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Platelets have the greatest risk of causing septic transfusion reactions due to their room temperature storage requirements. Numerous strategies have been implemented over the years to mitigate this risk including in-line sample diversion, large volume-delayed sampling, and automated testing platforms. While these developments have decreased the rate of septic transfusions, the risk remains.
In an effort to reduce this risk, the FDA released a guidance on strategies for bacterial mitigation in the collection and transfusion of platelets that went into effect on October 1, 2021. The guidance delineates several options including pathogen reduction technology (PRT), culture-based methods, and rapid testing. The 2021 AABB Platelet Survey showed that 62% of responding hospitals selected pathogen-reduced platelets (PR PLT) as their preference for meeting FDA guidelines, and this is expected to increase.
The INTERCEPT ® system by Cerus is currently the only FDA-approved PRT. INTERCEPT ® utilizes Amotosalen which docks between nucleic acids, then crosslinks when exposed to UVA, inhibiting replication of a variety of bacteria, viruses, spirochetes, protozoa, and human leukocytes. Amotosalen is a derivative of psoralens – UV-sensitive, naturally occurring compounds with antibiotic activity found in celery and citrus fruits. One concern among the medical community is about the safety of PR PLT for neonates and pediatric patients. Several studies have demonstrated that PR PLT are clinically equivalent to conventionally manufactured apheresis platelets (CONV PLT), but adult data cannot be reliably extrapolated to children and infants, and existing data on the use of PR PLT in this population are limited.
A retrospective review of platelet transfusions to pediatric and neonatal patients (<18 years) was conducted at the University of California, Los Angeles (UCLA) over a 300-day period in 2017. The neonatal cohort included patients in the low and very low birth weight categories. The hospital blood bank maintained a dual inventory of PR and CONV PLT that were distributed based on availability. Platelet transfusions were stratified by age and diagnosis most relevant to the transfusion. Transfusion reactions were obtained from both reports to the blood bank, as well as review of patients’ pre- and post-transfusion blood cultures when available.
A total of 191 patients received 1,010 platelet transfusions from 892 distinct units (506 PR, 386 CONV) averaging 5.3 transfusions per patient. Overall, 66.7% of the platelets were transfused to patients with hematologic malignancies. Of these patients, those undergoing hematopoietic stem cell transplant received of the largest number of transfusions per patient (24.9) relative to other diagnostic categories. Because the platelets were issued randomly and based on availability, these patients were also most likely to receive a combination of PR and CONV PLT, thus the data were not informative regarding potential differences in platelet usage between the two platelet products.
Cardiac surgery was the most common diagnosis (38% of patients) requiring platelet transfusions. These patients also received the fewest units per patient (1.5) and were therefore most likely to receive only one type of platelet product. Of these and all patients receiving only one type of platelet, the average usage was 1.8 transfusions and 1.3 units/patient for PR PLT vs 1.6 transfusions and 1.4 units/patient for CONV PLT. These differences were not statistically significant.
Review of adverse outcomes demonstrated no reports of bacterial contamination from either PR or CONV PLT. Four patients experienced a total of 7 acute transfusion reactions: one episode of circulatory overload, 3 mild allergic reactions and 3 moderate-to-severe allergic reactions. These were seen in response to both PR and CONV PLT, with no statistically significant differences.
Because psoralens are UV-sensitive and can increase skin sensitivity in patients, concerns have been raised regarding concurrent use in neonates undergoing phototherapy. FDA-approved phototherapy instruments emit light in the 430-490 nm range, while Amotosalen absorbs in the 320-400 nm range. Despite no expected reaction, neonates undergoing phototherapy who also received PR PLT were evaluated for rash. There were no reports of rash in these 13 patients.
The limitations of this study include a small patient cohort and a short study period. The rates of acute transfusion reactions are consistent with reported rates in adults in pediatric patients. The observed low rate of acute reactions aids in the adoption of PR PLT. While advances in bacterial mitigation have significantly improved the rates of septic transfusion reactions, continued vigilance is of utmost priority to ensure the safety of patients requiring transfusion, particularly in this vulnerable patient cohort. Long-term follow-up for pediatric patients, particularly neonatal and chronically transfused patients, is a necessary addition to currently available data.
Baia Lasky, MD
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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
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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.
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 8th grade reading level). The information should answer the following questions:
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.
Many facilities include the recommended products in their complement of products requiring signed consent. The decision to include additional products - or not - is facility defined.
Summary
Every transfusion service providing blood or blood product transfusions must create a unique informed consent tailored to meet applicable state and local laws, as well as those required by regulatory and accrediting agencies. Policies and procedures should address steps that staff should take to obtain informed consent from patients requiring blood transfusion.
Kelly Kezeor, MT(ASCP) and Kerry Burright-Hittner
References:
Additional American Red Cross Resources:
FDA – Informed Consent: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent
AMA Code of Medical Ethics: Consent, Communication, Communication, and Decision Making: https://www.ama-assn.org/delivering-care/ethics/code-medical-ethics-consent-communication-decision-making
ARC SUCCESS presentation: ‘Blood Administration in the Hospital Setting: Informed Consent’ https://successeducationna134.force.com/s/
Most of us are familiar with the applications of drones (also known as unmanned aerial vehicles or remotely piloted aircraft) for photography in the service of the military, media, geographic mapping, and personal entertainment. Now these flying robots are being put to a new use: providing life-saving blood and other medical supplies in remote areas and/or where conventional delivery methods pose a challenge.
The use of drones was first conceived during World War I as a remote-controlled airplane, but it would be several more decades before advancements in technology allowed for military implementation of this device. During the Vietnam war, these unmanned vehicles were exploited for surveillance purposes as well as outfitted to perform rescue operations. The first reported case of such an event was the use of a QH-50 Drone Anti-Submarine Helicopter programmed to airlift a stranded combat marine, who grabbed the skids of the aircraft to be carried off to safety. In more recent years we have seen drones pressed into service during humanitarian disasters including Hurricane Katrina in 2005 and the 2010 Haiti earthquake, delivering medical supplies and for reconnaissance of inaccessible areas to assess the extent of damage and locate signs of human life.
Since then, several companies have become involved in the development of drones for distribution of medical supplies, including blood. Zipline, an American based company, is at the forefront having deployed drones in Rwanda for blood delivery for more than five years. This country served as the test site due to its challenging geography, which is mountainous and with an inadequate transportation infrastructure (only about 25% of roads are paved). A recent paper in the journal Lancet Global Health provides an overview of the success of this initiative. Between March 17, 2017, and Dec 31, 2019, 12,733 blood product orders were delivered by drones; 43% (5,517) of these were for emergencies. The results were impressive with an average delivery time of 49.6 minutes: almost 80 minutes faster (range 3 – 211 minutes quicker) than transporting by road. The payload of these drones has been increasing; currently Zipline’s drones can carry almost four pounds, equivalent to 3 units of red cells.
America’s regulations regarding drones for medical use are restrictive; however, the US Department of Transportation and Federal Aviation Administration (FAA) have taken steps to develop rules, with the establishment of the Unmanned Aircraft System Integration Program (UAS) in 2017. In the year prior, the firm Flirtey partnered with John Hopkins School of Medicine and the FAA to test the transportation of medical supplies to Cape May, New Jersey, as well as to a vessel off the coast of New Jersey. In 2019, the FAA certified the United Parcel Service to deliver health care supplies by drone.
Red Cross has been working with the Unmanned Systems Operations Group Inc (USOG) to pilot the use of drones for blood delivery. On March 3rd, 2022, the organizations gathered on Pier 54 at Red Cross’s Northern California (San Francisco) distribution site and conducted a test to pick up and deliver a simulated payload of blood products and humanitarian services products. Phase II of this testing is slated for later this summer.
These early results are encouraging and the use of these pilotless aircraft in the US to deliver blood and other medications is only expected to grow.
Liz Marcus BSc, PMP
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Cryoprecipitated antihemophiliac factor (CryoAHF) is prepared from frozen plasma and contains fibrinogen, FVIII, FXIII, vWF and fibronectin. Among the conditions that CryoAHF is used to treat, the most common is to replenish fibrinogen during bleeding. CryoAHF utilization has increased disproportionately to other blood products over the past several years; however, manufacturing has not kept pace with the growing demand for this product causing a mismatch between supply and demand. A significant contributing factor to the supply constraint is the US requirement for the plasma to be frozen within 8 hours of collection in order to be used for making CryoAHF, which is the requirement to manufacture FFP.
This timing requirement restricts the number of blood drives that are targeted for CryoAHF collection while incurring the cost and logistical challenge of mid-drive product pickups to ensure timely processing. Most of the transfusable plasma in the US comes from Plasma Frozen within 24 Hours After Phlebotomy (PF24). If U.S. blood suppliers could manufacture CryoAHF from PF24, it would alleviate the operational challenges and improve the supply of CryoAHF source material.
To determine the impact on fibrinogen and FVIII levels in a feasibility study, American Red Cross Biomedical Services (ARCBS) produced and assessed 21 single units of CryoAHF. The feasibility study was designed to evaluate the worst-case scenario with three unfavorable conditions. The first was to manufacture CryoAHF as single units, which are more vulnerable to QC failure compared to the larger volume of pools, where the variability in FVIII levels are normalized. The second condition was use of blood type O donors, who are known to yield lower FVIII levels. Finally, the third condition was to use CryoAHF that was produced from PF24 frozen between 20 to 24 hours, in contrast to the ARCBS’ average freeze time of 17 hours for PF24.
The minimum AABB and FDA requirement is ≥ 80 IU of FVIII per unit and ≥ 150 mg of fibrinogen per unit. CryoAHF manufactured in our feasibility study from PF24 contained FVIII levels of 208 ± 61 IU (mean ± SD) and 509 ± 152 mg of fibrinogen levels per unit. The coagulation factor levels from each of the individual CryoAHF units thus exceeded the requirements.
These findings were corroborated in a larger follow-up process control/QC validation study, wherein 69 PF24 units were manufactured into CryoAHF across 3 separate manufacturing sites under standard processes.
Pursuant to these data, FDA has granted a variance to ARCBS to allow manufacturing of CryoAHF singles and pools from PF24 as the starting material.
In conclusion, ARCBS has demonstrated that CryoAHF produced from PF24 meets the AABB and FDA QC requirements. Producing CryoAHF from PF24 vastly increases the amount of frozen plasma that can be used to manufacture this blood product and will significantly improve the available national inventory of CryoAHF. Manufacturing of CryoAHF from PF24 offers several logistical advantages to ARCBS. It frees up capacity to scale-up production of other blood products with timed manufacturing requirements (e.g. low-titer O whole blood). Blood collection centers don’t have to transport products mid-blood drive to a manufacturing facility to meet stringent timing requirement for freezing 1st stage CryoAHF. ARCBS is projected to nationally implement this change to CryoAHF manufacturing in June 2022. Overall, this change is anticipated to improve manufacturing efficiency for CryoAHF production and augment the supply of this life-saving product.
Parvez M. Lokhandwala, MD, PhD
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