Goal 2: Reduce Human Disease

Consequences of ABO or Rh Type Specific versus Non-Type Specific Platelet Transfusions

What are the consequences, clinically and immunologically, of ABO or Rh type specific vs. non-type specific platelet transfusions? There is widely varying practice as to ABO and Rh matching of platelets for transfusion. Most studies demonstrate that use of ABO unmatched (non-identical) platelets are associated with increased 1) platelet refractoriness (small randomized trials), 2) red cell transfusion needs and hemolysis, ...more »

Submitted by (@cjoseph)

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

Details on the impact of addressing this CQ or CC :

Large randomized trials would answer the ABO and Rh related critical clinical outcomes question for platelet transfusions in all patients who commonly receive multiple platelet transfusions. This would include most patients with acute hematologic diseases, patients undergoing complex cardiac surgery, solid and stem cell transplant recipients and trauma patients. In addition, modeling the effects of ABO and Rh incompatibility/non-identity in animal models and in vitro would provide data on basic platelet immunobiology.

In vitro and animal model studies that might be relevant include effects of ABO immune complexes on endothelial cell and glycan interactions with other cells of the vasculature and blood. Effects on TLR, interleukin receptors and secreted cytokines are additional considerations.

Feasibility and challenges of addressing this CQ or CC :

A randomized trial in patients undergoing induction therapy for acute leukemia and/or allogeneic stem cell transplant would accrue enough patients rapidly to answer this question in, at most, two-three years, given the repeated transfusions of platelets to such patients. A comparison of current practice, or intentionally employing ABO/Rh major mismatched platelets (no risk of hemolysis) as the control arm, versus only ABO/Rh identical platelets in the experimental arm is feasible and ethical. Outcomes such as bleeding, time to engraftment and survival (100 day and long term) are important and scientifically of interest. Companion scientific mechanism studies of effects on inflammation, immunity (adaptive and innate) and hemostasis and thrombosis would be feasible in vitro, in animal models and in the patients in the clinical trial. A similar trial would be informative in patients undergoing complex adult or pediatric cardiac surgery (e.g., combined valve/CABG, LVAD insertion, single ventricle physiology operations) or adult/pediatric ECMO settings.

4. References

1. Carr R, et al. Br J Haematol 1990;75:408-13.

2. Heal JM, et al. Ann Hematol 1993;66:309.

3. Heal JM, et al. EurJHaematol 1993;50:110-7.

4. Blumberg N, et al. Transfusion 2001;41:790-3.

5. Shanwell A, et al. Vox Sanguinis 2009;96:316-23.

6. Inaba K, et al. Arch Surg 2010;145:899-906. 

Name of idea submitter and other team members who worked on this idea : Cassandra Josephson on behalf of the Platelet Committee from the State of the Science Meeting 2015

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Goal 2: Reduce Human Disease

Development of Optimally Hemostatic, Systemically Safe, Platelet Mimetics or Substitutes

What are the knowledge and technological gaps in production, evaluation and clinical translation of donor-independent platelets for transfusions? Specific questions include: a) How can stem or progenitor cells be expanded to maximize platelet production?; b) What are the hemostatically relevant design and function requirements and evaluation metrics for ideal/optimal “biologic” and “synthetic” platelets? c) What preclinical ...more »

Submitted by (@dtriulzi)

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

Details on the impact of addressing this CQ or CC :

Platelets produced from induced pluripotent stem or progenitor (megakaryocyte) cells (biologic production), as well as, manufactured from engineered biomaterials (synthetic production) could address clinical needs of supply issues and transfusion related function and safety concerns. However, there are key knowledge and technology gaps in both approaches, and in corresponding qualitative and quantitative correlation of the platelet products with hemostatic efficacy and safety. One important step is increasing both stem and progenitor cell expansion in culture. A parallel step is to develop synthetic platelet mimetics using biomaterials engineering. Finally, the hemostatic efficacy and safety of the products need to be established in clinically relevant models and patients.

Feasibility and challenges of addressing this CQ or CC :

The above questions can be addressed by establishing high throughput screens for compounds that expand CD34 or CD41 cells or trigger platelet release and ploidy, developing culture methods using 3D scaffolds to mimic bone marrow perivascular niche, using proteomics or RNA-sequencing to reveal molecules critical for terminal megakaryocyte maturation and platelet formation. Large-scale bioreactors can be adapted to test molecules, triggers and conditions for amplifying platelet production. For synthetic platelet mimics, the benefits of integrating natural platelet’s physico-mechanical properties with its hemostatic biochemical properties on synthetic biomaterial platforms, can be studied in vitro. Scaled-up particle fabrication technologies with control over particle geometries and surface chemistries, can be adapted for manufacturing synthetic platelets. Large-scale production of platelets through biologic and synthetic routes would enable studies in animal models with clinically relevant bleeding disorders, to correlate design and dosage with hemostatic function and safety. Subsequently, clinical studies can be carried out in Phase 1 for safety analysis in dose escalation and in vivo kinetics (recovery and survival for biologic, degradation and clearance for synthetic). Phase II studies can evaluate bleeding incidence, transfusion requirements and thrombotic events in a controlled population of thrombocytopenic patients under-doing chemotherapy or stem cell transplantation.

Name of idea submitter and other team members who worked on this idea : NHLBI 2015 State of the Science in Transfusion Medicine

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Goal 2: Reduce Human Disease

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Submitted by (@dtriulzi)

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

Details on the impact of addressing this CQ or CC :

duplicate

Feasibility and challenges of addressing this CQ or CC :

duplicate

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

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