This month Margaret V. Ragni, MD, MPH, discusses treatment options for a pregnant patient with type 2A von Willebrand disease.
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I have a patient at 37 weeks of her fourth pregnancy. She has a history of type 2A von Willebrand disease (vWD), requiring Humate-P replacement in the prior two deliveries and other bleeding occasions (epistaxis, hematuria, and heavy menses prior to last pregnancy, which required monthly doses of Humate-P 1,450 units). She will undergo vaginal induction delivery in two weeks. She weighs 161 pounds. Her current values are as follows: PT, PTT, and fibrinogen are normal; factor VIII (FVIII) is 96 percent; von Willebrand factor (vWF) antigen is 113 percent; and vWF activity is 34 percent. My recommendations include keeping activity level at 100 percent prior to delivery and three days postpartum, Humate-P 2,400 units 30 minutes prior to epidural, then the same dose every 12 hours for three days followed by Humate-P 1,450 units daily until hemostasis is achieved. Are my dosing recommendations correct?
Your question is important, as few guidelines exist that address managing delivery in women with vWD, and the guidelines that do exist are grade III, level C (expert opinion).1-3 It is recommended that vWF 50 IU/kg should be given pre-delivery/epidural followed by up to three days postpartum. The problem is that, despite treatment, women with vWD have a 1.4-fold greater blood loss and 1.4-fold lower vWF levels than those without.4 Why treatment fails and what the optimal treatment is for women with vWD at delivery is not known; however, it is the subject of a planned randomized controlled trial (PREVENT PPH).5
In normal pregnancy, blood volume increases, peaking by 1.5-fold by the third trimester.6-8 At the same time, vWF levels progressively increase, peaking at delivery and falling to pre-pregnancy levels within three weeks. Yet, guidelines suggest vWF 50 IU/kg only for those with third trimester vWF levels of <0.50 IU/mL, noticeably lower than the 80 IU/kg dose for general surgery. 1-3 The failure of 50 IU/kg to prevent postpartum bleeding suggests more effective treatment is needed. 4
vWF treatment is suggested for women with third-trimester vWF:RCo levels below 0.50 IU/dL. Yet, the basis for this recommendation is unclear. In a recent retrospective study of women with vWD, factors associated with postpartum bleeding (>500 mL) included low pre-pregnancy vWF, a high pre-pregnancy bleeding score (≥5), high pre-pregnancy weight, and a family history of bleeding.5 Although this was a small single-center study, it suggests pre-pregnancy disease severity is important in assessing postpartum bleeding risk.
The vWF dose recommended at delivery is 50 IU/kg. Delivery is a surgical procedure, and the basis for using a dose lower than what is used for general surgery is unclear. It is known that some experts avoid vWF doses above 50 IU/kg in pregnant women because of the increased risk of thrombosis associated with the gravid state. A literature review of 13 studies from 1992 to 2015 of 474 non-pregnant patients with vWD treated with up to vWF 220 IU/kg, the thrombosis rate was low at 0.4 percent.5 These data suggest the risk of thrombosis in pregnancy also may be low. The question of whether vWF dosing should be based on body weight or blood volume, which increases 1.4-fold during pregnancy, will require further study.6-8
Compared with plasma-derived vWF, recombinant vWF has no infectious agent transmission, prolongs half-life 1.4-fold, and has greater purity and potency promoting platelet and collagen binding and FVIII stabilization, with no increased risk of thrombosis, as it is degraded by patient’s own ADAMTS-13.9,10 Its longer half-life may potentially reduce dose frequency, compared with plasma-derived vWF.
Based on the above considerations, it would be reasonable to use plasma-derived vWF 50 to 80 IU/kg or recombinant vWF 50 to 80 IU/kg just prior to epidural or spinal anesthesia, or delivery, and for the first three to five days postpartum. Additional dosing would be indicated for continued or uncontrolled bleeding, which can last up to six weeks postpartum in women with vWD.
- Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute Expert Panel report (USA). Haemophilia. 2008;14:171-232.
- National Hemophilia Foundation. MASAC guidelines for perinatal management of women with bleeding disorders and carriers of hemophilia A and B. Medical and Scientific Advisory Committee, document #192. New York, 2009.
- Laffan MA, Lester W, O’Donnell JS, et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014;167:453-65.
- James AH, Konkle BA, Koudies P, et al. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Haemophilia. 2015;21:81-7
- Ragni MV, Machin N, Seaman CD, et al. The PREVENT trial: von Willebrand factor to prevent postpartum blood loss. Thromb Res. 2017;156:8-13.
- Hytten F. Blood volume changes in normal pregnancy. Clin Hematol. 1985;14:601-12.
- Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment in normal term pregnancy. Am J Obstet Gynecol. 1989;161:1439-42.
- Liu LX, Arany Z. Maternal cardiac metabolism in pregnancy. Cardiovas Res. 2014;101:545-53.
- Gill J, Castaman G, Windyga J, et al. Safety, efficacy, pharmacokinetics of recombinant VWF in patients with severe von Willebranddisease. Blood. 2015;126:2038-46.
- Turecek PL, Schrenk G, Rottensteiner H, et al. Structure and function of a recombinant von Willebrand factor drug candidate. SeminThromb Hemost. 2010;36:510-21.
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NEXT MONTH'S CLINICAL DILEMMA
A 33-year-old transgender female patient was involved in a motor vehicle accident that resulted in severe liver laceration, bile duct injury, and a subdural hematoma. She required multiple surgeries and was hospitalized for 91 days, followed by inpatient rehabilitation. At the time of the accident, she was on hormone replacement therapy (HRT), which was stopped during her stay in the intensive care unit. About 26 days into her hospitalization, she had a deep vein thrombosis and pulmonary embolism. She had an inferior vena cava filter placed and was started on anticoagulation. I saw her for the first time last week. Will she be able to go back on HRT? Would you consider lifelong anticoagulation in this patient who needs HRT? She had been on HRT for eight years with no problems prior to this event. There is no family history of thromboembolic disease.
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