Treatment of VWD Patients Requiring Elective Surgery with a Pasteurized von Willebrand Factor/FVIII Concentrate (Haemate®P) - The Use of a PK Guided Approach.

Efficacy and safety of a plasma-derived VWF/FVIII concentrate using VWF:RCo activities for the management of unselected VWD patients requiring elective surgery were assessed in an open, prospective, multinational clinical trial. The study was divided into two parts: Initially a PK assessment was performed for each patient prior to surgery. These data were then used to calculate the individual loading dose necessary to reach the presurgical plasma level for VWF:RCo and/or FVIII:C desired by the physician/surgeon. The second part started with the administration of the calculated loading dose before surgery. Twenty-nine unselected VWD patients with the following types of VWD with inadequate response to desmopressin were included in this study: type 1 VWD (n=10), type 2A (n=10), type 2M (n=1), type 3 (n=8). PK results: VWF:RCo: The overall median IVR was 1.9 [% per IU/kg] (range 0.8–3.6). Type 3 VWD patients had a median IVR of 2.5 [% per IU/kg] (range 0.8–3.2). The overall median response (observed peak activity in relation to the expected peak activity) was 73.6% (range 24.5–180.3). Type 3 VWD patients had a median response of 74% (range 32.6–125.5). Median value of Cmax was 154 IU/dL (range 60.0–269.0). Median half-life was 7.1 h (range 2.9–22.0), median clearance 4.24 [mL/kg/h] (range 0.97–17.75), with two extreme outliers influencing the values. FVIII:C: The median IVR was 2.4 [% per IU/kg] (range 1.3–3.9). Type 3 VWD patients had a median IVR of 2.3 [% per IU/kg] (range 2.0–3.8). The median response was 92.3% (range 48.6–144.3). Type 3 VWD patients had a median response of 97.8% (range 79.0–134.5). PK-guided dosing: Mean VWF:RCo plasma levels after surgery and during the first three maintenance infusions ranged between 60–70% before and 165–170% after infusion, thus providing the subjects with high enough levels to prevent post-operative bleeding. The presurgical plasma levels were close to the targeted range when using the PK-based calculated loading dose: deviations ranged between −27 to 83% for VWF:RCo and −40 to 39% for FVIII:C. Efficacy: There were 11 minor and 16 major surgeries (two subjects did not undergo surgery). Effective hemostasis was achieved in all cases. Only in one type 3 VWD patient the investigator’s assessment of hemostatic efficacy was moderate directly after surgery. Hemostatic efficacy assessed by the investigator at the end of the study (Day 14) was excellent or good for all cases. Safety: Five AEs were considered to be related to the study medication by the investigator, including a case of pulmonary embolism after major orthopedic surgery in an elderly woman. The event resolved without further sequelae. Several further case reports in the literature with different types of product used show that although patients with VWD suffer from a bleeding disorder, thrombotic events can occur, especially in the setting of additional risk factors. Summary: This study confirmed that Haemate P is an effective and safe treatment in subjects with VWD undergoing surgery. Given the wide range of interindividual pharmacokinetics of VWF:RCo a PK-based dosing prior to elective surgery is a recommendation to optimize dosing.