Thirty years of experience with solvent/detergent‐treated plasma for transfusion medicine

Fresh frozen plasma (FFP) is one of the most commonly prescribed hemostatic agents in clinical practice globally.1 Main FFP indications include acquired deficiency of multiple coagulation factors during active bleeding, bleeding prevention, and therapeutic plasma exchange (TPE).2, 3 Patients with thrombotic thrombocytopenic purpura (TTP) require recurrent TPE and account for significant plasma usage (average 40 L per admission).2, 4 Appropriate use of plasma transfusion is key in patient blood management to adequately restore hemostatic function and impact subsequent blood component requirements. However, plasma transfusion has various challenges, including ABO incompatibility, pathogen transmission, transfusion complications (e.g., transfusion-related acute lung injury [TRALI] or transfusion-associated circulatory overload [TACO]), anaphylactic reactions, and storage/logistical issues.2 Suboptimal hemostatic management can increase blood component usage, further risking patient safety and inflating costs. Advances in patient blood management may improve patient outcomes and have economic benefits. This review summarizes the published efficacy and safety data for octaplasLG, which is one of several types of plasma preparation currently available for bleeding management in adult and pediatric populations. Differences between octaplasLG and FFP are described, as are experiences of switching from FFP to octaplasLG, and its cost-effectiveness. OctaplasLG's efficacy in endothelium protection and the prehospital utility of octaplasLG powder as future directions for octaplasLG in transfusion medicine are also discussed. In addition to FFP, plasma is also available in other varieties, the key characteristics of which are outlined in Table 1.5-8 The different FFP varieties include plasma frozen within 24 h of phlebotomy (FP24) and thawed plasma (TP), which are commonly used in the United States (US).9 FP24 indications are identical to FFP10; TP indications are similar, although TP is not recommended for managing specific coagulation factor deficiencies due to its variable concentration of coagulation factors.10 Cryoprecipitate-reduced plasma (CRP) is the plasma remaining after cryoprecipitate has been prepared and is recommended only for TPE.11 While most plasma products are untreated (e.g., FFP and FP24), pathogens can be inactivated to further improve the safety of FFP using methylene blue (MB-FFP), INTERCEPT (amotosalen/ultraviolet [UV] pathogen inactivation), or Mirasol (riboflavin/UV light-based pathogen reduction) for single units, or by solvent-detergent (S/D) treatment for pooled plasma.12 Pathogen-inactivated plasma preparations are currently recommended to reduce transfusion-transmitted infections and infusion reactions for patients with major bleeding, trauma, TTP, or undergoing surgery (e.g., cardiac and liver) who require coagulation factor replacement.4, 13 OctaplasLG (Octapharma AG, Switzerland) is a frozen, S/D-treated plasma preparation produced from pooling 630–1520 FFP units collected from paid/voluntary plasma donations.14 It was first licensed in Germany as a blood product in 1989 and, in 1992, was registered as a pharmaceutical product under the trade name octaplas (the first-generation product) as an FFP alternative with the aim of increasing pathogen safety.15 While there is no evidence of prion protein transmission through plasma transfusion in humans, prion protein transmission has been shown by plasma transfusion even after leukodepletion in a preclinical animal model,16 and health authorities worldwide have encouraged plasma product manufacturers to investigate the potential of their processes to remove/inactivate prions and/or introduce new prion clearance technologies.17 Prion removal was addressed in 2009 during manufacturing of the second-generation octaplas product, octaplasLG (Octapharma AG, Switzerland). OctaplasLG is processed using affinity ligand chromatography to remove potentially present prions and thus reduce the possibility of prion disease transmission risk.18-20 Today, octaplas/octaplasLG has been available for >30 years and is licensed in 54 countries, although the trade name varies; it is marketed as octaplasma (Canada), omniplasma (Netherlands), and octaplas (US). Here, we refer to this product as octaplasLG, except when referencing studies performed with the first-generation product, octaplas. Unlike single-donor FFP, the pooling of multiple plasma donations and filtration steps in octaplasLG manufacturing reduces allergic/immunologic reaction risk through dilution, immune neutralization, and filtration of allergens, pathogenic antibodies, cell debris, and infectious agents (Figure 1).20-23 S/D treatment inactivates enveloped viruses like SARS-CoV-2,24 HIV, HBV, HCV, and Zika,5, 23 which further reduces viral transmission risk,20-23 but has no effect on non-enveloped viruses,5 such as B19V and HEV, where specific testing is used to reduce transmission risk. However, S/D treatment can affect protein constituent levels compared with untreated plasma.25, 26 S/D treatment duration was, therefore, optimized during octaplasLG development (reduced from 4–4.5 to 1–1.5 h), which demonstrated biochemical quality improvement, as well as significantly higher plasmin inhibitor (alpha-2 antiplasmin) activities.18, 20, 27 A quality assurance study to ensure no issues with lower protein S levels in patients undergoing liver transplantation was undertaken to monitor octaplas safety over a 4-year period (2005–2009) in 195 adult liver transplant patients.28 Hyperfibrinolysis and thromboembolic event (TEE) incidence in patients treated with octaplas was not significantly different compared with patients treated with standard FFP.28 Hyperfibrinolysis was observed in 9% of patients, although four patients already had evidence of hyperfibrinolysis at baseline, and thrombotic graft complications were seen in 2% of patients.28 No pulmonary embolisms (PEs) were reported and octaplas was well tolerated; however, further studies are needed to confirm its safety profile.28 Plasma unit pooling and octaplasLG's rigorous manufacturing process provides standardized clotting factor content with significantly lower variability than FFP, improving dosing accuracy.29-31 Dosage depends on the clinical situation and underlying disorder; however, 10–15 mL/kg body weight is the generally accepted starting dose.21 At present, octaplasLG is therapeutically indicated for coagulation factor deficiencies, such as coagulopathy due to hepatic failure,32, 33 massive transfusion,13, 34, 35 and TPE in patients with TTP.21, 36 Other indications include anticoagulation therapy reversal in emergency situations and specific coagulation factor deficiencies (factor V or XI) where factor concentrates are not available.21 Licensed octaplasLG indications may vary by country. Table 2 shows octaplasLG coagulation factor content,21 and Figure 1 illustrates the octaplas versus octaplasLG manufacturing process, with reference to parameter assessment according to European Pharmacopeia guidance.37 The following information on octaplasLG's efficacy and safety in bleeding management within adult and pediatric populations was obtained from studies identified through PubMed and Google Scholar searches, as well as additional articles suggested for inclusion by the authors. Search terms included ‘octaplas’, ‘octaplasLG’, ‘solvent-detergent plasma’, and ‘solvent/detergent-treated plasma’. Articles were assessed to identify potentially relevant information for this narrative review, with the collated data discussed and assessed by all authors. OctaplasLG is effective for multiple indications, including TPE for TTP and atypical hemolytic uremic syndrome (aHUS); key studies reporting octaplas/octaplasLG efficacy are summarized in Tables 3 and 4 for adult and pediatric populations, respectively. Studies have shown octaplasLG treatment improves standard coagulation and hemostasis markers.38-42 OctaplasLG has been associated with greater endothelium protection compared with FFP, which may lead to improved clinical benefits, such as reduced perioperative bleeding and transfusion requirements, as well as reduced ventilation time.43 OctaplasLG has demonstrated an excellent safety profile in both adult (Table 3) and pediatric (Table 4) populations, with lower incidences of allergic reactions, febrile nonhemolytic transfusion reactions (FNHTR), TACO, and a lower TRALI rate than with FFP after >13 million units transfused.44-46 octaplas versus FFP N = 122 undergoing elective open-heart surgery octaplas, n = 66 FFP, n = 53 N = 67 with complex coagulopathy after open-heart surgery octaplas, n = 36 FFP, n = 31 octaplasLG versus FFP N = 44 undergoing emergency surgery for thoracic aorta dissections octaplasLG, n = 23 FFP, n = 21 N = 25 undergoing liver Tx octaplas, n = 12 FFP, n = 13 octaplas versus FFP N = 24 with liver disease N = 25 undergoing liver Tx Liver disease: octaplas, n = 13 FFP, n = 11 Liver Tx: octaplas, n = 12 FFP, n = 13 Liver disease patients: Liver Tx patients: N = 63 patients undergoing liver Tx octaplas, n = 30 FFP, n = 33 N = 40 undergoing liver Tx octaplasLG, n = 20 FFP, n = 20 N = 40 with dilution coagulopathy, liver disease, DIC, polytrauma, or connected to extracorporeal circulation octaplas, n = 17 FFP, n = 23 N = 32 (50 admissions) with TTP: n = 12 episodes treated with CPP only; n = 21 treated with octaplas only; n = 17 episodes initially treated with CPP, then switched to octaplas (172 TPE procedures with CPP; 509 TPE procedures with octaplas) N = 90 with TMAs such as TTP, HUS, and aHUS (981 TPE procedures) N = 15 with TMAs; TTP and aHUS (166 TPE procedures) N = 20 with TTP octaplasLG, n = 10 FFP, n = 10 octaplas versus FFP N = 419 critically ill pediatrics (median [IQR] age 1.0 years [0.2–6.4]) octaplas, n = 62 FFP, n = 357 N = 34 critically ill mean [range] age 12.3 years (0.9–22.2) pediatrics requiring TPE n = 226 TPE procedures with octaplas only n = 72 procedures started with 5% human albumin and switched to octaplas to avoid hemodilution n = 25 TPE procedures with 5% human albumin only N = 105 pediatrics (aged <2 years) undergoing cardiac surgery octaplasLG, n = 65 FFP, n = 40 N = 50 pediatrics (n = 37 ≤ 2 years old [0–2 years]; n = 13 > 2 years old [3–16 years]) Cardiac surgery, n = 40; liver Tx, n = 5; liver dysfunction, n = 5 N = 41 aged ≥2 to ≤20 years requiring TPE (102 TPE procedures) n = 15 aged 2–<12 years (n = 37 TPEs) n = 13 aged 12–<17 years (n = 32 TPEs) n = 13 aged ≥17–20 years (n = 33 TPEs) N = 9 aged 13 months to 25 years n = 6 TPE; n = 3 simple plasma transfusion Octaplas/octaplasLG efficacy has been demonstrated in adults for indications such as cardiac surgery,25, 43, 47 coagulopathy resulting from liver disease and liver transplantation,28, 33, 38-40, 42, 48 hemodilution or blood loss,38, 49 TPE,4, 50-53 as well as obstetric and gynecological complications (Table 3).33 Real-world safety has also been evaluated by numerous clinical studies (Table 3) and extensive hemovigilance programs. The efficacy of octaplas was compared with that of FFP in 67 patients undergoing open-heart surgery. Octaplas and FFP showed comparable efficacy in terms of blood product usage and changes in coagulation factors, such as fibrinogen, factor VIII, antithrombin, protein C, free protein S, α1-antitrypsin, and plasminogen levels.25, 47 Octaplas and FFP also demonstrated comparable hemostasis and fibrinolysis improvements.25 In liver disease and liver transplantation, octaplas demonstrated comparable efficacy with FFP (Table 3), with randomized controlled trials (RCTs) showing comparable correction of clotting factors, and significant international normalized ratio (INR) improvements versus FFP (p = .037).39, 40 Although hemovigilance data from Denmark (1998–2003), Norway, Sweden, and the United Kingdom (UK; all from 2004) report TRALI to be the most commonly related adverse event (AE) with FFP transfusion, no TRALI cases were related to octaplas.54, 55 In 2007, a retrospective clinical study examined octaplas and cryosupernatant (also called cryo-poor plasma [CPP]) in 50 acute TTP episodes.4 Patients receiving octaplas experienced one-third the number of allergic (plasma) reactions (3.1%) compared with patients receiving treatment with CPP alone (9.3%; p = .001).4 Although a constant intravenous administration of calcium gluconate was used, citrate toxicity occurred in both groups; however, citrate reaction incidence was lower with octaplas versus CPP (6.9 versus 18.0%, respectively; p < .0001).4 OctaplasLG efficacy and safety were assessed in the Vasculopathic Injury and Plasma as Endothelial Rescue-OCTAplasLG (VIPER-OCTA) RCT of patients undergoing thoracic aortic dissection (n = 44). VIPER-OCTA showed that octaplasLG reduced intraoperative bleeding (by 22%; p = .046), total transfusion requirements within 24 h of surgery (by 36% for total transfusion volume; p = .040), use of goal-directed pro-hemostatic products (by 32%; p = .036), and time on ventilator after surgery (by 50%; p = .013) compared with FFP.43 Furthermore, octaplasLG was comparable with FFP in terms of serious adverse event (SAE) incidence, with no significant differences in TACO, TRALI, anaphylaxis, ischemia, or other adverse reaction incidence between treatment groups (Table 3).43 TP (FFP or FP24 that is thawed and refrigerated for ≤5 days before transfusion) is commonly used for reversing coagulopathy or TPE. A pilot study compared the efficacy of thawed octaplasLG with TP. OctaplasLG refrigerated for ≤5 days was as as TP for time and time was no in transfusion reactions, of in and incidence between blood total of octaplasLG units was comparable with that of TP units However, the standardized of octaplasLG in a lower transfusion to to the as the higher TP with thawed octaplasLG versus thawed and refrigerated TP (p = which be for patients at risk of evidence also that efficacy can be with a lower of octaplasLG compared with FFP, which is due to and factor content per octaplasLG unit versus variable FFP unit OctaplasLG safety has been in hemovigilance from the and the have also further evidence of octaplasLG of S/D plasma was associated with a risk of allergic reactions ratio = and = compared with untreated transfusion of S/D plasma was associated with a risk of allergic reactions = and = compared with untreated The lower risk of transfusion complications with octaplasLG may be due to the effect of pooling plasma from multiple The concentration of such as with allergic with and with is reduced in plasma A hemovigilance study demonstrated octaplasLG was well in 90 patients undergoing TPE procedures for acute thrombotic including TTP, HUS, and occurred in 11 patients included cases and 10 patients at time of with when patients were not undergoing TPE and their was within Here, the of was due to the underlying S/D S/D plasma is recommended by the European for and European of on patient blood management for adult cardiac surgery in to FFP due to risk of TRALI with massive FFP A for major in use of S/D plasma is to reduce the of to S/D plasma has also been suggested to reduce graft versus disease as FFP that may with the A review and S/D plasma over FFP for patients undergoing liver transplantation and due to lower transfusion the risk of transfusion complications and from the for on the and management of TTP and other TMAs currently S/D plasma for which has been shown to reduce allergic transfusion reactions and pathogen Octaplas/octaplasLG efficacy and safety has been in a of indications in pediatric patients (Table 33, of octaplas for TPE was in a retrospective of TPE in 35 pediatric patients mean age 12.3 of 24 had a disease and 23 cell for TPE were removal due to or disease or acute or or indications such as due to Octaplas improved all of hemostasis fibrinogen, and were four however, with TPE was and there were no cases of or S/D plasma is also effective and well in critically ill and pediatric 33, In 419 pediatric unit patients with indications such as bleeding, or bleeding the over 24 h was comparable between S/D plasma and octaplas demonstrated significant versus FFP (p = for significant including for octaplas was associated with a in (p = for the following indications of plasma bleeding, bleeding, risk of bleeding, and a risk of bleeding due to This be related to the of coagulation factors in octaplas units compared with FFP units, an in pediatric patients and who only one or units compared with 32 Real-world with octaplas has also been reported for pediatric patients with A review of blood in reported that for 37 patients who a mean of units octaplas over 5 octaplas was well with than with FFP (Table In a of pediatric cardiac surgery patients (n = <2 years of over a hemostatic in terms of coagulation effect and safety profile was with octaplasLG compared with and were significantly lower in the octaplasLG (p < and p = respectively; Table Furthermore, intraoperative blood component usage and of were comparable (p > but significantly patients who octaplasLG blood cell p = or further plasma (p = in the first 12 octaplasLG and were well in surgery, with no adverse reactions in or The of this retrospective study identical efficacy and safety for octaplasLG and and that it was not to be that octaplasLG over were changes in practice and may have occurred over the of the However, there were significantly infections observed with octaplasLG than with versus respectively; p < this was an and not a the retrospective studies also evaluated octaplasLG's safety in pediatric patients aged 63 A dosing was and were as used octaplasLG in patients requiring of single or multiple coagulation factors and reported no or thrombotic or were reported for patients but were not examined data on patients requiring TPE for immune and infections and and and in four patients were from (n = to (n = all of which by study one was multiple to which was but as to the study on transfusion in and from the for in S/D plasma for TTP, aHUS and bleeding In use of octaplasLG for pediatric patients requiring plasma transfusion in the is one of several over safety associated with plasma may potentially reduce associated with bleeding include and blood component usage, which also to an risk of transfusion-related reactions or vary from to but FFP is the However, studies have demonstrated octaplasLG to be compared with FFP different age groups and due to improved greater health benefits, and a lower risk of transfusion-related VIPER-OCTA reported reduced blood component usage for patients receiving octaplasLG versus FFP.43 OctaplasLG was than FFP in terms of total blood versus p = for and although lower with octaplasLG, were not different versus p = OctaplasLG versus FFP per patient undergoing transfusion in the and is in Table study used a and a to acute and Patients treated with octaplasLG were shown to and in all studies (Table was higher for the octaplasLG versus the FFP however, related to complications was lower for octaplasLG versus FFP, octaplasLG and the treatment for A study demonstrated octaplas to be significantly with patient age (p < per was for patients aged years and < per for aged This may the octaplas for pediatric use and patient groups with clinical at risk of transfusion key of with octaplasLG over FFP is the of transfusion-related OctaplasLG has been shown to be in associated with allergic reactions, which are the most complications associated with European have or FFP with octaplasLG to improve quality and safety of plasma In following a clinical the of FFP be by octaplas, produced from This to the first to FFP with S/D 47 to a total of million and octaplas units were with a total of reported complications or blood or were 27 complications per units for TRALI was reported in of however, were to In 2007, the switched to octaplas, FFP for all clinical FFP and octaplas from to and to showed an serious adverse reaction (p = with a in standard FFP with no observed cases of the switched from FFP to octaplasLG in octaplasLG was associated with a significant in anaphylactic reactions (n = 37 for FFP versus n = 9 for risk ratio to p < (Table At the time as the to octaplasLG in the studies on bleeding and hemostatic the from FFP to S/D-treated patient groups in Norway, and the transfusion with octaplasLG in of In other octaplasLG use in to FFP is for in of the plasma was the has their plasma to octaplasLG for to pathogen reduced the of octaplas over 30 years >13 million units have been this octaplas/octaplasLG has to be an effective and well FFP transfusion such as pathogen transmission, TRALI, and allergic reactions in both adult and pediatric In octaplasLG may be indicated for and new for which TPE may have potential benefits. TPE has been indicated as a treatment for disease Endothelial protection is potential associated with octaplasLG, which may it the plasma product of in This is of increasing due to the of the and the potential effect of on Endothelial has a effect in patients with 90 and In a RCT of 33 critically ill patients, FFP transfusion endothelium FFP levels of factor factor VIII, and and a However, VIPER-OCTA suggested a greater of protection with octaplasLG versus FFP in emergency cardiac surgery, injury and injury were significantly reduced for octaplasLG compared with FFP for emergency thoracic aortic Here, levels were significantly reduced at both the and time for octaplasLG versus FFP (p < and the increase in was significantly reduced in receiving octaplasLG (p < Figure potentially a greater of protection and observed with octaplasLG may have improved clinical benefits, such as reduced perioperative bleeding and transfusion requirements. However, the for octaplasLG's further OctaplasLG is currently frozen, and the thawed product is during refrigerated for ≤5 However, there is increasing in plasma a new of octaplasLG, octaplasLG powder and for for which has identical biochemical quality to has been registered in 17 European use is of for prehospital for where and improves and In a from resulting from and a was treated with While is a intravenous in this prehospital was the and use of as a in cases of was have also the for in and In prehospital administration of TP in lower (p = and a lower (p < compared with in patients at risk for be in this as it is to for the or in than a blood the 30 available evidence has demonstrated that octaplasLG is and well in adult and pediatric patient populations for multiple include reduced of blood component usage, and cost-effectiveness. on its safety octaplasLG is the plasma product of for patients at risk of transfusion such as requiring recurrent and pediatric patients, with to plasma However, further is octaplasLG's protection The clinical utility of octaplasLG is to products such as octaplasLG powder have potential to plasma management in the to improve patient reduce and new was by by was by by in with has no of is for and are of is an of has from

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