Comparative Analysis of Pure VWF and VWF/FVIII Complex in Orthopedic Surgery for Type 2B von Willebrand Disease

Introduction

von Willebrand disease (VWD) is a common autosomal-dominant inherited bleeding disorder caused by quantitative (type 1 or type 3) or qualitative (type 2) defects of von Willebrand factor (VWF) [1]. Type 2B von Willebrand disease (VWD2B) is a rare disorder with an estimated prevalence of 5–8% among all VWD types, which is typically characterized by enhanced ristocetin-induced platelet aggregation in platelet-rich plasma [2]. In VWD2B, VWF is normally synthesized and assembled by endothelial cells but has an increased affinity for the platelet receptor glycoprotein Ib-α, which can result in moderate to severe thrombocytopenia [2]. Worldwide, patients with VWD who do not respond to or who have a contraindication to desmopressin are treated with VWF/factor VIII (FVIII) concentrates [1]. For decades, this type of patient was treated only with VWF/FVIII complex concentrates, except in France, where FVIII-free VWF concentrates have been available since 1992 [3] (eg, Wilfactin®; LFB, commercialized in 2003 [3]), and the first VWF/FVIII concentrate (Voncento®; CSL Behring, VWF/FVIII ratio of 2.4/1) was marketed in France beginning in 2015 [4].

In theory, repeated administration of VWF/FVIII concentrates can lead to a greater accumulation of FVIII than with pure VWF concentrate, particularly in surgical patients. Supraphysiological levels (>200 IU/dL) of FVIII are associated with an increased risk for thromboembolic complications [5]. Even though the efficacy and safety of these 2 VWF concentrates have been described in real-life practice in a surgical context for all types of von Willebrand disease, particularly in France [4,6], the effect of VWF concentrates with or without FVIII can be very different from one type of VWD to another, and, as it is a rare disease, analysis of the VWD subtype has not been carried out systematically. In addition, to the best of our knowledge, only 2 case reports comparing VWF concentrates in the setting of gastrointestinal hemorrhage have been published: one comparing the efficacy of pure recombinant VWF concentrate (Veyvondi®) and a VWF/FVIII concentrate (Humate-P®) in a patient with type 2A VWD [7] and the other comparing the efficacy of Wilfactin® and Veyvondi® in a patient with type 3 VWD [8].

The present report describes a 55-year-old man with hypertension, hypercholesterolemia, and VWD2B associated with thrombocytopenia requiring 2 surgical total hip replacements managed with pure VWF concentrate (Wilfactin®) and VWF/FVIII complex concentrate (Voncento®).

Case Report

This 55-year-old man was followed at our center for VWD2B associated with thrombocytopenia (baseline platelet count: 130 G/L; normal range: 150–400 G/L). Before the VWD2B diagnosis, he had frequent hematomas, bleeding after a tooth extraction at the age of 10 years, and bleeding after a surgery to remove an iron splinter from his thigh at age 17 years. VWD2B was diagnosed at the age of 31 years as part of a family investigation. Laboratory testing showed normal prothrombin rate, partial thromboplastin time, and fibrinogen level, and platelet count 125 G/L, FVIII: C activity 55 IU/dL (normal range: 50–150 IU/dL), VWF: Ag 49 IU/dL (normal range: 50–150 IU/dL), VWF: RCo 34 IU/dL (normal range: 50–150 IU/dL; VWF: RCo/VWF: Ag ratio=0.69), and positive ristocetin-induced platelet aggregation assay at low ristocetin concentrations (0.5 and 0.25 mg/ml) and blood group (A). In plasma, VWF multimer analysis showed a reduction of high-molecular-weight multimers. The patient was heterozygous for the p.Arg1341Gln (R1341Q) mutation in exon 28 of the A1 domain of the VWF gene.

He developed bilateral coxarthrosis at a young age, unrelated to his inherited hemostasis disorder. Bilateral hip replacement was recommended at the age of 54 years due to functional consequences, particularly at work as a truck driver.

The patient’s weight was 102 kg and he was 1.73 m tall (BMI=34.4 kg/m2). He had several treated cardiovascular risk factors: arterial hypertension, hypercholesterolemia, non-insulin-dependent diabetes mellitus, and sleep apnea syndrome. He never had received transfusions of blood products before the hip replacement surgery. Before the first orthopedic surgery, the ISTH-BAT hemorrhagic score was 1: moderate gum bleeding, frequent bruises, and tendency to prolonged bleeding after minor wounds that did not require any specific treatment.

In April 2019, he underwent his first total hip replacement under general anesthesia on the right hip using a posterior approach and prosthetic material (HYPE® stem, Serf, France). He received Wilfactin® (39 IU/Kg; 4000 IU VWF) 1 hour before the start of surgery. In accordance with our protocol and experience with this product, he received a second injection at 10 hours post-operatively, prior to the availability (>48 hours post-injection) of immediate postoperative VWF: RCo and FVIII: C levels (150 and 140 IU/dL, respectively). The treatment and laboratory monitoring programs are summarized in Table 1. In addition to mechanical prevention of thrombosis, enoxaparin (4000 IU daily) was started the evening after surgery and continued for 45 days, with weekly monitoring of platelet counts. The moderate preoperative thrombocytopenia worsened slightly after surgery; however, the platelet count remained >70 G/L and no platelet transfusion was required. No intraoperative or late complications (eg, hemorrhage, thrombosis or infection) were reported during surgery.

The patient was able to stand up on the first day after the operation and started walking, with the help of a physiotherapist. The drain was removed on the second day after the first operation, when the serous (non-bloody) discharge stopped. The hospital stay lasted 7 days, rehabilitation was offered at home, and the sutures were removed on the 15th day after the operation.

Overall, prevention of bleeding required 9 injections of Wilfactin® and total consumption of 36 000 IU (352.9 IU/kg) over 7 days.

In July 2019, we performed the second total hip replacement (left side) under the same conditions: hospital, surgical/anesthetic/hemostasis teams and surgical technique/material. The patient received a preoperative injection of Voncento® (35 IU/Kg, 3600 IU VWF, and 14.7 IU/Kg, 1500 IU FVIII) 1 hour before surgery. Levels of VWF: RCo and FVIII: C immediately after the operation were available rapidly (8 hours after injection): 106 and 102 IU/dL respectively. In contrast to the first procedure, close laboratory monitoring was carried out, making it possible to omit postoperative administration at 10 hours. The treatment and laboratory monitoring regimens are summarized in Table 1.

As with the previous procedure, mechanical thrombosis prevention and enoxaparin (4000 IU daily) were started the evening after surgery and continued for 45 days, with weekly monitoring of platelet counts. The moderate preoperative thrombocytopenia worsened slightly; however, the platelet count remained >70 G/L and no platelet transfusion was required. The left upper-hip arthroplasty was performed without intraoperative or late complications. The patient was able to stand up on the first day after the operation and started walking, assisted by a physiotherapist. Due to prolonged serous discharge, the drain was removed on day 4. The patient remained in the hospital for 7 days. Rehabilitation was offered at home and the sutures were removed on the 15th day after the operation.

Overall, prevention of bleeding required 8 injections of Voncento® and a total consumption of 28 800 IU (282.3 IU/kg) over 7 days.

Discussion

Due to the lack of comparative studies of VWF concentrates, it is difficult to establish guidelines for the management of patients with VWD undergoing major or minor surgery, and individualized treatment plans are needed [6]. This was our first experience of orthopedic surgery management with Voncento®, thus explaining the closer monitoring of VWF and FVIII levels, compared with the surgery managed with Wilfactin®, which we are used to using. Our aim was to adapt the protocol in function of the laboratory results to optimize patient management while avoiding any FVIII level increase >200 IU/dL to limit the risk of thrombosis [5]. The preoperative doses of Wilfactin® and Voncento® were 39 and 35 IU VWF/kg, respectively. In 2 real-life studies of Voncento® [4] and Wilfactin® [6], the authors reported median loading doses of 43 and 50 IU/kg, respectively, during major surgery in all patients with type 2 VWD. As the immediately postoperative VWF and FVIII levels with Voncento® were optimal for good bleeding protection, the injection of this VWF/FVIII concentrate at 10 hours was skipped. For the first surgery, the results of VWF and FVIII levels were received too late (>48 h after blood sampling) to introduce this adjustment. Similarly, the laboratory results on day 6 were not available for the first surgery and were received at a later date for the second surgery. In both cases, the injection on day 7 could have been avoided if these data had been available earlier, which would have made it possible to reduce total concentrate consumption even further. Nevertheless, laboratory monitoring at shorter intervals allowed reducing the total postoperative consumption (312 IU/kg with Wilfactin® vs 245 IU/kg with Voncento®).

The patient has moderate thrombocytopenia and risk factors for venous thrombosis (2 orthopedic surgeries within 3.5 months with prolonged bed rest and moderate obesity) and cardiovascular risk factors (arterial hypertension and non-insulin-dependent diabetes mellitus), making management complex. Following surgery, thrombocytopenia was slightly increased as a result of the inflammatory response, as is frequently observed in people with the R1341Q variant [9].

Thrombotic risks were well managed by implementing the appropriate (mechanical and pharmacological) thromboprophylaxis and controlling the FVIII level, and no thrombotic events occurred, in line with the literature [3,4,6]. This confirms the importance of laboratory monitoring to individualize and optimize management, as previously shown by Rugeri et al [6], from both a hemostatic and a safety point of view.

Conclusions

Wilfactin® and Voncento® were effective and safe in preventing bleeding during orthopedic surgery in our patient with VWD2B and thrombocytopenia. This clinical case also highlights the value of close biological monitoring during the peri-operative period to personalize treatment and optimize management.