PLUS Spring 2021

The American Red Cross (ARC) strives to maintain blood inventories to meet hospital and patient needs, however, periodic shortages are inevitable. To aid our hospitals during these challenges, the ARC suggests several approaches that can be implemented to manage blood product shortages. The following is a summary of proposed actions that can be taken by hospitals when encountering restrictions in the blood bank’s inventory level. The full document is available in the hospital partner resource guide. More detailed information and guidance on blood utilization can be found in the Compendium of Transfusion Practice Guidelines. This resource provides detailed information on blood component therapy and transfusion strategies.

Notice:  the following guidelines are not intended to replace clinicians’ judgment about patient care.

In general it is  advised that hospitals Implement a prospective review of all blood product ordering before release from the blood bank and issue blood to the floor only when a transfusion is imminent (patient is in room, vascular access is established, etc.). Once clinical need is met, consider cancelling the remaining orders for blood product. Ensure restrictive transfusion triggers, as established by current scientific evidence, are developed and approved by the hospital’s blood utilization committee.  This will result in standardization of practice and reduce unnecessary transfusions.

The recommendations below are listed in order of shortage severity (with the least restrictive first) by blood product type.

Red Cells

• Transfuse RBCs units if Hgb is ≤7 mg/dL and the patient is otherwise clinically stable.
• Group O RBCs represent one product that is most frequently in demand. Implementrapid patient blood typing processes, particularly in trauma events where massive transfusion needs are required, to reduce excessive usage and shore up inventory.  
• Trigger internal interdepartmental communication that Group O blood will not be available for elective surgical cases without a current type and screen.
• Establish a clear line of communication between the emergency department/ operating room staff and the blood bank to expedite collection and testing of samples for type and screens.  Expectations must be met for rapid test turnaround response.
• Establish a mechanism, such as with the electronic health record which sets ‘hard stops’ limiting medical staff from ordering more than one product at a time, except for specific situations such as actively bleeding patients, which can then be overridden by consulting with the hospital blood bank. In the post-transfusion period, re-check labs and evaluate clinical response to determine if additional units are required.
• Provide antigen negative RBC only to patients who have formed an antibody or defined patient populations (e.g. Rh negative for pediatric patients and those females of child bearing age).
• Evaluate the possibility of postponing prophylactic red cell exchanges for the treatment of Sickle Cell Disease or perform a partial exchange if warranted.  In cases of significant anemia without an elevated Hemoglobin S level, a simple transfusion may suffice.
• Limit use of CEK negative units to sickle cell patients who are alloimmunized to at least one clinically significant alloantibody.  Use CEK negative units prophylactically only for females of childbearing potential.
• Adopt use of AS-1 or AS-3 for pediatric transfusions.  

Re-evaluate CMV negative guidelines.  Consider use of leukoreduced red cell units as equivalent as ‘CMV safe’ for most transfusions.

Platelets

• Restrict transfusion of platelets if the count is ≤10 x 10³ for hypoproliferative thrombocytopenia, or ≤50 x 10³ prior to invasive medical surgeries (the exception is neurological surgeries where the preferred threshold is 100 x 10³)
• Replace platelet with plasma transfusion if the INR is >2
• Consider alternative product type to meet immediate patient needs. PAS platelets, Pathogen Reduced (PR) platelets, and Large Volume Delayed Sampling (LVDS) platelets can be used interchangeably.
• Reserve ABO compatible platelet transfusions for stem cell transplant recipients and pediatric patients with small blood volume.
• Administer non-ABO/Rh matched platelets, except in the previously mentioned situations. Platelets in PAS (including PR platelets) have significantly reduced levels of ABO isohemagglutinins.   
• Restrict use of Rh compatible units, specifically to Rh negative females of childbearing potential. In some instances, Rh immune globulin might be administered; however, many centers forego this due to the extremely low incidence of alloimmunization from such exposure, especially as the RBC contaminant in apheresis platelet units is very low.
• Consider ABO incompatible platelet transfusions for stem cell transplant recipients and pediatric patients with small blood volume. The use of PAS platelets or volume reduction can further reduce exposure to plasma sourced antibody to avoid passive transfusion of blood group hemagglutinins.
• When possible, split platelet units into smaller doses, which is an evidence-based, practice-based method for adult oncology inpatients based on the PLADO study. (Slichter ref here)
• Avoid prophylactic transfusion of patients not actively bleeding, so platelets are available for actively bleeding patients needing therapeutic platelet transfusion.
• Consider using platelet counts of 5 x 10³ as the trigger for prophylactic platelet transfusions in stable patients.

Plasma/Cryoprecipitate

• Restrict use of Group AB plasma to patients of this blood type.
• Reduce plasma use by maximizing the use of albumin as a replacement fluid for therapeutic apheresis procedures except where contraindicated.
• Follow hospital procedures/policies in transfusing Group A plasma as an alternative when patient blood type is undetermined and for emergent transfusions and massive transfusions.
• Reduce pool size (from 10 units to 8 units, if hospital is pooling).
• Issue one pooled unit instead of two of pre- pooled cryoprecipitate.
• Evaluate a more permissive policy for Prothrombin Complex Concentrates (e.g., Kcentra). Consider using tranexamic acid when appropriate.
• Implement off-label use of fibrinogen concentrate (RiaSTAP or other FDA approved similar products) to reduce the use of cryoprecipitate.

Catherine A. Mazzei, MD

References:

• Slichter SJ et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010 Feb 18: 362(7): 600-613.
• Shander A, Gross et al A new perspective on best transfusion practices. Blood Transfus. 2013 11(2): 193-202.
• Bartley AN, Carpenter JP, Berg MP. D+ platelet transfusions in D- patients: cause for concern? Immunohematology. 2009;25(1):5-8.
• Ooley P, Chair. Standards for Blood Banks and Transfusion Services. 30th ed. Bethesda, MD: AABB; 2015 .
• Slichter SJ et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010;362:600-613).
• Dunbar NM et al. Safety of the use of group A plasma in trauma: the STAT study. Transfusion 2017;57: 1879-1884.
• Triage tool for the rationing of blood for massively bleeding patients during a severe national blood shortage: guidance from the National Blood Transfusion Committee. Doughty H et al. Br J Hem 2020;191(3):340-346 Abstract: https://pubmed.ncbi.nlm.nih.gov/32436251/
• Blood Banking and Transfusion Medicine Challenges During the COVID-19 Pandemic Ngo A et al. Clin Lab Med. 2020;40(4):587-601. Abstract: https://pubmed.ncbi.nlm.nih.gov/33121624/

Additional Resources:

• ARC SUCCESS Publication ‘A Compendium of Transfusion Practice Guidelines’:  https://successeducationna134.force.com/s/
• ARC SUCCESS Presentation ‘Suggestions for Trx Services to Navigate Long-Term Blood Shortages’:  https://successeducationna134.force.com/s/
• ARC Hospital Partner Resource Guide:  https://www.redcrossblood.org/content/dam/redcrossblood/hospital-page-documents/hprg__final__na_811.pdf
• Why CMV Negative Blood is so Important: https://www.redcrossblood.org/local-homepage/news/article/why-cmv-negative-blood-is-so-important.html

In the prior issue of PLUS we summarized several ways that blood collectors and hospitals can increase patient safety, namely by reducing the risk of transfusing a potentially contaminated platelet product. These mitigation strategies can be found in the FDA guidance titled “Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion – Guidance for Industry” (https://www.fda.gov/media/123448/download). Standardization of this guidance is expected to be implemented by all blood centers and transfusion facilities, by October 1, 2021.

Beginning in June 2021, the American Red Cross will be offering products that meet two of the FDA proposed bacterial mitigation strategies: pathogen reduction and large-volume delayed sampling (LVDS) platelets.

Pathogen reduced (PR) platelets uses technology that has been FDA-approved. Developed by Cerus Corporation,, an apheresis collected platelet is combined with an amotosalen compound and exposed to UV light. The amotosalen intercalates with the nucleic acid and upon exposure to UV light crosslinks the DNA or RNA, virtually eliminating the pathogen’s ability to replicate. PR is known to affect many known infectious agents including but not limited to HIV, HCV, CMV and bacteria. This then significantly reduces the infection rate of the transfused products.. Another benefit of PR platelets is doing away with the need for bacterial testing.

LVDS, as the name implies, uses the principle of larger volume product samples drawn later in the post collection period. The samples are cultured for bacteria using an automated device, such as the bioMérieux’s BacT^® ALERT system. Previously, this involved taking two 8-10 mL samples and inoculating each of two vials: one culture tube that favors aerobic (growth in an oxygen-rich environment) bacteria and the other for anaerobic (those that do not live or grow in oxygen) bacteria. These samples aretaken 24 hours after platelet collection and incubated for 12 hours to allow sufficient time for any bacteria present to grow to detectable levels

LVDS primarily differs from this approach in three ways. The first is that the samples are drawn from the final product containers rather than the collected unit, prior to splitting. The second is that a larger sample volume (20 mL) is drawn from each container, rather than the previously mentioned ~10 ml. The third is that the interval before sampling is longer: in the case of Red Cross LVDS platelets, at least 36 hours instead of 24 hours.

The specific steps taken are:

1.    Obtain a product volume and calculate the platelet yield

2.    Divide any double or triple apheresis platelets

3.    Hold apheresis platelets until at least 36 hours have elapsed since collection

4.    Collect a 20 mL sample from each final product for aerobic and anaerobic culture

5.    Obtain a new post-BacT sampling product volume and calculate a final platelet yield

6.    Complete manufacturing and assess products

7.    End-release label manufactured apheresis platelets

8.    Evaluate initial preliminary culture results (12 - 24 hours) “negative-to-date” culture results.

Although the longer interval before sampling will result in a platelet with a shorter shelf life post distribution, manufacturing procedures have been optimized to minimize the impact; for example, shipping the product during this wait time to a distribution site closer to the hospital requiring the product. A second consideration is the expected volume loss due to sampling can impact split rates, however Red Cross has successfully increased recruitment of platelet donors which should offset this reduction in number of products per procedure.

A recent study published by the Canadian Blood Services supports the safety and efficacy benefits of LVDS platelets. A testing environment was created which included spiking platelet products with known concentrations of bacteria including Staphylococcus epidermis, Staphylococcus aureus, Serratia marcescens, and Klebsiella pneumoniae. LVDS vs standard 24 hours sampling post-blood collection was then performed, with samples incubated in both aerobic and anaerobic culture bottles. The results clearly showed that bacteria were detectable sooner and at lower concentrations with the LVDS methodology

In summary, LVDS’s larger sample volume increases the likelihood that any bacteria in the product will be detected. The longer incubation phase between collection and sampling allows more time for any bacteria present to increase to a detectable level and therefore reduce the risk of distributing  a contaminated product.

Liz Marcus, BSc, PMP

References

• Ramirez-Arcos S et al. Extension of platelet shelf life with an improved bacterial testing algorithm. Transfusion 2020; 60:2918-2928. Abstract: https://pubmed.ncbi.nlm.nih.gov/33140420/

Additional Resources:

• ARC PLUS article ‘Stop Bugging My Platelets,’ 2021 First Quarter
• FDA  Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion Guidance for Industry, Dec 2020:  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bacterial-risk-control-strategies-blood-collection-establishments-and-transfusion-services-enhance
• Cerus Intercept website: https://intercept-usa.com/

Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system characterized by immune-mediated demyelination and axonal damage that targets the optic nerves and spinal cord. NMO was initially thought to be a variant of multiple sclerosis (MS) due to the overlap of symptoms; however, it is now known that an NMO-specific immunoglobulin G (IgG) autoantibody, anti-aquaporin 4 (AQP4), plays a role in NMO pathogenesis. The AQP4 antigen is a water channel protein that is highly concentrated in spinal cord gray matter and the astrocytic foot processes in the blood-brain barrier. The laboratory finding of anti-AQP4 antibodies is diagnostic for NMO and helps to distinguish NMO patients from those with MS, with higher serum levels correlating severity of disease activity.

The typical clinical features of NMO/NMOSD (NMO Spectrum Disorders) are acute and include varying degrees of vision loss (optic neuritis) and features of transverse myelitis, which can include limb weakness, sensory loss, and bladder dysfunction. Hypothalamic and brainstem involvement occurs in a minority of patients, which can manifest as hiccups, intractable nausea, and respiratory failure. NMO/NMOSD typically has a recurring, relapsing course.

The treatment for acute and chronic episodes of NMO/NMOSD includes glucocorticosteroids and therapeutic plasma exchange (TPE). TPE has been shown to be beneficial in the management of acute and chronic episodes of NMO/NMOSD, likely through the removal of the anti-AQP4 antibody and other inflammatory substances from the blood. Although observational studies show TPE is beneficial in NMO/NMOSD, limited specific information is known regarding these apheresis procedures, patients' degree of response to these procedures, and the characteristics of patients who benefited.  As part of the neurologic diseases subcommittee of the ASFA research committee, a multi-institutional retrospective study was conducted to help answer these questions with the purpose of gaining an understanding of specific TPE procedural information, response of acute NMO/NMOSD symptoms to TPE, and patient characteristics associated with TPE response. The study also determined the safety and efficacy of TPE in the treatment of NMO/NMOSD.

The multicenter retrospective study was conducted at 13 US hospitals performing apheresis procedures, of which two were pediatric and 11 were adult or adult/pediatric combined. Subjects studied were diagnosed with NMO/NMOSD who received TPE during a presentation of acute disease. A total of 114 patients were enrolled in the study. Patients were more likely to be female and Caucasian, with an average age at diagnosis of 43 years. The most common clinical findings in patients before plasma exchange was begun were: paraparesis, bilateral sensory loss, blindness, and sphincter dysfunction.

On average, five procedures were performed during each treatment series. The most frequently performed plasma exchange volume was 1.0 to 1.25, using 5% albumin for the replacement fluid. Most patients (52%) did not require an additional course of TPE and noted “mild” to “moderate” clinical status improvement. Maximal symptom improvement appeared by the fourth or fifth TPE treatment. A minority of procedures were associated with an adverse event (9.9%, 75/759), the most common being citrate toxicity (3.6%, 27/759).

TPE improved the clinical status of both adult and pediatric patients. Adults responded more favorably than children. Procedural characteristics, including number of TPEs, plasma volume exchanged, and replacement fluid used, were similar between institutions. TPE was well-tolerated and had a low severe adverse event profile.

Shanna Morgan, MD

References:

• Lennon VA,  et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
• Takahashi T,  et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain. 2007;130(pt 5):1235-1243.
• Drori T and Chapman J. Diagnosis and classification of neuromyelitis optica (Devic's syndrome). Autoimmun Rev. 2014;13 (4–5):531-533.
• Bonnan M and Cabre P. Plasma exchange in severe attacks of neuromyelitis optica. Mult Scler Int.;2012:787630.
• Lehmann HC,  et al.  Plasma exchange in neuroimmunological disorders. Part 1. Rationale and treatment of inflammatory central nervous system disorders. Arch Neurol. 2006;63(7):930-935.
• Huda S et al. Neuromyelitis optica spectrum disorders Neuromyelitis optica spectrum disorders Clin Med (Lond). 2019;19(2):169-176.

Additional Resources:

• ARC Therapeutic Apheresis website:  https://www.redcrossblood.org/biomedical-services/specialty-services/therapeutic-apheresis.html

Patients severely injured in rural settings experience greater morbidity and mortality than their urban counterparts. This is mostly due to the challenge of geography, where the nearest level I or II trauma center is located a distance greater than one hour away. Instead, these small medical facilities serve to stabilize the patient while awaiting transport to a tertiary hospital.

Central to hemorrhagic control is having access to an adequate blood supply which includes red blood cells, plasma, and platelets. Immediate transfusion support is critical as death due to uncontrolled blood loss can occur within 6 hours or less after sustaining injury. However, due to the nature of these blood products, namely platelets, which have a short shelf-life of five days, many rural hospitals cannot sustain a sufficient blood inventory to meet such acute demands.

The article authored by Dr. David Mair and Dr. Pampee Young, and recently published in Transfusion, visually depicts the challenges that the American Red Cross has in serving 249 medical facilities, the majority identified as rural type, with platelets. To meet this challenge, the authors evaluate the potential use of blood products that are amassing greater interest in the field of critical care, specifically cold (1 or 2 - 6 ºC) stored whole blood and platelet units.

The military experience with treatment of hemorrhagic trauma events has highlighted the benefits of whole blood (shelf-life of 21 days), which has since been FDA approved for use in civilian trauma therapy. Cold stored platelets were approved by the FDA for use up to 3 days post-collection with their use restricted to actively bleeding trauma patients. AABB further granted a variance from the requirements to store these platelets at 20-24°C with agitation and to perform bacterial detection testing on these products. A supporting study, published by James Williams et.al., demonstrated that the use of cold stored low titer group O whole blood in 198 patients not only increased rapid transfusion of all necessary blood components in a single product; but in doing so, may have reduced by as much as 53% the need for further blood demand in the post-ED hospital stay. This was performed in comparison to 153 patients who received standard blood transfusion therapy.

Another consideration is the use of cold stored platelets, for which the US Army was recently granted an FDA variance, to evaluate the potential extension of the shelf life beyond the standard of three days as described in the Circular of Information for this product. Although studies are ongoing, pilot studies with collaboration among the US Army and that of Norwegian military and civilian healthcare services, have demonstrated cold stored platelets have a safety profile that is equivalent to platelet products stored at room temperature. In addition, the patients who had received the platelets during cardiothoracic surgery were able to tolerate transfusion of cold platelets that were stored up to 14 days, with retention of platelet function and hemostatic control. This was observed by chest drain output and post-operative blood transfusion needs. Although preliminary studies are promising, additional research is needed to evaluate the efficacy of such products in these settings.

By prolonging the storage time, it is reasonable to assume that utilizing cold-stored blood components, such as whole blood and platelets, will assist rural hospitals in managing their inventory needs, and therefore improve access to blood products that are efficacious in controlling hemostasis. An increase in overall survival rate from massive bleeding events is expected as the patient awaits transfer to receive further medical care.

David Mair, MD

References

• Young P, Erhart J, and Mair D. Rural Hospitals and Access to Platelets for Treating Active Bleeding. Is the Heartland Bleeding? Transfusion. 2020; 60:2474 – 2475.
• Holcomb JB and Spinella PC. Optimal Use of Blood in Trauma Patients. Biologicals. 2010; 38:72 – 77.
• Strandenes G, Sivertsen J, Bjerkvig CK et.al. A Pilot Trial of Platelet Stored Cold versus at Room Temperature for Complex Cardiothoracic Surgery. Anesthesiology. 2020; 133:1173 – 1183.
• Williams J, Merutka N, Meyer D et.al. Safety Profile and Impact of Low Titer Group O Whole Blood for Emergency Use in Trauma. Journal of Trauma and Acute Care Surgery. 2020; 88:87 – 93.

Additional Resources:

• ARC Connect On-line [product ordering system]:  https://arc.bloodhub.com/
• ARC Hospital Partner Resource Guide:  https://www.redcrossblood.org/content/dam/redcrossblood/hospital-page-documents/hprg__final__na_811.pdf
• ARC SUCCESS Presentation: “Cold-Stored Platelets”: https://successeducationna134.force.com/s/

The process of obtaining informed consent prior to blood product administration provides an opportunity to establish mutual understanding between the patient and the licensed practitioner about the intended care, treatment, and services. Informed consent is a patient education process that considers patient needs and preferences, is compliant with the law and accrediting agency regulations, and assists patients in fully participating in care decisions.

Informed consent is required by law and is assessed by inspectors and accrediting agencies. Regulatory agencies, including the Joint Commission, College of American Pathologists, and AABB, all have specific requirements Not all agencies have the same requirements, so familiarity with accrediting agency needs, state laws, or local statutes is critical when developing a comprehensive informed consent process. The transfusion service medical director is responsible for the development of policies, processes, and procedures for informed consent. (Cite AABB or CLIA here?)

Elements of Informed Consent for Transfusion

Elements of the facility informed consent for transfusion include: 1) written policy, 2) patient discussion, and 3) consent documentation.

The written policy for informed consent includes all facets of the process. The policy should specify who is qualified to obtain informed consent and who will sign as the facility witness (this may include the patient’s physician or nurse administering the transfusion), the length of time the consent is valid (this may be the duration of the hospital stay or duration of intended treatment or a defined date range), specific services covered by this consent (which may include blood product or factor concentrate administration), and the expectations of the consent discussion.  The written policy should also define the content of supporting documentation, signatories, and where the informed consent documentation is stored.

Table 1 includes the elements of the informed consent discussion with the recipient or recipient’s legal guardian, and examples of items to include. It is not an all-inclusive list.

Many patients have concerns about transfusion transmitted disease.  Some facilities include the incidence of disease transmission on the consent form while others do not. Facilities should have a standard practice to determine how to address patient questions about acquiring a disease from blood transfusion.

Informed consent is a dialogue:  the patient must have the opportunity to ask questions and obtain clarification. Any materials provided and discussion with the patient should use terminology, easily understood by individuals without a medical background (suggested at no higher than an 8^th grade reading level). The information should answer the following questions:

• Why do I need a blood transfusion?
• What are the risks (e.g. infectious disease and other transfusion associated side effects) associated with transfusion?
• What is the risk if I refuse transfusion?
• What are my other treatment options?
• Can I refuse the blood transfusion?
• Is this informed consent confidential?

Facilities may elect to design a ‘Frequently Asked Questions’ document to enhance the dialogue and answer these questions.

Finally, there should also be a defined process for documenting a patient’s acceptance or refusal to receive blood or blood components in the medical record by having the patient apply his/her signature and date of documentation to the form. Maintain the signed (and witnessed) acceptance in the patient’s medical record. At a minimum, transfusion refusal should include notifying the patient’s attending physician and documenting any refusal. Manage refusal consistent with pertinent laws and regulations.

Schedule internal informed consent audits to ensure compliance with all requirements.

Blood Products that Require Informed Consent

Table 2 is a list of blood products that require informed consent prior to transfusion. Also included are those products for which informed consent is recommended.