0%. Amniocentesis results revealed no fetal chromosomal copy number variations, and whole-exome sequencing identified no pathogenic variants. Routine antenatal assessments, including nuchal translucency (1.4 mm), oral glucose tolerance testing, and fetal systematic ultrasound, were unremarkable, and fetal growth was appropriate for gestational age.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Peripartum Management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 36 weeks of gestation, the patient began experiencing occasional uterine contractions, raising concern for imminent labor. A third MDT consultation, led by obstetrics and including hematology, anesthesiology, intensive care, neonatology, and transfusion medicine, was convened to establish a delivery plan. The team opted for elective cesarean section at 37 weeks to avoid the unpredictable risks of precipitous labor, cervical lacerations, and perineal hematoma associated with vaginal delivery, and to enable precise timing of replacement therapy. Cesarean section was classified as major surgery, and a preoperative target VWF activity of\u0026nbsp;≥50% was established [8]. General anesthesia was chosen to eliminate the bleeding risk associated with neuraxial techniques. Postoperative intensive care unit observation was planned, along with coagulation testing of the neonate.\u003c/p\u003e\n\u003cp\u003eOn September 23, 2025 (37 weeks of gestation), 2600 IU of rVWF was infused at 6:00 AM. Coagulation testing at 10:00 AM showed VWF antigen 72.3%, VWF activity 51.2%, FVIII:C 55.2%, PT 12.8 s, INR 0.98, and APTT 40.3 s, meeting the target hemostatic levels for surgery. The patient was transferred to the operating room at 12:10 PM, and an additional 600 IU of recombinant human FVIII was administered preoperatively. General anesthesia was induced. A live female infant weighing 2850 g was delivered, with Apgar scores of 9 and 10. Umbilical cord blood was obtained for coagulation testing. Intraoperatively, uterine atony was managed with intravenous tranexamic acid 1 g, intravenous carbetocin 100μg, intramuscular carboprost tromethamine 250μg, and bilateral ascending uterine artery ligation to prevent postpartum hemorrhage. The subcutaneous tissue and skin were closed with interrupted 2-0 silk sutures to reduce the risk of subcutaneous hematoma. Meticulous surgical technique was employed to ensure adequate hemostasis. Total operative time was 40 minutes, with an estimated blood loss of 400mL. The neonate received routine vitamin K1 supplementation and did not develop cephalohematoma or intracranial hemorrhage.\u003c/p\u003e\n\u003cp\u003eCoagulation testing 2.5 hours postoperatively demonstrated VWF activity 55.2% and FVIII:C 82.3%. On postoperative day 1, VWF activity had decreased to 33.5%, while FVIII:C was 113.7%. On postoperative day 2, VWF activity was 14.6% and FVIII:C 73.1%; an additional 2600 IU of rVWF was infused. Intravenous tranexamic acid (1 g daily) was continued until postoperative day 10, with coagulation function monitored every other day. The patient had no abnormal vaginal bleeding postoperatively, lochia volume was normal, and the abdominal incision healed well. She was discharged on postoperative day 10. No adverse events, infusion reactions, thrombotic events, or treatment‑related complications were observed during hospitalization or within the postpartum period\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with type 3 VWD have complete VWF deficiency, resulting in impaired platelet adhesion and aggregation [9]. In addition, the absence of VWF-mediated protection of FVIII leads to a shortened FVIII half-life. Affected individuals often exhibit a severe bleeding tendency from childhood, including menorrhagia; the patient described here had a history of perioperative hemorrhagic shock and an International Society on Thrombosis and Haemostasis Bleeding Assessment Tool score of 8 [10-11]. The key challenge in managing pregnancy complicated by type 3 VWD lies in the persistent absence of physiological increases in VWF and FVIII throughout gestation, which confers a high bleeding risk [12]. Ensuring maternal and fetal safety therefore requires coordinated multidisciplinary care and proactive prophylactic replacement therapy [13].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreconception Counseling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWomen with bleeding disorders should receive preconception counseling at a comprehensive center, with close follow-up by a multidisciplinary team including specialists in hematology, maternal‑fetal medicine, clinical genetics, neonatology, pediatric hematology, and anesthesiology [14]. While VWF gene mutations are identified in only 62% of patients with type 1 VWD, detection rates exceed 90% in types 2 and 3[11, 15-16]. Genetic testing is therefore advisable for patients with type 2 or type 3 disease [17]. Type 3 VWD is typically inherited in an autosomal recessive manner, resulting from homozygous or compound heterozygous VWF mutations [18]. In the present case, the patient had a heterozygous VWF mutation but presented with a type 3 phenotype (undetectable VWF); her partner was wild-type, conferring a 50% risk of inheritance in offspring. For at-risk couples, preimplantation genetic testing can prevent up to 99% of hereditary transmission [19].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAntenatal Management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInvasive procedures during pregnancy\u0026mdash;such as cervical cerclage or amniocentesis\u0026mdash;carry increased hemostatic risks in women with VWD and require careful planning, active monitoring, and availability of replacement therapy [5]. In this case, serial coagulation testing before pregnancy and at 18, 24, and 32 weeks of gestation consistently showed VWF antigen below 10%, VWF activity undetectable, and FVIII:C between 3% and 10%, with no evidence of the physiological increase expected in pregnancy.\u003c/p\u003e\n\u003cp\u003eRegarding mode of delivery, VWD is not an absolute indication for cesarean section [20]. However, for type 3 VWD, elective cesarean section is often preferred because it reduces the unpredictability associated with labor and allows precise timing of replacement therapy. The planned cesarean delivery in this case illustrates the advantages of such an approach.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePostpartum Hemorrhage\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostpartum hemorrhage represents one of the most significant threats in - women with VWD [21]. Even with treatment, the reported incidence of PPH ranges from 20% to 51%. Hemorrhage may occur at delivery or during the puerperium, necessitating close monitoring of VWF and FVIII levels [5]. Operative vaginal deliveries (forceps or vacuum extraction) should be avoided to minimize traumatic bleeding for both mother and infant. In addition to ensuring appropriate VWD management, specific obstetric causes of PPH\u0026mdash;such as uterine atony and retained placenta\u0026mdash;must be addressed [22]. In this case, uterine atony was managed with uterotonic agents and bilateral ascending uterine artery ligation. Antifibrinolytic agents are effective for both PPH treatment and VWD management [22-24]. Guidelines from the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia recommend tranexamic acid for PPH prophylaxis in all patients with VWD, administered orally or intravenously for 10\u0026ndash;14 days postpartum [25]. In our patient, postoperative tranexamic acid was continued for 10 consecutive days, effectively covering the peak risk period for PPH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnesthesia Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEpidural or combined spinal-epidural anesthesia is generally contraindicated in patients with coagulation disorders [26]. Current guidelines suggest that neuraxial techniques may be considered when VWF activity is maintained above 50 IU/dL, with these levels sustained for at least six hours after catheter placement and removal [25, 27]. In the present case, although preoperative VWF activity reached 51.2% following rVWF replacement, the multidisciplinary team opted for general anesthesia. This decision was made based on the limited institutional experience with neuraxial anesthesia in patients with complete VWF deficiency, as well as the desire to eliminate any potential bleeding risk associated with epidural catheter insertion and removal. General anesthesia offers a well-established safety profile, excellent controllability, and the absence of procedure-related bleeding risk in this high-risk population [28]. This decision reflected institutional practice and experience rather than a universal contraindication to neuraxial anesthesia in all patients with VWD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTiming and Targets of Peripartum rVWF Replacement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnlike healthy pregnant women or those with type 1 VWD, patients with type 3 VWD do not exhibit a physiological increase in VWF, and FVIII:C remains persistently low. Maintaining effective VWF activity throughout pregnancy is therefore essential [5-6,8]. Current guidelines recommend that perioperative VWF activity and FVIII:C levels be maintained above 50% in patients with VWD, and for major surgeries such as cesarean section, these levels should be sustained for at least three days postoperatively. For type 3 VWD, replacement therapy is advised for at least five days after uncomplicated vaginal delivery and for seven to ten days following cesarean section [25].\u003c/p\u003e\n\u003cp\u003eCesarean section involves greater surgical trauma than amniocentesis, and complications such as uterine atony further increase bleeding risk, necessitating higher VWF activity targets. In this case, a 1300 IU rVWF infusion before amniocentesis raised VWF activity sufficiently to allow the procedure without bleeding complications. Prior to cesarean section, administration of 2600 IU of rVWF achieved the predefined hemostatic target. On postoperative day 2, when VWF activity declined to 14.6%, an additional 2600 IU rVWF was administered, effectively preventing PPH. These observations suggest that replacement doses can be tailored to procedural risk and individual patient characteristics, avoiding overtreatment [29]. The strategy of preoperative rVWF infusion followed by postoperative monitoring used here avoided the fluctuations in VWF levels associated with traditional replacement regimens and highlights the advantage of precision therapy with rVWF [30].\u003c/p\u003e\n\u003cp\u003eWhen rVWF is used for replacement, concurrent FVIII supplementation is required before surgery or invasive procedures. The combination of rVWF and FVIII may act synergistically: VWF supports platelet adhesion and stabilizes FVIII, while FVIII directly participates in the coagulation cascade [31]. Their combined use may contribute to effective control of surgical and postpartum bleeding in selected clinical settings. In this patient, postoperative tranexamic acid was also administered, providing additional synergy with rVWF to further reduce PPH risk [23]. Notably, tranexamic acid does not affect breastfeeding, aligning with perinatal medication safety considerations.\u003c/p\u003e\n\u003cp\u003eType 3 VWD is the most severe subtype. Traditional replacement options include cryoprecipitate, fresh frozen plasma, and plasma-derived FVIII concentrates containing VWF, each with limitations such as viral transmission risk and incomplete VWF multimer integrity [32]. Recombinant VWF, produced using genetic engineering technology, offers high purity and an intact multimer structure [33]. It specifically replenishes VWF while also raising FVIII:C levels, making it an attractive option for replacement therapy in type 3 VWD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNeonatal Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the neonatal period, VWF and FVIII levels may be falsely elevated owing to stress; umbilical cord blood testing is therefore important to establish baseline values [34]. In this case, cord blood showed VWF activity 58.0% and FVIII:C 67.2%, with no bleeding manifestations and normal coagulation function. Because amniocentesis had confirmed that the neonate did not carry the pathogenic variant, long-term coagulation follow-up was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eValue of Multidisciplinary Management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eManaging VWD in pregnancy requires a multidisciplinary team comprising specialists in adult hematology, maternal-fetal medicine, obstetrics, anesthesiology, and neonatology, with input from genetic counselors, specialized pharmacists, coagulation laboratories, and transfusion medicine services [25, 35]. The patient is also a key member of the team and should be actively involved in treatment decisions. In this case, three MDT consultations enabled individualized care from the preconception period through delivery, ultimately achieving favorable maternal and neonatal outcomes consistent with international consensus on peripartum VWD management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePregnancy complicated by type 3 von Willebrand disease is a rare and high-risk obstetric condition. Successful maternal and neonatal outcomes depend on early diagnosis, preconception counseling, and sustained multidisciplinary collaboration. Recombinant von Willebrand factor provides a precise, safe, and effective option for peripartum replacement therapy in pregnant women with type 3 VWD, substantially reducing bleeding risk associated with invasive procedures and the peripartum period itself. With careful monitoring of coagulation parameters and targeted rVWF replacement, life-threatening hemorrhage can be effectively prevented or managed, enabling favorable pregnancy outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the whole team members involved in the management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiaoxia Liu, Man Xiao，and Yang Zhang were involved in drafting the manuscript. Lijuan Chen, Defeng Shu, Huafang Wang and Jing Wu were the members of the MDT team and had given very professional opinions on patients\u0026apos; assisted reproduction, genetic counseling, hematology management and anesthesia management. Yin Zhao and Li Zou were the MDT leaders of this case and core members of obstetrics, and the manuscript was reviewed and edited by them. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Hubei Provincial Health and Well-ness Science and Technology Project (WJ2025M069).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent has been obtained from the patient to publish this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSeidizadeh O, Eickenboom JCJ, Denis CV, et al. von Willebrand disease. 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Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):552-558. https://pubmed.ncbi.nlm.nih.gov/34889375/\u003c/li\u003e\n \u003cli\u003eByrne B, Ryan K, Lavin M. Current Challenges in the Peripartum Management of Women with von Willebrand Disease. Semin Thromb Hemost. 2021 Mar;47(2):217-228. https://pubmed.ncbi.nlm.nih.gov/33636707/\u003c/li\u003e\n \u003cli\u003eWorld Health Organization, International Federation of Gynecology and Obstetrics, International Confederation of Midwives. Consolidated guidelines for the prevention, diagnosis and treatment of postpartum haemorrhage. Geneva: World Health Organization, 2025: 116. https://www.who.int/publications/i/item/9789240107472\u003c/li\u003e\n \u003cli\u003eAdepoju VA, Abdulrahim A, Olaniyi BO, et al. A Systematic Review and Meta-Analysis on the Effectiveness and Safety of Tranexamic Acid for Postpartum Haemorrhage in Patients with Haemorrhagic Disorders. 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Von Willebrand Factor. 2018 Dec 3. https://www.ncbi.nlm.nih.gov/books/NBK501387/\u003c/li\u003e\n \u003cli\u003eWinikoff R, Scully MF, Robinson KS. Women and inherited bleeding disorders - A review with a focus on key challenges for 2019. Transfus Apher Sci. 2019 Oct;58(5):613-622. https://pubmed.ncbi.nlm.nih.gov/31582329/\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Type 3 von Willebrand disease, Pregnancy, Multidisciplinary collaboration, Recombinant von Willebrand factor, Maternal-fetal safety","lastPublishedDoi":"10.21203/rs.3.rs-9485137/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9485137/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Type 3 von Willebrand disease is a rare and severe inherited bleeding disorder characterised by an almost complete deficiency of von Willebrand factor and markedly reduced factor VIII levels. During pregnancy, the physiological increase in coagulation factors seen in healthy women is absent, placing affected patients at high risk of maternal and neonatal haemorrhage. Management of invasive obstetric procedures and delivery therefore remains clinically challenging. This case highlights the use of a target-guided strategy with multidisciplinary collaboration and recombinant von Willebrand factor in a Chinese patient.\u003c/p\u003e\n\u003cp\u003eCase presentation: A 36 years old woman with type 3 von Willebrand disease conceived via in vitro fertilisation. She was managed throughout pregnancy and the peripartum period using a target-guided strategy with recombinant von Willebrand factor, coordinated through serial multidisciplinary team evaluations. To our knowledge, this is the first reported peripartum application of this agent in China. Recombinant von Willebrand factor was administered before amniocentesis to achieve a pre-procedural von Willebrand factor activity target of ≥30% (actual 31.9%) and before elective caesarean section to achieve a surgical target of ≥50% (actual 51.2%), with adjunct factor VIII supplementation as required. Caesarean delivery was completed with an estimated blood loss of 400 millilitres, and no postpartum or neonatal haemorrhagic complications occurred.\u003c/p\u003e\n\u003cp\u003eConclusions: This case demonstrates that pregnancy complicated by type 3 von Willebrand disease can be managed safely through anticipatory planning, multidisciplinary collaboration and dynamic laboratory monitoring with target-guided recombinant von Willebrand factor replacement, providing practical guidance for obstetricians managing high-risk pregnancies with severe inherited bleeding disorders.\u003c/p\u003e","manuscriptTitle":"MDT-based Comprehensive Management of Type 3 Von Willebrand Disease in Pregnancy: From Preimplantation Genetic Testing to Antenatal Care, Delivery and Postpartum Period","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 06:40:52","doi":"10.21203/rs.3.rs-9485137/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-05-01T12:45:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-23T06:21:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-23T06:21:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2026-04-21T13:30:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"387959d8-98b9-4e8e-a532-0e6660134541","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewersInvited","content":"4","date":"2026-05-01T12:45:18+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T06:40:53+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 06:40:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9485137","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9485137","identity":"rs-9485137","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}