NAC Recommendations for Solvent Detergent Plasma (S/D Plasma)
Douglas Morrison (MD)
Jason Quinn (MD)
Katerina Pavenski (MD)
Kathryn Webert (MD)
On March 27, 2023, the restrictions on the use of Octaplasma Solvent-Detergent Human Plasma (S/D Plasma) in Canada (outside the province of Quebec) will be removed. Prior to this date, S/D Plasma was restricted to specific patient groups as recommended by the Canadian Agency for Drugs and Technologies in Health. The restrictions on the use of S/D Plasma were based on clinical evidence showing no difference in effectiveness as compared to regular frozen plasma (FP), and a substantial increase in cost associated with S/D Plasma as compared to FP. In July 2022, the Canadian Blood Services announced a transition to pathogen-reduced to platelet and plasma components as an additional layer of safety to the blood supply system in Canada. The first phase in the implementation of pathogen-reduced plasma is the transition from FP and S/D Plasma with a target of 80% of all transfused plasma to be S/D Plasma by September 2023. The second phase (planned for 2024-25) is to replace the remaining 20% of FP with pathogen-reduced frozen plasma using the same technology (Intercept Blood System) currently in use to produce pathogen-reduced platelets.
S/D Plasma has been used in Canada since 2011 on a restricted basis, and in many European countries (Netherlands, Finland, Sweden, Norway, United Kingdom) as the primary plasma product with no concerns for either clinical efficacy or safety. S/D Plasma is made from large pools of plasma that undergo pathogen inactivation using a solvent-detergent process and is then divided into 200 mL units. As a result of the manufacturing process, S/D Plasma units have relatively standard or uniform levels of coagulation factors. The levels for all clotting factors are similar to those in FP with the exception of lower protein S and anti-plasmin levels. The pooling of units for S/D Plasma results in decreased allergic reactions and possibly a reduction in TRALI reactions.
The transition to S/D Plasma represents a significant change in hospital transfusion practice in Canada. While S/D Plasma and FP have the same clinical indications, there are some differences in the products themselves and the packaging of the product, which are important for health care practitioners and hospital transfusion medicine services. Further information from Canadian Blood Services on S/D Plasma and the transition to this product can be found at https://profedu.blood.ca/en/transfusion/publications/faq-solvent-detergent-sd-treated-plasma-octaplasma.
This document from the National Advisory Committee on Blood and Blood Products provides additional clinical recommendations regarding the indications, dosing, and the use in special populations.
The main indication for plasma transfusion is the replacement of deficient coagulation factor(s) in patients with active bleeding, or prior to a surgery or invasive procedures. Specific guidelines and recommendations for the use of plasma transfusion have been previous published.
In general, most patients who would be treated with FP can receive S/D Plasma, these would include the following indications:
- Bleeding patients or patients undergoing invasive procedures who require replacement of multiple plasma coagulation factors,
- Patients with massive transfusion with clinically significant coagulation abnormalities,
- Patients on warfarin who are bleeding or need to undergo an invasive procedure before vitamin K could reverse the warfarin effect, and where prothrombin complex concentrate is not available or is contraindicated,
- Patients with selected coagulation factor or with rare specific plasma protein deficiencies for which a more appropriate alternative therapy is not available,
- Preparation of reconstituted whole blood,
- Patients with thrombotic thrombocytopenic purpura (TTP).
There are a limited number of specific contraindications to S/D Plasma:
- Patients with IgA deficiency and documented anti-IgA antibodies. These patients will also potentially have allergic reactions to regular FP and should only receive FP from IgA deficient donors. IgA deficiency alone (no anti-IgA antibodies) is not a contraindication as most patients with this relatively common deficiency do not form antibodies and will not have an adverse reaction to blood components.
- Patients with severe deficiency of protein S. S/D Plasma has significantly lower levels of protein S as compared to FP, which may result in an increased risk of blood clots. If these patients with severe deficiencies of protein S require a plasma transfusion, they should receive FP.
(a) Pediatrics. Based on limited data, S/D Plasma and FP should be considered equally effective in pediatric patients and can be used interchangeably. Two studies which included 91 pediatric patients receiving S/D Plasma did not identify any safety concerns. A secondary analysis of a large multinational study identified 62 pediatric critical care patients who received S/D plasma; there was no difference in the reduction in the INR compared to patients receiving FP and S/D plasma was associated with reduced mortality. Adoption of S/D plasma for routine use in other jurisdictions has also not identified any concerns with pediatric patients.
(b) Neonatology. Based on limited data, there is no reason to expect differences in clinical efficacy with S/D Plasma as compared to FP. A retrospective study included 41 neonate patients reported no clinical or safety concerns with S/D Plasma15. One non-published study reported no adverse events in 55 neonates receiving S/D plasma. The reduction in adverse transfusion reactions associated with S/D Plasma may be advantageous.
(c) Pregnancy. Based on limited clinical data, SD Plasma and FP can be considered equally effective in pregnant patients and can be used interchangeably. A retrospective study including 37 obstetrical patients reported no clinical or safety concerns. Adoption of S/D plasma for routine use including obstetric and gynecology patients also did not identify any clinical concerns in gynecology or obstetrical patients.
(d) Geriatrics. S/D plasma and FP Plasma should be considered equally effective in geriatric patients and can be used interchangeably with FP. While there are no studies of evaluating S/D plasma specifically in geriatric patients, there are no physiologic reasons that S/D plasma would be less effective or have increased adverse effects in geriatric patients. The reduction in adverse events associated with S/D Plasma may be considered advantageous in this patient group who would be at greater risk on adverse outcomes associated with a transfusion reaction.
(e) Liver transplantation / Liver disease. S/D Plasma and FP can be considered equally effective in patients undergoing liver transplantation or coagulopathy associated with liver disease and can be used interchangeably. Three randomized controlled trial studies (n=115) evaluated S/D Plasma in patients with coagulopathy associated with liver disease or liver transplant patients. There were no differences in clinical efficacy or adverse events.
(f) TTP. Clinical studies have shown that S/D plasma is effective and safe when used as part of plasmapheresis treatments in patients with TTP. No clinical studies have compared the effectiveness of S/D plasma to FP or cryosupernatant. In the 2 clinical trials evaluating cryosupernatant in TTP patients, there was no evidence of improved outcomes as compared to FP. The reduction in adverse events and lower risk of transfusion transmitted infections with S/D plasma may be considered advantageous in patients receiving large volume plasma transfusions as part of plasmapheresis treatment.
An important factor in the dosing of S/D Plasma is the smaller unit volumes. FP units, which are made from individual blood donations, vary in size with an average volume of 289 mLs (± 16 mLs) and have more variability in coagulation factor levels as each unit is from an individual donor. Overall, the mean concentration of coagulation factors in S/D plasma and FP are similar, but as a pooled blood product, the concentrations are more uniform in S/D Plasma.
The correct dose of plasma is determined by either weight-based dosing (hemodynamically stable patients) or ratio-based dosing (massively bleeding patients):
- For the correction of coagulation factor levels in patients with acute bleeding, or prior to surgery or invasive procedures, the recommended dose for FP is 10-15 mLs/kg, which is the volume required to increase coagulation factors levels above the minimum hemostatic threshold of 30%. Given the similarity in coagulation factor levels, this dose is also appropriate for S/D Plasma. In pediatric patients weighing less than 40 kg, the plasma is usually ordered in mLs/kg. For larger pediatric patients and adult patients, plasma is usually ordered in units. As S/D Plasma is supplied in a smaller standard 200 mL bag compared to an average 289 mL per unit of FP, a larger number of units of S/D Plasma may be required to deliver a therapeutic dose of plasma. Most adult patients (60-90 kg) will require 4-6 units of S/D Plasma or 3-4 units of FP to achieve hemostatic levels of coagulation factors. The prescribed dose of plasma should be guided by the clinical situation and coagulation results.
- The NAC recommends that the number of plasma units prescribed in Massive Hemorrhage Protocols (MHPs) be the same whether S/D Plasma or FP is used. For patients with massive hemorrhage requiring transfusion support, resuscitation with fixed ratio of FP to Red Blood Cells (RBCs) is commonly used in MHPs. This practice is based on observational studies that report improved outcomes in military patients with massive hemorrhage secondary to trauma. While a high transfusion ratio of FP:RBC has been recommended in trauma patients requiring massive transfusion, the ideal ratio is unknown. In clinical practice, there is variability in the volumes of the FP and RBC units transfused, and often the desired ratio of FP:RBC units is not achieved. As a result, there is significant inherent variability in the actual volumes of plasma and red cells transfused. FP:RBC ratios of 1:1 to 1:3 have been recommended as sufficient to provide hemostatic levels of coagulation factors in trauma patients. Additionally, no benefit has been demonstrated for higher FP:RBC ratios in the resuscitation of patients with non-traumatic massive hemorrhage, who represent the majority of MHP activations in the civilian setting. Therefore, based on the limited evidence available, the NAC does not recommend increasing the initial ratio of plasma to RBC units in MHPs when using S/D plasma despite the lower volume of S/D plasma units. However, as per recent recommendations, patients requiring massive transfusion require frequent monitoring of coagulation tests and should be transitioned to laboratory guided administration of blood components as soon as possible.
- Optimal Therapy Recommendation for the use of Solvent/Detergent‐Treated Human Plasma. [Internet] Ottawa; Canadian Agency for Drugs and Technologies for Health, May 2011. 1, RECOMMENDATION
- Membe SK, Coyle D, Husereau D, Cimon K, Tinmouth A, Normandin S. Octaplas Compared with Fresh Frozen Plasma to Reduce the Risk of Transmitting Lipid-Enveloped Viruses: An Economic Analysis and Budget Impact Analysis. [Internet] Ottawa; Canadian Agency for Drugs and Technologies for Health (CADTH); May 2011 [cited 2023 02 24]. Technology report number 107. 2009.
- Krusius T AM, Tuimala J. Introduction of Octaplas® in clinical use decreased the rate of severe adverse reactions. Vox Sanguinis 2010;99s1: P-1018
- McGonigle AM, Patel EU, et al. Solvent detergent treated pooled plasma and reduction of allergic transfusion reactions. Transfusion 2020;60: 54-61.
- Saadah NH, Schipperus MR, Wiersum-Osselton JC, et al. Transition from fresh frozen plasma to solvent/detergent plasma in the Netherlands: comparing clinical use and transfusion reaction risks. Haematologica 2020;105: 1158-65.
- Cushing MM, Pagano MB, Jacobson J, et al. Pathogen reduced plasma products: a clinical practice scientific review from the AABB. Transfusion 2019;59: 2974-88.
- Klanderman RB, van Mourik N, Eggermont D, et al. Incidence of transfusion-related acute lung injury temporally associated with solvent/detergent plasma use in the ICU: A retrospective before and after implementation study. Transfusion 2022;62: 1752-62.
- FAQ: Solvent detergent (S/D) treated plasma (Octaplasma). Ottawa, Canadian Blood Services, 2022 [cited 2023 0301] Available from: https://profedu.blood.ca/en/transfusion/publications/faq-solvent-detergent-sd-treated-plasma-octaplasma
- O'Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. .Br J Haematol. 2004;126:11-28
- Davidson JC, Rahim S, Hanks SE, et al. Society of Interventional Radiology Consensus Guidelines for the Periprocedural Management of Thrombotic and Bleeding Risk in Patients Undergoing Percutaneous Image-Guided Interventions-Part I: Review of Anticoagulation Agents and Clinical Considerations: Endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe. J Vasc Interv Radiol. 2019 Aug;30(8):1155-1167.
- Khandelwal A, Clarke G, Goldman M. Anaphylactic transfusion reactions and IgA deficiency [Internet]. Ottawa: Canadian Blood Services; 2021 [cited 2023 02 24]. Available from: professionaleducation.blood.ca/en/transfusion/publications/anaphylactic-transfusion-reactions-and-iga-deficiency
- Spinella PC, Borasino S, Alten J. Solvent/Detergent-Treated Plasma in the Management of Pediatric Patients Who Require Replacement of Multiple Coagulation Factors: An Open-Label, Multicenter, Post-marketing Study. Front Pediatr. 2020;8:572.
- Josephson CD, Goldstein S, Askenazi D et al. Safety and tolerability of solvent/detergent-treated plasma for pediatric patients requiring therapeutic plasma exchange: An open-label, multicenter, postmarketing study. Transfusion. 2022;62:396-405
- Camazine MN, Karam O, Colvin R, et al. Outcomes Related to the Use of Frozen Plasma or Pooled Solvent/Detergent-Treated Plasma in Critically Ill Children*. Pediatric Critical Care Medicine. 2017;18(5):e215–23
- Chekrizova V and Murphy WG. Solvent-detergent plasma: use in neonatal patients, in adult and paediatric patients with liver disease and in obstetric and gynaecological emergencies. Trans. Med. 2006;16:85-91.
- Canadian Product Monograph, Octaplasma®, May 14 2020, https://www.octapharma.ca/api/download/x/9775dbca5e/octaplasma-pm-en-20200514.pdf
- Freeman JW, Williamson LM, Llewelyn C, et al. A randomized trial of solvent/detergent and standard fresh frozen plasma in the treatment of the coagulopathy seen during orthotopic liver transplantation. Vox Sanguinis. 1998;74(S1):225-229.
- Williamson LM, Llewelyn CA, Fisher NC, et al. A randomized trial of solvent/detergent-treated and standard fresh-frozen plasma in the coagulopathy of liver disease and liver transplantation: SD-treated plasma in coagulopathy of liver disease. Transfusion. 1999;39(11-12):1227-1234.
- Bindi ML, Miccoli M, Marietta M, et al. Solvent detergent vs. fresh frozen plasma in cirrhotic patients undergoing liver transplant surgery: a prospective randomized control study. Vox Sang. 2013;105:137-143
- Scully M, Longair I, Flynn M, et al. Cryosupernatant and solvent detergent fresh-frozen plasma (Octaplas) usage at a single centre in acute thrombotic thrombocytopenic purpura. Vox Sanguinis. 2007
- Edel E, Al-Ali HK, Seeger S, et al. Efficacy and Safety Profile of Solvent/Detergent Plasma in the Treatment of Acute Thrombotic Thrombocytopenic Purpura: A Single-Center Experience. Transfusion Medicine and Hemotherapy : Offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2010 ;37(1):13-19.
- Harrison CN, Lawrie AS, Iqbal A, Hunter A, Machin SJ. Plasma exchange with solvent/detergent treated plasma of resistant thrombotic thrombocytopenic purpura. Br J Haematol. 1996;94:756–758.
- Rock G, Shumak KH, Sutton DM, et al. Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura. Members of the Canadian Apheresis Group. Br J Haematol. 1996;94(2):383-6
- Rock G, Anderson D, Clark W, et al. Canadian Apheresis Group; Canadian Association of Apheresis Nurses. Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet. Br J Haematol. 2005;129(1):79-86.
- Circular of information for the use of human blood Components: Plasma Components. Ottawa: Canada, November 2022 [cited 2023 03 01]. Available from: https://www.blood.ca/sites/default/files/IM-00004_Revision_1.pdf.
- Sheffield WP, Bhakta V, Talbot K, et al. Quality of frozen transfusable plasma prepared from whole blood donations in Canada: an update. Transfus Apher Sci. 2013 Dec;49(3):440-6
- Gupta A, Bigham M. Blood components. In: Clarke G, Chargé S, editors. Clinical Guide to Transfusion [Internet]. Ottawa: Canadian Blood Services, 2021 [cited 2023 03 01]. Chapter 2. Available from: https://professionaleducation.blood.ca.
- Callum JL, Dzik WH.. The use of blood components prior to invasive bedside procedures: a critical appraisal. In: Mintz PD (ed), Transfusion therapy: clinical principles and practice, 3rd edn. Bethesda: AABB Press, 2010: 1–35
- Callum JL, Yeh CH, Petrosoniak A, et al. A regional massive hemorrhage protocol developed through a modified Delphi technique. CMAJ Open 2019. DOI:10.9778/cmajo.20190042
- da Luz LT, Shah PS, Strauss R, et al.. Does the evidence support the importance of high transfusion ratios of plasma and platelets to red blood cells in improving outcomes in severely injured patients: a systematic review and meta-analyses. Transfusion. 2019;59:3337-3349.
- Jason A. Gregory, Sonny S. et al. Optimizing Transfusion Ratios in Massive Transfusion Protocols: An Argument Against the 1:1:1 Dogma and Approach to Trauma Resuscitation, Laboratory Medicine, 2015;46:e46–e52