Thawed and Liquid Plasma for Massive Transfusion Protocols

Frozen_PlasmaThe most recent National Collection and Blood Utilization Survey, reporting data from 2011, noted US patients received 3.9 million plasma units that year. At 10 hospitals participating in the National Heart, Lung and Blood Institute sponsored Recipient Epidemiology and Donor Evaluation Study III (REDS III) program, at that time, patients received more than 72,000 plasma units or 1.9% of US plasma transfusions. Two units represented the median plasma transfusion dose with 39% of plasma infused as “thawed plasma.” (1) A survey of level I trauma centers, conducted in 2015, found 97% maintained thawed plasma inventories. (2) Once thawed, plasma has a 24 hour outdate, but can be relabeled “thawed plasma” with a 5-day shelf life if stored at refrigerated temperatures.

The REDS III investigators found no differences in INR responses to fresh frozen plasma versus thawed plasma after adjusting for pre-transfusion INR and plasma dose. (1) Thawed plasma provides inventory management advantages including rapid availability and reduced wastage since plasma is thawed prior to request and retains 5-days shelf life prior to expiry. In their discussion, REDS III clinicians questioned the use of plasma transfusions for INR levels less than 2.0 and the low plasma doses patients received.

In contrast, up to 25% of severely injured patients present with a coagulopathy at hospital admission. Almost 50% of trauma related fatalities occur within 24 hours of injury; 80% of intra-operative deaths are hemorrhage related. In response, multiple studies in military and civilian trauma situations demonstrate that massive transfusion protocols requiring multiple plasma, platelet, and red cell transfusions improve outcomes. Recent American College of Surgeons guidelines recommend immediate availability of plasma in the liquid state for balanced resuscitation (1:1:1 or 1:1:2 ratios of plasma, platelets, and red cells).   Future accreditation standards will make this a requirement.

The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial randomized trauma patients to a 1:1:1 or 1:1:2 ratio, requiring the transfusion service to provide “universal donor plasma” in the liquid state, platelets, and red cells within 10 minutes of request. Experiences at the 12 level I trauma centers participating in the PROPPR trial demonstrated delivery of six units of plasma in the liquid state from group AB or group A donors within 10 minutes at 11 sites and within 15 minutes at the remaining institution. Sites met the 10 minute criteria by using thawed AB plasma, liquid plasma (i.e. never frozen plasma with a shelf life extending 5 days beyond the expiration time of donor derived whole blood when stored at 1 to 6 C— 26 days for blood collected with CPD anticoagulant preservative solutions), or anti-B low titer or not tittered group A plasma instead of AB plasma (in limited supply since only 4-5% of the population phenotypes as AB). (3)

Group A plasma in lieu of AB plasma as “universal donor” plasma takes advantage of a calculation showing 87% compatibility when un-typed recipients receive group A plasma; only group B and AB patients would receive incompatible plasma albeit with a high likelihood of low titer anti-A. In studies at the Mayo Clinic, the median anti-B titer was 1:16; 92% of donors had titers of 1:64 or less. (4) The Mayo Clinic implemented group A thawed plasma for emergency transfusions in 2008. They report a significant reduction in AB plasma use with no significant difference in adverse reactions in patients receiving incompatible group A plasma as a “universal donor” product as observed, similarly, in the PROPPR trial. (3,4) Among the level I trauma centers surveyed in 2015, 88% keep thawed group A plasma available and 69% use group A plasma for trauma patients for whom blood type information is not available; many implemented this strategy within the past year. (2)

With thawed plasma, losses occur in labile clotting factors and Protein S. Factor VIII declines significantly, falling to approximately 53-75% of baseline levels 5 days post-thawing with most of the decline occurring within the first 24 hours after thawing. Factor V levels drop to 70-86% of baseline and variable decreases occur in Protein S activity. Other Factor levels remain relatively constant although some studies show increased levels of Factors VII and XII, presumably related to cold or contact activation at refrigerated temperatures. (5) Factor XI increases, reported in some studies, correlates with venous thromboembolism in patients receiving immune globulin preparations, although this concern may not be relevant in bleeding patients. Indications for thawed plasma partially reflect these observations emphasizing its use for management of preoperative or bleeding patients, massive transfusions, and rapid reversal of warfarin therapy.

Recommendations for never frozen or liquid plasma, a product not readily available in the US at the current time but the subject of discussion, include massive transfusions in patients with life threatening hemorrhage. In one study, procoagulant and anticoagulant factor levels, determined on aliquots stored frozen and thawed immediately prior to testing, found retention of at least 50% activity for all factors after 15 days of storage, significant declines in Factors V, VII, VIII, vWF, and Protein S activity on day 15 compared to day 1, a significant reduction in thrombin generating capacity, and an increase in Factor VII activity after day 15. Those involved in this study, questioned whether liquid (never frozen) plasma stored for longer than 15 days was optimal, especially in light of significant depletion of Factor V and Protein S levels. (6)

Another study, assaying factor levels on freshly obtained aliquots that did not undergo freezing, found higher levels of platelet micro particles (which contribute to clot strength) in liquid plasma on day 26 of storage compared to day 0, more than 80% of initial factor levels on day 26 other than Factors V, VIII, and Protein S activity (the latter falling to 39%, 60%, and 29% of initial activity respectively). Thromboelastography studies found liquid, never frozen plasma had better clot forming capacity than thawed plasma. (7)

These three new approaches support adequate inventory maintenance and rapid plasma availability with reduced wastage for patients receiving massive transfusions—group A plasma as a supplement to group AB universal donor plasma, thawed plasma, and liquid or never frozen plasma. Available data encourage their usage with the expectation that additional clinical experience will provide greater perspective for optimizing and expanding their roles.


1. Triulzi D, Gottschall J, Murphy E, et al. A multicenter study of plasma use in the United States. Transfusion 2015;55:1313-1319.

2. Dunbar NM and Yazer MH. A possible new paradigm? A survey-based assessment of the use of thawed group A plasma for trauma resuscitation in the United States. Transfusion 2015; doi:10.1111/trf.13266

3. Novak DJ, Bai Y, Cooke RK, et al. Making thawed universal plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. Transfusion 2015;55:1331-39.

4. Stubbs JR, Zielinski MD, Berns KS, et al. How we provide thawed plasma for trauma patients. Transfusion 2015 doi:10.1111/trf.13156

5. Cardigan R and Green L. Thawed and liquid plasma-what do we know? Vox Sang 2015; 109:1-10.

6. Gosselin RC, Marshall C, Dwyre DM, et al. Coagulation profile of liquid-state plasma. Transfusion 2103;53: 579-90.

7. Matijevic N, Yao-Wei W, Cotton BA, et al. Better hemostatic profiles of never-frozen liquid plasma compared with thawed fresh frozen plasma. J Trauma Acute Care Surg 2012;74:84-91.

Plasma Use in the United States


Triulzi D. et al. A multicenter study of plasma use in the United States. Transfusion 2015; 55: 1313-1319

Plasma transfusion, historically, has been steeped in much mystery and myth, with wide variability and inappropriate practice.1,2 The literature and guidelines for plasma transfusion have lagged somewhat behind the more robust studies for red cell transfusions. The NBCUS report noted 3.9 million plasma transfusions occurred in 2011 which clearly reflects the broad scope of use that persists in the United States.3

The recent publication by Triulzi et al. in Transfusion, cited above, represents an epidemiological study to more optimally define plasma use in ten U.S. hospitals over a one-year period. Over 9,200 patients were identified and over 72,000 plasma units transfused. Several characteristics were noted which were likely not unanticipated, however, there were other findings that might prove to be less expected.IV bag flat icon with long shadow,eps10

Plasma transfusions were typically not given in isolation. Approximately 77% of the patients received other blood components. Intuitively this is not a surprise, particularly in the arena of massive hemorrhage protocols secondary to trauma or non-trauma situations. Cardiovascular surgery had the highest use. The primary reason documented for plasma transfusion, across all facilities, was “treatment of coagulopathy” i.e., not for diagnosis of TTP or other illnesses that might necessitate plasma exchange. Again, not unanticipated. Over 22,000 invasive procedures were performed on the same day as transfusion with central venous catheter placement “leading the pack”, followed closely behind by UGI endoscopy, paracentesis, thoracentesis and bronchoscopy. All of these minimally invasive procedures have been identified in previous meta-analyses as not benefiting from prophylactic plasma transfusion, in terms of bleeding outcomes.4,5

The study found pre-transfusion INR to be available in 71% of patients and the majority of patients had a post-transfusion INR as well, to identify treatment effect. These are much higher than in my anecdotal experience, so perhaps a bit comforting? The median INR for which plasma transfusion was given was 1.9. Thirty-three percent of plasma was given for INR between 1.6 and 2.0 and 22.5% for INR < 1.6. No change in INR or a minimal decrease (median change = 0.2) was noted in 25% of patients. This data is in synch with prior studies that found similar minimal changes particularly when INR is ≤ 1.7.6

The use of standard FFP, plasma 24, or thawed plasma made no differences in pre- or post-INR values.

Unexpected and interesting findings, in my view, included: Over one-third of units were given on general Med/Surg wards andnot within operating suites or emergency departments. Only 10.7% of plasma transfusions occurred within the O.R. and only 3.7% in the E.D. Single unit and double unit transfusions were reported at 15% and 46% respectively.

Thus, this publication provides further documentation of the broad and often unnecessary use of plasma, particularly outside of surgical suites and emergency departments for minimally invasive procedures. The use of prophylactic plasma transfusion for a perceived coagulopathy (INR <2.0) obviously persists in spite of more recent literature that speaks to the contrary. Inadequate dosing is also pervasive as >60% of transfusions were single or double-unit which is not considered an adequate adult dose.

The authors state that “…the opportunities for practice improvement are clear and substantial.” Based on their results I would strongly agree. As advocates for patient blood management, we must leverage these types of studies to help push forward the message of avoiding unnecessary, inadequate, and inappropriate transfusions.


  1. Tinmouth A et al. Transfusion 2013; 53: 2222-2229
  2. Stanworth S et al. Transfusion 2011; 51: 62-70
  4. Segal J and Dzik W. Transfusion 2005; 45: 1413-1425
  5. Yang L et al. Transfusion 2012; 52: 1673-1686
  6. Holland L and Brooks J. Amer J Clin Pathol 2006; 126: 133-139

Pathogen Reduction Systems Attain FDA Approval

Blood DonorThe US Food and Drug Administration (FDA) deploys a five-layer system to safeguard the volunteer-driven blood system: (1) Donor screening (upfront information about donor eligibility and specific and direct questions), (2) Donor deferral lists (all donors checked against the registry), (3) Extensive donation testing, (4) Quarantine of all collected blood until tested, and (5) Problem and deficiency investigation/ process improvement.

In December, 2014, the FDA added a sixth layer: Pathogen Reduction (PR), i.e. photochemical treatment to achieve at least a 4 log reduction of viral and bacterial infectivity, and T-lymphocyte inactivation in single donor apheresis platelets and plasma. Additionally, PR protects against emerging or novel threats to the blood supply such as Dengue, Chikungunya, Babesia, and so forth.

The PR process approved by the FDA uses a psoralen compound, amotosalen, in the presence of UV-A light exposure to form DNA and RNA monoadducts and cross-links in pathogens contaminating platelets and plasma rendering them incapable of causing disease (photochemical process).

Another process, in clinical trials for platelets and plasma and expected to achieve FDA approval, uses Riboflavin (vitamin B2) and UV light exposure that causes direct DNA and RNA damage and guanine modification (photodynamic reaction involving reactive oxygen species). Riboflavin/UV treatment of whole blood, now in clinical trials, applies a higher UV dose than used with platelets and plasma, and expands PR treated products to include red cells.

Another process, FDA approved previously for reducing pathogen infectivity in pooled volunteer or paid plasma donations, uses a solvent, tri-n-butyl phosphate, and a detergent, octoxynol, to disrupt lipid membranes of enveloped viruses. Since the solvent/detergent process affects lipid membranes, it is not applicable to cellular blood components.

Recognizing hemoglobin absorbs UVA light, an additional process in clinical trials for red cell PR, involves a frangible anchor-linker effector (S 303) and a quencher glutathione. In a pH-dependent reaction and taking advantage of its amphipathic character, the chemical compound passes through membranes and intercalates helical regions of pathogen nucleic acids. Previously, this approach resulted in red cell neo-antigen formation and antibody response now mitigated by a revised process.

Reported PR studies demonstrate inactivation of enveloped viruses such as HIV (cell free and cell associated), hepatitis B and C, HTLV-I/II, West Nile Virus, and CMV effectively eliminating infectivity of existing or new infections such as those in the “window period” between exposure and test detection.   PR also reduces transmission risks associated with protozoa: Trypanosoma cruzi, plasmodia, leishmania, and babesia.

Non-enveloped viruses such as hepatitis A and E and Parvovirus B19 are resistant as are prions.

PR inactivates Gram positive, Gram negative, and Gram positive anerobic bacteria in platelets. An important intervention since clinical sepsis occurs after 1 per 100,000 platelet transfusions and 1 per 3000 platelet components contain bacteria. FDA addressed this hazard in a December, 2014 Draft Guidance document advising hospital transfusion services to perform rapid testing (point-of-care testing) on day 4 or day 5 platelets. Although not addressed in the Draft Guidance, PR treatment of platelets would obviate the need for such testing by hospital transfusion services.

Some spore-forming bacteria escape inactivation by current PR techniques.

Toxicity studies involving toxicology, genotoxicity, and carcinogenicity demonstrate adequate safety margins. No novel (neo-) antigens occurred in plasma or platelet testing.

The results of multiple clinical trials seeking efficacy endpoints show PR treated platelets have reduced post-transfusion corrected count increments (CCI), days to next platelet transfusion, and increased number of platelet transfusions compared to non-treated platelets. Notably, the non-inferiority designed SPRINT trial involving 645 patients and powered to detect clinical bleeding rather than surrogate post-transfusion platelet count increments, found no differences in incidence of WHO Grade 2 bleeding or time to onset of WHO Grade 2 bleeding in those receiving PR treated or control platelets.

PR treated plasma provides similar results to non-treated plasma although there is a 20%-30% loss of Factor VIII.

Chemical and UV light exposure of lymphocytes in PR treated blood components reduces the risk of transfusion-associated Graft-versus-Host Disease (T-A GvHD), thereby avoiding gamma or x-ray irradiation of platelets for T-A GvHD prevention.

Additional benefits of PR include: elimination of bacterial testing including point-of-care testing for platelets, extension of platelet shelf life to 7 days, avoidance of blood donor travel deferrals to malaria endemic areas, and prophylactic inactivation of novel pathogens and those not discovered currently.

Barriers to PR implementation include: cost/affordability, availability at this time only for platelets and plasma, perceived safety of the blood supply, success of emerging pathogen surveillance, and decreased platelet recovery despite no difference in bleeding incidence.

Predictions: Universal PR adaption will occur via implementation by early adapters followed by others or via FDA regulation. Some currently performed procedures (platelet bacterial testing and irradiation to prevent T-A GvHD) will be eliminated resulting in cost savings. Some currently performed blood donation tests (i.e. use of both serology and nucleic acid tests) will be eliminated resulting in cost savings. Emerging or novel infectious agents will be interdicted at an early stage enhancing blood safety without the need for additional tests. The paradigm change of transitioning the focus on product safety to transfusion (recipient) safety will accelerate with greater emphasis on patient blood management and prevention of blood specimen and patient misidentification errors.


McCullough J, Vesole DH, Benjamin RJ, et al. Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT trial. Blood 2004;104:1534-41

Prowse CV. Component pathogen inactivation: a critical review. Vox Sang 2013;104:183-99

FDA, CBER. Bacterial detection testing by blood and blood collection establishments and transfusion services to enhance the safety and availability of platelets for transfusion. Draft guidance for industry. December, 2014

Okoye OT, Reddy H, Wong MD, et al. Large animal evaluation of riboflavin and ultraviolet light- treated whole blood transfusion in a diffuse, nonsurgical bleeding porcine model. Transfusion 2015;55:532-43

Snyder EL, Stramer SL, Benjamin RJ. The safety of the blood supply-time to raise the bar. N Engl J Med 2015;372:1882-5

Platelet-Rich Plasma: My View from the Transfusion Service

Image1Platelets play a significant role in primary hemostasis, however they also serve as a reservoir of a number of important growth factors, including but not limited to platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). Thus, autologous platelets applied topically or injected into areas of recent surgical reconstruction or to wounds are thought to stimulate angiogenesis and aid in tissue repair and regeneration. Several instruments are available to harvest platelets, (re-suspended in plasma a.k.a. platelet-rich plasma (PRP)), and this provides a vehicle for delivery as a topical or injectable product.

There is no doubt that basic science and in vitro studies substantiate the release of platelet-derived growth factors and their potential role in healing, however robust trials and in vivo studies are lacking and often show conflicting results. The lack of strong clinical evidence is due to the marked heterogeneity of PRP preparations, platelet counts, and growth factor yields or activity. Differences in the site of use, type of injury and tissue, and patient comorbidities likewise contribute to the broad range of study results. Dosing regimens for optimal use are also unknown. There are no evidence-based studies of head-to-head comparisons of these products or their relative efficacies on patient outcomes.  Current literature maintains that there is insufficient evidence to support the routine use of PRP in clinical practice. In spite of this, there continues to be extensive utilization of this product.

And I purposefully highlight the word product.

In my view, when allowing the use of instruments to acquire PRP, this represents manufacture of a blood product and constitutes a transfusion activity for which the Transfusion Service and specifically, the Transfusion Service Medical Director are ultimately responsible. All relevant transfusion activities fall under the auspice of the Transfusion Service and applicable standards would demand oversight of policies, processes and procedures. The AABB Standards for Blood Banks and Transfusion Services¹ clearly identify elements to be included such as equipment, suppliers, informed consent, document and record control, along with relevant quality and patient safety activities.

There are limited standards applicable to PRP specifically, such as storage temperature, expiration and conditions of use listed in the AABB Standards for Perioperative Autologous Blood Collection and Administration.² To this end, the International Cellular Medical Society,³ in 2011, noted a serious lack of guidelines surrounding the use of PRP and submitted a draft document which outlined elements for training, indications and contra-indications, informed consent, preparation, injection or application, safety issues and patient follow-up. A 2014 Cochrane Review called for standardization of PRP methods.

Overall, I would venture to say that few hospital Transfusion Services are aware of the scope of use of PRP within their facility(s). Regardless of one’s opinion of the current literature, I would urge all of us involved in transfusion practice to be informed of the use of PRP and to be vigilant in oversight of this activity. It is not merely a regulatory and accreditation issue, but our duty as laboratory physicians and clinical scientists to provide quality, safe and effective transfusion therapies for all patients. This will require educating our clinical colleagues and enabling them to understand our role in this critical process.

Carolyn Burns MD
Independent Patient Blood Management Consultant

References and Suggested Reading:

  1. AABB Standards for Blood Banks and Transfusion Services, 29th edition, 2014
  2. AABB Standards for Perioperative Autologous Blood Collection and Administration, 5th edition, 2013
  4. Morae VY et al. Platelet-rich therapies for musculoskeletal soft tissue injuries. The Cochrane Library 2014
  5. Griffin XL et al. Platelet-rich therapies for long bone healing in adults. The Cochrane Library 2012
  6. Leitner GC et al. Platelet content and growth factor release in platelet-rich plasma: A comparison of four different systems. Vox Sang 2006; 91: 135-138
  7. Everts PA et al. Platelet-rich plasma and platelet gel: A review. J Extra Corpor Technol 2006; 38: 174-187

Chronic Kidney Disease: Better Care = Better Outcomes

Chronic kidney disease (CKD) is a global health problem.  In the United States, the incidence and prevalence is rising.  CKD results in poor health outcomes, is often associated with and/or caused by comorbid conditions such as hypertension, diabetes mellitus, etc.  Treatment of causes and comorbidities improves overall health for these patients and serves to slow the progression of disease.

Patients with moderate to severe CKD, along with those with overt renal failure, have a significant risk of developing anemia.  Data from the National Kidney Foundation indicate that more than 40% of patients with Stage 3-4 CKD are anemic and the prevalence is roughly 75% in those with Stage 5 disease.¹   Anemia is a result of many factors, including decreased erythropoietin synthesis, occult or overt blood loss, poor red blood cell survivability, nutritional deficiencies of vitamin B12, folate, and very commonly both an absolute and functional iron deficiency.

As iron-deficiency anemia is common, early assessment of iron status is vitally important.  Iron deficiency is likely present if transferrin saturation (TSAT) is less than 20% and serum ferritin is less than 200ng/mL.  Even those with ferritin levels above 200ng/mL may suffer from functional iron deficiency i.e. dysfunctional absorption and distribution of iron stores.

Anemia is an independent risk factor for increased mortality in patients with CKD, with a risk of death equivalent to patients diagnosed with congestive heart failure and diabetes combined.²  There is strong evidence that aggressive diagnosis and treatment of anemia, particularly iron-deficiency anemia, may slow progression of disease and improve overall outcomes for these patients.³

Historically, treatment modalities for iron-deficiency anemia have included erythropoietin stimulating agents (ESAs) either with or without iron supplementation.  Four randomized controlled trials in both non-dialysis and dialysis-dependent CKD patients have cast some doubt on the safety of ESAs, particularly if hemoglobin (Hgb) targets of ≥ 13 g/dL  and high ESA doses are utilized. ⁵ ⁶ ⁷  The DRIVE Study, published in 2007, found the addition of I.V. iron resulted in a faster response and a greater magnitude of response while requiring a lower dose of ESA.⁸  A 2010 study in non-dialysis-dependent CKD patients showed an increase in TSAT and Hgb response with the use of I.V. iron alone.⁸

Current recommendations by the Kidney Disease: Improving Global Outcomes (KDIGO) group include early assessment for anemia, particularly iron deficiency anemia.⁹   Treatment options include ESAs with iron supplementation or an initial trial with I.V. iron alone.  Maintenance of TSAT above 30% and serum ferritin levels above 200ng/mL are recommended.  Hgb levels between 9.0-11.5 g/dL may be targeted, with caution not to exceed Hgb levels of 13g/dL due the increased risk of thromboembolic adverse events.  TSAT above 50% and/or ferritin levels above 500ng/mL should be avoided in order to prevent iron overload.  Treatment options must be customized for individual patients based on severity of illness, age, gender, comorbid conditions, etc.  Cost of treatment, especially the use of ESAs should be evaluated in each case.

The use of red cell transfusion to treat chronic anemia in CKD patients is not recommended in the 2012 KDOQI guidance document.  Acute anemia in hemorrhaging patients or significant symptomatic anemia in the unstable patient with an acute coronary syndrome may necessitate transfusion.  The risks of transfusion, including but not limited to, acute transfusion reactions and pulmonary complications should be considered in the transfusion decision.  For those patients eligible for kidney transplantation, transfusion should be avoided unless absolutely necessary to minimize the risk for alloimmunization.

In the end, the primary goal for the millions of patients diagnosed with CKD is to treat the underlying cause(s) and to slow progression of this potentially devastating illness.  The current literature and clinical practice guidelines highlight the many options to intervene on behalf of patients with CKD and concomitant anemia.  Early diagnosis, aggressive treatment and on-going continuous monitoring are necessary to achieve improved outcomes and quality of life.


  1. National Kidney Foundation Am J Kidney Dis 2006; 47 (suppl 3): S1-S45
  2. Astor B et al. Am Heart J 2006; 151: 492-500
  3. Gouva C et al. Kidney Int 2004; 66: 753-760
  4. Besarb A et al. N Engl J Med 1998; 339: 584-590
  5. Singh A et al. N Engl J Med 2006; 355: 2085-2098
  6. Dreucke T et al. N Engl J Med 2006; 355: 2071 -2084
  7. Pfeffer M et al. N Engl J Med 2009; 361: 2019-2032
  8. Coyne D et al. J Am Soc Nephrol 2007; 18: 975-984
  9. KDOQI. Kidney Int 2012; 2 (suppl): 283-287

Issues for Blood Management in Hematology/Oncology

Hematology/Oncology patients comprise a unique subpopulation for whom transfusion therapy is often necessary in both the acute care setting as well as for long-term support. Red blood cells (RBCs) and platelets are the most common components transfused particularly in patients undergoing high-dose chemotherapy, intensive radiation therapy and human hematopoietic stem cell transplantation (HSCT).

Restrictive transfusion practice has become the “new world order” particularly for general medical and surgical patients. Those with hematologic malignancies or solid tumors have not frequently been a large part of many of the randomized controlled trials that speak to this approach.  Literature is available, however, that provides evidence that judicious use of blood components via restrictive transfusion and single unit transfusions for inpatients and outpatients can be clinically effective, safe, and will decrease the potential for transfusion-associated adverse events.

Feasibility studies of restrictive RBC transfusion in the Hematology/Oncology population have been reported. These studies provide compelling evidence that lower transfusion triggers, targets and single unit use are not associated with increased bleeding episodes and will reduce overall transfusion exposure.¹ ² ³  The American Society of Hematology (ASH), as part of their Choosing Wisely Campaign, advises against liberal transfusion of RBCs with hemoglobin (Hgb)  targets of 7- 8 g/dL, along with implementation of single-unit transfusions when possible.

Recent RCTs and consensus from the AABB point to similar restrictive practice for platelet transfusion with a trigger of 10,000/µL for prophylactic transfusion in most patients.⁵ Subgroups of patients, such as those with autologous HSCTs, may not require prophylactic transfusion at this level, but can be effectively transfused using a therapeutic-only strategy.⁶  The use of lower doses of platelets has been shown to be safe and effective.⁷ Similar strategies may also be applicable for outpatients.⁸

Pursuant to those patients receiving radiation therapy, historically, there have been reports in the literature that found loco-regional control to be improved in patients whose Hgb is maintained at a higher level, typically > 10 g/dL.  Many, if not most of these studies had significant confounding and have not adjusted for comorbidities.  A publication in 2012, however, concluded “…that hypoxia is a well-established cause of radio-resistance, but modification of this cannot be achieved by correcting low Hgb levels by…transfusion and/or [ESAs[.”⁹  Similarly, a recent study covering over 30 years of experience with cervical cancer patients undergoing radiation therapy (the original target population from a historical perspective) adjusted for confounders and found no evidence that anemia represented an independent predictor of outcomes associated with diagnosis or treatment. ¹°  Transfusion, in and of itself,  has significant negative immunomodulatory effects via cell-to-cell interactions and cytokines.   Thus, maintenance of Hgb levels for these patients should not be considered an absolute necessity.

Other interventions may prove successful for Hematology/Oncology patients as part of a Blood Management Program.  Identification and treatment of concomitant iron deficiency anemia or other nutritional deficiencies can potentially decrease or eliminate the need for transfusion.  Drugs that might increase the risk for bleeding or hemolysis should be eliminated if possible as these cause or potentiate anemia.  Use of new targeted drugs such as lenalidomide in patients with 5q deletion-associated MDS may prevent the need for long-term transfusion dependence. The use of antifibrinolytics in patients who have become refractory to platelet transfusions can enable platelet function even at low levels and prevent the unnecessary use of limited platelet resources.

Outpatient transfusion in the Hematology/Oncology arena comes with some unique circumstances.  Many outpatients remain stable and will be capable of lower transfusion thresholds and longer intervals for both RBCs and platelets.  Evidence-based restrictive transfusion can and should be a part of outpatient treatment strategy, just as with inpatients if the accessibility to post-transfusion care is adequate. No national guidelines are available for outpatient transfusion and each patient scenario must be considered on an individual basis, but certainly the absolute need for “standing” transfusions and obligatory 2-unit transfusions should be discouraged.  Consider, as well, that patients often have their own view of the “need” for transfusion when symptoms and signs do not necessarily make it requisite.  Discussion with our patients is essential to allow them to understand transfusion decisions.

The risks of transfusion are both immediate and delayed, particularly for those with chronic transfusion needs. Febrile non-hemolytic, allergic, hemolytic reactions, TRALI and TACO may occur as in other patient populations and should be recognized and treated as appropriate. Alloimmunization and transfusion-related iron overload are more common in the Hem/Onc arena given the potential for increased component exposure during the acute care setting and the high percentage of those that necessitate chronic transfusion support. The potential for transfusion-associated graft vs. host disease is also more worrisome given the degree of immunosuppression in these patients. Specialized products are often necessary including leukoreduced, antigen negative, irradiated or HLA-matched components.  These specialized products may not be available on a STAT basis and add significantly to the overall transfusion cost. Careful consideration is warranted and inclusion of the Transfusion Service is key.

In the end, transfusion practice for Hematology/Oncology patients should include restrictive transfusion practices with assessment of the risks and benefits at the time of each potential transfusion episode. Each patient, whether inpatient or outpatient, should be evaluated based on their current state of stability, clinical course and availability and access to care. Nutritional assessments and subsequent interventions along with pharmaceutical agents may provide additional ways by which transfusion exposure can be decreased. Special products are often necessary and needs should be discussed with the Transfusion Service. Limiting transfusion ultimately avoids unpleasant, potentially severe acute and delayed adverse events as well as preserving resources within our communities.


  1. Jansen et al.  Transfus Med 2004; 14: 33
  2. Berger et al.  Haematologica 2012; 97: 116
  3. Webert et al.  Transfus 2008; 48: 81
  5. Kaufman et al. Ann Intern Med 2014; doi: 10.7326/M14-1589
  6. Stanworth et al. Transfus 2014; 54: 2385
  7. Slichter et al. N Engl J Med 2010; 362: 600
  8. Sagmeister et al.  Blood 1999; 93: 3124
  9. Hoff  Acta Oncologica 2012; doi: 10.3109/0284186X.2011.653438
  10. Bishop et al. Int J Radiat Oncol Biol Phys 2014; doi: 10.1016/j.ijrobp.2014.09.023

Nursing roles in blood management

Improving patient safety should always be the top priority in patient care. When we expose patients to blood transfusion we expose them to the risk of harm. Nurses can improve the safety of transfused patients by utilizing best practices at the bed side. For example, start the transfusion slowly for RBC, platelet and plasma transfusions and conduct frequent patient assessments during and after transfusion with an emphasis on the three symptoms of transfusion reaction: fever, rash and dyspnea. Keep in mind the following points when transfusing a non-hemorrhaging patient: a blood transfusion is a human tissue transplant, anemia tolerance is based on the patient’s clinical signs and symptoms, all blood products must be verified at the patient’s bedside following facility policy, only one unit of RBC’s should be transfused at a time with patient reassessment after each transfusion, monitor the patient for six hours after transfusion for signs and symptoms of an adverse reaction.

  • Thinking critically and accurately communicating symptoms of anemia, if any, with lab values can be a simplistic pivotal avenue to appropriate treatment and restrictive transfusion practice.
  • In attempts to provide the best of care and do no harm, nurses along with physicians need to understand the current evidence regarding the risks versus benefits of transfusion therapy.
  • Every nurse can support transfusion safety by implementing current blood management strategies into nursing practice.

Infuse Platelets as Slowly as Medically Necessary

Bacterial contamination of platelet products is a serious risk of transfusion. As many as 1 in every 1000 units may be contaminated from the introduction of low concentrations of skin bacteria at the time of donation, less commonly from asymptomatic underlying infection at time of donation or rarely during processing.1 In the United States, transfusion-associated sepsis has been recognized and culture-confirmed in at least 1 of 100,000 recipients, and has led to immediate fatal outcome in 1 in 500,000 recipients.2 The actual risk of transfusion-associated sepsis is likely higher, as infections due to contaminated blood products are under-reported.2

Platelets are the most common source of transfusion-associated sepsis because platelets must be stored at room temperature which allows bacterial proliferation and, platelets are often given to neutropenic patients with impaired immune system function.1

Common nursing transfusion practice today is to infuse platelet products within an hour from start time. There is no scientific evidence supporting this practice. Nurses have long been advised by Laboratorians and blood bankers to transfuse platelets “as rapidly as tolerated” by the patient. Busy nurses have interpreted this instruction to mean that the product should be infused rapidly for the benefit of the patient when in reality the laboratory professionals are advising nurses to use their critical thinking skills to determine a safe, patient specific infusion rate when the physician has not ordered an infusion rate.

By simply slowing down the infusion rate during the first 15 minutes of platelet transfusion for non-hemorrhaging patients, nurses can improve patient safety and reduce the incidence and severity of transfusion-associated sepsis. The same nursing intervention that allows nurses to immediately recognize a severe allergic or hemolytic transfusion reaction during the first 15 minutes of a pRBC transfusion should be employed with platelet transfusions. This slow rate of infusion will expose the patient to the least amount possible of a potentially contaminated product and continuous nursing assessment during the first 15 minutes allows the nurse to immediately stop the transfusion at the first sign of an adverse response to the product.

Appropriate critical nursing analysis of platelet transfusion would have the nurse recognize the risk of transfusion-associated sepsis and start platelet transfusions at a rate of 60 – 100 mL/hour for the first 15 minutes.3 After confirming that there has been no change in the patient’s clinical status by repeating the nursing assessment, the transfusion rate may be increased up to 300 mL/hour depending upon the patient’s ability to tolerate the volume.

The risk of transfusion-associated sepsis supports a cautious and deliberate approach to platelet transfusion. Nurses can reduce the risk of life threatening sepsis by slowly infusing platelets during the first 15 minutes and immediately stopping the infusion at the first sign of clinical comprise thus reducing the amount of potentially contaminated product exposure. Rather than infusing platelets as rapidly as the patient tolerates, transfuse all blood products as slowly as medically necessary.


  1. Vamvakas EC. Blood still kills. Trans Med Rev 2010;24(2):77-124.
  3. AABB Technical Manual, 17th edition, Roback, J. et al: Bethesda, MD. 2011

Packed Red Blood Cell Transfusions and Health Care Associated Infections

Rohde J et al.  Health care-associated infection after red blood cell transfusion: A systematic review and meta-analysis. JAMA 2014; 311: 1317-1326

Transfusion of blood products is the most common procedure performed in U.S. hospitals with approximately 14 million units of blood products transfused in 2011.¹ Blood products today undergo rigorous testing to prevent disease transmission and the United States’ blood supply is safer than ever before. However, the testing of our blood supply does not prevent transfusion related immunomodulation (TRIM). TRIM represents an immune system suppression which may affect infection risk, although the pathophysiology has not been fully elucidated.

The recent meta-analysis by Rohde et al, JAMA, 2014, reviewed the link of health-care-associated infection (HCAI) and the relationship to restrictive vs. liberal transfusion practice. The researchers included 18 trials with 7593 patients. Trials were conducted in facilities in multiple countries. The meta-analysis included the well-known Transfusion Requirements in Critical Care (TRICC) trial, ³ the trial of symptomatic coronary artery disease by Carson et al.⁴ and the de Gast-Bakker and coauthors trial in pediatric cardiac patients.⁵ The study revealed an adult hemoglobin range of 6.4 g/dl to 9.7 g/dl in the restrictive groups and 9.0 g/dl to 11.3 g/dl in the liberal groups.

The meta-analysis showed an association with lower risk of serious infection in the restrictive groups even when leukoreduction was considered. The authors concluded that one patient could potentially avoid a HCAI for every 20 patients who were treated if using the restrictive strategy (target Hgb <7.0 g/dl). The authors also state that this review further supports the clinical practice guidelines set up by the AABB on restrictive use of blood and blood products.⁶

So what does this mean for those of us performing transfusion at the bedside, in our operating suites, and other clinical areas? What can we do to help prevent HCA transfusion infections in our patients?

We must remember that blood management is an evidence-based, multidisciplinary approach that includes transfusion safety. The first step in a patient-centered blood management program is to determine if the transfusion is medically necessary. Nurses and mid-level providers can have great influence, helping to reduce the number of transfusions and the total number of products transfused. The medical decision to transfuse should be considered by all members of the clinical team. The decision to transfuse a patient must include a clinical picture of the patient and is not made solely on the hemoglobin level.

The number of units of PRBCs transfused has an effect on increased patient morbidity and mortality.⁷ When transfusion is clearly indicated to improve the patient’s condition, it might not be necessary to transfuse multiple units. Single unit transfusion with reassessment of the clinical condition should be considered outside of the context of massive hemorrhage.

In conclusion, this recent review and meta-analysis by Rohde and colleagues once again highlights TRIM and the association of transfusion with HCAI. This amplifies the need for adherence to a restrictive transfusion practice for the majority of hospitalized patients.

It is vital that the health care professionals ordering or performing transfusions stay up–to-date with the latest evidence, become pro-active in preventing adverse reactions, and remain vigilant in recognizing and responding to possible transfusion-associate adverse events, including HCAIs. 

  1. Whitaker B and Hinkins S. The 2011 national blood collection and utilization survey.
  2. Hebert P et al. N Engl J Med. 1999; 340: 409-417
  3. Carson J et al. Am Heart J.  2013; 165: 964-971
  4. deGast-Bakker D et al. Intensive Care Med. 2013; 39: 2011-2019
  5. Carson J et al Ann Intern Med. 2012; 157: 49-58
  6. Bernard A et al.  J Am Coll Surg. 2009; 208: 931-939

The Rise of “Designer” Blood Products: 4 Factor PCCs

Blood factor concentrates are not new, but most U.S. physicians are only vaguely familiar with them.  Single or multiple blood factor concentrates were originally developed to treat patients with congenital clotting deficiencies, such as hemophilia A or B.  Although some of these clotting factors are made with recombinant technologies (such as recombinant factor VIIa), most are derived by extracting and purifying clotting factors from pooled plasma.  The post-HIV concern with this approach was that these clotting factor extracts come from pooled plasma from hundreds or thousands of donors, but the EU and now the FDA feel that pooled blood products are “safe” using mini-pool testing techniques to screen for transmissible diseases along with pathogen inactivation methods such as solvent- detergent technology.  The latest iteration of these concentrated blood factors include a combination of clotting factors designed to treat acquired clotting deficiencies from vitamin K antagonist drugs (warfarin/ Coumadin®).  These so-called four factor prothrombin complex concentrates (4F-PCCs) contain therapeutic doses of clotting factors II, VII, IX and X.  Previously available in Europe, the FDA has now approved a 4F-PCC (KCentra®) with the specific indication for the urgent reversal of vitamin K antagonist (VKA) drugs in adults with acute major bleeding.  Most recently,  Kcentra® was also approved for the urgent reversal of VKA drugs in adults needing urgent surgery or an invasive procedure. There is also active investigation on the use of 4F-PCCs as part of a management strategy for patients with bleeding on novel oral anticoagulant drugs (NOACs) such as rivaroxaban, apixaban and dabigatran1.

Sarode published a head to head study comparing safety and efficacy of a 4F-PCC (Beriplex®) to plasma (the standard of care) in patients on VKAs with an acute major bleed2.  This RCT looked at hemostatic efficacy at 24 hours (rated as excellent/good/none), time to INR correction, plasma levels of clotting factors, and adverse effects.  Overall, the 4F-PCC patients did as well or better than the plasma patients:

  • 4F-PCC was non-inferior to plasma for hemostatic efficacy at 24 hours (71% vs. 68%);
  • 4F-PCC was superior to plasma in INR reversal at 30 min post-treatment (62% vs. 10%);
  • 4F-PCC had a faster increment of FII, VII, IX, X and proteins C and S than plasma;
  • 4F- PCC had a much lower volume delivered (100 vs. 820 mL).

Of equal importance, safety endpoints were generally similar between the 4F-PCC and plasma groups and consistent with patients experiencing acute major bleeding.  Significantly, fluid overload and pulmonary edema were the most frequent adverse events, and all fluid overload events possibly related to treatment occurred in the plasma group.  This is of particular importance since transfusion associated circulatory overload (TACO) is now the leading serious transfusion related adverse event, with an incidence of 5- 6% and a mortality rate of 1- 2%3.

Given the results of this study, it should be clear that 4F-PCC will become the treatment of choice in bleeding patients on VKAs who require a rapid, low volume reversal strategy, such as patients with intracranial bleeding.  Of note, plasma is no longer indicated for the reversal of VKAs in Europe given the widespread availability of 4F-PCCs along with safety concerns for plasma. The U.S. leads the world in a number of areas of medicine, but we continue to lag behind Europe and Canada in transfusion safety.  The arrival of 4F-PCCs gives us another tool to improve patient care in a select group of patients.

Selected References

1. Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology. 2013;118(6):1466–74. Available at: Accessed November 14, 2013.

2. Sarode R, Milling TJ, Refaai M a, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234–43. Available at: Accessed November 12, 2013.

3. Alam A, Lin Y, Lima A, Hansen M, Callum JL. The prevention of transfusion-associated circulatory overload. Transfus. Med. Rev. 2013;27(2):105–12. Available at: Accessed December 2, 2013.