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P-PBM Blog: the Role of Lyophilized Factor Concentrates in P-PBM

Posted: By: Jyoti Shrestha

Tae-Yop Kim explores the extended role of lyophilized factor concentrates in the perspectives of perioperative-patient blood management (P-PBM)

By Tae-Yop Kim, MD, PhD 

Patient blood management (PBM) is a patient-centered, systematic, evidence-based approach to improve patient outcomes by managing a patient’s own blood through diagnosis and etiology-specific treatment of anemia and preserving the patient’s own blood by minimizing blood loss and bleeding while promoting patient safety and empowerment.1  

The World Federation of Societies of Anesthesiologists (WFSA) focuses on Perioperative PBM (Perioperative-PBM), which manages a patient’s blood before, during, and after surgery. This concept also focuses on improving patient outcomes, enhancing the efficiency of costly resource utilization, and reducing the risks of allogeneic blood transfusions in perioperative settings. While wisely managing anemia and minimizing blood loss are the core pillars of WFSA’s Perioperative-PBM, the rapid restoration and optimization of patients’ coagulation profiles are essential for reducing perioperative blood loss, minimizing allogenic blood transfusion, and improving patient outcomes. 

Despite the long-time beneficial role of frozen plasma products in managing coagulopathy, there is a growing concern about the seriousness of various transfusion-related adverse effects upon using allogeneic plasma products, including fresh frozen plasma (FFP) and cryoprecipitate. In most clinical settings, a large volume of FFP (approximately 10-20 ml/kg) is required for appropriately managing coagulopathy, but it is associated with transfusion-associated circulatory overload (TACO). Furthermore, it dilutes other blood components (e.g., red blood cells and platelets), exacerbating dilution-induced risks and paradoxically increasing bleeding and transfusion.2-4

Simultaneous administration of cellular components in donor’s plasma can be associated with transfusion-related acute lung injury (TRALI), the leading cause of transfusion-related mortality and mortality after transfusing plasma-containing blood products.5 Furthermore, the significant time delay due to the time-consuming process for ABO blood-type crossmatching and thawing before their administration can compromise their efficacy and increase their requirements. Any delays in optimizing coagulation in patients with ongoing or massive perioperative bleeding can exacerbate and paradoxically increase transfusion requirements for allogeneic blood products. Therefore, achieving a targeted plasma- and platelet-to-RBC ratio by early administration of plasma and platelet transfusion is the key factor in reducing in-hospital mortality during massive transfusion protocol (MTP) activation in bleeding trauma patients. However, despite tremendous effort, it is difficult or often impossible to transfuse FFP without considerable delay and achieve the ratio rapidly. As shown in a prospective, observational, and multicenter trial for transfusion in major trauma (PROMMTT Study), even applying MTP targeting for the 1:1:1 ratio, achieving the ratio within 30 minutes is almost impossible.6  

Lyophilized factor concentrates, prothrombin complex concentrate (PCC) and fibrinogen concentrates (FC), have recently emerged as effective alternatives to frozen plasma products, FFP and cryoprecipitate, in treating excessive perioperative bleeding. The main benefits of lyophilized factor concentrates include their rapidity, higher efficacy, and safety profiles. In addition to the absence of significantly time-consuming blood type crossmatching and thawing procedure: they are stored at ambient temperature (no need for freezers and thawing devices) and can be rapidly administered immediately after reconstitution. All these features enable more rapid and appropriate correction of perioperative clotting factor deficiency, even when initiating or running an MTP, than conventional plasma-based strategies.  

The high-purity and high-concentrates formulas have distinct advantages from the perioperative-PBM perspective. The absence of cellular blood components and cytokines (released from white blood cells) can be. a much safer feature than conventional plasma products: it can minimize the risks of transfusion-related reactions, including TRALI, bacterial or viral transmission.7, 8 High-concentration with precise dosing feature is also beneficial for rapidly correcting coagulopathy in a predictive manner without producing TACO (frequent in FFP transfusion), even during ongoing massive perioperative bleeding. Their more condensed and safer features are superior to conventional plasma in promoting more PBM-perspective patient care and patient safety. 

Initially, PCC had been introduced as an alternative option for the urgent reversal of Vitamin K-dependent anticoagulants. However, recent guidelines have steadily recommended its use for treating bleeding-induced coagulopathy and restoring coagulation factors in perioperative settings. PCC is made by human plasma and has a concentration of coagulation factors II, VII, IX, X, protein S, and protein C (and some heparin). PCC has a greater concentration of clotting factors, approximately 25 times greater than normal plasma: a single dose of PCC has clotting factors corresponding to those of FFP 8 to 10 units. This small-volume, high-dosage feature would be beneficial in avoiding iatrogenic dilution of RBCs and platelets, which is common in FFP transfusion for managing severe coagulopathy. Compared to the FFP-based strategy, the PCC-based strategy could reduce the RBC and platelet transfusion in coronary artery bypass surgery.4 It provided more effective management of excessive post-CPB bleeding, the most common factor for inducing allogeneic blood transfusion in cardiac surgery, without increasing thromboembolic or other adverse events.3, 9 The PCC-based strategy has gained superiority in managing post-CPB bleeding over the conventional FFP-based strategy.2, 10 The off-label use of PCC to treat coagulation factor–mediated bleeding in cardiac surgical patients has steadily increased. 

A recent update in the clinical practice guidelines of the Society of Thoracic Surgeons, the Society of Cardiovascular Anesthesiologists, the American Society of ExtraCorporeal Technology, and the Society for the Advancement of Blood Management (released in 2021 vs. 2011) added an expanded uses of PCC for managing perioperative bleeding and coagulation deficiencies on its previous edition and newly recommended to use of PCC as the first-line therapy for refractory post-CPB coagulopathy, before considering FFP.11, 12 

Fibrinogen is the first factor to fall to critical levels in massive bleeding, and its dilution, “hypofibrinogenemia,” should be managed in the earlier stage of hemodilution and coagulopathy. Now, either cryoprecipitate or fibrinogen concentrate (FC), depending on local availability, can be used to manage hypofibrinogenemia. However, there has been more of a switch from a plasma-based strategy to an FC-based strategy. This paradigm shift turned out to be effective in coagulopathy management with the reduced use of total blood product, the reduced number of patients requiring transfusion, and the reduced incidence of TACO.13  

The latest update in European guidelines on the management of major bleeding and coagulopathy following trauma (released in 2023 vs. 2019) recommended using PCC for warfarin reversal and delayed clot initiation in viscoelastic tests, and it also suggested not using FFP for hypofibrinogenemia when FC or cryoprecipitate is available.14-16  

Meanwhile, intraoperative point-of-care (POC) viscoelastic tests help determine the etiology of coagulopathy more quickly than standard laboratory tests.17-19 The rapidity of POC tests will undoubtedly reinforce the valuable efficacy of the factor concentrates, “the rapidity,” enabling faster restoration of coagulation even in active and massive perioperative bleeding. The combination of POC viscoelastic tests and lyophilized concentrates significantly improves clinical progress through rapid restoration of hemostasis and reduces the use of additional blood products.20, 21 

In conclusion, we should be aware of the paradigm shift from a conventional strategy using plasma products to one using lyophilized factor concentrates. The higher efficacy and safety profiles of lyophilized concentrates would be consistent with the fundamental concept of PBM, which is improving patient outcomes. Their features, along with rapid preparation and reconstitution time, would also be the most significant benefit of prompting fast treatment of coagulopathy in ongoing and massive perioperative bleeding.

Implementing the factor concentrate-based strategy to perioperative-PBM would facilitate much quicker restoration of optimal coagulation and reduce or minimize transfusion-related risks such as TRALI, TACO, and infection, primarily inevitable in conventional plasma transfusion. As a measure for implementing perioperative PBM, more effort may be warranted to expand the factor concentrate-based strategy for improving perioperative patient safety and outcomes in various surgical settings. 

Tae-Yop Kim works in the Department of Anaesthesiology at Konkuk University Medical Centre in Seoul, Republic of Korea.

This article is also available on our Virtual Library

References 

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  • 2. Karkouti K, Bartoszko J, Grewal D et al. Comparison of 4-Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of Hemorrhage During and After Cardiac Surgery: A Randomized Pilot Trial. JAMA Netw Open 2021; 4:e213936. 
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  • 17. Jeong D, Kim SY, Gu JY, Kim HK. Assessment of Rotational Thromboelastometry and Thrombin Generation Assay to Identify Risk of High Blood Loss and Re-Operation After Cardiac Surgery. Clin Appl Thromb Hemost 2022; 28:7. 
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