Solvent detergent (S/D) treated plasma (Octaplasma)

Authors: Shuoyan Ning, MD, FRCPC, DRCPSC; Isabelle Blais-Normandin, MD, FRCPC; Bryan Tordon, MD, FRCPC; Johnathan Mack, MD, MSc, FRCPC; and Kathryn Webert, MD, FRCPC

Primary target audiences: transfusion medicine physicians, non-transfusion medicine physicians, nurses, medical laboratory technologists in a hospital laboratory 

NOTE: Please also see our FAQ on S/D treated plasma (Octaplasma).

Introduction

This publication provides information on Octaplasma—blood group specific, pathogen-inactivated human plasma for transfusion—based on its product monograph and evidence available in the literature. Octaplasma is manufactured by Octapharma using solvent detergent (S/D) treated pooled human plasma and is currently licensed for use in Canada. In 2011 Octaplasma was approved for use in select patient populations.¹ Starting March 27, 2023, Octaplasma is available for routine use for all adult and pediatric patients requiring plasma transfusion. The goal of transitioning to a pathogen-reduced plasma supply as the main source for plasma transfusion is to provide an additional layer of protection for Canadian patients. 

Octaplasma manufacturing and product description

Manufacturing

Octaplasma is a pooled human plasma formulation that is pathogen inactivated through solvent detergent (S/D) treatment. The S/D treatment involves thawing and pooling plasma donations from 630–1,520 individuals with the same ABO blood group (A, B, AB, or O). 

The pathogen inactivation process used in S/D treatment differs from the process used at Canadian Blood Services to manufacture pathogen-reduced platelet components (for more information on pathogen-reduced platelets see Chapter 19 of the Clinical guide to transfusion). The S/D process used for plasma inactivates lipid-enveloped viruses, such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. Other enveloped viruses (e.g., West Nile, Chikungunya, influenza strains) are also susceptible to S/D treatment.²  

Stringent controls are applied by Octapharma to the selection and screening of donors for hepatitis B, hepatitis C, and HIV. The plasma pools are tested for hepatitis B surface antigen and anti-HIV 1/2 antibodies; nucleic acid testing is performed for hepatitis A, B, C, and E, HIV and parvovirus B19 prior to manufacturing. S/D treatment does not inactivate non-enveloped viruses, such as hepatitis A and parvovirus B19.³  

Pooled plasma undergoes filtration steps after pooling to remove cells such as leukocytes and cell fragments. Plasma pools are treated with S/D reagents [1% tri(n-butyl) phosphate (TNBP) and 1% octoxynol] to inactivate lipid-enveloped viruses. The S/D reagents are removed, and the product is then applied through an affinity ligand resin column that selectively binds prion proteins. After sterile filtration, the final product is divided into individual units and stored at 18°C or colder (the same storage conditions as frozen plasma [untreated]). Octaplasma contains coagulation factors and other plasma proteins (albumin, immunoglobulins, other globulins, complement, protease inhibitors). Please refer to the product monograph for details.³  

Packaging and storage

Octaplasma units are contained within sterile, plasticized polyvinyl chloride (PVC) bags over-wrapped with polyamide/polyethylene film. Each individual unit is packaged in a cardboard carton. Each unit contains 200 mL of S/D plasma. The product is stored frozen at ≤ -18°C or colder (the same storage conditions as frozen plasma [untreated]); when stored in these conditions, Octaplasma has a shelf life of 48 months. There are two transfusion ports, which are used to access the product. Blood group O, A, B, and AB plasma are available. Once thawed, the shelf life of Octaplasma is 5 days when stored at 2–8°C or 8 hours when stored at room temperature (20-25^oC). Once thawed, Octaplasma must not be refrozen. Please refer to the product monograph for details.³  
 

Image

Figure 1. A frozen unit of Octaplasma (right) beside a unit of untreated frozen plasma (left). The Octaplasma bag is smaller and the plastic is thicker compared to frozen plasma (untreated). Each unit of Octaplasma has a volume of 200 mL. Please see the product monograph for thawing instructions.³

Dosing and product characteristics

Dosing is comparable to that of untreated frozen plasma (12–15 mL of Octaplasma/kg and 10–15 mL frozen plasma [untreated]/kg). For a 70 kg patient, 4–5 units of Octaplasma may be required to increase clotting factor levels by approximately 25%. Please refer to the product monograph for details.³  

Octaplasma contains human plasma proteins, sodium citrate dihydrate, sodium dihydrogen-phosphate dihydrate, and glycine. The total human plasma protein concentration is between 45–70 mg/mL. In vitro studies have shown a mild reduction (10 –20%) of some coagulation factors and coagulation inhibitor activity in S/D plasma compared to untreated frozen plasma.^2,4,5 All pathogen inactivation systems are known to lead to some reduction of coagulation and inhibitor activities⁶, with notable reductions in factors V and VIII across systems.⁷ However, it should be noted that all coagulation factor levels in Octaplasma remain within normal ranges expected for frozen plasma (untreated) and studies have not suggested clinical significance of minor clotting factor reductions; exceptions include protein S and alpha-2 antiplasmin (see the section on drawbacks and contraindications below), which are significantly reduced. 

Individual coagulation factors in Octaplasma are > 0.5 IU/mL, even at day six of storage.^3,8,9 All Octaplasma batches are routinely tested for factor V, factor VIII, and factor XI (specification > 0.5 IU/mL), as well as protein C (> 0.7 IU/mL), protein S (> 0.3 IU/mL), and alpha-2 antiplasmin (> 0.2 IU/mL).⁶   

Table 1: Plasma protein levels of Octaplasma compared to fresh frozen plasma  

Administration

The administration of Octaplasma must be ABO blood group compatible. Like frozen plasma, high dosages or infusion rates may induce hypervolemia, pulmonary edema, and/or cardiac failure. High infusion rates may also lead to citrate toxicity; due to this risk, the infusion rate should not exceed 1 mL Octaplasma/kg body weight/minute. The effect of citrate can be minimized by giving calcium gluconate using another line to administer. Please refer to the product monograph for details.³  

Clinical use of S/D plasma

In 2011, S/D plasma became available for use in select patients requiring high volume or chronic plasma transfusions (congenital thrombotic thrombocytopenic purpura (TTP), plasmapheresis requiring plasma as replacement fluid, clotting factor deficiencies for which licensed concentrates are not readily available), and recurrent allergic reactions or an existing lung disorder with increased risk of transfusion related acute lung injury (TRALI). S/D plasma also became available for use in patients for whom group compatible plasma was not available, as well as for patients with a historical life-threatening reaction to plasma.^1,10   

Octaplasma has been available for use in select patient populations in Canada since 2011. On March 27, 2023, restrictions for ordering Octaplasma were removed and it is now available for routine use in all adult and pediatric patients requiring plasma transfusion. Octaplasma has been used widely in Europe for several decades, with some countries (e.g., Norway, Sweden, Finland, United Kingdom, The Netherlands) using Octaplasma as the primary plasma product for transfusion.  

Hemostatic efficacy

There is limited evidence comparing S/D plasma to frozen plasma (untreated). Available evidence suggests that S/D plasma is comparable to frozen plasma (untreated) with respect to hemostatic efficacy. Clinical studies have shown that S/D plasma is effective in improving coagulation parameters and achieving clinical hemostasis in various patient populations.^10-15 A 2016 systematic review found six randomized controlled trials (total of 561 patients) that compared efficacy and safety of S/D plasma to various other plasma formulations in common clinical scenarios (1 cardiac bypass, 3 liver transplantation, 1 coagulopathy, 1 prolonged prothrombin time). There were no clinically significant differences, but studies were small and underpowered.¹¹ Among cardiac surgery patients with complex coagulopathies, coagulation parameters and clinical hemostasis were not different following transfusion of S/D plasma versus frozen plasma – with the exception of anticipated lower protein S and plasmin inhibitor activity.¹⁶ Of note, clotting factor levels in single donor plasma products and coagulation factor levels after frozen plasma infusions may be highly variable.^5,17 A recently published cohort study comparing S/D and frozen plasma in a heterogenous patient population showed no differences in clinical outcomes (subsequent plasma requirements, transfusions of other blood components, length of hospital stay, in-hospital mortality) between the study groups.¹³ A pilot randomized trial comparing Octaplasma to standard plasma (VIPER-OCTA) for bleeding patients undergoing emergency thoracic aorta dissection surgery also reported favourable hemostatic outcomes.¹⁸   

For factor V deficiency where no factor concentrates are available, in vitro studies have shown that S/D plasma is equivalent to untreated  plasma in improving thromboelastrometry (ROTEM) indicators of hemostasis (EXTEM) and in increasing factor V.¹⁹ The use of S/D plasma resulted in a median factor V level of 25.5% (25.0–27.3%), comparable to the factor V increment when using untreated  plasma 27.0% (20.0-29.5%). Small case series have also described the use of S/D plasma in treating other hereditary factor deficiencies with good clinical effect.^20,21  

Liver disease patients

There have been a small number of randomized trials and cohort studies examining the use of S/D plasma among liver cirrhosis patients and those undergoing liver transplantation. A randomized trial of 48 patients requiring plasma for invasive procedure or transplantation were randomized to receive either untreated frozen plasma or S/D plasma.²² Compared to frozen plasma, improved prothrombin time (PT) and no differences in activated partial thromboplastin time (aPTT) corrections were observed. No overt hemorrhagic complications were seen in both groups, and no patients required blood transfusion after the procedure.  Two randomized controlled trials of patients undergoing liver transplantation (N = 293 total patients in one study²³ and 63 total patients in the other²⁴) comparing S/D plasma to frozen plasma showed no differences in correction of coagulopathy, intraoperative blood loss and overall clinical efficacy.^23,24 Another study by Bindi et al., which used thromboelastography to guide transfusion among cirrhotic patients underlying transplant surgery, reported a significant reduction in the volume of plasma required in the S/D arm compared to the frozen plasma arm (i.e., 2,617 ± 1,297 mL for the frozen plasma arm versus 1,187 ± 560 mL for the S/D plasma arm, p <0.0001).²⁴  

Thrombotic thrombocytopenia purpura (TTP), hemolytic-uremic syndrome (HUS) with factor H deficiency 

There are no published randomized data comparing S/D plasma to frozen plasma among patients with TTP or HUS. Biochemically, S/D plasma production process reduces high molecular weight von Willebrand factor multimers that trigger the shear stressed-induced platelets aggregation seen in TTP.^25,26 A normal level of ADAMTS13 necessary for TTP therapy is retained in the S/D product. S/D plasma also retains factor H1122 – a regulatory protein in the alternative complement pathway that may be reduced in HUS.²⁶ 

In lieu of randomized studies, case series and observational studies have provided safety data on the use of S/D plasma in these settings.^25,27,28 In one retrospective cohort of 50 TTP episodes treated with plasma exchange using cryosupernatant or S/D plasma, no differences were noted in the median number of plasma exchanges to remission and volume of plasma used; less allergic and citrate reactions were also observed with the S/D product.²⁷ The benefits of S/D plasma (outlined below in the section on benefits), including reduced allergic reaction and TRALI risks, are important considerations in this setting given the high volumes of plasma required.  

Neonatal, pediatrics, and intrauterine transfusions  

The safety and efficacy of S/D plasma among pediatric patients have been evaluated in clinical studies and from hemovigilance databases. Two recently published open label, post-market phase IV studies, reported on the use of S/D plasma among 50 critically ill patients (including 37 patients under age 2) with liver dysfunction and/or undergoing major surgery²⁹, and 41 patients (age 2 and up) undergoing 102 plasma exchanges.³⁰ S/D plasma was well tolerated overall, and not felt to be associated with any thrombotic or hyperfibrinolytic complications. A large observational study of 419 pediatric ICU patients (median age 1 year) among 101 pediatric ICUs in 21 countries also reported no safety concerns with S/D plasma. This study described post-transfusion international normalized ratio (INR) and ICU mortality, which were noted to be not different from patients transfused with untreated frozen plasma.³¹ Published retrospective cohorts have also reported on the short-term safety and efficacy of S/D plasma among neonates and pediatric patients.^32-37 The youngest patients receiving S/D plasma were described in one study that included 136 extreme preterm infants of less than 28 weeks of age.³³ Indications for S/D plasma transfusion varied between studies; clinical settings described were broad and included therapeutic plasma exchange, cardiac surgery, liver dysfunction, prevention of intracranial hemorrhage, and critical illness. European hemovigilance data from as early as the 1990s of S/D plasma have also been reassuring.² 

Overall, short-term data suggest safety of S/D plasma among neonates and pediatric patients, but long-term data are currently limited. There are no published studies addressing the use of S/D plasma in intrauterine transfusions. Benefits and risks should be assessed and balanced before using S/D plasma in these settings. Please refer to the product monograph for details.³  

Pregnant patients

There are limited studies describing the use of S/D plasma among pregnant patients. While there are no indications of harm, data are from small observational cohorts or case series.^32,38-40 There are no harmful effects expected due to the TNBP and octoxynol in the product from animal studies. Please refer to the product monograph for details.³  

Benefits

Reduces transfusion-transmitted infectious risks

The pathogen inactivation process reduces the risks of transfusion transmitted infections. S/D treatment damages lipid membranes and provides safety against lipid enveloped bacteria, protozoa, and viruses such as HIV, HBV, HCV, West Nile virus and Zika virus.¹¹ While S/D treatment has no effect on non-enveloped viruses (such as hepatitis A and parvovirus B19), pooling of plasma reduces possible viral load through dilution and provides neutralizing antibodies.^2,41 Nucleic acid testing is also performed for hepatitis A and parvovirus B19 for the plasma pools. The S/D treatment includes sterile filtration that depletes leukocytes and bacteria, as well as a column to remove prions – which reduces prion transmission risks.^3,42-44  

Reduces adverse transfusion reactions and TRALI risks  

S/D plasma may lower risks of adverse transfusion reactions and TRALI compared to untreated plasma, possibly in part due to dilution of antigens, antibodies, and cytokines present in individual plasma units.^11,45,46 Filtration steps used in S/D plasma production reduces bioactive particles, cell fragments and cytokines which may contribute to reactions.¹¹  

A 2019 clinical practice scientific review from the AABB identified 15 observational trials and 7 randomized controlled trials that evaluated the safety of S/D plasma. None of the studies identified an increased risk of adverse transfusion reactions, and allergic reaction rates were consistently lower with S/D plasma compared to untreated  plasma.⁴⁷ In France, a regional 10-year survey reported an allergic reaction rate of 4.86/10,000 S/D plasma transfusions compared to 7.14/10,000 untreated plasma transfusions.⁴⁸ Hemovigilance data from UK, Norway, France, and Italy have shown similar low risks of reported adverse events^11,49-51 with S/D plasma. From a TRALI risk perspective, the dilution of human leukocyte antigen (HLA) and human neutrophil antigen (HNA) antibodies⁵² reduces TRALI risks following S/D plasma transfusion compared to untreated plasma.^47,50 There have however been rare cases of TRALI reported following transfusion with S/D plasma.^53,54 

Standardized clotting factor levels

Unlike single donor plasma, there is substantially improved standardization of factor levels in S/D plasma due to the pooling process.^{4,8,9,41,42,55-58} Untreated single donor plasma carry significant fluctuations in clotting factor content (factor variations between 50% to 200%). Studies have shown that clotting factor levels in and following untreated plasma infusions may be highly variable.^17,5 All Octaplasma batches are routinely tested for Factor V, Factor VIII, and Factor XI (specification > 0.5 IU/mL), as well as protein C (> 0.7 IU/mL), protein S (> 0.3 IU/mL), and alpha-2 antiplasmin (> 0.2 IU/mL).^3,6 Functionally, there are no differences in PT and aPTT corrections, changes in thrombin generation, or viscoelastic point-of-care resting results between these two products.^{16,17,24,55,59} Hemostatic efficacy of S/D plasma versus untreated plasma is considered equivalent and described above. The standardization of coagulation factor content in S/D plasma may be particularly beneficial to pediatric patients who receive plasma transfusions of lower volumes. 

Drawbacks and contraindications

Reduced protein S and alpha2-antiplasmin content

There is significantly reduced protein S and alpha2-antiplasmin (a plasmin inhibitor) content in S/D plasma compared to untreated plasma. S/D treatment causes partial inactivation of protein S leading to reduced activity.⁴ In one study, the protein S level in S/D plasma was 0.41 U/mL on day 0 and deteriorated to 0.18 U/mL by day 6 of storage⁹ (range in frozen plasma 0.56-1.68 IU/mL); protein S requirements from the manufacturer for product release is > 0.3 IU/mL. For alpha2-antiplasmin, the activity is approximately 0.23 IU/mL (the range in frozen plasma is 0.72–1.32 IU/mL)³; the requirement for product release is > 0.2 IU/mL. As such, severe protein S deficiency is a contraindication for the use of S/D plasma.^2,60 The clinical impact of reduced alpha2-antiplasmin levels is unclear. There are no reports of persistent bleeding in patients with congenital/acquired plasmin inhibitor deficiencies who received S/D plasma therapy.⁴² However, Octaplasma should not be used to correct hyperfibrinolysis caused by specific deficiencies in alpha2-antiplasmin. Please refer to the product monograph for details.³  

Earlier formulations of S/D plasma produced in the U.S. (1998 –2002, produced by Vitex USA) were associated with bleeding and thromboembolic complications after liver transplantation and apheresis for TTP, leading to its withdrawal from the U.S. market in 2002. In comparison to European S/D plasma, the U.S. product had lower levels of alpha-2 antiplasmin and protein S, as well as other biochemical differences. These quality differences were attributed to differences in manufacturing and potentially contributed to complications observed with the U.S. product.^47,61-64 The current formulation of Octaplasma has not been reported to be associated with an increased risk of bleeding or thrombosis.⁴² A cohort study examining hyperfibrinolysis and thrombosis complications in an S/D plasma transplant centre compared to untreated plasma centres showed no differences in these outcomes.⁶⁵  

Other considerations

There is paucity of long-term data among pediatric and neonates transfused with S/D plasma (literature reviewed above). There are no published studies of S/D plasma use for intrauterine transfusions. There are also limited studies describing the use of S/D plasma among pregnant patients, although published data suggests no harm. 

S/D plasma is not considered IgA deficient. As per the product monograph, Octaplasma is contraindicated in patients with IgA deficiency with documented antibodies IgA as it may cause anaphylactic or anaphylactoid reactions. S/D plasma should also be avoided in patients who have hypersensitivities to the product or any ingredients in the formulation. Please refer to the product monograph for details.³  

Additional resources

FAQ: Solvent detergent (S/D) treated plasma (Octaplasma)

• This FAQ was developed in collaboration with Octapharma to support hospitals in transitioning to pathogen-reduced plasma and reflects evidence available at time of publication.

Octaplasma (S/D plasma): One-page clinical summary 

• This one-page clinical summary can be printed by blood bank staff and provided with Octaplasma units when they are sent to the floor for transfusion.

(Slide deck) Octaplasma (Solvent detergent [S/D] plasma): Clinical overview

• This slide deck may be downloaded for use in presentations. It provides health-care professionals with an overview of Octaplasma, including product characteristics, safety, indications and contraindications, and benefits of pathogen inactivation.

(Slide deck) Octaplasma (Solvent detergent [S/D] plasma): Clinical overview - Short version

• This slide deck may be downloaded for use in presentations. It provides health-care professionals with a shorter version of the clinical overview, highlighting key points about Octaplasma.

  Octplasma - clinical overview (short).pptx

  8.52 MB

  Updated: April 4, 2023

  Download

(Slide deck) Octaplasma: Information for laboratory technologists

• This slide deck may be downloaded for use in presentations. It provides laboratory technologists with an overview of information from the Octaplasma product monograph, including key points about labelling, packaging, storage and thawing. 

NAC recommendations for the use of solvent-detergent plasma in Canada

• This document from the National Advisory Committee on Blood and Blood Products (NAC) provides additional clinical recommendations regarding the indications, dosing and use of S/D plasma in special populations.
   

Suggested citation

Ning S, Blais-Normandin I, Tordon B, Mack J, Webert K. Solvent detergent (S/D) treated plasma (Octaplasma) [Internet]. Ottawa: Canadian Blood Services; 2023 [cited YYYY MM DD]. Available from: https://profedu.blood.ca/en/solvent-detergent-sd-treated-plasma-octaplasma

References

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35. Kalsi, A.S., Al-Azzawi, O. & Gill, R. Comparison of the Coagulation Effect Achieved by OctaplasLG Versus Fresh Frozen Plasma in Pediatric Cardiac Surgical Patients. Clin Appl Thromb Hemost 24, 1327-1332 (2018). 
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39. O'Connell, M.P., Eogan, M., Murphy, K.M., et al. Solvent-detergent plasma as replacement therapy in a pregnant patient with factor V deficiency. J Matern Fetal Neonatal Med 16, 69-70 (2004). 
40. Verghese, L., Tingi, E., Thachil, J., et al. Management of parturients with Factor XI deficiency-10year case series and review of literature. Eur J Obstet Gynecol Reprod Biol 215, 85-92 (2017). 
41. Hellstern, P. & Haubelt, H. Manufacture and composition of fresh frozen plasma and virus-inactivated therapeutic plasma preparations: correlation between composition and therapeutic efficacy. Thrombosis research 107 Suppl 1, S3-8 (2002). 
42. Liumbruno, G.M., Marano, G., Grazzini, G., et al. Solvent/detergent-treated plasma: a tale of 30 years of experience. Expert review of hematology 8, 367-374 (2015). 
43. Neisser-Svae, A., Bailey, A., Gregori, L., et al. Prion removal effect of a specific affinity ligand introduced into the manufacturing process of the pharmaceutical quality solvent/detergent (S/D)-treated plasma OctaplasLG. Vox sanguinis 97, 226-233 (2009). 
44. World Health Organization. WHO Guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma products, Annex 4, TRS No 924. Vol. 2023 (World Health Organization, 2004). 
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