Betwixt Scylla and Charybdis

Abstract

This unfortunate case report raises several pertinent issues, some scientific which are addressed in the article and some of policies that are worth further consideration. Transfusion-associated graft-versus-host-disease (TAGVHD) is a well-described and often underreported complication of transfusion, with highest risk in immunosuppressed or immune-incompetent patients. It results from donor lymphocytes proliferating and identifying host antigens as foreign. Hence, very fresh and white blood cell–rich products create the highest risk for inducing TAGVHD, which certainly describes fresh whole blood (FWB) transfusions. Conversely, prestorage leukoreduction reduces the risk, likely approaching 90%.1 While the most prevalent modality for risk elimination is X-ray or gamma irradiation of cellular components to patients at risk, this procedure is clearly not practical in the setting of a military campaign. With better recognition of risk factors for TAGVHD in immunocompromised recipients, the most frequent occurrence in developed countries is among immune-competent recipients where the donor cells are HLA similar to the cells of the recipient but the recipient's cells appear foreign. This transfusion scenario may result when a donor is homozygous for a given HLA haplotype for which the recipient is heterozygous and occurs most commonly in 1) populations of less diverse HLA types (e.g., Japan) and 2) after a transfusion of cellular products from a related donor.2,3 This phenomenon was sufficiently frequent in Japan, a country with less diversity among HLA types, that they currently irradiate all cellular components.4 The case describes delayed onset of pancytopenia, fevers, diffuse macular rash sparing palms and soles, and hepatic dysfunction, all classic for TAGVHD. Like most cases recognized at the stage of advanced symptoms and complete cytopenias, the outcome was fatal, despite treatment with very strong immunosuppressive agents. Some discussion is made distinguishing the typical process of T-cell-mediated TAGVHD and typically B-cell-mediated red blood cell (RBC) hemolysis, as documented by a decreasing hemoglobin (Hb) and high titers of anti-A. In fact, in the absence of the ability to retrospectively titer isohemagglutinin levels in all of the donors of group O blood products the recipient received (including the 2 units of group O RBCs received just before the 4+ anti-A observed on Day 10), it is not possible to entirely rule out a passive source for the anti-A titer. However, passenger lymphocyte syndrome with hemolysis of recipient-type RBCs is not a rare complication of solid organ transplantation after, for example, transplant of heart or lung from a group O donor into a group A recipient.5 Hence, it is entirely plausible that the implicated donor that caused the TAGVHD was both blood group O (and carried lymphocytes capable of making anti-A) and was HLA homozygous for antigens for which the recipient was heterozygous. This brings us to the exigencies of military medicine. Amazing advances have been made in the ability to bring transfusion capabilities closer to the battlefield.6 Lessons learned in Vietnam and the first Gulf war have yielded dramatic improvements in in-field survival after massive trauma.7 Recognition of the limits of crystalloid and colloid resuscitation has led to giving preference to prescreening soldiers at the front line, to allow group O donors to donate FWB for immediate transfusion even before the injured soldier is evacuated to the field trauma treatment station. It is my understanding that with rapid blood typing, ubiquitous prescreens of potential donors, that FWB donation is not confined to group O donors. In fact, guidelines call for ABO group specific for female recipients. We must appreciate that almost 10,000 units have been transfused in combat theater and therefore thousands of soldiers' lives have likely been saved by having immediate access to transfusion, in comparison to a relatively few complications resulting from the policy of using FWB. By that equation, the balance would appear to be far in favor of using fresh blood. In prior conflicts with a largely all-male fighting force, the issue of group O donors with high-titer isohemagglutinins was likely moot. It is my understanding that group O soldiers were subjected to anti-A titering before deployment during the Vietnam conflict. However, the new type of conflict occurring in Iraq and Afghanistan is characterized by a lack of a clear combat front and a much more sex-diverse force, inevitably allowing fresh blood donations from female donors. More female donors raise prospects of transfusion-related lung injury or higher-titer isohemagglutinin titers from females sensitized by prior pregnancies. Current policy, however, precludes donation by females with prior pregnancy, which should mitigate both these risks. One important retrospective study documented the equivalence of outcome for soldiers receiving component therapy in a 1:1 ratio of RBCs to plasma compared to FWB.8 While one can raise methodologic concerns about how the authors drew conclusions about the RBCs-to-plasma ratio, there was no observed outcomes difference between whole blood versus component therapy. Even this observation is disputed. Another retrospective study observed better outcomes in recipients of warm fresh whole blood (WFWB) but this study compared a group that received WFWB, RBCs, and plasma but not apheresis platelets (PLTs) to others that received RBCs, plasma, and apheresis PLTs but not WFWB.9 While the title of the article claims superiority of WFWB, an equally valid conclusion using that logic is that apheresis PLTs are bad for outcome! It is significant that many of the same authors subsequently published a comparison of combat trauma patients receiving PLT transfusion with components to FWB and failed to find any statistical difference in outcome.10 Whether there is anything magic about FWB deserved further study, in a way where clear conclusions can be drawn.11 Having plasma and PLT components readily available is vital to being able to prevent a dilutional coagulopathy that, once in place, is difficult to escape from during resuscitation. Since delivery of fresh blood products to remote bases in Afghanistan may occur no more frequently than every 2 weeks, it is not possible to maintain a PLT supply. If, in fact, no difference in outcome comparing FWB versus component therapy is eventually determined, then consideration should be given to using components, where available, treated in some way to prevent the complications described in this case. This strategy raises the possibility of providing irradiated blood (but the shortened storage time, the remoteness of irradiation facilities, and higher potassium make this a less desirable solution), universal prestorage leukoreduction (under active implementation), or eventually, implementation of a pathogen inactivation treatment that would both preclude the need for irradiation and deal with geographic-specific pathogens that cannot practically be tested for (e.g., leishmaniasis, that would otherwise preclude donation from a recently returned soldier who spent time in Iraq or Afghanistan).12 Again, given a choice of immediate access to blood from a soldier in the field versus having to wait for blood from a donor that meets all US stateside eligibility criteria, one would usually choose expediency! The Department of Defense is actively studying pathogen inactivation. In the situations where most FWB is transfused, the biggest factor is timeliness. The immediacy of the need would preclude use of components treated in any way. However, for components such as PLTs where normally a delay of 24 hours is instituted for bacterial screening, there would also be a window of time to allow for pathogen inactivation. I am concerned that the authors of this article imply that fresh blood is categorically to be preferred: “Relatively fresh FDA-licensed, nonleukoreduced, nonirradiated group O blood products have also been utilized extensively in the current conflicts due to concerns regarding the detrimental effects of prolonged storage on RBCs” (italics added). Having personally visited Afghani military and civilian hospitals in Kabul, Afghanistan, I fully understand the emotional desire to “do everything possible” for the injured soldier, but it is vital to step back to the dispassionate level of evidence-based medicine. While the retrospective analyses suggest that early administration of FWB or a 1:1 ratio is superior to prior treatment algorithms, this conclusion has been demonstrated to be affected by survival bias, yet the authors of the military transfusion medicine article in this same issue note that “the Joint Theater Trauma System (JTTS) clinical practice guideline (CPG) indicates that a 1:1:1 ratio of plasma, RBCs, and PLTs should be transfused until bleeding is controlled. (And that) … as a result the ratio of plasma to RBCs now approaches 1:1 at almost all military treatment facilities in Afghanistan.”6 However, what the ideal resuscitation ratio is remains uncertain. Indeed, one civilian trauma retrospective trial observed lower mortality at a plasma:RBC ratio of 1:2 or 1:3 compared to 1:1.13 Therefore, until randomized prospective trials can sort out the ideal ratio of components in massive trauma resuscitation, it is premature to conclude that 1:1 is the ideal ratio.14 Similarly, until ongoing trials comparing outcomes from fresh versus older blood are completed, some practitioners' opinions that favor “fresh” blood may be well intentioned, but as illustrated in this case, they are not without their own attendant risks. Indeed, a randomized controlled trial from Mayo failed to show any short-term pulmonary, immunologic, or coagulation status advantage to patients receiving a single “fresh” versus a standard-date RBC unit.15 In fact, the authors' statement italicized above does not reflect the Joint Theater Trauma System Clinical Practice Guideline. The FWB clinical practice guidelines in theater state: “It is NOT appropriate, as a matter of convenience, to use FWB as an alternative to more stringently controlled blood products for patients who do not have severe, immediately life-threatening injuries. FWB is to be used only when other blood products are unable to be delivered at an acceptable rate to sustain the resuscitation of an actively bleeding patient, when specific stored components are not available (e.g., RBCs, PLTs, Cryo, FFP) or when stored components are not adequately resuscitating a patient with an immediately life-threatening injury. Since FWB has both RBCs and plasma, it must be ABO type-specific.” In settings as in the reported case, FWB may be the only source of blood components available for the management of hemorrhagic shock and its associated coagulopathy in casualties (personal communication with Col. F. Rentas Director, Armed Services Blood Program Office [ASBPO]). The enthusiastic adoption of the procoagulant rVIIa in the field of combat without any controlled trials to truly delineate its risk-benefit ratio may be the quintessential example of a well-intended programmatic decision in the absence of an evidence base. A recent publication documents that more than 95% of US usage of rVIIa is off label.16 I can only comment that I observed a contributing factor for the enthusiasm to adopt its usage at my institution for trauma victims was from medical personnel including CRNAs who had served in the Iraq and Afghanistan conflicts. This example gives some perspective on the impact that military medicine can have on civilian transfusion practices. A recent review of this understandable but expensive and possibly dangerous tendency among clinicians was recently published using rVIIa as an example.17 In short, our troops demand the best care practically available. While one should not deny potentially helpful therapies in the absence of complete proof of their benefit, we should, when feasible, avoid therapies with potential for harm or at least have strategies to mitigate those risks. One can only hope for a true equipoise between the Scylla of withholding beneficial treatments and Charybdis of creating harm. While retrospective studies can help assist in defining variables to be studied with respect to important outcomes, only controlled prospective trials can sort out the value of fresh versus standard-age blood, the optimal ratio of component therapy in resuscitation after massive trauma, and the role of pharmacologic adjuvants for treatment of hemorrhage. In that spirit, we should salute our colleagues in military medicine for their proven track record of progress and applaud that they are supporting studies that will continue to improve and optimize therapy and allow us to extrapolate learnings to civilian medicine. For example, they are currently supporting trials studying RBCs-to-plasma ratio, fresher blood, earlier use of plasma, and pathogen inactivation. Not all observations are immediately transferrable. The typical soldier wounded in battle is young and has considerable physiologic reserve, in contrast to civilian motor vehicle trauma, for example, that often involves elderly patients with comorbidities. In addition, the majority of battlefield trauma involves penetrating injuries, as opposed to blunt trauma, far more common in the civilian setting. It may be neither practical, nor politically tenable, to perform consent-waived clinical trials in the field of combat. Indeed, current thinking on consent-waived trauma trials is that extensive community notification is required, as was performed in civilian trials of Hb substitutes,18 yet the opportunity exists to capitalize on synergies between military and civilian trauma transfusion experts. The report on the Canadian consensus conference on massive transfusion that critically reviewed the literature advocating a 1:1:1 component ratio is an excellent example.19 I quote from its conclusion: “Key findings include a lack of evidence to support the use of 1:1:1 blood component ratios as the standard of care.” As a transfusion specialist at a large level one civilian trauma hospital, I look forward to participating in studies where the military helps identify therapeutic dilemmas and trauma centers perform cooperative prospective studies with true equipoise. JBG is a consultant on a CDC grant to UMN to provide technical assistance to Afghanistan National Blood Safety and Transfusion Services.