Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study

Jordi Ponce; Amparo García-Tejedor; Marc Barahona; Serena Cappuccio; Barbara Costantini; Camilla Fedele; Lola Marti-Cardona; Giovanni Scambia

doi:10.1371/journal.pone.0331376

. 2025 Sep 11;20(9):e0331376. doi: 10.1371/journal.pone.0331376

Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study

Jordi Ponce ^1,², Amparo García-Tejedor ^1,^2,^*, Marc Barahona ^1,², Serena Cappuccio ³, Barbara Costantini ^3,⁴, Camilla Fedele ³, Lola Marti-Cardona ^1,², Giovanni Scambia ^3,⁵

Editor: Hideto Sano⁶

PMCID: PMC12425258 PMID: 40934160

Abstract

Objective

To evaluate the safety and effectiveness of an absorbable modified polymer starch powder hemostat (AMP-SPH) compared with standard care to control hemostasis when used in adult subjects during open or laparoscopic gynecological procedures for both benign and malignant diseases. Methods: Prospective, multi-center, randomized, and interventional phase IV study conducted on consecutive patients, aged ≥18 years, who underwent an open or laparoscopic gynecological procedure between November 2015 and July 2017 in a third-level Hospital. Study participants were randomly assigned (1:1) to receive either treatment with an AMP-SPH (AMP group) or usual standard care (SC group). The hemostatic treatment administered to the SC group was at the investigator’s discretion. The primary effectiveness endpoint of the study was the achievement of hemostasis (yes/no) within 10 minutes. Results: Ninety patients, 44 (48.9%) in the AMP group and 46 (51.1%) in the SC group were included in the analysis. the AMP group, 97.7% (43/44) of patients achieved hemostasis as compared to the 93.5% (43/46) of subjects in the SC group (mean difference: 4.2%; 95%CI: −4.1% to 12.6%; p = .337). The time required to achieve hemostasis was lower in the AMP group (1.91 ± 1.15 minutes) than in the SC group (2.28 ± 2.09 minutes), although not significant (p = .309). A higher proportion of patients in the SC group (17.9%) was observed to require blood products compared to those in the AMP group (4.8%).A total of 29 adverse events (AEs) (24 non-serious and 5 serious AEs) were reported, 12 AEs in the AMP group and 17 in the SC group.

Conclusions

According to the results of this study, AMP-SPH was not inferior to standard care in the control of bleeding for patients undergoing gynecology procedures and the cessation of bleeding was trending to be faster with the use of AMP-SPH than with standard methods.

Trial registration

ClinicalTrials.gov NCT02835391.

Introduction

Hysterectomy is one of the most performed gynecological, surgical procedures worldwide and is second only to cesarean section, with high rates reported in many countries [1–5]. Other surgical procedures are frequently performed in gynecology for both benign and malignant pathologies, such as myomectomy, ovarian cystectomy, endometrial resection or ablation, lymphadenectomy, and others [6,7].

All gynecological surgical procedures carry a bleeding risk, and intraoperative hysterectomy hemorrhage rates of 1% to 2% have been reported [8]. These rates may vary depending on the surgical procedure (0.07%−6.98%) [9], and the presence of underlying medical conditions (i.e., the use of anticoagulant drugs or coagulation disorders).

There are several techniques that surgeons may use to achieve hemostasis when bleeding occurs, including hemoclips or electrocautery. However, in many situations, such as diffuse small vessel bleeding or bleeding near vital structures, these techniques are not sufficient, and hemostatic agents can be used as an adjunctive tool to obtain hemostasis without collateral damage to vital tissue [10–12]. The use of topical hemostatic agents has been shown to not only reduce thermal damage, devascularization, and tissue necrosis, but to also reduce time to hemostasis, and potentially prevent conversion to laparotomy during minimally invasive surgery [10,11].

The aim of this study was to evaluate the safety and effectiveness of an absorbable modified polymer starch powder hemostat (AMP-SPH) compared to usual care when used in adult subjects during open or laparoscopic gynecological procedures in the management of benign or malignant diseases. This study also aimed to assess the clinical outcomes of the AMP-SPH during gynecological procedures.

Methods

Study design

This prospective, multi-center, randomized, and interventional phase IV study conducted on patients who underwent an open or laparoscopic gynecological procedure between November 2015 and July 2017.

The study protocol was approved by the Ethic Committee of the Hospital Universtari de Bellvitge and the Ethics Committee of the Policlinico Universitario Agostino Gemelli, and was registered (http://www.clinicaltrials.gov; NCT02835391). This clinical study was conducted in compliance with the protocol, International Conference on Harmonization – Good Clinical Practice (ICH-GCP) and all applicable regulatory requirements. Participating investigative sites were responsible for complying with applicable regional or national regulations governing the conduct of post market surveillance (follow-up) studies.

Prior written consent was obtained for all patients who were enrolled into the study before any study-specific procedures were performed. To ensure patient confidentiality, any information that could lead to an individual being identified has been encrypted or removed, as appropriate.

Study participants

This study included consecutive patients, aged ≥18 years; who planned to undergo a gynecological procedure, such as hysterectomy, ovarian cystectomy, myomectomy, endometrial excision or ablation; signed the informed consent; experienced generalized oozing or mild to moderate intraoperative bleeding which was consistent with the requirement for a hemostatic treatment and were willing to comply with the investigators and protocol procedures.

Surgical routes accepted were both open and minimally invasive, including traditional laparoscopic and robotic approaches.

Subjects with a history of pelvic or abdominal radiotherapy within 8 weeks prior inclusion; with a previous ruptured ectopic pregnancy; medical history of abnormal coagulopathy or bleeding; sensitivity to starch or starch derived materials; potential infection at the surgical site; enrolled in another trial at the time of the study; and pregnancy or lactation were excluded.

Additionally, subjects with any major intraoperative bleeding incidences (i.e., American College of Surgeons Advanced Trauma Life Support Class II, III or IV Hemorrhage) (24) were excluded from the study.

Study groups

Subjects who met eligibility criteria were randomly assigned to receive either treatment with an AMP-SPH (PerClot® Polysaccharide Hemostatic System, Baxter Healthcare Corporation Deerfield, IL 60015 USA) (AMP group) or usual standard care (SC group).

In patients randomized to the AMP group, and accordingly to the manufacturer instructions for use (IFU), a liberal amount of the hemostatic agent was applied directly to the site and source of the bleeding [13].

It was at the Investigator’s discretion what treatment they choose for subjects randomized to receive usual care. Hemostatic treatments administered as part of usual care included diathermy or electrocautery, or two commonly used gelatin-thrombin-based flowable hemostatic agents, namely Floseal® (Baxter Healthcare Corporation Deerfield, IL 60015 USA) or Surgiflo® (Ethicon Incorporated, Somerville, NJ) [14].

Randomization occurred, intraoperatively (once it was clear the patient had met the intra-operative inclusion/exclusion criteria) on a 1:1 basis and was assigned by an electronic randomization system.

Follow-up visits

Patients were approached for consent and were screened up to 2 months prior to enrollment and reviewed pre-operatively, intra-operatively, 24 hours post operatively, prior to discharge (if the subject was discharged within 24 hours of surgery, then only discharge data was required) and at 30 days after their procedure (between day 21 and day 35).

Visits conducted outside this window were considered non-compliant and a protocol deviation.

Outcomes

The primary effectiveness endpoint of the study was the achievement of hemostasis (yes/no) within 10 minutes. Time to hemostasis was also assessed at 1, 2, 3, 5, 7, and 10 minutes. The primary safety endpoint of the study was the absence of proven infection and bleeding related adverse events (AEs).

The secondary effectiveness endpoint was the absence of reintervention for post- operative bleeding. Other secondary outcomes evaluated in this study included duration of the surgical procedure; incidence of postoperative hematoma; duration of drainage, drainage volume; postoperative pain measured by a visual analogue scale (VAS); and incidence of AEs.

Definitions

Hemostasis was defined as the absence of any blood egressing from the applied hemostatic agent, or from the diathermy site if no topical agent was used, within 10 minutes.

Bleeding was classified as Oozing (The rate of bleeding was slow. This was what one may expect from capillary, venular, or arteriolar bleeding); Mild (The rate of bleeding was slightly faster than oozing. There was no pulsatile flow present. This was what one may expect from capillary, venular, or arteriolar bleeding); Moderate (There might be a weak pulsatile flow present. If there was a pulsatile flow, the rate of blood flow was like the rate of flow for mild bleeding. If there was not pulsatile flow, the rate of blood flow was faster than mild bleeding); and Severe (for the most part, pulsatile flow was present. If there was no pulsatile flow, then the rate of blood flow was extremely rapid).

Pain scores were measured post-operatively using the visual analogue scale (VAS) (100 mm scale). Subjects were asked to rate their pain on the scale from no pain to worst possible pain. If the pain score was taken via telephone, subjects were asked to rate their pain between 0 and 10 with no pain being 0 and the worst pain possible being 10.

Statistical analysis

The protocol estimated that approximately 90 patients should be enrolled.

The Intent-to-Treat (ITT) population included all randomized subjects, regardless of treatment received. The Per Protocol (PP) population included all subjects, who were randomized and treated with AMP-SPH, and had no major protocol deviations. Additionally, “As Treated” (AT) population (subjects assessed according to the treatment received rather than treatment assigned) was evaluated.

Mean and standard deviation (SD); mean and 95% confidence interval (95% CI); median and interquartile range (IqR), and number (percentage) were used as appropriate.

Results

Preoperative demographic and clinical characteristics

A total of 90 patients were enrolled across two study sites between November 2015 and July 2017. Screening concluded in July 2017 upon reaching the target enrollment. The study duration was 21 months, from the first patient’s initial visit to the last patient’s final visit. Of the 90 enrolled participants, 44 (48.9%) were assigned to the AMP group and 46 (51.1%) to the SC group (Fig 1).

Fig 1 — AMP-SPH: Absorbable modified polymer starch powder hemostat.

In the overall study sample, mean age was 57.2 ± 13.5 years, with no significant differences between AMP (55.7 ± 14.7 years) and SC (58.6 ± 12.2 years) groups (mean difference: −2.9 ± 13.5 years, 95%CI: −8.6 to 2.8; p.310).

Table 1 summarizes the main demographic characteristics of the study sample.

Table 1. Overview of the main preoperative demographic and clinical characteristics of the study population.

	Overall (n = 90)	AMP (n = 44)	SC (n = 46)	Mean difference (95%CI)	P value
Age, years Mean±SD	57.2 ± 13.5	55.7 ± 14.7	58.6 ± 12.2	−2.9 (−8.6 to 2.8)	0.2784^a
Race, % (n/N) Caucasian	96.7% (87/90)	97.7% (43/44)	95.7% (44/46)	2.1% (−5.3% to 9.4%)	0.6821^b
BMI, Kg/m² Mean±SD	26.8 ± 5.7	27.7 ± 5.7	26.1 ± 5.7	1.6 (−0.8 to 4.0)	0.1792^a
Temperature, ºC Mean±SD	36.5 ± 0.4 (n = 74)	36.5 ± 0.4 (n = 37)	36.4 ± 0.4 (n = 37)	0.1 (−0.1 to 0.2)	0.2858^a
SBP, mmHg Mean±SD	123.8 ± 18.2 (n = 74)	125.1 ± 18.5 (n = 37)	122.6 ± 18.2 (n = 37)	2.5 (−6.0 to 11.0)	0.5597^a
DBP, mmHg Mean±SD	74.0 ± 11.3 (n = 74)	75.1 ± 9.9 (n = 37)	73.0 ± 12.6 (n = 37)	2.1 (−3.2 to 7.4)	0.4280^a
HR, bpm Mean±SD	77.8 ± 10.0 (n = 72)	75.8 ± 9.6 (n = 37)	80.0 ± 10.0 (n = 35)	−4.2 (−8.8 to 0.4)	0.0694^a
Preop INR Mean±SD	0.98 ± 0.06 (n = 51)	0.98 ± 0.06 (n = 22)	0.97 ± 0.06 (n = 29)	0.01 (−0.03 to 0.04)	0.5582^a
Use of Blood Modifiers, % (n/N)	7.8% (7/90)	4.6% (2/44)	10.9% (5/46)	−6.3% (−17.2% to 4.6%)	0.2685^b
Hypertension, % (n/N)	30.0% (27/90)	29.6% (13/44)	30.4% (14/46)	−0.9% (−19.8% to 18.0%)	0.9344^b
Tachycardia, % (n/N)	2.2% (2/90)	0.0% (0/44)	4.4% (2/46)	−4.3% (−10.2% to 1.5%)	0.1617^b
Menorrhagia, % (n/N)	32.6% (29/89)	37.2% (16/43)	28.3% (13/46)	8.9% (−10.5% to 28.4%)	0.3734^b
Dysmenorrhea, % (n/N)	14.6% (13/89)	18.2% (8/44)	11.1% (5/45)	7.1% (−7.6% to 21.7%)	0.3426^b
Malignancy, % (n/N)	70.0% (63/90)	61.4% (27/44)	78.3% (36/46)	−16.9% (−35.6% to 1.8%)	0.0819^b
History of Endometrial Disease, % (n/N)	5.6% (5/90)	4.6% (2/44)	6.5% (3/46)	−2.0% (−11.4% to 7.4%)	0.6961^b
Uterine Fibroids, % (n/N)	39.3% (35/89)	44.2% (19/43)	34.8% (16/46)	9.4% (−10.8% to 29.6%)	0.3670^b

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a Independent samples t Student test.

b Chi-squared test.

AMP: Absorbable modified polymer starch powder hemostat; SC: Standard care; SD: Standard deviation; 95%CI: 95% Confidence interval; BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: heart rate; bpm: Beats per minute; INR: International normalized ratio; NA: Not applicable.

There was no statistical difference between the height, weight, or body mass index (BMI) between groups.

The proportion of patients with a history of menorrhagia (32.7% versus 28.3%, p = .373) or incidence of dysmenorrhea (18.2% versus 11.1%, p = .343) was greater in the AMP group than in the SC group, although such differences were not statistically significant. Women treated for malign pathology were 61.4% (27/44) and 78.3% (36/46) in the AMP and SC groups, respectively. There were no significant differences between groups in any of the preoperative demographic and clinical characteristics (Table 1).

Surgical procedures and type of surgery

There were no significant differences between study groups in either indication of surgical procedure or type of surgical procedures (Table 2).

Table 2. Overview of the surgical procedure and type of surgery among the study population.

Indication*, % (n/N)	Overall (N = 90)	AMP Group (N = 44)	SC Group (N = 46)	Mean difference (95%CI)	P value^a
Hysterectomy	81.1% (73/90)	79.6% (35/44)	82.6% (38/46)	−3.1% (−19.3% to 13.1%)	0.7176
Endometrial Resection	0.0% (0/90)	0.0% (0/44)	0.0% (0/46)	0.0% (N/A)	N.A.
Cystectomy	4.4% (4/90)	6.8% (3/44)	2.2% (1/46)	4.6% (−3.9% to 13.2%)	0.2927
Myomectomy	4.4% (4/90)	6.8% (3/44)	2.2% (1/46)	4.6% (−3.9% to 13.2%)	0.2927
Other	77.8% (70/90)	72.7% (32/44)	82.6% (38/46)	−9.9% (−27.0% to 7.2%)	0.2616
Lymphadenectomy	36.7% (33/90)	36.4% (16/44)	37.0% (17/46)	−0.6% (−20.5% to 19.3%)	0.9532
Type of Surgery, (n/N)	Overall (N = 90)	AMP Group (N = 44)	SC Group (N = 46)	Mean difference (95%CI)
Open	46.7% (42/90)	47.7% (21/44)	45.7% (21/46)	2.1% (−18.5% to 22.7%)	0.8501
Laparoscopic	46.7% (42/90)	45.5% (20/44)	47.8% (22/46)	−2.4% (−23.0% to 18.2%)	0.8279
Other^#	6.7% (6/90)	6.8% (3/44)	6.5% (3/46)	0.3% (−10.0% to 10.6%)	0.9547

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*Not mutually exclusive. Most patients had concomitant procedures along with, e.g., hysterectomy. ^#E.g.: robotic, vaginal, etc.

a Chi-squared test.

AMP: Absorbable modified polymer starch powder hemostat; SC: Standard care: SD: Standard deviation; 95%CI: 95% Confidence interval; NA: Not applicable.

Most patients enrolled (81.1%) required a hysterectomy with or without a concomitant procedure. In the overall study population, open surgery was performed in 42 (46.7%) subjects, a laparoscopic approach was performed in 42 (46.7%) patients, and 6 (6.7%) patients underwent robotic procedures.

Primary and secondary effectiveness outcomes

Most of the subjects experienced oozing (37.8%; 34/90) or mild (47.8%; 43/90) bleeding, with no significant differences between AMP (36.4% and 52.3%, respectively) and SC (39.1% and 43.5%, respectively) groups, p = .649. Twelve (13.3%) patients had moderate bleeding, 4 (9.1%) in the AMP group and 8 (17.4%) in the SC group (p = .250). Only 1 (1.1%) patient, who was assigned to the AMP group, had severe bleeding.

The primary effectiveness endpoint was the achievement of hemostasis, as defined as the absence of any blood egressing from the applied hemostatic agent or from the diathermy site (if no topical agent was used) within 10 minutes of application.

There was no statistically significant difference between the two groups with a slightly higher rate of achieved hemostasis in the AMP group compared to SC group (97.7% (43/44) VS 93.5% (43/46); Mean difference: 4.2%; 95%CI: −4.1% to 12.6%; p = .337.

An overview of the proportion of patients who achieved hemostasis in the ITT, PP, and AT populations is shown in Table 3.

Table 3. Proportion of patients who achieved hemostasis.

	AMP (n = 44)	SC (n = 46)	Mean difference (95%CI)	P value^a
ITT, % (n/N)	97.7% (43/44)	93.5% (43/46)	4.2% (−4.1% to 12.6%)	0.3366
AT, % (n/N)	97.7% (43/44)	93.5% (43/46)	4.2% (−4.1% to 12.6%)	0.3366
PP, % (n/N)	95.5% (21/22)	96.2% (25/26)	−0.7% (−12.1% to 10.7%)	0.8684

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^aChi-squared test.

AMP: Absorbable modified polymer starch powder hemostat; SC: Standard care; 95%CI: 95% Confidence interval; ITT: Intent-to-treat; AT: As Treated; PP: Per protocol.

The time required to achieve hemostasis was lower in the AMP (1.91 ± 1.15 minutes) versus the SC (2.28 ± 2.09 minutes) group, although this difference was not statistically significant (mean difference: −0.37 ± 1.68 minutes; 95%CI: −1.09 to 0.35; p = .309).

One patient was randomized to usual care and did not achieve hemostasis within 10 minutes, but subsequently had AMP-SPH applied as a secondary measure to cease bleeding. Other hemostats were only used in 20.4% of SC group patients. FloSeal® was used in 13.6% of procedures and Surgiflo® in 6.8% of procedures.

The total time of surgery was 204.8 ± 109.9 and 216.7 ± 114.4 minutes in AMP and SC groups, respectively, without a significant difference between groups (mean difference: −11.9 ± 112.2 minutes; 95%CI: −58.9 to 35.1 minutes; p = .616). During the procedure, red blood cell units were given to a total of 9 (10.2%) patients. More patients in the standard care arm required blood products (17.9%) compared to those in the AMP group (4.8%), although this difference was not statistically significant (p = .055).

During this study, no patients required reintervention for post-operative bleeding.

Safety outcomes

The AMP-SPH was applied to the pelvis or pelvic floor in 30 patients (69.7%). A full list of application sites can be found in S1 Table.

The most commonly reported AE in the AMP group was hematoma, which occurred in 5 cases: 2 cases of pelvic hematoma (one with vaginal spotting); 1 Douglas hematoma; 1 vaginal cuff hematoma; and 1 cupula hematoma. There was one occurrence of hematoma in the SC group.

A total of 29 AEs (24 non-serious and 5 serious AEs) were reported, 12 AEs in the AMP group and 17 in the SC group (Table 4).

Table 4. Overview of the adverse events (AEs) classification.

	Events (Subjects, %)
	Overall n = 90)	AMP (n = 44)	SC (n = 46)	Mean difference (95% CI)	P value^a
Non-Serious AE	19 (21.1%)	8 (18.2%)	11 (23.9%)	−5.7% (−22.5%, 11.1%)	0.5101
Non-Serious Device Related AE	3 (3.3%)	3 (6.8%)	0 (0, 0.0%)	6.8% (−0.6%, 14.3%)	0.0737
Serious AE	5 (5.6%)	2 (4.5%)	3 (6.5%)	−2.0% (−11.4%, 7.4%)	0.6797
Serious Device Related AE	1 (1.1%)	1 (2.3%)	0 (0, 0.0%)	2.3% (−2.1%, 6.7%)	0.3036

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^aChi-squared test.

AMP: Absorbable modified polymer starch powder hemostat; SC: Standard care; AE: Adverse event.

Detailed information of the different AEs, both non-serious and serious, are shown in S2, S3, and S4 Tables, respectively.

At 24 hours postoperatively, pain was 4.04 ± 2.19 and 4.64 ± 2.21 in the AMP and SC groups, respectively (mean difference: −0.60 ± 2.22; 95%CI: −1.61 to 0.44; p = .254). Pain at discharge was 2.36 ± 1.13 and 2.53 ± 1.6 in the AMP and SC groups, respectively (−0.17 ± 1.40; 95%CI: −0.84 to 0.50; p = .614). At Day 30 postoperatively, pain was 1.04 ± 0.96 and 0.98 ± 0.96 in the AMP and SC groups, respectively (mean difference: 0.06 ± 0.97, 95%CI: −0.42 to 0.54; p = .804).

At 24 hours postoperatively, a greater proportion of subjects in the SC group had a drain in situ (incidence rate difference: 11.2%; 95%CI: −17.7% to 40.1%; p = .455), although such a difference was not statistically significant. Nine (19.6%) and 3 (6.8%) patients in the SC and AMP groups, respectively, had a drain at discharge (incidence rate difference: 12.8%; 95%CI: −2.3% to 27.8%; p = .108).

Although drainage volume was lower in the AMP group at both 24 hours postoperatively (mean difference: −74.4 ± 285.9 mL; 95%CI: −250.0 to 01.2 mL; p = .397) and discharge (mean difference: −544.0 ± 753.1; 95%CI: −1662.7 to 574.7; p = .304), such differences were not statistically significant.

In the AMP-SPH group, hemostasis within 10 minutes was achieved in all but one patient; bleeding in this case was subsequently controlled by unspecified methods. In the SC group, three patients failed to achieve hemostasis within 10 minutes. Bleeding was controlled in these cases using AMP-SPH (n = 1), sutures (n = 1), and unspecified methods (n = 1). No intraoperative rebleeding events or postoperative reinterventions for bleeding were reported during the study.

Discussion

Hemorrhage is a rare but serious potential complication of gynecological surgery, and postoperative bleeding may occur despite meticulous surgical technique [15,16]. Indeed, acute postoperative hemorrhage is the most frequent cause of return to the operating theatre [16].

The capacity to improve hemostasis in surgical procedures is a key factor for preventing blood loss, reducing perioperative morbidity and surgery times, and improving surgical outcomes [17].

While hemostasis is typically achieved through suturing, electrocautery, or surgical clips, several adjunctive hemostatic agents have been developed for use over the last two decades [10–12]. For instance, the use of local hemostatic agents can be considered an addition to traditional surgical coagulation and ligation in gynecologic oncology to obtain adequate hemostasis [18].

In general terms, hemostatic agents can be divided into active and passive agents, with both groups having utility in different procedures as adjunctive therapies for controlling surgical bleeding [19].

Active hemostatic agents work at the end or independent of the coagulation cascade and thus also work in patients with compromised coagulation [20–22]. These agents can be used effectively in patients with spontaneous or drug-induced coagulation disorders and are effective for a wide range of bleeding grades (including pulsatile arterial bleeding) [20–24].

Passive hemostatic agents generally provide a structure for platelets to aggregate and activate, while forming a matrix at the site of bleeding, which then allows the coagulation cascade to be activated through contact activation, finally leading to the formation of a fibrin clot [20–22]. The efficacy of passive agents depends on the patient’s own endogenous presence of clotting factors that result in fibrin production to achieve hemostasis, so they are only effective in patients who have an intact coagulation system [20–22,25–28]. These hemostatic agents are most effective when used in areas where the bleeding is of a lower grade, or to treat large oozing surfaces [9–12,29].

The AMP-SPH has been developed for use in surgical procedures or injuries as an adjunct hemostat when control of bleeding from capillary, venous or arteriolar vessels by pressure, ligature or other conventional means is either ineffective or impractical.

The current study compared the effectiveness and safety of an AMP-SPH to usual care when used in adult subjects during open or laparoscopic gynecological procedures.

The AMP-SPH alone was not inferior to standard care, both in the proportion of subjects who achieved hemostasis within 10 minutes (primary endpoint) and in every one of the secondary effectiveness endpoints. In addition, it is important to consider that, within the standard care group, the use of other hemostatic agents was allowed, and active hemostatic products were used in 20.4% of cases.

Regarding safety, the incidence of AEs, both non-serious and serious, was similar in both groups.

The most commonly reported AE in the AMP group was hematoma, which occurred in 5 cases, while there was one case of hematoma in the SC group.

The incidence of hematoma formation following pelvic gynecological surgery is highly variable, ranging from 25% to 98% [30]. Established risk factors include the type of surgery, patient comorbidities, surgical technique, oncologic resections, difficult anatomical exposure, prior surgeries, recurrent tumors, and previous radiation therapy [31]. Although these factors may have influenced the observed, non-significant differences in hematoma rates between the study groups, no differences in the distribution of these risk factors were identified.

Infection was reported in 4 cases, two patients in each group. Although a higher proportion of patients in the SC group (17.9%) was observed to require blood products compared to the AMP group (4.8%), this difference did not reach statistical significance. Even though cost analysis was beyond the scope of the current study, the finding may suggest a potential reduction in procedural costs.

There are some limitations that need to be taken into consideration when interpreting the results of this study, the most important of which was that standard care strategy was at the investigator’s discretion. In fact, in addition to the usual hemostatic techniques, the SC group could receive two commonly used gelatin-thrombin-based flowable active hemostatic agents (FloSeal® and Surgiflo®).

This fact could have skewed the results in favor of the SC group.

Another important limitation of this study is the lack of a statistically valid sample size justification. While a prospective sample size calculation would have been the ideal approach, a post-hoc analysis was performed to estimate the number of patients required to detect significant differences based on the observed results. With an alpha risk of 0.05 in a two-sided test and sample sizes of 44 patients in the AMP group and 46 in the SC group, the statistical power to detect the observed differences as significant was only 16%. Furthermore, to achieve a power of 80% with an alpha of 0.05, a total of 353 patients per group would have been required for the observed differences in the proportion of patients achieving hemostasis within 10 minutes to reach statistical significance.

Additionally, the absence of a multivariate analysis to assess potential covariate associations with hemostasis, which could have offered a more detailed statistical evaluation, may be considered a limitation of the study.

Finally, the current study did not evaluate the cost-effectiveness of both hemostatic strategies, which could have provided additional context to the findings.

Conclusions

The AMP-SPH product was safe and effective and not inferior to standard care in the control of lower grade bleeding for patients undergoing gynecology procedures and the cessation of bleeding tended to be faster with the use of AMP-SPH than with standard methods.

Based on these findings, future studies are warranted to analyze the cost-effectiveness of the use of hemostatic agents in gynecological surgery, in addition to head-to-head comparisons between different hemostatic agents.

Clinical trial registration

NCT02835391. Registered July 31, 2015.

Supporting information

S1 Table. Sites of application of the absorbable modified polymer (AMP) starch powder hemostat.

(DOCX)

pone.0331376.s001.docx^{(14.4KB, docx)}

S2 Table. Overview of the different non-serious adverse events reported in the study.

(DOCX)

pone.0331376.s002.docx^{(18.7KB, docx)}

S3 Table. Overview of the Serious adverse events documented over the study follow-up.

(DOCX)

pone.0331376.s003.docx^{(15.1KB, docx)}

S4 Table. Time of onset and evolution of the different serious adverse events reported during the study.

(DOCX)

pone.0331376.s004.docx^{(14.9KB, docx)}

Acknowledgments

The writing up and formatting of the manuscript by Ciencia y Deporte S.L. is greatly acknowledged. Alberto Izarra and Rafella De Santis, both Baxter Medical Affairs, supported in data analysis and coordinating the author collaboration on this manuscript.

Data Availability

Our study utilizes third-party data that are the property of Artivion, formerly known as CryoLife Europa. As these data are proprietary, they cannot be publicly shared. However, interested researchers may contact Artivion directly to inquire about potential access to the data (https://artivion.com/; 1655 Roberts Blvd., NW; Kennesaw, GA 30144 USA) E-mail address: customerservice.us@artivion.com.

Funding Statement

Cryolife, Europe Baxter (Founded Medical writing). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

1.Oliphant SS, Jones KA, Wang L, Bunker CH, Lowder JL. Trends over time with commonly performed obstetric and gynecologic inpatient procedures. Obstet Gynecol. 2010;116(4):926–31. doi: 10.1097/AOG.0b013e3181f38599 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Global Obstetric & Gynecological Surgery Market Trends & Opportunities 2017-2022 - Number of Procedures Per Year is Forecast to Reach 90.7 Million by 2022 - ResearchAndMarkets.com. Business Wire. August 15, 2019. Accessed December 18, 2024. https://www.businesswire.com/news/home/20190815005261/en/Global-Obstetric-Gynecological-Surgery-Market-Trends-Opportunities-2017-2022---Number-of-Procedures-Per-Year-is-Forecast-to-Reach-90.7-Million-by-2022---ResearchAndMarkets.com
3.Lepine LA, Hillis SD, Marchbanks PA, Koonin LM, Morrow B, Kieke BA. Hysterectomy surveillance--United States, 1980-1993. MMWR CDC Surveill Summ. 1997;46(4):1–15. [PubMed] [Google Scholar]
4.Neis KJ, Zubke W, Fehr M, Römer T, Tamussino K, Nothacker M. Hysterectomy for Benign Uterine Disease. Dtsch Arztebl Int. 2016;113(14):242–9. doi: 10.3238/arztebl.2016.0242 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Rahman R, Gupta S, Manyonda I. Hysterectomy for benign gynaecological disease. Obstetrics, Gynaecology & Reproductive Medicine. 2017;27(4):125–31. [Google Scholar]
6.Colombo N, Sessa C, Bois A du, Ledermann J, McCluggage WG, McNeish I, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Int J Gynecol Cancer. 2019;29(4):728–60. doi: 10.1136/ijgc-2019-000308 [DOI] [PubMed] [Google Scholar]
7.Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Radiother Oncol. 2021;154:327–53. doi: 10.1016/j.radonc.2020.11.018 [DOI] [PubMed] [Google Scholar]
8.Parker WH, Wagner WH. Gynecologic surgery and the management of hemorrhage. Obstet Gynecol Clin North Am. 2010;37(3):427–36. doi: 10.1016/j.ogc.2010.05.003 [DOI] [PubMed] [Google Scholar]
9.Cao Z. Prevention and management of severe hemorrhage during gynecological. Operations. Zhonghua Fu Chan Ke Za Zhi. 2001;36(6):355–9. [PubMed] [Google Scholar]
10.Wysham WZ, Roque DR, Soper JT. Use of topical hemostatic agents in gynecologic surgery. Obstet Gynecol Surv. 2014;69(9):557–63. doi: 10.1097/OGX.0000000000000106 [DOI] [PubMed] [Google Scholar]
11.Ito TE, Martin AL, Henderson EF, Gaskins JT, Vaughn VM, Biscette SM, et al. Systematic Review of Topical Hemostatic Agent Use in Minimally Invasive Gynecologic Surgery. JSLS. 2018;22(4):e2018.00070. doi: 10.4293/JSLS.2018.00070 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Cullifer RM, Makai G, Pacis M, Huynh T. Topical hemostatic and tissue-sealing agents in gynecologic surgery. Curr Opin Obstet Gynecol. 2020;32(4):285–91. doi: 10.1097/GCO.0000000000000632 [DOI] [PubMed] [Google Scholar]
13.PerClot® Polysaccharide Hemostatic System Indications and Important Risk Information. Baxter Advanced Surgery. 2024. Accessed September 1, 2024. https://globaladvancedsurgery.baxter.com/perclot
14.Tackett SM, Calcaterra D, Magee G, Lattouf OM. Real-world outcomes of hemostatic matrices in cardiac surgery. J Cardiothorac Vasc Anesth. 2014;28(6):1558–65. doi: 10.1053/j.jvca.2014.05.010 [DOI] [PubMed] [Google Scholar]
15.Tomacruz RS, Bristow RE, Montz FJ. Management of pelvic hemorrhage. Surg Clin North Am. 2001;81(4):925–48. doi: 10.1016/s0039-6109(05)70174-2 [DOI] [PubMed] [Google Scholar]
16.Sak ME, Turgut A, Evsen MS, Soydinc HE, Ozler A, Sak S, et al. Relaparotomy after initial surgery in obstetric and gynecologic operations: analysis of 113 cases. Ginekol Pol. 2012;83(6):429–32. [PubMed] [Google Scholar]
17.Wu B, Song K, Gong Q, Zhan H, Chen W, Wang Z. Perioperative outcomes and hospital costs associated with flowable gelatin hemostatic matrix for lumbar surgeries in real world hospital setting. J Med Econ. 2019;22(9):917–23. doi: 10.1080/13696998.2019.1623809 [DOI] [PubMed] [Google Scholar]
18.Fotopoulou C, Planchamp F, Aytulu T, Chiva L, Cina A, Ergönül Ö, et al. European Society of Gynaecological Oncology guidelines for the peri-operative management of advanced ovarian cancer patients undergoing debulking surgery. Int J Gynecol Cancer. 2021;31(9):1199–206. doi: 10.1136/ijgc-2021-002951 [DOI] [PubMed] [Google Scholar]
19.Lewis KM, Spazierer D, Urban MD, Lin L, Redl H, Goppelt A. Comparison of regenerated and non-regenerated oxidized cellulose hemostatic agents. Eur Surg. 2013;45(4):213–20. doi: 10.1007/s10353-013-0222-z [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Chiara O, Cimbanassi S, Bellanova G, Chiarugi M, Mingoli A, Olivero G, et al. A systematic review on the use of topical hemostats in trauma and emergency surgery. BMC Surg. 2018;18(1):68. doi: 10.1186/s12893-018-0398-z [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Slezak P, Heher P, Monforte X, Keibl C, Redl H, Spazierer D, et al. Efficacy of Topical Hemostatic Agents: A Comparative Evaluation of Two Gelatin/Thrombin-Based Hemostatic Matrices in a Porcine Kidney Surgical Model. J Invest Surg. 2019;32(7):646–53. doi: 10.1080/08941939.2018.1447619 [DOI] [PubMed] [Google Scholar]
22.Slezak P, Keibl C, Labahn D, Schmidbauer A, Genyk Y, Gulle H. A Comparative Efficacy Evaluation of Recombinant Topical Thrombin (RECOTHROM®) With A Gelatin Sponge Carrier Versus Topical Oxidized Regenerated Cellulose (TABOTAMP®/SURGICEL®) In A Porcine Liver Bleeding Model. J Invest Surg. 2021;34(8):862–8. doi: 10.1080/08941939.2019.1705444 [DOI] [PubMed] [Google Scholar]
23.Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL Jr, Reynolds TC, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256–65. doi: 10.1016/j.jamcollsurg.2007.03.020 [DOI] [PubMed] [Google Scholar]
24.Echave M, Oyagüez I, Casado MA. Use of Floseal®, a human gelatine-thrombin matrix sealant, in surgery: a systematic review. BMC Surg. 2014;14:111. doi: 10.1186/1471-2482-14-111 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Ragusa R, Faggian G, Rungatscher A, Cugola D, Marcon A, Mazzucco A. Use of gelatin powder added to rifamycin versus bone wax in sternal wound hemostasis after cardiac surgery. Interact Cardiovasc Thorac Surg. 2007;6(1):52–5. doi: 10.1510/icvts.2005.126250 [DOI] [PubMed] [Google Scholar]
26.Tscholl V, Spann F, Moses J, Nagel P, Bellmann B, Biewener S, et al. Prospective randomized study evaluating the effects of PerClot® (Polysaccharide Hemostatic System) application in patients with high bleeding risk undergoing cardiac rhythm device implantation. Int J Cardiol. 2017;248:84–91. doi: 10.1016/j.ijcard.2017.08.038 [DOI] [PubMed] [Google Scholar]
27.Rao K, Gomati A, Yuen Hao Tong E, Ah-See W, Shakeel M. Use of PerClot® in head and neck surgery: a Scottish centre experience. Eur Arch Otorhinolaryngol. 2021;278(6):1965–9. doi: 10.1007/s00405-020-06247-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
28.ATLS Subcommittee; American College of Surgeons’ Committee on Trauma; International ATLS working group. Advanced trauma life support (ATLS®): the ninth edition. J Trauma Acute Care Surg. 2013;74(5):1363–6. doi: 10.1097/TA.0b013e31828b82f5 [DOI] [PubMed] [Google Scholar]
29.Wright JD, Ananth CV, Lewin SN, Burke WM, Siddiq Z, Neugut AI, et al. Patterns of use of hemostatic agents in patients undergoing major surgery. J Surg Res. 2014;186(1):458–66. doi: 10.1016/j.jss.2013.07.042 [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Kuhn RJ, de Crespigny LC. Vault haematoma after vaginal hysterectomy: An invariable sequel? Aust N Z J Obstet Gynaecol. 1985;25(1):59–62. doi: 10.1111/j.1479-828x.1985.tb00605.x [DOI] [PubMed] [Google Scholar]
31.Oderich GS, Panneton JM, Hofer J, Bower TC, Cherry KJ Jr, Sullivan T, et al. Iatrogenic operative injuries of abdominal and pelvic veins: A potentially lethal complication. J Vasc Surg. 2004;39(5):931–6. doi: 10.1016/j.jvs.2003.11.040 [DOI] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0331376.r001

Decision Letter 0

Hideto Sano

21 Mar 2025

PONE-D-25-02293Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study.PLOS ONE

Dear Dr. Garcia-Tejedor,

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PLOS ONE

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Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

**********

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Reviewer #1: The study lacks a statistically valid sample size justification. That could not be found in the protocol, either. The paper mentions that 90 subjects are needed as per the protocol. How was that calculated? This reviewer found no valid statistical design section in the protocol unless it is under another section. One should not have to search for this information. Section 9.0 (Statistical Considerations) of the protocol is totally inadequate. All it mentions is an ITT and per protocol strategy. Where or what was the intended non inferiority margin? Since non inferiority was mentioned in the manuscript, it should have been incorporated into the design of the study.

Apparently the ITT and per protocol results compare as they are the same as noted in Table 3. However, even though the groups look fairly balanced was there any attempt to look at covariate association for achieving hemostasis along with treatment in a multivariate setting such as the logistic regression? The investigation does seem incomplete, unless other possible associative factors with hemostasis are examined in a more rigorous statistical setting. The statistical handling of this data (design and analysis) is obviously incomplete.

Reviewer #2: I found the manuscript, to be of high quality. The methodology is sound, the data are presented clearly, and the discussion is insightful. The authors have effectively addressed the research question, and the article is well-designed for publication

**********

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PLoS One. 2025 Sep 11;20(9):e0331376. doi: 10.1371/journal.pone.0331376.r002

Author response to Decision Letter 1

25 Apr 2025

Response to the reviewers, manuscript PONE-D-25-02293, entitled

“Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study”.

Dear Editor-in-Chief, I have considered the comments made by the reviewers and I hope that the paper improves greatly thanks to these comments.

I am sending you the revised manuscript and the rebuttal letter providing a point-by-point response to each of the numbered reviewer comments.

#Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

It was corrected.

No specific numbers have been assigned to the Grants received.

3. Thank you for stating the following financial disclosure:

[Cryolife, Europe

Baxter (Founded Medical writing)].

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

Thank you very much indeed for the comment, we highly appreciate it.

The following sentence was added in the Funding section and in the cover letter: “Cryolife was involved in study funding, study design, provision of study materials, data collection and analysis”.

“Baxter was involved in medical writing funding, preparation of the manuscript, decision to publish”.

4. Thank you for stating the following in the Competing Interests section:

[Barbara Costantini, Jordi Ponce and Giovanni Scambia served as speakers for Baxter and have received speaker honoraria according to fair market value.].

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

The following sentence was added in the “Conflict of Interests” section and in the cover letter: “This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

Before we proceed with your manuscript, please address the following prompts:

Please update your Data Availability statement in the submission form accordingly.

The following sentence was added in the Data Availability Statement: “Our study utilizes third-party data that are the property of Artivion, formerly known as CryoLife Europa. As these data are proprietary, they cannot be publicly shared. However, interested researchers may contact Artivion directly to inquire about potential access to the data (https://artivion.com/; 1655 Roberts Blvd., NW; Kennesaw, GA 30144 USA.”.

It was corrected.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #2: Yes

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

3. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

4. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

5. Review Comments to the Author

Reviewer #1:

1. The study lacks a statistically valid sample size justification. That could not be found in the protocol, either. The paper mentions that 90 subjects are needed as per the protocol. How was that calculated? This reviewer found no valid statistical design section in the protocol unless it is under another section. One should not have to search for this information. Section 9.0 (Statistical Considerations) of the protocol is totally inadequate. All it mentions is an ITT and per protocol strategy. Where or what was the intended non inferiority margin? Since non inferiority was mentioned in the manuscript, it should have been incorporated into the design of the study.

Thank you very much indeed for the comment, we highly appreciate it.

We fully agree with the reviewer about the limitation of the lack of statistically valid sample size justification. This was added as a study limitation.

The current study was a Phase IV, observational (post-market) study designed to provide descriptive and exploratory data rather than confirmatory evidence. As stated in the study protocol, the sample size was not determined to achieve a specific statistical power to detect differences between the PerClot and Standard of Care (SoC) patient populations. Instead, this study followed an observational, case-controlled design, in which patients were grouped based on treatment exposure rather than through true randomization, which is characteristic of experimental studies such as randomized controlled trials (RCTs). The PerClot group represented the case study cohort, while the SoC group served as the control, allowing for comparative assessment of specific clinical characteristics between the two cohorts.

Given the exploratory nature of this study, our primary objective was to gather preliminary evidence rather than to definitively establish non-inferiority. Although prospective sample size calculation is the preferred methodological approach, as the reviewer correctly noted, a post-hoc analysis was conducted to estimate the number of patients required to detect significant differences based on the observed results. This analysis provided valuable insights into the potential adequacy of the study’s sample size, reinforcing the descriptive and hypothesis-generating role of this investigation.

The following paragraph was added as a study limitation: “Another important limitation of this study is the lack of a statistically valid sample size justification. While a prospective sample size calculation would have been the ideal approach, a post-hoc analysis was performed to estimate the number of patients required to detect significant differences based on the observed results. With an alpha risk of 0.05 in a two-sided test and sample sizes of 44 patients in the AMP group and 46 in the SC group, the statistical power to detect the observed differences as significant was only 16%. Furthermore, to achieve a power of 80% with an alpha of 0.05, a total of 353 patients per group would have been required for the observed differences in the proportion of patients achieving hemostasis within 10 minutes to reach statistical significance”.

2. Apparently the ITT and per protocol results compare as they are the same as noted in Table 3. However, even though the groups look fairly balanced was there any attempt to look at covariate association for achieving hemostasis along with treatment in a multivariate setting such as the logistic regression? The investigation does seem incomplete, unless other possible associative factors with hemostasis are examined in a more rigorous statistical setting. The statistical handling of this data (design and analysis) is obviously incomplete.

Thank you for your insightful comment. We fully acknowledge the importance of examining potential covariate associations with hemostasis in a more rigorous statistical framework, such as logistic regression, to strengthen the analysis. Unfortunately, we do not have access to the original dataset but only to the statistical report provided by the study promoter, which limits our ability to perform additional multivariate analyses. Consequently, we are unable to explore potential confounding factors that may influence hemostasis outcomes. While our study primarily focused on comparing ITT and per-protocol results, we recognize that a more comprehensive statistical approach could provide further insights. We appreciate your valuable suggestion and acknowledge this as a limitation of our study.

The following sentence was added as a limitation of the study: “Additionally, the absence of a multivariate analysis to assess potential covariate associations with hemostasis, which could have offered a more detailed statistical evaluation, may be considered a limitation of the study”.

Reviewer #2:

I found the manuscript, to be of high quality. The methodology is sound, the data are presented clearly, and the discussion is insightful. The authors have effectively addressed the research question, and the article is well-designed for publication.

Thank you very much indeed for this insightful comment; we truly appreciate it.

Attachment

Submitted filename: Rebuttal letter PerClot PlosOne R1 1.1.docx

pone.0331376.s006.docx^{(27KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0331376.r003

Decision Letter 1

Hideto Sano

19 Jun 2025

PONE-D-25-02293R1Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study.PLOS ONE

Dear Dr. Garcia-Tejedor,

Please submit your revised manuscript by Aug 03 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Hideto Sano

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: (No Response)

Reviewer #3: No

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #3: No

Reviewer #4: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #3: No

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #3: In this revised submission, Dr. Garcia-Tejedor and colleagues compare the use of absorbable modified polymer starch powder hemostat (AMP-SPH) compared to standard of care (SC). The submission could be improved with respect to technique, data, and statistics by the following:

1. The bleeding severity descriptions provided suggest that AMP-SPH may have been used outside of its approved labeling. Providing an explanation of why this was permitted would be useful.

2. Achieving hemostasis at 10 minutes was the primary endpoint, but 10 minutes is considered long for the primary endpoint in time to hemostasis studies in the current environment. Supplying a table with the results for the degree of hemostasis at all observed time points would be helpful.

3. The bleeding severity score use was only semi-quantitative. Providing a discussion of why a quantitative bleeding severity score was not employed, what such scores exist, and how not using one may effect results would be appropriate.

4. Addition to the discussion of how electrocautery was the SC when AMP-SPH is approved for use when conventional treatments are ineffective or impractical. Explaining why it would not have been more appropriate to use another established hemostat (for example a flowable) as the SC in all SC subjects should be discussed.

5. Reporting of the incidence of rebleeding after 10 minutes intraoperatively.

6. Explanation of what were the pre-analysis criteria for statistical non-inferiority.

7. Clarification as to why all subjects were not able to be included in the final analysis.

8. Discussion of why there was a trend toward more hematomas in the AMP-SPH group.

9. In the abstract as well as on page 2 line 44-45 and page 16, line 357-9, the word “observed” could be added for the comparison on amount of blood transfusions being less in the AMP-SPH group as this difference was not statistically significant.

Reviewer #4: The authors of the manuscript have properly addresed all the Reviewer´s comments and concerns. Congratulations.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #3: No

Reviewer #4: No

**********

PLoS One. 2025 Sep 11;20(9):e0331376. doi: 10.1371/journal.pone.0331376.r004

Author response to Decision Letter 2

8 Jul 2025

Response to the reviewers, manuscript PONE-D-25-02293R1, entitled

“Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study”.

Dear Editor-in-Chief, I have considered the comments made by the reviewers and I hope that the paper improves greatly thanks to these comments.

I am sending you the revised manuscript and the rebuttal letter providing a point-by-point response to each of the numbered reviewer comments.

# Journal Requirements:

Reference list has been reviewed.

# Review Comments to the Author

Reviewer #1: (No Response)

1. The bleeding severity descriptions provided suggest that AMP-SPH may have been used outside of its approved labeling. Providing an explanation of why this was permitted would be useful.

According to the study protocol, and the intraoperative inclusion criteria: Subject experiences generalized oozing or mild to moderate bleeding which is consistent with the requirement for a hemostatic agent. Bleeding was defined and documented in the CRF as:

• Oozing - The rate of bleeding is slow. This is what one may expect from capillary, venular, or arteriolar bleeding.

• Mild bleeding - The rate of bleeding is slightly faster than oozing. There is no pulsatile flow present. This is what one may expect from capillary, venular, or arteriolar bleeding.

• Moderate bleeding. There may be a weak pulsatile flow present. If there is a pulsatile flow, the rate of blood flow is similar to the rate of flow for mild bleeding. If there is no pulsatile flow, the rate of blood flow is faster than mild bleeding.

• Severe bleeding. For the most part, pulsatile flow is present. If there is no pulsatile flow, then the rate of blood flow is extremely rapid.

If we were to apply the Vibe Scale (Lewis KM, Li Q, Jones DS, Corrales JD, Du H, Spiess PE, Lo Menzo E, DeAnda A Jr. Development and validation of an intraoperative bleeding severity scale for use in clinical studies of hemostatic agents. Surgery. 2017 Mar;161(3):771-781. doi: 10.1016/j.surg.2016.09.022.) to these definitions for bleeding in this chart:

• Oozing - Vibe 1 >1-5ml/min

• Mild - Vibe 2 >5-10ml/min

• Moderate - Vibe 2-3

• Severe - Vibe 3 >10-50ml/min (not Vibe 4)

Except for the 1 outlier that was reported to have severe bleeding; All the patients bleeding did fall into the labeling. Probably this severe bleeding patient should have been excluded from the study as this patient is an outlier - although, this patient apparently did not meet the specific criteria to be excluded by the surgeon - according to the blood loss classification of the ATLS classification chart. The patient was not a Class II-IV.

Intraoperative Exclusion Criteria:

Subject has any major intraoperative bleeding incidences (i.e., American College of Surgeons Advanced Trauma Life Support Class II, III or IV Hemorrhage [2013])

ATLS classification of blood loss is classified into four classes based on the estimated percentage of blood volume loss. Class I involves up to 15% blood loss (750ml), Class II involves 15-30% (750-1500ml), Class III involves 30-40% (1500-2000ml), and Class IV involves >40% blood loss (>2000ml). These classifications correlate with changes in vital signs like heart rate and blood pressure. (Spahn, D.R., Bouillon, B., Cerny, V. et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 17, R76 (2013). https://doi.org/10.1186/cc12685).

While 10 minutes may not represent the current clinical study bleeding assessment criteria, this study was started in 2015. If we apply the Vibe bleeding scale rates (Lewis KM, Li Q, Jones DS, Corrales JD, Du H, Spiess PE, Lo Menzo E, DeAnda A Jr. Development and validation of an intraoperative bleeding severity scale for use in clinical studies of hemostatic agents. Surgery. 2017 Mar;161(3):771-781. doi: 10.1016/j.surg.2016.09.022.) to the bleeding scale established for this study the majority of patients would bleed 1-10ml/min so over 10 minutes that would be 10-100mls max. None of these patients even meet criteria of Class 1 of 750ml in the STS ATLS Trauma bleeding scale.

While we do not have this data available, we provide in the article the data for time to hemostasis: The time required to achieve hemostasis was lower in the AMP group (1.91±1.15 minutes) than in the SC group (2.28±2.09 minutes), although not significant (p=.309).

For this study the investigators decided to devise a study specific bleeding severity score because in 2015 there were no validated quantitative bleeding scales published and peer reviewed. The only validated quantifiable bleeding chart available at the time was the STS ATLS Trauma bleeding scale from 2013.

There were bleeding scales used in many clinical trials. We acknowledge that they are

⦁ “Subjective” description of bleeding

⦁ Valid for investigators only within a particular clinical specialty

⦁ Valid for only a particular type of intervention

For example:

Oz et al used a bleeding scale in cardiovascular surgery in 2000 to describe the initial level of bleeding so as to evaluate the efficacy of a flowable hemostat.

The bleeding severity at each site was characterized as "oozing" or "heavy bleeding" (flowing or spurting). They considered success at 3 minutes and at 10 minutes by severity of bleeding. (Oz MC, Cosgrove DM 3rd, Badduke BR, Hill JD, et al. Controlled clinical trial of a novel hemostatic agent in cardiac surgery. The Fusion Matrix Study Group. Ann Thorac Surg. 2000 May;69(5):1376-82.)

Izzo et al used a bleeding scale for hepatic surgery in 2008 to measure and evaluate the efficacy of a hemostatic matrix before and after treatment.

A hemostatic matrix was applied directly to areas of bleeding. The severity of bleeding before and after application was graded on a 5-point scale (0 = no bleeding, 1 = oozing, 2 = moderate blood flow, 3 = heavy blood flow, 4 = spurting blood). The time to complete hemostasis was also recorded. After application of the gelatin matrix, bleeding severity was assessed at 1-min intervals until hemostasis was complete. (Izzo F, Di Giacomo R, Falco P, Piccirillo M, et al. Efficacy of a hemostatic matrix for the management of bleeding in patients undergoing liver resection: results from 237 cases. Curr Med Res Opin. 2008 Apr;24(4):1011-5.)

The first quantitative validated bleeding scale for intraoperative bleeding is the one published by Lewis KM et al. in 2017 (Lewis KM, Li Q, Jones DS, Corrales JD, Du H, Spiess PE, Lo Menzo E, DeAnda A Jr. Development and validation of an intraoperative bleeding severity scale for use in clinical studies of hemostatic agents. Surgery. 2017 Mar;161(3):771-781. doi: 10.1016/j.surg.2016.09.022.), but as previously mentioned this study started before it was published.

Electrocautery has long been recognized as a standard method for achieving hemostasis in various surgical procedures. Its widespread use and acceptance in clinical practice make it a relevant control for evaluating new hemostatic agents. Electrocautery is effective for controlling bleeding in many situations, particularly in cases of minor to moderate bleeding, and is often the first-line approach in surgical settings.

The primary aim of our study was to assess the efficacy of AMP-SPH in situations where conventional treatments may be insufficient. While AMP-SPH is approved for use when conventional methods are ineffective or impractical, it is essential to establish its effectiveness against a widely accepted standard. The choice of electrocautery as the control group reflects real-world clinical scenarios where surgeons often rely on this method. By comparing AMP-SPH to electrocautery, we can provide insights into its potential advantages in practice, particularly in complex cases where bleeding control is critical.

While flowable hemostatic agents are indeed established alternatives, they may not be universally applicable in all surgical contexts. The choice of hemostatic agent often depends on the specific surgical procedure, the nature of the bleeding, and the surgeon's preference. Additionally, many flowable hemostatic devices also contain thrombin making the device an “Active” hemostatic device which is in a different category than AMP-SPH which is considered a “Passive” hemostat. Electrocautery remains a versatile tool that can be employed in a variety of situations, making it a suitable control for our study.

We acknowledge the importance of exploring the comparative effectiveness of AMP-SPH against other established hemostatic agents in future studies. This could provide a more comprehensive understanding of its role in the surgical armamentarium and help refine guidelines for hemostatic management in various clinical settings.

5. Reporting of the incidence of rebleeding after 10 minutes intraoperatively.

In the AMP-SPH group, only 1 patient did not achieve hemostasis within 10 minutes. Bleeding was controlled after the 10 min by other methods (not described).

In the SC group, 3 patients did not achieve hemostasis within 10 minutes. Bleeding was controlled in 1 patient with AMP-SPH, in another with sutures, and in the last one by other methods not described by the investigator.

During this study, no other rebleeding events were described intraoperatively and no patients required reintervention for post- operative bleeding.

The following paragraph was added in the results section: “In the AMP-SPH group, hemostasis within 10 minutes was achieved in all but one patient; bleeding in this case was subsequently controlled by unspecified methods. In the SC group, three patients failed to achieve hemostasis within 10 minutes. Bleeding was controlled in these cases using AMP-SPH (n=1), sutures (n=1), and unspecified methods (n=1). No intraoperative rebleeding events or postoperative reinterventions for bleeding were reported during the study”.

6. Explanation of what were the pre-analysis criteria for statistical non-inferiority.

We acknowledge the study limitation of the lack of statistically valid sample size justification. This was added as a study limitation.

The current study was a Phase IV, observational (post-market) study designed to provide descriptive and exploratory data rather than confirmatory evidence. As stated in the study protocol, the sample size was not determined to achieve a specific statistical power to detect differences between the AMP-SPH and Standard of Care (SoC) patient populations. Instead, this study followed an observational, case-controlled design, in which patients were grouped based on treatment exposure rather than through true randomization, which is characteristic of experimental studies such as randomized controlled trials (RCTs). The AMP-SPH group represented the case study cohort, while the SoC group served as the control, allowing for comparative assessment of specific clinical characteristics between the two cohorts.

The following paragraph was added as a study limitation: “Another important limitation of this study is the lack of a statistically valid sample size justification. While a prospective sample size calculation would have been the ideal approach, a post-hoc analysis was performed to estimate the number of patients required to detect significant differences based on the observed results. With an alpha risk of 0.05 in a two-sided test and sample sizes of 44 patients in the AMP-SPH group and 46 in the SC group, the statistical power to detect the observed differences as significant was only 16%. Furthermore, to achieve a power of 80% with an alpha of 0.05, a total of 353 patients per group would have been required for the observed differences in the proportion of patients achieving hemostasis within 10 minutes to reach statistical significance.

7. Clarification as to why all subjects were not able to be included in the final analysis.

The Per Protocol (PP) population includes all subjects who were randomized and

treated with PerClot, and had no major protocol deviations, where major protocol

deviations are defined as:

• Failure to meet any preoperative inclusion/exclusion criteria;

• Failure to meet any intraoperative inclusion/exclusion criteria; or

• Any informed consent violation.

The patients excluded from the PP population had major protocol deviations. Four (4) deviations were determined to be subjects not meeting the Inclusion Criteria or meeting the Exclusion Criteria of the study and the remaining deviations were Informed Consent Form deviations. All subjects were consented to the study, but there were various deviations for the method and/or process of consenting, which included signing the wrong version of the informed consent, the incorrect person dating the consent, or an unauthorized Investigator signing the consent. It was verified that the changes in the different versions of the informed consent were minor and would not have impacted the safety of the patient.

8. Discussion of why there was a trend toward more hematomas in the AMP-SPH group.

In our study, the most commonly reported AE in the AMP group was hematoma, which occurred in 5 cases: 2 cases of pelvic hematoma (one with vaginal spotting); 1 Douglas hematoma; 1 vaginal cuff hematoma; and 1 cupula hematoma. There was one occurrence of hematoma in the SC group. This translated into an incidence of 11.4% in the AMP group and 2.2% in the SC group, but despite this, the difference was not statistically significant.

The following paragraph was added in the discussion section: “The incidence of hematoma formation following pelvic gynecological surgery is highly variable, ranging from

Attachment

Submitted filename: Rebuttal letter PerClot PlosOne R2 1.1.docx

pone.0331376.s007.docx^{(25KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0331376.r005

Decision Letter 2

Hideto Sano

25 Jul 2025

PONE-D-25-02293R2Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study.PLOS ONE

Dear Dr. Garcia-Tejedor,

Please submit your revised manuscript by Sep 08 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Hideto Sano

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: WELL DESIGNED AND WRITTEN STUDY REGARDING HEMOSTATIC AGENTS WHICH DO HAVE PROFOUND IMPACT IN OUR DAILY PRACTICE

Reviewer #3: In this second revision of the submission, Dr. Garcia-Tejedor and colleagues have contrasted the use of absorbable modified polymer starch powder hemostat (AMP-SPH) compared to standard of care (SC).

The submission has been significantly improved.

An additional modification would further strengthen the submission.

1. Provide the time span over which patient enrollment occurred in terms of chronological dates.

Reviewer #4: The authors of the manuscript have addressed all possible reviewers concerns. Nothing else to comment

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

**********

PLoS One. 2025 Sep 11;20(9):e0331376. doi: 10.1371/journal.pone.0331376.r006

Author response to Decision Letter 3

25 Jul 2025

Response to the reviewers, manuscript PONE-D-25-02293R2, entitled

“Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study”.

Dear Editor-in-Chief, I have considered the comments made by the reviewers and I hope that the paper improves greatly thanks to these comments.

I am sending you the revised manuscript and the rebuttal letter providing a point-by-point response to each of the numbered reviewer comments.

# Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: WELL DESIGNED AND WRITTEN STUDY REGARDING HEMOSTATIC AGENTS WHICH DO HAVE PROFOUND IMPACT IN OUR DAILY PRACTICE

Thank you very much indeed for the comment, we highly appreciate it.

The submission has been significantly improved.

An additional modification would further strengthen the submission.

1. Provide the time span over which patient enrollment occurred in terms of chronological dates.

The following paragraph was added in the results section: “A total of 90 patients were enrolled across two study sites between November 2015 and July 2017. Screening concluded in July 2017 upon reaching the target enrollment. The study duration was 21 months, from the first patient’s initial visit to the last patient’s final visit. Of the 90 enrolled participants, 44 (48.9%) were assigned to the AMP group and 46 (51.1%) to the SC group (Figure 1).”

Reviewer #4: The authors of the manuscript have addressed all possible reviewers concerns. Nothing else to comment

Thank you very much indeed for the comment, we highly appreciate it.

Attachment

Submitted filename: Rebuttal letter PerClot PlosOne R3 1.0.docx

pone.0331376.s008.docx^{(14.9KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0331376.r007

Decision Letter 3

Hideto Sano

15 Aug 2025

Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study.

PONE-D-25-02293R3

Dear Dr. Garcia-Tejedor,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Hideto Sano

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #3: The authors of the manuscript have addressed all the suggested changes and there are no other comments.

Reviewer #4: THE AUTHORS OF THE MANUSCRIPT HAVE ADDRESSED ALL THE REVIEWERS COMMENTS AND SUGGESTIONS. NOTHING ELSE TO ADD FURTHER

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #3: No

Reviewer #4: No

**********

PLoS One. doi: 10.1371/journal.pone.0331376.r008

Acceptance letter

Hideto Sano

PONE-D-25-02293R3

PLOS ONE

Dear Dr. Garcia-Tejedor,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

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You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps.

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on behalf of

Dr. Hideto Sano

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Sites of application of the absorbable modified polymer (AMP) starch powder hemostat.

(DOCX)

pone.0331376.s001.docx^{(14.4KB, docx)}

S2 Table. Overview of the different non-serious adverse events reported in the study.

(DOCX)

pone.0331376.s002.docx^{(18.7KB, docx)}

S3 Table. Overview of the Serious adverse events documented over the study follow-up.

(DOCX)

pone.0331376.s003.docx^{(15.1KB, docx)}

S4 Table. Time of onset and evolution of the different serious adverse events reported during the study.

(DOCX)

pone.0331376.s004.docx^{(14.9KB, docx)}

Attachment

Submitted filename: Rebuttal letter PerClot PlosOne R1 1.1.docx

pone.0331376.s006.docx^{(27KB, docx)}

Attachment

Submitted filename: Rebuttal letter PerClot PlosOne R2 1.1.docx

pone.0331376.s007.docx^{(25KB, docx)}

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Submitted filename: Rebuttal letter PerClot PlosOne R3 1.0.docx

pone.0331376.s008.docx^{(14.9KB, docx)}

Data Availability Statement

[pone.0331376.ref001] 1.Oliphant SS, Jones KA, Wang L, Bunker CH, Lowder JL. Trends over time with commonly performed obstetric and gynecologic inpatient procedures. Obstet Gynecol. 2010;116(4):926–31. doi: 10.1097/AOG.0b013e3181f38599 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref002] 2.Global Obstetric & Gynecological Surgery Market Trends & Opportunities 2017-2022 - Number of Procedures Per Year is Forecast to Reach 90.7 Million by 2022 - ResearchAndMarkets.com. Business Wire. August 15, 2019. Accessed December 18, 2024. https://www.businesswire.com/news/home/20190815005261/en/Global-Obstetric-Gynecological-Surgery-Market-Trends-Opportunities-2017-2022---Number-of-Procedures-Per-Year-is-Forecast-to-Reach-90.7-Million-by-2022---ResearchAndMarkets.com

[pone.0331376.ref003] 3.Lepine LA, Hillis SD, Marchbanks PA, Koonin LM, Morrow B, Kieke BA. Hysterectomy surveillance--United States, 1980-1993. MMWR CDC Surveill Summ. 1997;46(4):1–15. [PubMed] [Google Scholar]

[pone.0331376.ref004] 4.Neis KJ, Zubke W, Fehr M, Römer T, Tamussino K, Nothacker M. Hysterectomy for Benign Uterine Disease. Dtsch Arztebl Int. 2016;113(14):242–9. doi: 10.3238/arztebl.2016.0242 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref005] 5.Rahman R, Gupta S, Manyonda I. Hysterectomy for benign gynaecological disease. Obstetrics, Gynaecology & Reproductive Medicine. 2017;27(4):125–31. [Google Scholar]

[pone.0331376.ref006] 6.Colombo N, Sessa C, Bois A du, Ledermann J, McCluggage WG, McNeish I, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Int J Gynecol Cancer. 2019;29(4):728–60. doi: 10.1136/ijgc-2019-000308 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref007] 7.Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Radiother Oncol. 2021;154:327–53. doi: 10.1016/j.radonc.2020.11.018 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref008] 8.Parker WH, Wagner WH. Gynecologic surgery and the management of hemorrhage. Obstet Gynecol Clin North Am. 2010;37(3):427–36. doi: 10.1016/j.ogc.2010.05.003 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref009] 9.Cao Z. Prevention and management of severe hemorrhage during gynecological. Operations. Zhonghua Fu Chan Ke Za Zhi. 2001;36(6):355–9. [PubMed] [Google Scholar]

[pone.0331376.ref010] 10.Wysham WZ, Roque DR, Soper JT. Use of topical hemostatic agents in gynecologic surgery. Obstet Gynecol Surv. 2014;69(9):557–63. doi: 10.1097/OGX.0000000000000106 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref011] 11.Ito TE, Martin AL, Henderson EF, Gaskins JT, Vaughn VM, Biscette SM, et al. Systematic Review of Topical Hemostatic Agent Use in Minimally Invasive Gynecologic Surgery. JSLS. 2018;22(4):e2018.00070. doi: 10.4293/JSLS.2018.00070 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref012] 12.Cullifer RM, Makai G, Pacis M, Huynh T. Topical hemostatic and tissue-sealing agents in gynecologic surgery. Curr Opin Obstet Gynecol. 2020;32(4):285–91. doi: 10.1097/GCO.0000000000000632 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref013] 13.PerClot® Polysaccharide Hemostatic System Indications and Important Risk Information. Baxter Advanced Surgery. 2024. Accessed September 1, 2024. https://globaladvancedsurgery.baxter.com/perclot

[pone.0331376.ref014] 14.Tackett SM, Calcaterra D, Magee G, Lattouf OM. Real-world outcomes of hemostatic matrices in cardiac surgery. J Cardiothorac Vasc Anesth. 2014;28(6):1558–65. doi: 10.1053/j.jvca.2014.05.010 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref015] 15.Tomacruz RS, Bristow RE, Montz FJ. Management of pelvic hemorrhage. Surg Clin North Am. 2001;81(4):925–48. doi: 10.1016/s0039-6109(05)70174-2 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref016] 16.Sak ME, Turgut A, Evsen MS, Soydinc HE, Ozler A, Sak S, et al. Relaparotomy after initial surgery in obstetric and gynecologic operations: analysis of 113 cases. Ginekol Pol. 2012;83(6):429–32. [PubMed] [Google Scholar]

[pone.0331376.ref017] 17.Wu B, Song K, Gong Q, Zhan H, Chen W, Wang Z. Perioperative outcomes and hospital costs associated with flowable gelatin hemostatic matrix for lumbar surgeries in real world hospital setting. J Med Econ. 2019;22(9):917–23. doi: 10.1080/13696998.2019.1623809 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref018] 18.Fotopoulou C, Planchamp F, Aytulu T, Chiva L, Cina A, Ergönül Ö, et al. European Society of Gynaecological Oncology guidelines for the peri-operative management of advanced ovarian cancer patients undergoing debulking surgery. Int J Gynecol Cancer. 2021;31(9):1199–206. doi: 10.1136/ijgc-2021-002951 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref019] 19.Lewis KM, Spazierer D, Urban MD, Lin L, Redl H, Goppelt A. Comparison of regenerated and non-regenerated oxidized cellulose hemostatic agents. Eur Surg. 2013;45(4):213–20. doi: 10.1007/s10353-013-0222-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref020] 20.Chiara O, Cimbanassi S, Bellanova G, Chiarugi M, Mingoli A, Olivero G, et al. A systematic review on the use of topical hemostats in trauma and emergency surgery. BMC Surg. 2018;18(1):68. doi: 10.1186/s12893-018-0398-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref021] 21.Slezak P, Heher P, Monforte X, Keibl C, Redl H, Spazierer D, et al. Efficacy of Topical Hemostatic Agents: A Comparative Evaluation of Two Gelatin/Thrombin-Based Hemostatic Matrices in a Porcine Kidney Surgical Model. J Invest Surg. 2019;32(7):646–53. doi: 10.1080/08941939.2018.1447619 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref022] 22.Slezak P, Keibl C, Labahn D, Schmidbauer A, Genyk Y, Gulle H. A Comparative Efficacy Evaluation of Recombinant Topical Thrombin (RECOTHROM®) With A Gelatin Sponge Carrier Versus Topical Oxidized Regenerated Cellulose (TABOTAMP®/SURGICEL®) In A Porcine Liver Bleeding Model. J Invest Surg. 2021;34(8):862–8. doi: 10.1080/08941939.2019.1705444 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref023] 23.Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL Jr, Reynolds TC, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256–65. doi: 10.1016/j.jamcollsurg.2007.03.020 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref024] 24.Echave M, Oyagüez I, Casado MA. Use of Floseal®, a human gelatine-thrombin matrix sealant, in surgery: a systematic review. BMC Surg. 2014;14:111. doi: 10.1186/1471-2482-14-111 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref025] 25.Ragusa R, Faggian G, Rungatscher A, Cugola D, Marcon A, Mazzucco A. Use of gelatin powder added to rifamycin versus bone wax in sternal wound hemostasis after cardiac surgery. Interact Cardiovasc Thorac Surg. 2007;6(1):52–5. doi: 10.1510/icvts.2005.126250 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref026] 26.Tscholl V, Spann F, Moses J, Nagel P, Bellmann B, Biewener S, et al. Prospective randomized study evaluating the effects of PerClot® (Polysaccharide Hemostatic System) application in patients with high bleeding risk undergoing cardiac rhythm device implantation. Int J Cardiol. 2017;248:84–91. doi: 10.1016/j.ijcard.2017.08.038 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref027] 27.Rao K, Gomati A, Yuen Hao Tong E, Ah-See W, Shakeel M. Use of PerClot® in head and neck surgery: a Scottish centre experience. Eur Arch Otorhinolaryngol. 2021;278(6):1965–9. doi: 10.1007/s00405-020-06247-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref028] 28.ATLS Subcommittee; American College of Surgeons’ Committee on Trauma; International ATLS working group. Advanced trauma life support (ATLS®): the ninth edition. J Trauma Acute Care Surg. 2013;74(5):1363–6. doi: 10.1097/TA.0b013e31828b82f5 [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref029] 29.Wright JD, Ananth CV, Lewin SN, Burke WM, Siddiq Z, Neugut AI, et al. Patterns of use of hemostatic agents in patients undergoing major surgery. J Surg Res. 2014;186(1):458–66. doi: 10.1016/j.jss.2013.07.042 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331376.ref030] 30.Kuhn RJ, de Crespigny LC. Vault haematoma after vaginal hysterectomy: An invariable sequel? Aust N Z J Obstet Gynaecol. 1985;25(1):59–62. doi: 10.1111/j.1479-828x.1985.tb00605.x [DOI] [PubMed] [Google Scholar]

[pone.0331376.ref031] 31.Oderich GS, Panneton JM, Hofer J, Bower TC, Cherry KJ Jr, Sullivan T, et al. Iatrogenic operative injuries of abdominal and pelvic veins: A potentially lethal complication. J Vasc Surg. 2004;39(5):931–6. doi: 10.1016/j.jvs.2003.11.040 [DOI] [PubMed] [Google Scholar]

PERMALINK

Effectiveness and safety of an absorbable modified polymer starch powder hemostat versus usual care in gynecology procedures: A prospective, multi-center, and randomized study

Jordi Ponce

Amparo García-Tejedor

Marc Barahona

Serena Cappuccio

Barbara Costantini

Camilla Fedele

Lola Marti-Cardona

Giovanni Scambia

Roles

Abstract

Objective

Conclusions

Trial registration

Introduction

Methods

Study design

Study participants

Study groups

Follow-up visits

Outcomes

Definitions

Statistical analysis

Results

Preoperative demographic and clinical characteristics

Fig 1. CONSORT diagram showing the flow of participants through each stage of this randomized trial.

Table 1. Overview of the main preoperative demographic and clinical characteristics of the study population.

Surgical procedures and type of surgery

Table 2. Overview of the surgical procedure and type of surgery among the study population.

Primary and secondary effectiveness outcomes

Table 3. Proportion of patients who achieved hemostasis.

Safety outcomes

Table 4. Overview of the adverse events (AEs) classification.

Discussion

Conclusions

Clinical trial registration

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Hideto Sano

Roles

Author response to Decision Letter 1

Decision Letter 1

Hideto Sano

Roles

Author response to Decision Letter 2

Decision Letter 2

Hideto Sano

Roles

Author response to Decision Letter 3

Decision Letter 3

Hideto Sano

Roles

Acceptance letter

Hideto Sano

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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