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This report is being filed to provide additional information in h.6 and h.11 and corrections in d.2a, d.2b and d.4 investigation: an investigation was conducted for a journal article that references terumo bct product.Journal article, titled vascular access for autologous peripheral blood stem cells collection by large volume leukapheresis: single center experience by bojanic et al was reviewed with primary purpose of screening for allegations of terumo bct device causing or contributing to death/injury or device malfunctions.The purpose of the journal article study is noted in the article abstract: abstract: introduction: peripheral blood stem cell (pbsc) harvesting requires reliable and safe vascular access.In our institution, a change of practice was implemented and the central venous catheter (cvc) placement for all autologous pbsc collections was abandoned in favor of a careful evaluation of peripheral venous access (pva) for each individual patient.The aim of this prospective study was to evaluate the rate of patients with adequate peripheral veins for autologous pbsc collection and compare patient characteristics, collection efficacy, and complication rate between patients with pva and cvc.Method: peripheral veins were assessed by the apheresis nurse team in all patients referred between january 2020 and july 2021 to autologous pbsc collection.Only in case of difficult venous access, cvc was inserted.Large volume leukapheresis (lvl) procedures, which processed 3 total blood volumes, were performed.Results: in 65 (57%) patients pva was used, while 49 (43%) patients required placement of short-term cvc.Peripheral venous access was successfully used significantly more often in males (69.8%) (p = 0.010), and patients with multiple myeloma (71.0%) than in patients with non-hodgkin's lymphoma (35.9%) and hodgkin's lymphoma patients (33.3%) (p 0.001).There was a significant difference in the type of prior administered chemotherapy; in the patients who received cytostatics free chemotherapy, pva was used more often (75.0%) (p = 0.007).In terms of the efficacy and safety of lvls, there were no differences between procedures performed using pva and cvcs.Conclusion: peripheral venous access is feasible for autologous pbsc collection in more than a half of patients, in particular in those with multiple myeloma.Changes in the treatment of multiple myeloma, using new proteasome inhibitors-based and immunomodulatory agents that do not adversely affect peripheral veins, have enabled the use of pva even at the high blood flow rates required by lvl.Peripheral venous access is not associated with safety issues or with a lesser collection efficiency, and it is cost-effective as well.Each patient referred to autologous pbsc collection needs to be evaluated individually by the experienced apheresis team for the most appropriate venous access.Materials and methods patients the study prospectively analyzed all adult patients referred to the apheresis unit between january 2020 and july 2021 for autologous pbsc collection.Vascular access assessment peripheral vein assessment was performed by apheresis nurse in all patients referred for leukapheresis, usually before the start of pbsc mobilization.When pva was deemed questionable, a second assessment by another apheresis nurse was performed.In case of difficult venous access, cvc placement was required.The results of the vein assessment were documented in the hospital information system and communicated both by phone call and by written report to the hematologist responsible for the patient who organized cvc placement if necessary.Peripheral venous access establishment and central venous catheter placement bilateral pva was usually established via veins of the forearm just before starting the collection, using intravenous cannulas or apheresis steel needle for access, and intravenous cannula for blood return.In patients with good pva, pbsc collections were done as an outpatient procedure if it was organizationally possible; however, if a temporary cvc was required, patients were hospitalized.The cvc placement was usually performed on the day before the collection by hematology clinic staff or by the intensive care staff in case an experienced hematologist was not available.Subclavian vein was the preferred site for cvc insertion followed by internal jugular vein.Double lumen dialysis catheters dualysecath (vygon, aachen, germany) were used, and the catheter size was in the range of 10-12 french, according to the patient's body weight (bw) and height.The cvc was removed after the confirmation of an adequate cd34+ cell dose and successful product cryopreservation.2.4 | peripheral blood stem cell mobilization the pbsc mobilization regimens are presented in table 1.The mobilization regimens mostly consisted of combination of chemotherapy and granulocyte-colony-stimulating factor (g-csf) 5 mg/kg/day s.C.(accofil, accord healthcare, uk).Peripheral blood stem cell collection started when cd34+ cell count in peripheral blood reached 10 x 106/l.If only g-csf was used for mobilization (10 mg/kg, s.C.), it was given daily, divided into two doses, and collection started on the fifth day of mobilization.In case the patient was poor mobilizer and cd34+ cell count was 10 x 106/l, plerixafor (mozobil, genzyme europe b.Th., amsterdam, the netherlands) was administered in the evening, and leukapheresis was performed the next morning.If the target number of cd34+ cells/kg bw was not collected, g-csf and plerixafor administration were continued, and additional procedures were performed on the following days until target cd34+ counts were reached.Pbsc collection and the monitoring of the patients apheresis procedures were performed using spectra optia system and the cmnc protocol (software version 11, terumo bct, lakewood, usa).Large volume leukapheresis, defined as the processing of 3 total blood volumes, was targeted generally for all autologous pbsc collections.5 a combination of acd-a solution (anticoagulant citrate dextrose solution usp [acd] solution a, terumo bct, lakewood, usa) and heparin (heparin, belupo, koprivnica, croatia) was used as an anticoagulant.The addition of 6 iu of heparin per 1 ml of acd-a enabled the increase of inlet:ac ratio and allowed a higher inlet blood flow rate.Only in 2 patients who mobilized high number of cd34+ cells standard volume leukapheresis were performed and 2 total blood volumes (tbvs) were processed with the anticoagulation with acd-a solution alone, with inlet:ac ratio of 12:1.During all procedures, a blood warmer was used on the return line (astotherm plus, stihler electronic gmbh, leinfelden-echterdingen, germany) to reduce the risk of hypothermia which potentially may increase the symptoms of citrate toxicity.To prevent symptoms of hypocalcemia, all patients received a prophylactic infusion of calcium gluconate (0.1 g/kg bw) in 100 ml of saline solution at 0.4 ml/min using the infusomat fms system (b.Braun, melsungen, germany).Patients were closely monitored and, if symptoms suggestive of hypocalcemia were observed, ionized calcium levels were determined, and calcium replacement levels adjusted accordingly.All adverse reactions, the adequacy of blood flow, and any manipulation needed to improve blood flow or catheter function during session were documented.Medical records in the hospital informatic system were reviewed for any complication related to cvcs use, from placement to removal.Recorded adverse reactions were classified by the attending physician according to the world apheresis association registry's grading of adverse events based on patient experience and outcome.6 the target yield of cd34+ cells was from 3 to 6 x 106/kg bw, dependent on the disease and treatment protocol.Results over the study period, a total of 254 leukapheresis were performed in 114 patients, and the median of procedures per patient was 2 (range 14).Patient characteristics and their previous chemotherapy are presented in table 1.The median age of the patients was 58 years (range 2070).Patients were more commonly female (53.5%); 60.5% of the patients were treated for multiple myeloma (60.5%), and the rest for non-hodgkin's lymphoma (34.2%) and hodgkin's lymphoma (5.3%).In 65 (57%) patients, pva proved sufficient to provide an adequate blood flow, while in other 49 (43%) patients the placement of cvc was necessary due to poor quality of peripheral veins.Type of vascular access used, and blood flow achieved according to the size of pva devices are presented in table 2.The catheters were placed in femoral vein only in 2 patients that previously had thrombosis of subclavian and jugular veins, respectively.All patients who required cvc placement were hospitalized.Although in patients with good pva pbsc collections could be done as an outpatient procedure, in our study due to organizational reasons it was done only in 8 patients (12.3%), while others were hospitalized.Patient characteristics and leukapheresis procedure characteristics according to the type of vascular access are shown in tables 3 and 4, respectively.Peripheral blood laboratory parameters before and after leukapheresis, and leukapheresis product characteristics are presented in table 5.Adverse reactions related to the apheresis procedure and complications of vascular access are shown in table 6.In 22 (19.3%) patients 32 (12.6%) adverse reactions related to apheresis were reported.Fourteen patients experienced one reaction, and 6 experienced repeated reactions.Mild vasovagal reactions were reported in 2 patients.Reactions related to citrate toxicity were most often reported (n = 30, 94%).The symptoms of citrate toxicity were mainly paraesthesia and tingling in the face and extremities.These reactions were mostly mild and tolerated well without medication in 22 cases (73.3%), and moderate in 8 cases (26.7%) in which additional infusion of calcium gluconate was required.Citrate toxicity occurred more frequently in women (n = 24, 75%).There was no significant difference in the occurrence of any type of apheresis related adverse reactions between two groups.No leukapheresis procedures had to be terminated due to adverse reactions.There was no significant difference in the occurrence of complications related to vascular access between two groups.Central lines were placed successfully in all patients, and no pneumothorax, bleeding, infection nor venous thrombosis occurred.In 8 patients the in/out flow of the lumens of the catheter was reduced, and it was necessary to inverse the arterial and venous cvc lines.During the follow-up period, no major adverse events related to cvcs were reported.Repeated insertion attempts were the most common complications of pva and were required in 10 patients, during 11 leukapheresis.The issue of blood clots clogging the peripheral access was noted in only 1 procedure.Discussion peripheral blood stem cell collection by leukapheresis is generally considered a safe procedure.4 the incidence of overall apheresis-related complications in our patients was 12.6%, similar as in donmez et al.'s study, although some studies reported lower incidence.40,41 the adverse reactions were more frequent in women (75%), as was reported in other studies.13,20 the most frequently reported adverse reactions in our study were mild symptoms of citrate toxicity, such as tingling in the fingers and mild circumoral paresthesias, and their incidence did not differ significantly between pva and cvc groups.Higher incidence of adverse reactions in our patients compared to others can be explained by the prospective nature of our study recording all, even mild reactions, which some studies did not even report.41 vasovagal reactions in our study occurred only in 1 patient in each group with incidence of 0.8%.The literature does not provide incidence data of vasovagal reactions specifically for leukapheresis donors, but it is considered wise to take precautions when establishing pva, and carefully observe patients especially at the beginning of the apheresis.4 in our study, problems with vascular access occurred in 7.8% of procedures using cvcs versus 7.9% using pva.We observed no major complications related to cvc placement and use, such as hemothorax, pnemothorax, thrombosis, or infections reported in some studies.11-14 occlusive complications defined as difficulty infusing fluids or withdrawing blood from cvc were reported in 7.8% of leukapheresis.Although the change in the patient's position sometimes resolves the problem, in 8 of our patients these situations required inversion of lines.Level et al.Reported that the use of cvc in an inversed position can result in a higher recirculation rate and may lead to less effective hemodialysis, and it seems particularly important for the nursing staff to be aware of this phenomenon.42 in the case of pbsc collection, recirculation could potentially cause inaccuracy when formulas for the prediction of cd34+ cell yield are used.4,43 although in our study there was no major adverse event related to the use of cvc, it must be noted that cvc placement was associated with more pain as well as local discomfort at the site of puncture than use of pva.Use of cvc may require hospitalization, while procedures using pva can be done safely in an outpatient setting eliminating the cost related to the cvc insertion and hospital admission, which simplifies the procedure and improves patient comfort.Moreover, cvcs are time consuming to set up, and may impose logistic constraints and delay the apheresis procedure if implemented in a different unit or hospital.7 in our study, the collections were performed in outpatient setting in only 12.3% of patients with pva due to organizational issues because the study took place from january 2020 until july 2021, during coronavirus disease 2019 (covid-19) pandemic.At that time restrictions and lockdown measures were imposed, and we did not encourage patients to go home between two collections to avoid infection during travel to and from the hospital.In our cohort, no major complication of peripheral veins cannulation was observed, with only a few repeated insertion attempts and clots.It should be highlighted that over the course of the apheresis the peripheral access can deteriorate, and flow rates can drop caused not only by unfavorable line placement but also constricted superficial vessels due to hypothermia or hypovolemia.13 the imminent failure of pva should thus be addressed by careful repositioning of the line, possibly switching inlet and return lines or even re-phlebotomy, application of local warmth, heating the blood in the return line, or saline infusions.Apheresis team should be aware of other factors which can improve or adversely affect vein cannulation.Dehydration causes the decrease of blood volume and venous pressure, thereby rendering the detection of veins and cannulation difficult.24 therefore, our patients were advised to optimize their hydration status and to avoid other peripheral venous punctures prior to the procedure, which was emphasized also by other authors.7 since anxiety may lead to peripheral vasoconstriction, informing the patient about the procedure and gaining their trust can reduce tension before the procedure, enabling better cannulation.24 conclusions our study demonstrates that autologous pbsc can be collected efficiently and safely by lvl using pva in more than a half of patients, minimizing the potential adverse events associated with cvc placement and use, as well as the cost.Male sex, diagnosis of multiple myeloma, and previous chemotherapy containing non-cytotoxic agents were significantly associated with successful pva use.Changes in the treatment of multiple myeloma, using new proteasome inhibitors-based and immunomodulatory agents that do not adversely affect peripheral veins, have enabled the use of pva even at the high blood flow rates required by lvl procedures.In terms of the efficacy and safety of lvls, there were no differences between procedures performed using pva and cvcs, indicating that enough high and stable blood flow rate could be obtained by peripheral veins.We recommend that each patient needs to be evaluated individually by apheresis team for the most appropriate venous access.Peripheral veins should be the first choice for most patients, and cvc should only be used after a thorough evaluation of peripheral veins by experienced apheresis team.Since this was a journal publication to evaluate the rate of patients with adequate peripheral veins for autologous pbsc collection and compare patient characteristics, collection efficacy, and complication rate between patients with pva and cvc performed between january 2020 and july 2021, the lot numbers were not requested; therefore, a disposable lot history search could not be conducted.According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of 4.8%.Some of the most common reactions include fever, urticaria, hypocalcemic symptoms, pruritus, dyspnea, tachycardia, and mild hypotension.Vasovagal incidents occur around 0.5% of procedures.The reactions generally manifest as pallor and diaphoresis.In a full blown attack, the reaction progresses from pallor and sweating to pulse slowing and blood pressure decreasing.More severe vasovagal reactions may include nausea, vomiting, and/or convulsions.According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of 4.8%.Some of the most common reactions include fever, urticaria, hypocalcemic symptoms, pruritus, dyspnea, tachycardia, and mild hypotension since this was a journal publication to evaluate the rate of patients with adequate peripheral veins for autologous pbsc collection and compare patient characteristics, collection efficacy, and complication rate between patients with pva and cvc performed between january 2020 and july 2021, the lot numbers were not requested; therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.Root cause: a root cause assessment was performed for the reported vasovagal reactions.Based on the available information a definitive root cause could not be determined.Vasovagal are common side effects of therapeutic apheresis procedures.They are typically caused by the patient's disease state, the rate of ac infusion, the length of the procedure, the patient's sensitivity to the procedure and/or the hemodynamic stress of the procedure.A root cause assessment was performed for the reported citrate reactions.These reactions occur due to decreased ionized calcium in circulation as a result of exogenous citrate administered during the apheresis procedure and are influenced by donor physiology, the rate of ac infusion, and/or the length of the procedure.These symptoms may be treated with oral or intravenous calcium supplements or by adjusting the ac infusion rate.A root cause assessment was performed for the reported vascular access issues.Vascular access issues can occur if the access is being restricted.Possible causes for this alarm include but are not limited to: patient access was not properly positioned issues with the patient's vein inlet or return was obstructed due to kinks, clamps, or clumping inlet or return pump flow rate was too high for the size of the patient access a root cause assessment was performed for the reported clot.Possible causes include but are not limited to: improper anti-coagulation of the extracorporeal system.Patient's physiology citation: bojani, i., novosel, g., barie vi, m.L., krnjug, p., horvat, e., mazi, s., batini, j., kinda, s.B., & epuli, b.G.(2023).Vascular access for autologous peripheral blood stem cells collection by large volume leukapheresis: single center experience.Journal of clinical apheresis, 39(1).Https://doi.Org/10.1002/jca.22095.
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