Evidence-based Plasma Transfusion Carolyn Burns MD, physician advisor Current guidelines include the following indications for plasma Plasma is prepared by transfusion: centrifugation from whole blood donation. The familiar standard is Management of patients with coagulopathy, congenital or acquired, for which FFP (fresh frozen plasma), which specific factors concentrates are not available is, by regulation, plasma frozen Management of bleeding patients who necessitate multiple factors, including within 8 hours of whole blood massive hemorrhage protocols donation (WBD). Plasma 24 is As replacement fluid for patients undergoing plasma exchange for treatment of plasma frozen within 24 hours of thrombotic thrombocytopenic purpura (TTP) WBD. This allows more time for Management of patients with rare C1-esterase deficiency for whom specific donor centers to process whole blood, opening a broader factor concentrates or drugs are not available timeframe and donor outreach. Thawed plasma has been of benefit to hospital transfusion services as this component represents FFP or Plasma 24 which has been thawed, not utilized, and returned to the transfusion service. This product may be relabeled and stored for five days at 1 to 6 degrees Celsius. Prior to the approval of this product, plasma that was thawed and returned had an expiration of 24 hours, often resulting in significant wastage. Thawed plasma is most beneficial for hospitals with high volume plasma use, e.g. trauma centers, high-risk cardiovascular surgery and obstetrics, and solid organ transplant. It is an excellent way to maximize inventory, prevent waste, and provide rapid access. All three of these plasma products have relatively equivalent content of coagulation factors. There are additional plasma components, such as liquid plasma, cryo-poor plasma, and solvent/detergent plasma, but these are not frequently utilized and thus we will not include these in routine discussion. The content of plasma represents blood proteins, i.e. albumin, fibrinogen, procoagulant and anticoagulant factors, as well as immunoglobulins and antibodies such as anti A & B; thus, plasma must be ABO compatible. Each unit is roughly 250 to 300 mls. The typical adult dose (if truly indicated) is roughly 4 Evidence Provides Clear units based on the size of the patient. If one calculates strictly, then a dose of Contraindications for plasma should be 10-15 mls./kg BW. Strict calculation is most important in Plasma: neonates, the elderly, and those at risk for volume overload. The timing of plasma transfusion is very important as several coagulation factors, specifically factor V, Do not transfuse plasma for the factor VII, and vWF, have relatively short t1/2s of around 4-6 hours. Thus, following: providing plasma within this timeframe for a planned procedure (again, IF truly indicated) would ensure adequate plasma levels. Follow-up testing is • Volume replacement or nutrition recommended within 15 to 60 minutes post-transfusion to assess the response. • Disseminated intravascular Current guidelines include the following indications for plasma transfusion: coagulopathy without bleeding management of patients with coagulopathy, congenital or acquired, for which • Fluid replacement during plasma specific factors concentrates are not available; management of bleeding patients exchange for entities other than who necessitate multiple factors (this includes massive hemorrhage protocols), as TTP replacement fluid for patients undergoing plasma exchange for treatment of • To prevent periventricular thrombotic thrombocytopenic purpura (TTP); and management of patients with hemorrhage in premature rare C1-esterase deficiency for whom specific factor concentrates or drugs are not neonates available. Additionally, evidence provides clear contraindications for plasma. Do not transfuse plasma for the following: volume replacement or nutrition, • As prophylaxis for mild to disseminated intravascular coagulopathy without bleeding, fluid replacement moderate elevations of INR in during plasma exchange for entities other than TTP to prevent periventricular non-bleeding patients hemorrhage in premature neonates, or as prophylaxis for mild to moderate elevations of INR in non-bleeding patients. The last situation is worth considerable discussion, as this clinical scenario represents the majority of plasma use and current literature points to a lack of evidence for prophylactic plasma transfusion, especially in the peri-procedural arena. Plasma transfusions are associated with adverse events and poor outcomes similar to what we see with other blood components. Immune-modulation, increased infections, LOS, ventilator dependence, IN A SURVEY OF PRACTICE, and increased CA recurrence have been associated in many studies with RBC transfusions. New evidence is pointing toward similar findings 72% OF PHYSICIANS ADMITTED TO associated with plasma transfusion, specifically infections and multi- NONTHERAPEUTIC ADMINISTRATION organ failure. In particular, TACO and TRALI, significant pulmonary complications, are often associated with plasma. TACO and TRALI OF FFP. remain the No. 1 and No. 2 causes of transfusion-associated-death as reported to the U.S. Food and Drug Administration. Allergic and CALDWELL S ET AL. HEPATOLOGY 2006; 44:1039 anaphylactic reactions, as well, can be serious and life-threatening. These risks must be recognized when considering transfusion. All of these potential adverse events should be considered as part of our medical decision to transfuse, discussion of patient choice, and the consent process. So why do HCPs most often transfuse plasma outside of active hemorrhage? Interesting and a bit alarming, a 2006 study highlighted that plasma transfusions were performed for perceived medico-legal risk rather than true therapeutic goals, with 72 percent of physicians admitting to nontherapeutic administration of FFP in a survey of practice.1 Therefore, it is critical that we all acknowledge and embrace the most recent evidence. Plasma, as with RBC and platelet transfusion, should not be transfused without a clear indication. With the serious, potentially life-threatening adverse events associated with plasma in mind, we should focus on the most frequent use of plasma, i.e. prophylactic transfusion in the non-bleeding patient. Let’s explore the reasons why HCPs might feel compelled to give plasma, and then we will launch into the literature that provides contrary evidence. Again, we will not be discussing the exsanguinating patient as everyone would agree that plasma will be included in hemorrhage protocols. Let’s begin with three assumptions as outlined in Dr. Paul Mintz’s textbook on transfusion practice:2 1) abnormal coagulation studies can accurately predict bleeding risk, 2) transfusion of plasma prior to procedures will correct the presumed hemostatic abnormality, and 3) prophylactic transfusion given prior to a procedure is of greater benefit than therapeutic transfusion given after the procedure if clinical bleeding actually occurs. These assumptions are misplaced and will lead to inappropriate and unnecessary plasma transfusion. What are some basics about plasma that must be remembered? Why might plasma not be effective when used prophylactically? First, all plasma is not “created equal.” Plasma derived from WBD has a similar volume, as mentioned; however, there is not an equal amount of plasma proteins. Each of us has different quantities and activity levels of our procoagulant factors. Even different blood types are associated with different levels. Donor centers do not quantify the factor levels in each bag of plasma. This is not required. An interesting study by Holland et al. showed that INRs performed on blood donors showed a range of values with normal healthy donors having INRs outside the reference range.3 Does this imply that the person with an INR of 1.4 or 1.5 that is otherwise healthy is prone to bleeding? Indeed not. A subsequent study by the same investigators also showed that transfusing plasma to those with mildly elevated INRs (<1.7) did not result in a significant decrease in the post-transfusion INR.4 The INR does not have a linear relationship to coagulation factor levels, as noted in this accompanying graph. A 2018 study supports this.5 In more than 6,700 non-bleeding patients with elevated INR at a single institution, 20 percent, or one-fifth, received prophylactic plasma. A “normal” INR was only achieved in 12 percent of patients. To drive this point further, what is a normal INR? In actuality, the INR was developed as a mathematical calculation to standardize the PT for patients taking a Vitamin K antagonist (VKA), such as warfarin. The normal reference range provided by the laboratory represents a sampling of the demographic, resulting in a typical bell-shaped Gaussian curve, which thus implies some lab values outside of two standard deviations. As noted in the original Holland study, the INR does not reflect bleeding risk and should reflect a therapeutic range more than a so- called normal range. It was not until the latter part of 2010 that evidence-based guidelines were reviewed using the GRADE methodology to look at clinical situations where plasma was typically transfused. Roback and colleagues found only two scenarios that showed the necessity for plasma transfusion.6 These were massive transfusion in trauma and active intracranial hemorrhage in patients on VKAs. This latter situation was prior to the approval of 4-factor prothrombin complex concentrates (4FPCC). Plasma