Recombinant Von Willebrand Factor for Pediatric Patient with Von Willebrand Disease: First Report in Korea

Clinical Pediatric Hematology-Oncology Volume 28ㆍNumber 1ㆍApril 2021 CASE REPORT

Recombinant von Willebrand Factor for Pediatric Patient with von Willebrand Disease: First Report in Korea

Seoin Kim and Young Shil Park

Department of Pediatrics, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, Seoul, Korea

von Willebrand disease (VWD) is the most common hereditary bleeding disorder. The pISSN 2233-5250 / eISSN 2233-4580 https://doi.org/10.15264/cpho.2021.28.1.54 treatment of VWD consists mainly of desmopressin and plasma-derived von Willebrand Clin Pediatr Hematol Oncol factor (pd-VWF) concentrate. We report on the first patient with VWD to be treated 2021;28:54∼57 with recombinant VWF (rVWF) concentrate in Korea. Our patient was diagnosed with type 2 VWD at 10 months of age and suffered persistent severe epistaxis despite ther- Received on March 12, 2021 apeutic levels of VWF activity and factor VIII (FVIII). At 34 months of age, rVWF was Revised on April 14, 2021 initiated and administered a total of 15 times in the following 8 months. No drug-re- Accepted on April 15, 2021 lated adverse events were observed and the patient was neither admitted nor given any transfusions during this period. Unlike pd-VWF/FVIII concentrates, rVWF did not increase FVIII to the excessively high levels that constitute a risk factor for throm- boembolism, and was also preferable to pd-VWF/FVIII concentrates in that it con- Corresponding Author: Young Shil Park tains ultra-large multimers of VWF. This is the first reported case in Korea in which Department of Pediatrics, Kyung rVWF was used to treat VWD. rVWF may be well tolerated and effective in VWD pa- Hee University Hospital at tients, especially those with refractory bleeding. Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Korea Tel: +82-2-440-6133 Fax: +82-2-440-7175 Key Words: Recombinant von Willebrand factor concentrate, Plasma derived von E-mail: [email protected] Willebrand factor concentrate, von Willebrand disease ORCID ID: orcid.org/0000-0002-6643-4245

dality of treatment depends on the type and severity of Introduction VWD, as well as the intensity of the hemorrhagic event [3]. von Willebrand disease (VWD) is a hereditary bleeding Pd-VWF/FVIII concentrates have inherent limitations, disorder caused by deficiency or dysfunction of von since they lack larger molecular weight multimers nor- Willebrand factor (VWF), which is the largest soluble mally found in plasma and vary considerably in VWF multimeric plasma glycoprotein [1]. Until today, the most multimer composition and VWF:FVIII ratio even within commonly adopted treatment methods to manage bleed- the same product [2]. Recombinant VWF (rVWF) could ing in VWD patients include human plasma-derived co- change the treatment approach to VWD by avoiding the agulation factor concentrates containing VWF and factor risks associated with plasma-derived products, while VIII (pd-VWF/FVIII), desmopressin that increases VWF maintaining efficacy and consistency [3,4]. and FVIII plasma concentrations by releasing endoge- In this article, we report on the first patient with VWD nous VWF from endothelial cells, and adjuvant agents to be treated with rVWF in Korea. that promote local hemostasis and wound healing without altering plasma concentrations of VWF [2]. The mo-

Copyright ⓒ 2021 Korean Society of Pediatric Hematology-Oncology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://c reativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

54 rVWF for Patient with VWD: First Report in Korea

Case Report

A 14-month-old girl with VWD visited the emergency department at our hospital for uncontrolled epistaxis. She suffered epistaxis for over 5 hours, even after administration of 50 IU/kg pd-VWF/FVIII concentrates. The patient was first diagnosed with VWD at another hospital at 10 months old, when an immunization resulted in severe bruising. Her test results at the time of diagnosis were as follows: FVIII, 45.9%; VWF antigen (Ag), 45.7%; Fig. 1. Changes in values over time after administration of re- von Willebrand factor ristocetin cofactor (VWF:RCo), combinant von Willebrand factor (rVWF) concentrate (50 IU/kg). 20.6%; and blood type A+. After 30 minutes, VWF antigen (Ag) and von Willebrand factor The patient’s initial vital signs were as follows: blood ristocetin cofactor (VWF:RCo) rose to effective hemostatic con- centration levels without a significant increase in factor VIII (FVIII). pressure, 100/51 mmHg; heart rate, 199 beats/minute; body temperature, 36.2oC; and peripheral oxygen saturation (SpO2), 96%. Upon physical examination, she displayed (vonicog alfa, 50 IU/kg) instead of pd-VWF/FVIII concen- pallor, loss of activity, and postnasal blood drip. Her trates. The patient was given rVWF for the first time at blood tests revealed the following: white blood cell count, 34 months. She was observed for signs of any adverse re- 16.75×103/µL; hemoglobin, 7.5 g/dL; hematocrit, 23.1%; action to rVWF. Thirty minutes after administration, VWF platelet count, 327×103/µL; prothrombin time (PT), 12.4 Ag rose to 151% and vWF:RCo to 80%. FVIII was mildly s; PT international normalized ratio, 1.11; activated par- elevated to 38-45.7% during rVWF treatment, whereas it tial thromboplastin time 37.5 s; VWF Ag, ＞200%; and increased to over 100% after pd-FVIII/VWF admin- VWF:RCo, 62%. istration (Fig. 1). Epistaxis was also well controlled. The patient was admitted and given multiple doses of In the 8 months during which the patient was treated pd-VWF/FVIII concentrates and intravenous tranexamic with rVWF, we performed mixing test after 5th and 14th acid, after which symptoms improved. At the outpatient administration to check if any neutralizing antibodies to clinic 1 month later, and without any additional pd-VWF/ rVWF had been formed, and concluded that they had not. FVIII concentrates, her results were as follows: FVIII, The patient was given rVWF a total of 15 times in an 82.1%; VWF Ag, 44%; and VWF:RCo, ＜1%. In addition, 8-month period, during which she was not admitted or VWF multimer analysis revealed a decrease in the high given any transfusions. Bleeding was well-controlled with molecular weight forms of VWF multimers. This is sug- each administration of 1-2 doses. gestive of type 2B or 2A VWD. In the following 20 months, the patient has visited our Discussion hospital for treatment of bleeding 39 times, all of which were epistaxes except for one case of gum bleeding. She This was the first reported case in Korea in which was admitted four times and given repeated doses of VWD was treated with rVWF. There were no thromboem- pd-VWF/FVIII concentrates, as well as packed red blood bolic events or any adverse reactions to the drug. Our cell transfusions. Although her blood tests after pd-VWF/ case is noteworthy in that, prior to rVWF treatment, the FVIII concentrates administration showed VWF Ag from patient had persistent epistaxis despite achieving ther- 74-200%, VWF:RCo from 49-99%, and FVIII＞100%, the apeutic levels of VWF [5]. She had type 2B or 2A VWD, bleeding continued. Eventually, we decided to use a rVWF characterized by an absence or decreased levels of high-

Clin Pediatr Hematol Oncol 55 Seoin Kim and Young Shil Park molecular-weight multimers (HMWMs) [3]. She continued Vonicog alfa, the first rVWF, has been licensed for treat- to bleed even when treatment with pd-VWF/FVIII con- ment of bleeding episodes and perioperative manage- centrates elevated VWF Ag, VWF:RCo activity, and FVIII ment of bleeding in the United States [14]. In Europe, it levels. Analysis of the multimeric profile of VWF after has been approved for the treatment of hemorrhage and rVWF may have been helpful, but could not be per- surgical bleeding, as well as for prevention of surgical formed. bleeding [15]. Two additional phase 3 studies exploring In general, treatment methods for VWD vary by its type the use of vonicog alfa in pediatric patients (NCT02932618) and severity. Patients are treated with desmopressin or and as a prophylactic agent for recurrent bleeding VWF-containing concentrates when acute hemorrhage or (NCT02973087) are ongoing [8]. trauma occurs, or in order to prevent severe loss of blood Our patient, who had type 2B or 2A VWD, continued during surgery [6,7]. to bleed despite achieving high levels of VWF Ag, Pd-VWF/FVIII concentrates, originally licensed to treat VWF:RCo activity and FVIII after treatment with pd- hemophilia A patients who lack FVIII, can also be used VWF/FVIII concentrates. All rVWF infusions were given in VWD to address VWF and FVIII deficiencies that do due to bleeding episodes, not for prophylaxis against not respond well to desmopressin [8]. Products licensed bleeding. While no adverse events were observed in our to treat VWD are generally labeled for their VWF and patient, known side effects of rVWF include dizziness, FVIII contents. These pd-VWF/FVIII concentrates vary in vertigo, tachycardia, nausea vomiting, etc. These may af- their VWF and FVIII concentrations, with the levels de- fect up to 1 in 10 patients [15]. pending on the manufacturing process as well as the We could not confirm whether anti-VWF neutralizing plasma used [5,8]. These products may raise safety con- or binding antibodies were formed, but the mixing test cerns regarding post-transfusion transmission of blood- and appropriate elevation of VWF level indicated no an- borne agents and neutralizing anti-VWF alloantibodies, tibody formation. but such issues are very rare now [8]. The more pressing In summary, we report a case of rVWF administration concerns are that bleeding is sometimes poorly con- in pediatric VWD. rVWF was well-tolerated and controlled despite adequate levels of VWF, and excessively trolled bleeding that could not be managed with pd- high FVIII increases thrombotic risk [9]. In addition, the VWF/FVIII concentrates. multimeric structure of VWF is abnormal in VWF/FVIII products, and to varying degrees, these products lack Acknowledgments HMWMs [5,10]. This is because during plasma fractiona- tion, HMWMs are cleaved by VWF protease ADAMTS13 Vonicog alfa is currently unregistered in Korea and the (a disintegrin and metalloproteinase with a thrombo- product was supported by Takeda Pharmaceutical Com- spondin type 1 motif, member 13) [11]. pany through Early Access Program. VWF is a huge, structurally complex protein, and nu- merous hurdles had to be overcome to produce recombi- Conflict of Interest Statement nant VWF on a large scale [8]. One distinct feature of rVWF, attributed to its production in the absence of The authors have no conflict of interest to declare. ADAMTS13, is that it contains the ultra-large VWF multimers present in endothelial cells and platelets (but not References plasma) [12,13], in addition to all of the VWF multimers normally present in plasma. Several studies of rVWF have 1. Yee A, Kretz CA. von Willebrand factor: form for function. Semin Thromb Hemost 2014;40:17-27. demonstrated its efficacy and safety in patients with all 2. Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics types of VWD, leading to its licensing for therapeutic use. and safety of a novel recombinant human von Willebrand

56 Vol. 28, No. 1, April 2021 rVWF for Patient with VWD: First Report in Korea

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