Real-World Efficacy and Safety of Plasma-Derived Von Willebrand Factor-Containing Factor VIII Concentrates in Patients With Von Willebrand Disease in Italy

Abstract

Plasma-derived von Willebrand factor-containing factor VIII concentrates (pd-VWF/FVIII-C) are the mainstay of treatment in von Willebrand disease (VWD). Real-world data on efficacy and safety of these pd-VWF/FVIII-C are required. To retrospectively evaluate the efficacy and safety of pd-VWF/FVIII-C (Fanhdi® and Alphanate®, Grifols) in clinical practice in Italy. A multicentric, observational, retrospective study at 10 Italian centers was conducted. Eligible patients diagnosed with inherited VWD (ISTH criteria) were treated with either Fanhdi® or Alphanate® for bleeding episodes, prevention of surgical bleeding and secondary long-term prophylaxis (SLTP) according to clinical practice with medical records collected from January 2007 to December 2019. Efficacy/safety of pd-VWF/FVIII-C was assessed according to FDA-agreed objective criteria following regulatory procedures. Fifty-seven patients (M/F: 21/36) were enrolled in the study with the following VWD types: VWD1 (n = 29, 52%), VWD2A (n = 10, 18%), VWD2B (n = 7, 12%), VWD2M (n = 2, 4%), VWD2N (n = 1, 2%), VWD2 unclassified (n = 1, 2%), and VWD3 (n = 7, 12%). These pd-VWF/FVIII-C were used to manage 58 bleeding episodes (n = 24 patients), 100 surgeries (n = 47 patients), and 7 SLTP (n = 6 patients). Global clinical efficacy with these pd-VWF/FVIII-C was reported to be excellent/good in 85% of bleeding episodes, 98% of surgeries, and 100% of SLTP. As far as safety, no adverse-drug-related episodes, immunogenic or thrombotic events were reported. This study confirmed that Fanhdi® and Alphanate® were effective and safe in the management of bleeding episodes, the prevention of bleeding during surgeries and for SLTP in Italian patients with inherited VWD.

Keywords

plasma-derived von Willebrand factor / factor VIII concentrate bleeding surgery secondary long-term prophylaxis von Willebrand disease

Introduction

Von Willebrand disease (VWD) is considered the most frequent inherited bleeding disorder but occurs with a wide degree of bleeding phenotype. von Willebrand disease estimated prevalence ranges between 0.1 and 16.5 per 100 000 inhabitants and, in Italy, it is 5.4 per 100 000 inhabitants.¹ von Willebrand disease is caused by reduced or abnormal von Willebrand factor (VWF), the high-molecular glycoprotein involved in early phases of hemostasis and can be classified in 6 VWD types.² Type 1 (VWD1) represents mild to moderate deficiency in the VWF protein. Type 2 is further subdivided into VWD2A, VWD2B, VWD2M, and VWD2N based on their phenotype. Type 3 (VWD3) represents the most severe form because it is characterized by unmeasurable levels of circulating VWF with reduced factor VIII (FVIII).²

The goal of VWD therapy is to correct abnormal platelet adhesion and restore normal abnormal coagulation by normalizing both VWF and FVIII activities in circulating blood. von Willebrand disease management include treating on-demand (OD) such as spontaneous or traumatic bleeding events, during surgeries, and under secondary long-term prophylaxis (SLTP). Mild to moderate bleeding events are commonly reported in most patients with VWD,^3,4 although in severe VWD types, patients may have hemarthrosis, severe gastrointestinal bleeds, and life-threatening bleeding events.⁵ von Willebrand disease patients undergoing surgery and/or invasive procedures are also at risk of hemorrhage, depending on the severity of the bleeding phenotype and the type of surgery. Secondary long-term prophylaxis aims to prevent or reduce bleeding episodes for those patients with frequent and severe bleeding events,^6–8 which is especially relevant in patients with severe bleeding phenotypes.^9,10

Treatment options to patients with VWD are aimed at increasing endogenous VWF levels using nonreplacement therapy such as desmopressin (DDAVP), or by replacement therapy using VWF/FVIII concentrates.¹¹ Replacement therapies for VWD include plasma-derived VWF/FVIII concentrates (pd-VWF/FVIII-C) with VWF:RCo/FVIII content ratios <10 and ≥10, and recombinant VWF. These therapies correct hemostatic abnormalities by restoring platelet adhesion to the vascular endothelium at the site of vascular damage and by binding to endogenous FVIII to stabilize the protein and avoid its degradation.¹² This great variety of VWF/FVIII-C currently available might present a challenge in the treatment of patients with VWD. Therefore, selecting the optimal pdVWF/FVII-C might help to individualize VWF replacement therapy through better informed treatment decisions.

Fanhdi® (Grifols, Barcelona, Spain) and Alphanate® (Grifols, Los Angeles, CA, USA) are high-purity pd-VWF/FVIII-C indicated for treating bleeding and prophylaxis of surgical bleeding in VWD patients, when DDAVP is ineffective or contraindicated, with efficacy/safety extensively demonstrated in prospective clinical trials.^13–16 Fanhdi® and Alphanate® share the same manufacturing process and are considered equivalent products.¹⁷ To date, a limited number of retrospective studies have been reported about their use to treat bleeding episodes OD, prevent bleeding during surgical procedures, and in SLTP.^8,18–20 Therefore, further real-world data are required to evaluate their efficacy and safety in a larger cohort of VWD patients treated according to current clinical practice. The aim of the study was to evaluate retrospectively efficacy/safety of these 2 similar pd-VWF/FVIII-C in current clinical practice in Italian VWD patients.

Materials and Methods

Design of the Study and Eligibility of the VWD Patients

This observational retrospective study was based on the clinical and laboratory analysis collected from VWD patients followed by Italian investigators according to their clinical practice. All patients with VWD enrolled in the study were treated with the 2 highly purified pd-VWF/FVIII-C (Fanhdi® or Alphanate®) for treating acute bleeding episodes, prevention of bleeding during surgeries and for SLTP. Fanhdi, which is marketed in Italy since 1999, is characterized by a high content in VWF, with a mean (SD) VWF:RCo/FVIII:C ratio of 1.58 (0.20). Individual vales for the von Willebrand Factor:ristocetin cofactor activity (VWF:RCo) can be checked for each batch.²¹

The study was conducted at 10 Italian investigational sites with retrospective data (from January 2007 to December 2019) collected between October 2021 and July 2022. Data of both pd-VWF/FVIII-C, Fanhdi® and Alphanate®, being equivalent pd-VWF/FVIII products, were analyzed together because most patients received Fanhdi® during their clinical observation treatments with only 2 cases treated with Alphanate®. Patients included in this study were followed up at their reference center.

The study was conducted in conformity with appropriate local laws and regulations and the Declaration of Helsinki. All regulatory requirements in Italy related to the study were fulfilled. The original protocol was reviewed and approved by the Institutional Review board/Ethics Committee.

Patients were eligible for the study if they were compliant with the following inclusion criteria: male and female patients diagnosed with congenital VWD according to International Society of Thrombosis and Hemostasis criteria,²² who have received treatment with highly purified pd-VWF/FVIII-C as part of standard clinical practice during the study period, with record of at least one set of baseline and posttreatment efficacy and one safety data, and who provided their informed consent prior to participating.

Data Collection

The following demographic and clinical variables were obtained from medical records: bleeding score based on the ISTH/SSC bleeding assessment tool,²³ family history of VWD, blood group, FVIII activity (FVIII:C), VWF:RCo, von Willebrand factor antigen (VWF:Ag), VWF collagen binding assay (VWF:CB), multimers, and previous exposition to VWF/FVIII concentrate. Data were recorded in an electronic case report form for further analysis.

Three clinical situations were assessed: bleeding episodes, surgery procedures, and SLTP. For the assessment of bleeding episodes and surgical bleedings, the information of each bleeding or surgical event was described, as well as the concomitant treatment received during the episode. Bleeding episodes were classified by type (spontaneous or traumatic) and by anatomical site. Surgery procedures were classified as major or minor with time between start of treatment and surgery recorded. Major surgeries were defined as those that usually involved the use of regional or general anesthesia and penetrated and exposed one of the major body cavities (eg, skull, chest, neck, abdomen) or one of the major joints (eg, shoulder, hip, spine) or stresses vital organs. Minor surgeries were any surgery or procedure not considered major.^13,15 For SLTP, the regimen, dose, frequency, and days of follow-up were assessed. In addition, the number of bleeding episodes per year (annualized bleeding rate, ABR), of days spent in hospital stays, and of red blood cells (RBC) transfusions was compared before and after SLTP.

Efficacy

The primary objective was to evaluate the efficacy of pd-VWF/FVIII-C in these 3 clinical settings: bleeding episodes, prevention of surgical bleeding, and SLTP. Efficacy was assessed according to FDA-agreed objective criteria following regulatory procedures by describing the clinical variables and, according to the efficacy scale it was classified as excellent, when hemostasis was comparable to expected, with no other bleeding cause and no increase of pd-VWF/FVIII-C dose; good, when hemostasis was slightly below expectation, with no other bleeding cause and requiring a low increase in pd-VWF/FVIII-C dose; poor, when reduced hemostasis was less than expected, with no other associated bleeding cause and requiring a significant increase in pd-VWF/FVIII-C dose; and no response, when severe bleeding despite pd-VWF/FVIII-C therapy, required a significant increase in pd-VWF/FVIII-C dose, and/or an alternative therapy was needed to stop bleeding.

Secondary objectives were to assess the treatment characterization for each clinical situation: the regimen and duration of the treatment, dose per infusion, episode duration, number of infusions, concomitant treatment, and total dose of the product, for the 3 clinical situations (bleeding, prevention of bleeding in surgery, and SLTP).

Safety

Safety assessments included reporting of adverse drug reactions (ADR) with a causal relationship between the event and the study drug. Patients were also monitored for immunogenicity events to determine the occurrence of hypersensitivity, infusion reactions, and immunological abnormalities including inhibitors development (anti-VWF inhibitors). The occurrence of thrombotic events associated with the use of repeated pd-VWF/FVIII-C administrations was also assessed during the study period.

Sample Size

No formal sample size calculation was conducted, and it was estimated based on the approximate number of patients who may have been treated with the pd-VWF/FVIII-C during the study period in Italy. The evaluable population was defined as all patients who met all the inclusion criteria and was used to all efficacy analyses. Safety population consisted of those enrolled patients who were treated as part of standard clinical practice with pd-VWF/FVIII-C.

Statistical Analysis

Descriptive statistics were calculated as appropriate for each variable. Categorical variables were presented by absolute and relative frequencies. Continuous variables were described using means, standard deviations, medians, and 25th to 75th interquartile ranges. Efficacy variables were analyzed using paired Student t or nonparametric tests (U Mann-Whitney), when applicable. Efficacy analyses were conducted on data from the evaluable population and safety analyses were performed on the safety population. For all statistical analyses, P < .05 was set as significant. SAS software, version 9.4 (SAS, Cary, NC, USA) was used for all statistical analyses.

Results

Characterization of the VWD Patients Enrolled in the Study

A total of 57/58 (98.3%) recruited patients with VWD met the inclusion criteria and could be analyzed for assessing the efficacy/safety of the 2 pd-VWF/FVIII-C. Both concentrates were used during 165 clinical events: (1) for treating bleeds OD (58 episodes, n = 24 patients); (2) for prevention of bleeding in major and minor surgeries (100 episodes, n = 47 patients); for SLTP (7 programs, n = 6 patients) as in Figure 1.

Figure 1.

Patient recruitment and flow diagram showing the distribution of patients in the study and the number of episodes for each clinical situation. Evaluable and safety populations were considered for efficacy and safety analyses, respectively.

Demographic, clinical, and laboratory data of the 57 VWD patients are summarized in Table 1 with their classification in the following types: VWD1 (n = 29), VWD2A (n = 10), VWD2B (n = 7), VWD2M (n = 2), VWD2N (n = 1), VWD2 unclassified (n = 1), and VWD3 (n = 7). Of the 20 patients with the bleeding score reported, a bleeding score ≥5 was present in 13 (65%) of them. Anti-VWF inhibitors were negative in all these VWD patients.

Table 1.

Demographic and Baseline Patient Characteristics.

	Total, n = 57	Type of VWD
		Type 1, n = 29	Type 2^a, n = 21				Type 3, n = 7
		Type 1, n = 29	Type 2A, n = 10	Type 2B, n = 7	Type 2M, n = 2	Type 2N, n = 1	Type 3, n = 7
Demographic
Sex, male/female	21/36	6/23	6/4	2/5	2/0	1/0	4/3
Age, years	53 (40-71)	53 (37-71)	58 (38-83)	51 (49-53)	41 (22-60)	81 (81-81)	65 (49-73)
Weight, kg	65 (60-75)	63 (55-75)	71 (60-85)	63 (54-71)	58 (43-73)	65 (65-65)	65 (63-71)
Clinical data
Bleeding score	5 (4-8)	5 (3.5-7)	6 (4-11.5)	NA	NA	NA	NA
Bleeding score ≥5, n (%)^b	13 (65)	11 (69)	2 (50)	NA	NA	NA	NA
Positive VWD familiar history, n (%)	26 (46)	10 (35)	7 (70)	6 (86)	1 (50)	0 (0)	2 (29)
Blood group, n (%)
O	25 (44)	10 (35)	5 (50)	5 (71)	2 (100)	1 (100)	2 (28.6)
Non-O	21 (37)	13 (45)	2 (20)	2 (29)	0 (0)	0 (0)	4 (57)
FVIII:C, IU/dL	36.5 (22.5-63.8)	34.4 (22-71)	48.2 (32-64.5)	63 (43-77)	19.5 (13-26)	24.1 (24.1-24.1)	12 (6-24)
FVIII:C < 20 IU/dL, n (%)^c	11 (19)	6 (21)	0 (0)	0 (0)	1 (50)	0 (0)	4 (67)
VWF:RCo, IU/dL	12 (6-31)	27 (8-36)	10.5 (8-19.1)	11.5 (10-12)	1.5 (0-3)	69 (69-69)	4 (1-6)
VWF:RCo < 10 IU/dL, n (%)^d	22 (42)	9 (31)	5 (50)	1 (20)	2 (100)	0 (0)	5 (100)
VWF:Ag, IU/dL	32 (12-43)	32 (14-42)	32.5 (22-39)	64 (38-71)	9.5 (8-11)	71.9 (71.9-71.9)	2.5 (1.5-4)
VWF:CB^e	25 (18-61.5)	42 (15-68)	22.5 (10-64)	14 (14-14)	6.5 (5-8)	83.3 (83.3-83.3)	0 (0-0)
Multimer analysis	11 (19.3)	4 (13.8)	4 (40)	2 (28.6)	0 (0)	0 (0)	1 (14.3)
Normal multimer pattern	3 (27.3)	1 (25)	2 (50)	0 (0)	NA	NA	0 (0)
Previous exposition to other VWF concentrates, n (%)	8 (14)	1 (3.4)	3 (30)	2 (28.6)	0 (0)	0 (0)	2 (28.6)

Abbreviations: FVIII:C, factor VIII activity; VWF:RCo, von Willebrand factor:ristocetin co-factor activity; VWF:Ag, von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding assay; VWF, von Willebrand factor; NA, not available.

There was one patient with type 2 diagnosed, but with subtype not reported.

Bleeding score: total, n = 20; type 1, n = 16; type 2A, n = 4.

FVIII:C < 20 IU/dL: total, n = 56; type 3, n = 6.

VWF:RCo < 10 IU/dL: total, n = 53; type 1, n = 29; type 2A, n = 10; type 2B, n = 5; type 2M, n = 2; type 2N, n = 1; type 3, n = 5.

VWF:CB, total, n = 28, type 1, n = 29; type 2A, n = 4; type 2B, n = 1; type 2M, n = 2; type 2N, n = 1; type 3, n = 1.

Data are expressed are n (%) or median (IQR). Percentages are based on the evaluable patients (n = 57).

Bleeding Episodes

A total of 24 VWD patients were treated OD for a total of 58 bleeding episodes with Fanhdi® as pd-VWF/FVIII-C, mainly as spontaneous bleeds (69%), in the remaining (31%) cases, bleeds were traumatic. Most of bleeding episodes were observed in VWD1 (55.2%), followed by those in VWD3 (24.1%). The most common sites of these events were epistaxis (n = 11, 19%), hematoma (n = 7, 12%), and gastrointestinal bleeds (n = 5, 8.6%), while 22 bleeding episodes (38%) were comprised as other sites of bleeds (Figure 2).

Figure 2.

Number of bleeding episodes (A) by type and (B) by location, according to VWD type in patients (n = 24) treated for bleeding episodes (n = 58) with Fanhdi® as pd-VWF/FVIII-C.

Median dosage of pd-VWF/FVIII-C given OD was 33.5 (27-43.5) IU/kg with lower doses per infusion of 30 (25-42.3) IU/kg to treat epistaxis and higher doses of 55.7 (26-85.4) IU/kg, required for the treatment of gingival bleeding (Table 2). Treatment duration of pd-VWF/FVIII-C varied for each bleeding event according to bleeding sites. Median (range) episode duration was 5 (2-25) days with a median duration of treatment of 5 (1-15) days. The longest bleeding episode lasted a median of 10 (6-20) days with 11 (6-18) days of treatment and 8.5 (6-10) infusions, whereas the shortest bleeding episode lasted 1 (1-3) days, with only one day of treatment and one single infusion of pd-VWF/FVIII-C. Overall, global clinical efficacy of the pd-VWF/FVIII-C given OD achieved an excellent outcome in 56.9% (33 episodes), good in 27.6% (16 episodes), and poor in 15.5% (9 episodes), as shown in Figure 3A. Remarkably, efficacy in VWD3 patients was rated as excellent in 42.9% (6 episodes) and good in 50% (7 episodes).

Figure 3.

Global clinical efficacy of treatment (%) with pd-VWF/FVIII-C in (A) bleeding episodes: excellent (n = 33), good (n = 16), poor (n = 9), and no response (n = 0); (B) the prevention of surgical bleeding: excellent (n = 84), good (n = 14), poor (n = 2), and no response (n = 0); and (C) secondary long-term prophylaxis: excellent (n = 1), good (n = 6), poor (n = 0), and no response (n = 0).

Table 2.

Description and Treatment of Bleeding Episodes With pd-VWF/FVIII-C.

	All bleeding episodes, n = 58	By type		By location
	All bleeding episodes, n = 58	Spontaneous	Traumatic	Epistaxis	Muscular hematoma	Gastrointestinal bleeding	Other hematoma	Menorrhagia	Joint hemarthrosis	Gingival bleeding	Other^a
Dose of Fanhdi®
Dose per infusion, IU/kg	34.2 (30-43)	31 (27-43.5)	37.7 (33.3-42.3)	33.9 (25-42.3)	34.2 (27-40)	44 (31.5-55)	37 (29.2-51.2)	34.3 (22.5-44.3)	50 (25.6-50)	36.5 (36.5-36.5)	32.8 (31-43)
Median dose, IU/kg	33.5 (27-43.5)	31 (26.6-44.0)	36 (33.3-42.3)	30 (25-42.3)	34.2 (27-35)	44.0 (31.5-55)	38.0 (30.2-51.2)	35.0 (22.5-43.5)	50 (25.6-50)	55.7 (26-85.4)	32.8 (31-43)
Total, IU	6500 (3000-16 000)	9500 (2500-28 000)	3500 (3000-12 000)	3000 (1000-10 000)	3000 (2000-12 000)	12 000 (12 000-36 000)	9000 (4000-13 500)	2500 (1000-4500)	12 000 (2000-28 000)	19 500 (7000-32 000)	11 500 (3000-39 000)
Duration
Episode^b, days	5 (2-25)	4.5 (1.5-27.5)	5 (2-13)	1 (1-3)	10 (6-20)	4.5 (3-25.5)	4 (2-31)	1.5 (1-17.5)	5 (4-8)	9 (3-15)	6.5 (2-35)
Treatment^c, days	5 (1-15)	3.5 (1-25)	5 (1.5-11)	1 (1-7)	11 (6-18)	3.5 (3-24.5)	3.5 (1.5-5.5)	1 (1-1)	5 (3-7)	9 (3-15)	6.5 (2-35)
N° of infusions	4 (1-9)	3 (1-9)	5 (1.5-8.5)	1 (1-4)	8.5 (6-10)	3.5 (3-11)	3.5 (1.5-5.5)	1 (1-1)	5 (3-7)	3 (3-3)	5 (2-13)
Concomitant treatment, n (%)	46 (79.3)	34 (85)	12 (66)	20 (91.9)	5 (71.4)	4 (80)	3 (75)	2 (50)	2 (66.7)	2 (100)	20 (91.9)
Outcome^d, Excellent/ Good, n (%)	49 (84.5)	32 (80)	17 (94.4)	11 (100)	6 (85.7)	5 (100)	4 (100)	2 (50)	3 (100)	2 (100)	20 (91.9)

List of n = 22 other localizations reported: hematuria (n = 5); rectorrhagia (n = 4); superior lip (n = 2); hemoptysis (n = 2); anemia and rectorrhagia (n = 1); cut of first finger left hand (n = 1); cutaneous (n = 1); distal phalanx - third finger left hand (n = 1); fracture of sacrum and coccyx (n = 1); hematuria by renal calculosis (n = 1); intravitreal bleeding (n = 1); lips (n = 1); and mouth bleeding (n = 1).

Episode duration was calculated by number of days between the end and the start date of the episode.

Treatment duration was calculated as the number of days between the end and the start of the treatment.

Efficacy of treatment according the investigator's discretion.

Data are expressed as n (%) or median (IQR).

Percentages based on number of cases in each row.

Prevention of Surgical Bleeding

Forty-seven patients, 82.4% of evaluable population, were treated with pd-VWF/FVIII-C for the prevention of 100 surgical bleedings (97% with Fanhdi® and 3% with Alphanate®). Most of surgery procedures were classified as minor (n = 74, 74%). A total of 62 surgical events were observed VWD1 patients, 28 in all VWD2 types, and 10 in VWD3. In general, pd-VWF/FVIII-C was administered during the same day of the surgery. A preoperative dose was given in 98 cases of surgical bleedings, with a median dose of 43 (30-60) IU/kg. The surgical procedures reported in ≥2% of cases were tooth extraction (n = 14), cystoscopy (n = 3), colonoscopy (n = 3), gingivectomy (n = 3), multiple dental extraction (n = 3), gingival curettage (n = 2), and tooth reconstruction (n = 2), as shown in Table 3.

Table 3.

Description of Surgical Bleeding Episodes and Treatment With pd-VWF/FVIII-C in the Prevention of Surgical Bleeding.

	Major, n = 26	Minor, n = 74	Total, n = 100
VWD type, n (%)
Type 1	12 (19.4)	50 (80.6)	62 (62)
Type 2A	6 (46.2)	7 (53.8)	13 (13)
Type 2B	2 (33.3)	4 (66.7)	6 (6)
Type 2M	0 (0)	4 (100)	4 (4)
Type 2N	1 (20)	4 (80)	5 (5)
Type 3	5 (50)	5 (50)	10 (10)
pd-VWF/FVIII-C, n (%)
Fanhdi®	26 (100)	71 (95.9)	97 (97)
Alphanate®	0 (0)	3 (4.1)	3 (3)
Pd-VWF/FVIII-C dose
Preoperative, IU/kg	50 (36.5-57.5)	42 (30-60)	43 (30-60)
Postoperative, IU/kg	36.1 (30.5-45.9)	40.5 (31-60)	39 (31-54)
Total, IU	6000 (3000-29 000)	3000 (2000-4000)	3000 (2000-7500)
Treatment duration, days	4 (1-12)	1 (1-2)	1 (1-3)
Number of infusions	2 (1-14)	1 (1-2)	1 (1-3)
Concomitant treatment, n (%)	18 (69.2)	48 (64.9)	66 (66)

Data are expressed as n (%) or median (IQR).

Percentages based on number of cases in each row.

Patients who underwent major surgery were treated with a median preoperative dose of 50 (36.5-57.5) IU/kg and postoperative dose of 36.1 (30.5-45.9) IU/kg. Treatment lasted for a median of 4 (1-12) days and 18 patients (69.2%) required concomitant medication. One VWD3 patient underwent an endoscopic cautery of tenuous angiodysplasia. For minor surgeries, median drug exposure to pd-VWF/FVIII-C was shorter, 1 (1-2) days, compared with major surgeries and 48 (65%) episodes required concomitant treatment. Overall, global clinical efficacy of replacement therapy with pd-VWF/FVIII-C for the prevention of surgical bleeding achieved excellent (84%) efficacy rates in 84 procedures, good (14%) in 14 procedures, and poor efficacy rates in 2% (2 procedures). In VWD3 patients, 90% achieved excellent (60%) and good (30%) responses (Figure 3B).

Secondary Long-Term Prophylaxis

Six patients were enrolled in 7 SLTP programs (Table 4). Three of 7 in VWD1 (67%), 1 of 7 (17%) in VWD2A, and 2 of 7 (34%) VWD3. All these programs of SLTP were treated with Fanhdi®. The reasons to enroll a patient in SLTP programs were bleeding control (n = 3, 50%), gastrointestinal bleeding (n = 2, 33.3%), and recurrent epistaxis (n = 1, 16.7%). The frequency of treatment in the SLTP programs was 2 days/week in 71.4% of them with a median duration of 58.3 (43.7-62.1) days. von Willebrand disease patients enrolled in the SLTP program received a median dose per infusion of 2000 (2000-3000) IU and a total amount of 408 000 (290 000-459 000) IU of pd-VWF/FVIII-C. FVIII:C baseline levels were 57 (17-95) IU and bleeding score (n = 3) at baseline was 20 (15-20).

Table 4.

Description of Bleeding Episodes of Patients With von Willebrand's Disease (VWD) Before Enrolment into a Secondary Long-Term Prophylaxis (SLTP) Program and During the Prophylaxis Period and Treated With pd-VWF/FVIII-C.

Patient number	VWD type	Sex	Age	Baseline levels				Bleeding episodes before prophylaxis		Bleeding episodes during prophylaxis		Prophylaxis with pdVWF/FVIII-C – Fanhdi® (n = 6, 100%)
Patient number	VWD type	Sex	Age	Bleeding score^a	FVIII:C, IU	VWF:RCo, IU	VWF:Ag, IU	Number	Location	Number	Location	Follow-up, days	Reason to prophylaxis	Frequency, days per week	Mean dose per infusion, IU	Outcome
1	3	Male	70	NA	NA	NA	NA	0	Not applicable	0	Not applicable	NA	NA	2	2000	Good
2	3	Male	73	NA	24	0	2	1	Digestive tract	NA	NA	145	Bleeding control	3	2000	Good
3	1	Male	72	NA	15	0	13	3	Digestive tract	1	Digestive tract	153	Bleeding control	2	3000	Good
4	1	Female	89	20	26.8	6	11	1	Digestive tract	1	Digestive trat	59	Gastrointestinal bleeding	1	3000	Good
4				20	26.8	6	11	1	Digestive tract	NA	NA	204	Gastrointestinal bleeding	2	2000	Excellent
5	2A	Male	40	NA	41.3	6.8	23.1	NA	NA	1	NA	NA	Recurrent epistaxis	2	3000	Good
6	1	Female	24	15	32	4	12	1	Menorrhagia	1	Epistaxis	1120	Bleeding control	2	2000	Good

Abbreviations: FVIII:C, factor VIII activity; VWF:RCo, von Willebrand factor:ristocetin cofactor activity; VWF:Ag, von Willebrand factor antigen; NA, not available.

Bleeding score at the start of prophylaxis.

Seven bleeding episodes were reported in 4 patients in the previous year before initiating SLTP. Six of the bleeding episodes (86%) were in the digestive tract and one menorrhagia (14%). During SLTP, there were only 4 bleeding events, being 2 of 4 in the digestive tract, 1of 4 epistaxis, and 1 of 4 in other location. No significant differences were reported in the median ABR before initiating SLTP program, 1 (0-3), compared with the period of SLTP, 0.3 (0-2.4); median absolute change 0.7 (0.6-1); P = .5625. For the 5 SLTP programs in which ABR information was available before and during the program, prophylaxis decreased ABR in 4 of 5 (80%) compared to the year before, whereas 1 of 5 program presented an increase in ABR during SLTP.

To evaluate whether SLTP affects hospitalizations for recurrent bleeding, the number of days for hospitalizations due to bleeding was assessed. The duration of hospitalization remained unchanged when comparing the period before prophylaxis, 3.5 (0-33.5) days/year, and during prophylaxis, 0.0 (0.0-9.3) days/year; median absolute change 30.0 (0.0-60.0); P = .99. There were only 2 programs with available data about the hospital stay: SLTP decreased hospital stay in one program (50%) and remained equal in the second program (50%). Considering 3 of 7 SLTP programs with available data about RBC transfusions, patients required a median of 3 (0-10) RBC transfusion units before SLTP, whereas only 1 (0-2.5) RBC unit was needed during the SLTP period.

Overall, global clinical efficacy of pd-VWF/VWF-C was rated as excellent in the 14% of the SLTP programs and good in the 86% of them. A good efficacy response was observed in all SLTP programs conducted in VWD3 patients (Figure 3C).

Safety Assessment

No VWD patients experienced a confirmed ADR after a total of 891 infusions with the pd-VWF/FVIII-C during the whole study period. More importantly, there were no thromboembolic events nor immunogenicity-related events associated with the use of pd-VWF/FVIII-C during the study period.

Discussion

This real-world evidence study retrospectively analyzed 57 patients with VWD in 10 centers in Italy. The salient finding of this study is that the use of pd-VWF/FVIII-C, Fanhdi® or Alphanate®, was safe and efficacious in 3 clinical situations: given OD for bleeding episodes, to prevent bleeding episodes during surgery and for SLTP. Furthermore, this study confirmed and extended the data previously published in clinical studies. In the current study, the percentage of VWD1 patients was (50.9%), VWD2, 36.8% (type 2), and VWD3, 12.3% (type 3) was somewhat different compared to the patient distribution reported in the Italian registry of congenital coagulopathies for VWD1 (75.2%), VWD2 (21.1%), and VWD3 (3.7%) and to the overall VWD prevalence.¹ The higher distribution of VWD2 and VWD3 patients could be explained because here, eligible patients were treated with pd-VWF/FVIII-C, which is the treatment of choice for these patients. Most of VWD patients (65%) presented a high bleeding score (≥5) and 42% had low basal VWF:RCo activity (≤10 IU/dL), indicating that they had clinically severe disease and were prone to suffer from bleeding events.^24,25 Indeed, a significant association has been shown between patients with high bleeding score and the probability to suffer from bleeding event in VWD patients.²⁶ A total of 14% of patients switched from other pd-VWF concentrates to the pd-VWF/VWF-C Fanhdi® or Alphanate® because their previous therapy did not improve clinical symptoms, whereas the rest of patients (86%) were not previously exposed to any VWF concentrate. All patients used pd-VWF/FVIII-C for treating bleeding episodes, preventing bleeding during surgery as OD therapy, and for SLTP.

On-demand replacement therapy with the pd-VWF/FVIII-C Fanhdi® to treat bleeding episodes achieved an 84.5% of clinical efficacy (excellent, 56.9% and good, 27.6%). These results were consistent with earlier studies, in which the percentage of treatments with excellent and good efficacy assessment was ranged between 82% and 99%, depending on the bleeding site.²⁷ Regarding the dose of pd-VWF/FVIII-C, our patients received a dose, 33.5 (27-43.5) IU/kg, which was aligned with VWD management recommendations.²⁸ This could be explained because bleeding events were predominantly mild to moderate such as epistaxis and muscular hematomas and required a small number of infusions and dosage. In any case, the regimen used in this study successfully controlled bleeding episodes, as previously shown with similar VWF/FVIII-C.^29,30

The efficacy of pd-VWF/FVIII-C was also evaluated in 47 patients undergoing major and minor surgeries. During major surgery procedures, the treatment duration and the number of infusions of pd-VWF/FVIII-C were higher compared with minor procedures. The regimen used herein for the treatment of bleeding episodes during surgery was highly efficacious since most of them were easily resolved, and no alternative therapy was needed to stop bleeding. Both duration and dosage remained within the standard recommended range: 40 to 60 IU/kg once daily until wound healing is complete for major surgeries and 30 to 50 IU/kg once daily for 1 to 3 days, for minor surgical procedures.^2,31 In this context, global clinical efficacy was graded as 98% (excellent, 84% and good, 14%). These are valuable findings aligned with the efficacy rates reported in the literature for both pd-VWF/FVIII-C in surgeries.^13,18–20

Secondary long-term prophylaxis results showed that all programs were successfully treated with pd-VWF/FVIII-C with excellent/good responses, and there were no SLTP programs rated as poor or no response. Indeed, no patients required a significant increase in the FVIII/VWF dose or an alternative therapy to control bleeding. Extensive research has demonstrated the use of replacement therapy with pd-VWF/FVIII-C for SLTP,^9,32–35 particularly for severely affected VWD patients with VWF:RCo activity ≤ 10 IU/dL,²⁴ regardless of their VWD type. Similarly, the severity of VWD is increased when the VWF:Ag levels are <30 IU/dL and patients present a high bleeding score.³⁶ In our study, patients representing all VWD types with VWF:RCo and VWF:Ag levels below those thresholds and with high bleeding scores were selected for initiating prophylaxis. Global clinical efficacy of pd-VWD/FVIII-C was rated as excellent/good in all SLTP. These results confirm the usefulness of SLTP with pd-VWF/FVIII-C for this cohort of severe VWD patients. The main reasons to initiate SLTP included bleeding control, gastrointestinal bleeding, and recurrent epistaxis. Although there is no consensus on standard regimen,^34,37 the dosage and administration frequency remained within the usual range of 30 to 60 IU/kg of VWF activity and between 2 and 3 times per week.³⁸

Secondary long-term prophylaxis in the study cohort of VWD patients resulted in a lower ABR compared to the previous period, although the absolute change (0.7 bleeding/year) was nonstatistically significant. By contrast, SLTP with other pd-VWF/FVIII-C have evidenced statistically significant reductions in ABR in earlier investigations.^7,34,35,39 The comparison between our results and the literature is challenging because published studies were largely focused on larger cohort of patients with higher ABR. In addition, the reduction in ABR is suggested to be greater for epistaxis and joint bleeding than for gastrointestinal bleeding.⁷ The low ABR before initiating prophylaxis (one bleeding/year), the gastrointestinal origin from most of bleeding episodes, and the small sample size (n = 6 patients) could have hindered a significant small reduction in ABR when comparing both groups. Similarly, SLTP did not significantly reduce the number of days spent in hospital stay in these patients. Again, the small sample size may have underpowered the analysis to detect a true difference between groups. Thus, further research is warranted to identify those patients who may benefit most from SLTP.

Regarding safety, pd-VWF/FVIII-C showed a good safety profile with no safety signals, consistent with the known profiles for pd-VWF/FVIII-C.^8,15,16,19 A few cases of thromboembolic events have been described in VWD patients in the literature after repeated infusions of VWF/FVIII-C.^40,41 The optimal management of patients undergoing surgery or treated for a bleeding episode suggests conducting a pharmacokinetic analysis to avoid FVIII:C activity >150 IU/dL because the thrombotic event risk is increased.⁴² Although assessed level of the FVIII:C activity was not available in the medical records, there were no thromboembolic events associated with the use of drugs. These findings were in line with a prospective study conducted with the same pdVWF/FVIII-C in patients with VWD undergoing surgeries.¹⁵ In that prospective study, FVIII:C, VWF:RCo activity, and VWF:Ag levels were monitored, and no patients received thromboprophylaxis treatment during the postoperative period. Similarly, there were no immunogenicity-related ADR associated with development of anti-VWF antibodies, hypersensitivity, or any infusion reaction. It is estimated that 5% to 10% of patients with VWD3 may develop alloantibodies to VWF, which is manifested as a lack of hemostatic response or even with an anaphylactic response.⁴³ Remarkably, no patients developed inhibitors to VWF. Altogether, Fanhdi® and Alphanate® were well tolerated and no safety concerns were raised when analyzing data of this retrospective study. Of note is that the manufacturing process of both concentrates is almost identical and comprise purification based on affinity chromatography, salt/glycine precipitation, and pathogen removal steps with solvent/detergent and dry heat treatment.^16,18 The selection of each pd-VWF/FVIII-C was based on its availability at the site when the patient was included.

Our study does entail some limitations. For instance, the small sample size in the study cohort, especially in SLTP, and the unbalanced use of each pd-VWF/FVIII-C in each clinical situation. The initial study protocol intended to conduct a pharmacokinetic analysis but, due to the nature of this retrospective study, data were often missing or unclear. Nevertheless, this retrospective study design allowed us to evaluate data for a 12-year period. It should be noted that, since medical records were used, a lower bleeding rate is expected compared with those studies that use a validated bleeding assessment tool.⁴⁴

Conclusion

Overall, this real-world evidence study provided further support that both highly purified pd-VWF/FVIII-C, Fanhdi® and Alphanate®, were efficacious and well-tolerated treatment in patients with VWD for the management of bleeding episodes, the prevention of bleeding during surgery, and prophylactically in high-risk patients with severe VWD.

Footnotes

Acknowledgments

Eugenio Rosado, PhD and Jordi Bozzo, PhD CMPP (Grifols) are acknowledged for medical writing and editorial support in the preparation of this manuscript, under the direction of the authors. Antonino Natoli (Grifols) is acknowledged for providing his expert contribution to the study. The authors wish to thank all the patients who contributed to this study.

Authors’ Note

Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Informed Consent: Informed consent for patient information to be published in this article was not obtained because of the retrospective nature of the study. Presentations at Meetings: The manuscript has been presented, in the form of an abstract, at the meetings EAHAD February 7-10, 2023; UK; BIC International Conference September 9-10, 2023; Italy; and WFH April 21-24, 2024, Spain. Ethical Approval: Ethical approval to report this study was obtained from the ethics committee “Comitato Etico Milano Area 1” (study registry number 2021/ST/053).

Author Contributions

A.B. Federici: Conceptualization, methodology, data curation, resources, formal analysis, and investigation; R. Mir: conceptualization, project administration, supervision, and visualization; E. Mairal: project administration, supervision, and visualization; R.C. Santoro, C. Santoro, L. Pieri, R. Santi, G. Barillari, A. Borchiellini, A. Tosetto, E. Zanon, and R. De Cristofaro: data curation, investigation, and resources. All authors critically revised, edited, and approved the final manuscript.

Declaration of Conflicting Interests

R. Mir is full-time employee of Grifols. E. Mairal is a former full-time employee of Grifols. A.B. Federici has been involved in advisory boards of Baxalta/Shire/Takeda, CSL Behring, Grifols, Kedrion, LFB and Octapharma with honoraria related to VWD. The remaining authors declare that there is no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Grifols, manufacturer of the pd-VWF/FVIII-C, Fanhdi® and Alphanate®.

ORCID iD

Augusto B. Federici

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