Strategic Goal: Goal 2: Reduce Human Disease

Making It Real: Affordable Physiologically Relevant In Vitro Environments

We have done the best we can to mimic the human internal environment in vitro for the discovery, testing, and validation of therapeutics, but there is a critical need to do better. The use of more complex cell-based in vitro models is the result of the recognition of how little predictive power there is in current experimental conditions, even with animal models. With an in vitro environment that goes beyond temperature ...more »

Submitted by (@ahenn0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Physiologically relevant in vitro environments could potentially impact research on every tissue type, disease, and intervention, including transfusion-based treatments. Basic research, drug-testing, and translational medicine would all be fundamentally altered. Individualized medicine, cellular therapies, and regenerative medicine could all benefit from in vitro conditions that best support the care of the patient's cells and guide those cells in the direction needed for effective treatment.

Feasibility and challenges of addressing this CQ or CC :

Research and Industry are in the early stages of developing the techniques and know-how needed to address the technical challenges in establishing human-relevant in vitro environments. We already have the technology to control in vitro oxygen and other critical gas components. Mimicking cell-cell interactions and variable cell states such as states of differentiation or stress are areas under active research. Computational and analytical techniques are being developed that can gain insight from large data sets. More of a challenge may be assessing distant effects like metabolism of drugs by the liver or potential drug and cellular interactions with the external environment. However, making a human-predictive in vitro environment affordable is the challenge that could define success or failure of any particular approach. It is feasible within the next ten years to have truly predictive in vitro environments for drug cellular therapy development.

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Strategic Goal: Goal 2: Reduce Human Disease

Re-evaluating Hemoglobin Thresholds for Red Blood Cell Transfusion Decisions

Are there specific conditions where a liberal transfusion strategy results in lower 30-day mortality as compared to a restrictive transfusion strategy?

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

 Clinical trial data show that in multiple patient populations, a 7 to 8 g/dL hemoglobin threshold for red blood cell transfusion is safe. However, equipoise for transfusion thresholds persists in patients with ischemic heart disease and acute neurological conditions where a higher hemoglobin level may decrease ischemic injury to myocardial and cerebral tissues, respectively. Alternatively, liberal red blood cell transfusion may be associated with adverse outcomes such as pulmonary edema or increased rates of heart failure. In other populations, it is possible that even lower transfusion thresholds than 7 g/dL would be safely tolerated. On the other hand, if a 7 g/dL threshold is found to be superior to a lower threshold, this would establish a minimal appropriate threshold to initiate red blood cell transfusion.

Feasibility and challenges of addressing this CQ or CC :

Multicenter clinical trials that utilize markers of oxygen consumption are needed to answer these questions. A pilot study in patients with acute myocardial infarction demonstrated that recruitment was feasible for clinical scenarios in which equipoise exists. An international setting where the safety and availability of the blood supply remain significant issues may be best suited to answer the question of whether transfusion thresholds lower than 7 g/dL are safe.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Strategic Goal: Goal 2: Reduce Human Disease

Transfusion strategies in pediatric and neonatal populations

What are the optimal strategies for transfusion of blood products in pediatric and neonatal population?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Blood is the most prescribed drug in the PICU, and 95% of all neonates are transfused during their stay in the NICU. Currently, there are no evidence-based guidelines for the optimal hemoglobin levels or platelet counts for these populations. There is a balance that must be achieved between hemostasis and thrombosis for this vulnerable population.

Feasibility and challenges of addressing this CQ or CC :

Clinical trials have begun to assess the optimal hemoglobin levels in neonates, but there are no trial to asses the optimal platelet count. Neonatologists, pediatric intensivists, and transfusion medicine physicians are beginning to come together to work on solutions to these problems.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Strategic Goal: Goal 2: Reduce Human Disease

Evidence based approaches to Red Blood Cell transfusion

What are the optimal RBC transfusion thresholds for adult and pediatric cancer patients undergoing chemotherapy regimens that may improve functional status and quality of life?

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Cancer patients undergo intensive medical and surgical therapies to treat their underlying disease. Treatment commonly results in anemia requiring RBC and platelet transfusions to support the patient through the hypoproliferative phase of chemotherapy. This is particularly true for those patients requiring hematopoetic stem cell transplantation (HSCT). Following therapy, cancer outpatients commonly receive RBC transfusions for weeks to months to maintain their functional status.

 

Common causes of death in patients with hematological malignancies and other cancers are infections and bleeding. A meta-analysis of clinical trials suggested that liberal transfusion is associated with greater risk of infection. Conversely, restrictive transfusion could adversely affect quality of life and functional status in oncology populations. In addition, pre-clinical and clinical studies support that concomitant anemia and thrombocytopenia significantly compound bleeding risk, and that hemostasis can be optimized in thrombocytopenia by maintaining a higher hematocrit. Although bleeding risks in relation to platelet transfusion thresholds are well studied in patients with hematological malignancy, optimal hemoglobin levels in thrombocytopenic patients are not known. Despite the significant allocation of blood components to cancer patients as a whole, RBC transfusion practices are not well studied within this group.

Feasibility and challenges of addressing this CQ or CC :

Randomized controlled clinical trials and other studies investigating optimal transfusion thresholds and other measures of practice are required to provide health care providers with evidence to guide one of the most common therapies administered in the setting of malignancy. The clinically important end points of well-designed studies could include: 1) quality of life and functional status for both inpatients and outpatients; 2) neurocognitive development in pediatric populations; 3) bleeding events / bleeding scores; 4) impact on immunity including immunomodulation and infection; 5) reconstitution of hematopoiesis; and 6) survival and/or recurrence of disease.. Besides a generalizable study population, certain target populations of interest are those with high risk disease, HSCT patients, patients undergoing radiation therapy, and pediatric patients.

 

There are >1.6 million new cases of cancer annually in the USA, including >50,000 with leukemia and >6,000 with HSCT. Cancer therapies are rapidly advancing in the era of genomics and immunotherapy. Capitalizing on the tradition of research in cancer, single and multicenter studies of RBC transfusion are feasible using randomized controlled designs in conjunction with clinical trials of chemotherapeutic regimens. The results of these studies will impact a large patient population’s quality of life, and may ultimately impact healthcare cost and blood demand.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Strategic Goal: Goal 2: Reduce Human Disease

Innovations in Red Cell Transfusion in Sickle Cell Disease

Challenges that need to be overcome in blood transfusion, especially in SCD, include: a. Adopting molecular genotyping as the standard in blood transfusion therapy. b. Advancing new generation, anti-oxidant hemoglobin-based oxygen carriers (HBOCs) for use in emergencies such as trauma, stroke, acute hemolysis, and in transfusion in SCD and related disorders. In SCD, HBOCs have the capacity to not only serve as substitutes ...more »

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Transfusion of RBC is major adjunct in the management of trauma, acute and chronic illness. Issues in blood transfusion include availability of donors, RBC typing and crossmatching, cold storage of donor cells, and limited viability of stored RBC. Globally, in many situations where blood is critically needed, these systems are not available.

An increasing percentage of people with SCD require regular RBC transfusion to prevent stroke and other major complications. In addition, RBC transfusion is employed repeatedly in the management of serious acute complications of SCD. Transfusion of normal RBC to replace or supplement the patient’s defective RBC is the most effective intervention in the management of SCD.

 

Impacts:

• Molecular genotyping of RBC will reduce alloimmunization.

• Use of new generation HBOCs that do not require blood typing, crossmatching, refrigeration, and that do not transmit infection, would save lives in conditions of severe hemorrhage, stroke, possibly heart attack, especially where there is no immediate access to adequate medical facilities.

• In SCD, HBOCs could prevent pain or reduce its severity and duration, prevent stroke, reduce severity of acute chest syndrome, and other vasoocclusive complications. Finally, HBOCs have the potential to alter the pathogenesis of SCD.

Feasibility and challenges of addressing this CQ or CC :

The problems in managing chronic RBC transfusion in SCD remain the same as they have been for decades: all immunization, iron overload, and infection transmission. It is clear that traditional serological RBC phenotyping is unable to detect several variants of RBC antigens, especially those in the Rh system, in populations of African descent. This leads to erroneous phenotyping and the appearance of “auto antibodies” that are truly alloantibodies resulting from transfusion of mismatched blood. As a result, people with SCD are the most frequent users of the American Rare Donor Program.

Name of idea submitter and other team members who worked on this idea : Kwaku Ohene-Frempong, MD

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Strategic Goal: Goal 2: Reduce Human Disease

Optimal hemoglobin threshold for transfusion in children with ARDS?

Do different hemoglobin transfusion thresholds alter outcomes in children with ARDS? What is the optimal *minimum* transfusion threshold for children with ARDS? What patient-centered outcomes can be affected by transfusion strategies: ventilator free days, time to organ function recovery, duration of intensive care stay, survival?

Submitted by (@greg.martin)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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Strategic Goal: Goal 3: Advance Translational Research

Genomics in transfusion medicine

How can RBC genomics be utilized to improve outcomes with transfusion?

Submitted by (@barbarak)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Prevention of alloimmunization with transfusion

Improved understanding of RBC epitope diversity

Feasibility and challenges of addressing this CQ or CC :

Utilize advances in genomics medicine to better understand impact of transfusion and to improve outcomes.

Limited donor pool, particularly in minority populations, presents challenges

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Strategic Goal: Goal 2: Reduce Human Disease

How should platelet (PLT) transfusions be used to treat active bleeding?

Multiple randomized controlled trials have been performed to evaluate the use of prophylactic PLT transfusions in non-bleeding, thrombocytopenic hematology-oncology patients. However no high-quality data exist to guide PLT transfusions in actively bleeding patients inclduing pediatric and adult medical and surgical patients. After hematology-oncology patients, cardiac surgery patients are the next largest group of PLT ...more »

Submitted by (@bldbuddy)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

PLT count is almost always the only laboratory result considered in deciding to transfuse PLTs. But PLT counts provide no information about PLT hemostatic function and its contribution to bleeding. A variety of in vitro coagulation tests have been developed: viscoelastography, whole blood PLT aggregometry, etc. But while testing-based transfusion algorithms may reduce blood product utilization, it has not been established that any in vitro test can either predict or help reduce bleeding. There is a gold standard method to assess clinical efficacy of transfused PLTs: incidence of grade 2 or higher bleeding in clinical trials of thrombocytopenic hematology-oncology patients receiving prophylactic PLT transfusions. No analogous gold standard of PLT hemostatic efficacy exists for therapeutic PLT transfusions to treat active bleeding. There is a pressing need to develop such a standard. Establishing reliable methods for evaluating the effects of PLT transfusion in actively bleeding patients will improve our understanding of how different factors (storage conditions, pathogen reduction etc.) affect the functional performance of PLTs.

Feasibility and challenges of addressing this CQ or CC :

PLT transfusions are administered routinely to support bleeding pediatric and adult medical and surgical patients. Opportunities to conduct clinical trials in various settings (cardiac surgery, neurosurgery, orthopedic surgery, trauma, etc.) are widely available. PLT transfusion is commonly used to support bleeding patients receiving perioperative supportive therapies such as extracorporeal membrane oxygenation (ECMO). These clinical situations represent critical opportunities to improve the care of bleeding patients. This approach will simultaneously facilitate comprehensive evaluation and validation of both current and novel in vitro tests of hemostasis. If a given in vitro test were reproducibly shown to correlate strongly with bleeding reduction caused by PLT transfusion, then by definition that would be a clinically meaningful test. Finally, this line of inquiry will allow assessment of the adverse effects of PLT transfusion in bleeding patients.

Name of idea submitter and other team members who worked on this idea : Terry Gernsheimer, University of Washington, for the 2015 NHLBI for the State of the Science in Transfusion Medicine

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Strategic Goal: Goal 2: Reduce Human Disease

Hemostatic treatment with plasma versus 4-factor PCC in the critically ill

For patients in the ICU with coagulopathy and associated World Health Organization (WHO) grade 3 or 4 bleeding, which hemostatic therapy -- plasma versus 4-factor prothrombin complex concentrates -- is preferred?

Submitted by (@darylkor)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Bleeding is frequently encountered in the ICU and is associated with substantial morbidity and associated mortality. When bleeding occurs, coagulopathy is often present and the optimal coagulation factor management regimen remains a matter of debate. Traditionally (and presently in the US), plasma transfusion has been a cornerstone therapy for the replacement of coagulation factor content in this setting. Moreover, recent evidence supporting the use of plasma in the setting of trauma-related hemorrhage seems to have also generated a renewed enthusiasm for plasma transfusion in other critical care settings.

 

In many locations, there is interest in alternatives to plasma transfusion such as four-factor prothrombin complex concentrates (PCC4) for ICU patients with bleeding. In some locations, factor concentrates have entirely replaced plasma transfusion. However, evidence regarding the benefits and risks of PCC4 versus plasma in ICU patients is lacking. Therefore, we would aim to study the comparative efficacy and risks of a hemostatic strategy relying on PCC4 versus plasma for ICU patients with coagulopathy and bleeding.

Feasibility and challenges of addressing this CQ or CC :

Coagulopathy and associated bleeding are common in the intensive care unit environment. Therefore, we believe a multicenter clinical trial evaluating the knowledge gap identified above would be feasible with NHLBI support. Of note, due to the labeled contraindication of disseminated intravascular coagulation for PCC4, such patients would need to be excluded from this trial. Similarly, coagulation abnormalities resulting from congenital coagulation factor deficiencies for which there is a specific coagulation factor product available would also be excluded.

 

Notably, improved management of coagulopathic bleeding has the potential to impact both clinical outcomes and healthcare resource utilization. Therefore, the outcomes of a trial addressing this knowledge gap would include patient-important outcomes (e.g. mortality, length of hospital stay, bleeding, transfusion-related respiratory complications, thromboembolic complications) as well as outcomes related to healthcare utilization (e.g. product cost, total blood products consumed, interventions required to achieve hemostasis such as surgery or embolization).

Name of idea submitter and other team members who worked on this idea : Daryl J. Kor, MD and Walter H. Dzik, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Strategic Goal: Goal 2: Reduce Human Disease

Evidence-based, optimized transfusion practice

What are optimal transfusion practices for acute coronary syndrome?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Blood transfusion is the most commonly employed therapeutic procedure in the US affecting about 5 million patients per year. Having evidence-based transfusion practice guidelines would result in optimized clinical management of patients who need blood transfusions (red blood cells, platelets, plasma) whether for specific conditions (e.g., acute coronary syndromes, sickle cell disease, prenatally) or in specific age groups. Factors that need further evaluation include transfusion trigger in various patient populations, component type and volume transfused, storage age of blood products, patient blood management tools, donor factors that impact on product characteristics, and component processing and storage.

Feasibility and challenges of addressing this CQ or CC :

It is increasingly being recognized that much of the transfusion practice has been empirical, without vigorous scientific evaluation, and thus should be evaluated and optimized. For example, it is not clear if patients with acute coronary syndrome would benefit more from a liberal than a more restrictive red blood cell transfusion strategy; and it is not clear whether plasma transfusion benefits patients with slightly elevated INR (international normalized ratios). Additionally, research capabilities both at the molecular level and at the population level have now made such scientific evaluations possible.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Strategic Goal: Goal 2: Reduce Human Disease

Mitigating risks due to the RBC storage lesion and vulnerable patients

What are the underlying dependencies (genomic, metabolic, disease) in individual donors that either accelerate or delay the changes to red blood cells during refrigerated storage? What methods of preparation might protect patients from the risks posed by the accelerated degradation of RBCs provided by "poor storers"? What characteristics of individual patients make them particularly vulnerable to transfusion of red ...more »

Submitted by (@andrew.dunham)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The changes in red blood cells during refrigerated storage have been well documented and associated with negative clinical sequelae in the peer reviewed literature. While the impact of this so-called storage lesion does not impact every patient during every transfusion it is reasonable to expect that when a unit of blood is transfused to a particularly vulnerable patient from a donor that has red blood cells pre-disposed to degradation, stored in a manner that has allowed significant change to occur, the risk of a negative clinical sequelae is increased. In this case it will be important to understand what underlies the likelihood of a donors blood to store poorly, the changes that occur during storage that could impact vulnerable patients and design approaches to mitigate the degradation that could result.

Feasibility and challenges of addressing this CQ or CC :

We believe mitigating the impact of the storage lesion is feasible by reducing and controlling the oxygen concentration in the RBC unit prior to refrigerated storage. We are continuing our development of a device to do this and to generate the data demonstrating the effect of deoxygenation and anaerobic storage.

Name of idea submitter and other team members who worked on this idea : Andrew Dunham

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Strategic Goal: Goal 2: Reduce Human Disease

Optimization of Existing Therapies for Sickle Cell Disease

How can the safety, dosing and benefits of existing therapies for sickle cell disease such as hydroxyurea, be optimized in order to increase its efficacy and improve patient adherence?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Hydroxyurea is a widely available disease-modifying therapy for sickle cell disease (SCD), but its effectiveness is currently limited by inadequate utilization, and less than optimal response. Research is needed to improve adherence to this evidence-based therapy and emphasis needs to be placed on determining whether therapy with hydroxyurea can prevent or even reverse organ dysfunction. In addition, research identifying new adjunct therapies to blood transfusion and hydroxyurea, as well as disease-specific therapies for co-morbidities such as kidney disease, hypertension, obstructive lung disease, and pulmonary hypertension will be valuable in the management and treatment of SCD.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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