Showing 7 ideas for tag "plasma"

Goal 2: Reduce Human Disease

Apheresis Medicine in the Management of Sickle Cell Disease

Despite advances in care, patients with sickle cell disease have significant morbidity and mortality. One challenge is the optimal use of simple vs exchange transfusion vs no transfusion when managing these patients. Simple transfusions lead to iron overload while exchange transfusions may expose patients to increase numbers of red blood cell units. The mechanism of benefit from transfusion (oxygen delivery vs marrow... more »

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

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SCD is the most common genetic disease in the United States affecting 100,000 individuals or 1 in 400 African American births. Pain, stroke, acute chest syndrome and priapism are common morbidities affecting patients with sickle cell disease, which often result in emergency room visits and/or hospitalizations. Despite advances in treatment, sickle cell disease is associated with significant mortality and shortened life expectancy. Defining the optimal role of red blood cell exchange and plasma exchange (which may be used to remove plasma molecules such as inflammatory factors and free hemoglobin) in the management and prevention of the complications of sickle cell disease and may not only prolong the life of these patients but is expected to improve the quality of their lives. In addition, clearly defining the indications for simple verses exchange transfusion therapy has the potential to minimize both alloimmunization to red blood cells (reported to occur in up to 75% of patients with sickle cell disease) and iron overload associated with transfusion.

Transfusion therapy may be efficacious to sickle cell patients by providing increased oxygen delivery to tissues and/or decreasing the amount of sickle hemoglobin present by suppression of erythropoiesis. Understanding the relative contributions of these mechanisms will assist with optimal use of transfusion therapy as well as inform the development of novel alternative therapies

Feasibility and challenges of addressing this CQ or CC

Multi-center trials should be feasible, given the number of patients with sickle cell disease in the US. Participation by larger academic centers which care for sickle cell patients should facilitate trials. Methods for automated red cell exchange and plasma exchange are available and in common use at many centers. Great interest exists among physicians caring for sickle cell patients (as exemplified by the recent NIH consensus document and ASFA sickle cell consensus conference) which is a strength of this proposal. Challenges include agreement on standard treatment protocols across centers and long term follow up of patients. Maintaining vascular access in sickle cell patients is another challenge when performing apheresis procedures on sickle cell patients

Name of idea submitter and other team members who worked on this idea Bruce Sachais on behalf of ASFA

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Goal 3: Advance Translational Research

Immunologic predictors of cardiac function following apheresis for dilated cardiomyopathy

Apheresis has been used to treat dilated cardiomyopathy yet the mechanism of action and predictors of response are unknown and clinical utility needs to be confirmed. What is the clinical utility, mechanism of action, and predictors of response?

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

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Dilated cardiomyopathy (DCM) is progressive ventricular enlargement and dysfunction, responsible for 10,000 deaths and 46,000 hospitalizations in the U.S. annually. It is the primary indication for heart transplantation. It may represent viral infection triggered autoimmunity with myocardial autoantibodies identified in 80% of patients and higher autoimmune disease prevalence in patients.

Immunoadsorption and plasma exchange have been used to treat DCM. Staphylococcal protein A agarose (SPAA) columns have the largest published evidence with improved left ventricular (LV)ejection fraction, decreased LV circumference, decreased BNP, improved exercise tolerance, improved oxygen uptake, increased regulator T-cells, decreased stimulatory T-cells, decreased costimulatory T-cells, and improved quality of life. Decreased morbidity and mortality with fewer patients progressing to transplantation and lower health care costs has been described. Given organ shortages, morbidity, and expense of transplantation, a treatment that delays or avoids transplantation would improve health and reduced costs.

Immunological variables such as IgG subtypes, Th1, Th2, Th17 and T regulatory cell number, associated cytokines, and nuclear transcription factors implicated in DCM pathogenesis could correlate with LV function following apheresis and identify apheresis selection criteria and offer a novel mechanism to investigate how autoantibody reduction influences cellular immune components.

Feasibility and challenges of addressing this CQ or CC

DCM is the most common cause of cardiac transplantation with a large number of patients available for study. There are numerous standardized tools for measuring patient quality of life and function for those suffering from congestive heart failure. There are readily available assays for examining potential immunologic variables. If TPE is examined, this procedure is readily available.

Challenges would include the fact that the immunoadsorption columns that have been used are not cleared by the Food and Drug Administration and therefore there is limited to no experience with their use in the U.S. Immunologic evaluations could also require endomyocardial biopsy which represents an invasive procedure which could limit patient enrollment and increase risk.

Name of idea submitter and other team members who worked on this idea Bruce Saichais on behalf of ASFA

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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?

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

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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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43 up votes
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Goal 2: Reduce Human Disease

Liberal versus restrictive plasma prior to invasive procedures

At what INR threshold does prophylactic plasma transfusion, in non-bleeding critically ill patients who are planned to undergo an invasive procedure, prevent bleeding complications and improve patient outcomes?

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

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Millions of plasma units continue to be transfused to non-bleeding critically ill patients. This practice persists despite the lack of high quality evidence indicating improved patient outcomes with prophylactic plasma transfusion triggered by the INR. Studies testing restrictive versus liberal transfusion triggers are now well-established in academic medicine for Red Blood Cell products. More recently, multicenter clinical trials of prophylactic platelet transfusion vs no-prophylaxis have been conducted as well. However, there remains substantial equipoise on the topic of prophylactic plasma transfusion. A large definitive clinical trial that aims to identify the INR threshold at which prophylactic plasma transfusion prevents bleeding complications in non-bleeding critically ill patients would impact clinical practice in a very meaningful way.

Feasibility and challenges of addressing this CQ or CC

Abnormal coagulation tests are common in the ICU and plasma is frequently administered in this specific clinical setting. Indeed, more plasma is administered in the ICU environment than in any other clinical area. Therefore, a multi-center clinical trial addressing the knowledge gap identified above would be feasible with NHLBI support.

Importantly, healthcare providers become increasingly uncomfortable with the avoidance of coagulation factor replacement as coagulation screening test results drift further from the normal range. To address this concern, an adaptive clinical trial may be desirable. In this design, a targeted cohort with modest elevations in the INR measurement would be screened for enrollment (e.g. INR results ranging from 1.5 - 2.0). If the avoidance of plasma transfusion is noted to be safe, the study would advance to the next stage of recruitment, targeting a higher range of INR values (e.g. 2.0 - 2.5).

Finally, the value of the INR in predicting bleeding complications is increasingly scrutinized. Therefore, it can be argued that the INR is not the ideal "trigger" for plasma transfusion. Despite this, it must be acknowledged that the INR remains the primary driver of decisions related to plasma transfusion. Therefore, a large definitive trial specifically detailing the the efficacy of the current practice versus a more conservative approach to prophylactic plasma transfusion would be practice changing and potentially very transformative.

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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39 up votes
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Goal 2: Reduce Human Disease

Viscoelastic vs traditional coagulation tests as a guide to hemostatic treatments

Does the use of viscoelastic testing to guide plasma transfusion improve outcomes when compared to traditional coagulation testing?

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 PT/INR are frequently used to guide hemostatic interventions, particularly in the ICU where the risk for hemorrhage is increased. In part, this is the result of long standing misconceptions regarding the relationship between PT/INR values with in vivo coagulation factor concentrations and clinical coagulation or hemostasis. Indeed, this misinformation almost certainly contributes to the well-documented inappropriate use of plasma products. To this point, it has now been demonstrated in a variety of clinical settings that the PT/INR is often poorly predictive of clinical coagulopathy or peri-procedural bleeding complications.

The last decade has seen a resurgence of interest in viscoelastic tests as alternatives assessments of hemostasis and guides to blood component use. Indeed, a body of literature supports the potential value of these tests in specific clinical settings. However, the value of such testing strategies has not been well described in the setting of the intensive care unit. Ongoing equipoise regarding the optimal assessment of coagulation status in the ICU suggests that a well conducted trial in this domain would have the potential to be truly transformative.

Feasibility and challenges of addressing this CQ or CC

The assessment of coagulation status and decisions related to plasma transfusion occurs multiple times throughout the day in essentially every intensive care unit across the US. Therefore, an adequately sized study population is clearly present and therefore, a multicenter trial is feasible with NHLBI support.

A potential challenge with a study evaluating the optimal coagulation testing strategy is the incomplete penetration of viscoelastic testing in current clinical practice raising concerns related to the resource and educational requirements if such a trial were pursued. Additionally, viscoelastic testing can take several forms, each of which may impose specific confounders. Therefore, specific technologies and transfusion algorithms would likely need to be employed.

Importantly, innovative trial designs may also help us to address some of the feasibility concerns noted above. One such design that may prove valuable in this setting is the stepped-wedge cluster randomization design. Implementation of such a design might be expected to improve investigator/clinician cooperation/compliance and may help reduce treatment group contamination.

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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19 net votes
43 up votes
24 down votes
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Goal 2: Reduce Human Disease

Goal-directed versus Fixed-ratio plasma resuscitation in surgical (non-trauma) hemorrhage

For surgical patients meeting criteria for the critical RBC administration threshold (CAT) due to an associated coagulation disorder, which hemostatic resuscitation strategy (goal-directed versus ratio-based) is superior?

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

Details on the impact of addressing this CQ or CC

Perioperative hemorrhage remains a significant concern. Coagulopathy frequently develops in the setting of surgical hemorrhage and the optimal strategy for addressing this issue remains a matter of debate.
Military experience suggests the application of ratio-based plasma transfusion practices may improve clinical outcomes in the setting of massive hemorrhage. However, numerous concerns (e.g. survival bias, uniqueness of a military population, risk for adverse events related to high-volume plasma transfusion) preclude the broad generalization of such strategies to non-trauma surgical populations.
Goal-directed hemostatic resuscitation strategies (e.g. coagulation management based upon the results of hemostasis testing) have shown promise in specific surgical environments such as cardiac surgery and liver transplantation. However, definitive direct comparisons between goal-directed strategies and alternative approaches such as fixed-ratio plasma transfusion have not been performed. Moreover, the role of such strategies in more heterogeneous surgical populations remains uncertain. To better define the optimal approach to plasma transfusion strategies in the setting of intraoperative (non-trauma) hemorrhage, we propose a multicenter clinical trial directly comparing fixed-ratio and goal-directed plasma resuscitation strategies in the operating room environment.

Feasibility and challenges of addressing this CQ or CC

Surgical patients with increased risk of hemorrhage may be targeted to improve subject recruitment (e.g. cardiac surgery, liver transplantation, aortic vascular surgery, multi-level instrumented spinal fusions or tumor resections, etc). Therefore, an adequately sized study population is likely to be present in a multicenter study and we believe such a trial would be feasible with NHLBI support.

To further enhance the feasibility of identifying a surgical population experiencing significant hemorrhage in a time-efficient manner, predictive algorithms such as the critical RBC administration threshold (CAT) could be also be employed.

The optimization of decisions related to plasma transfusion has the potential to improve not only clinical outcomes, but also healthcare resource utilization. Therefore, the outcomes of a trial in this domain could include both patient-important outcomes (e.g. mortality, bleeding complications), as well as outcomes related to healthcare utilization (e.g. total blood products consumed, hospital length of stay).

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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30 up votes
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Goal 2: Reduce Human Disease

Efficacy and safety of concentrated FFP

Will the development of a clinical grade “concentrated FFP” not only provide comparable efficacy to standard FFP, but also reduce the incidence of complications, especially transfusion-associated circulatory overload?

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

Details on the impact of addressing this CQ or CC

Much of the impetus for the use of a growing formulary of clotting factor concentrates—both recombinant and plasma derived— stems from concern that an equivalent degree of hemostasis from FFP results in circulatory overload. There are decades of clinical experience with the use of hyper-oncotic concentrated albumin suspended in isotonic saline (25% albumin), representing a 5x concentration. A similarly concentrated form of FFP has not been yet developed. Lyophilized plasma was first used in World War II and later for treatment of hemophiliacs. Lyophilized plasma has also been used for decades as a control reagent for coagulation testing in the laboratory. Currently, FFP is transfused at 12-15 mL/kg (approximately 1 Liter for an 80 kg recipient). A 5-fold concentrated product would translate to 200 mL for a full therapeutic dose. Concentrated FFP might be expected to provide a balanced amount of all circulating coagulation proteins, natural anticoagulants, immunoglobulins and albumin. The development of concentrated FFP might provide a cost-effective alternative to current and future recombinant or plasma-derived factor concentrates; and could find broad application in the treatment of surgical patients, trauma, obstetrics, solid organ transplantation, and critical care medicine. A cost-effective alternative to existing concentrates would be of value not only for American healthcare, but also for transfusion needs in countries with emerging economies.

Feasibility and challenges of addressing this CQ or CC

Several strategies have already been explored to develop concentrated FFP. These include freeze-drying1, lyophilization2 and spray-drying plasma followed by reconstitution in sterile water.3 Funding is needed to develop a large scale production method suitable for broad clinical evaluation in human phase 1, 2, and 3 clinical trials.

Name of idea submitter and other team members who worked on this idea Darrell J. Triulzi MD for the 2015 NHLBI State of the Science in Transfusion Medicine

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