Prophylactic plasma: Can we finally let go?

Abstract

In this issue of TRANSFUSION, Carson and colleagues report the results of a pilot trial on the efficacy of administering plasma to hospitalized patients with a prolonged INR who were scheduled to undergo an invasive procedure outside of the operating room. The majority of patients had liver disease. The trial found no evidence of any beneficial effect of prophylactic plasma. This finding may be in line with the absence of a pathophysiologic rationale underlying the clinical practice of pre-procedural plasma transfusion. To start with, risk of bleeding following an invasive procedure (such as an endoscopy, paracentesis, catheter insertion or biopsy) in patients with a prolonged INR is low, with incidences ranging between 0% and 1%. Also, inclusion of patients with a prolonged INR assumes that an INR reflects an increased risk of bleeding. As the authors acknowledge, this is not the case. In patients with liver disease and prolonged INR, mean coagulation factor levels range from 30% to 70%, which is consistent with adequate concentrations of factors to support hemostasis. It is generally acknowledged that the extrapolation of PT to INR is valid only to monitor vitamin K antagonist treatment and not for the assessment of bleeding risk. In addition to an ill-defined study population, there is a lack of rationale for the assumption that plasma transfusion reduces any bleeding risk. Plasma contains normal coagulation factor levels and as such, plasma can reduce a prolonged INR. However, as plasma also contains anticoagulant proteins, the net effect of plasma on thrombin generation, which may be considered a central process in coagulation, is zero. In addition to a lack of rationale, there is a lack of evidence for efficacy of plasma to correct coagulopathy or bleeding. This holds true even in settings associated with substantially more blood loss than that seen following a minor invasive procedure. Several RCTs have been conducted in cardiac surgery. Collectively, these trials show that prophylactic plasma reduces INR (not surprisingly, as highlighted already), but actually increases the amount of perioperative red blood cell transfusion, most likely due to dilution of red blood cells. In bleeding trauma patients, efficacy of plasma to improve outcome has not been related to a correction of coagulopathy. Rather, it has been argued that a possible benefit of plasma in trauma may be attributable to maintaining vascular integrity, as suggested experimentally. Of interest, in large parts of Europe, bleeding trauma patients are treated without a drop of plasma, but rather with coagulation factor concentrates, demonstrating favorable outcome. In the setting of liver disease, which comprised the majority of the patients included in the trial under discussion, the current concept is that even patients with a severely prolonged INR undergoing liver transplantation do not benefit from prophylactic plasma. Coagulation tests in these patients are deranged, but their risk of bleeding is not increased, as low factor and platelet levels are thought to be counterbalanced by decreased anticoagulant protein levels and increased von Willebrand Factor activity, a condition termed “rebalanced hemostasis.” In fact, in liver patients, increasing the intravascular volume with plasma is thought to increase the risk of bleeding, as pressure on varices and portal vein increases. Despite an absence of a rationale or supporting evidence, authors of the pilot trial under discussion state that “large trials are required to establish if plasma is safe and efficacious.” They also advocate to “educate clinicians on the rationale of the trial to establish widespread equipoise.” These statements are based on the fact that divergent clinical practice exists. However, divergent practice is not the only prerequisite to perform a trial. Based on the low bleeding rates of most invasive procedures, as well as on mildly reduced coagulation factor levels concomitant with reduced levels of natural anticoagulants, we argue that plasma is administered based on false assumptions. Also, there is potential harm of plasma, not only related to volume overload as already mentioned but also related to other transfusion reactions. Therefore, there is no equipoise about the question whether prophylactic plasma is beneficial. In line with this, current guidelines do not support the use of prophylactic plasma. Obviously, performing a trial requires a huge amount of resources as well as the efforts ofmany people. It took 4 years for this pilot trial to accrue 57 patients, and our own previous (very similar) trial was also terminated early due to hampered inclusion. The data from this current well-executed trial are useful to feed into meta-analyses that can help to educate clinicians that it is safe to abandon the practice of prophylactic plasma. But let us not use resources to perform another trial on prophylactic plasma.We propose that efforts should be made to improve identification of patients who indeed have an increased bleeding risk. Also, enhancing knowledge about plasma among clinicians should be a Received: 5 June 2021 Accepted: 5 June 2021