Platelets: Frozen and Freeze-Dried Current Products in Development and Regulatory Licensing Challenges
Cryopreserved and lyophilized platelets have a long, but limited, history of human use that dates back to the 1950s yet involves a small number of total study subjects (Fig. 9.1). Despite decades of research characterizing the quality and nature of these products, questions remain regarding the relationship between in vitro performance and in vivo function to control bleeding. That said, results to date indicate promising in vivo hemostatic potential in several animal models. Although the data is retrospective and cannot definitively establish causality, human use of cryopreserved platelets in military settings also appears to be associated with benefit. The regulatory pathway for these products, particularly in the case of cryopreserved platelets, has been decades long, and more trials are needed to provide high-quality data to regulatory bodies. These products could be life-saving in settings where other good alternatives are limited or unavailable.
KeywordsHistory of platelets Cryopreserved platelets Frozen platelets DMSO Lyophilized platelets Freeze-dried platelets Trehalose Paraformaldehyde US military FDA
Anticoagulant Citrate Dextrose Solution
Australian Defense Force
Australian Red Cross
Biomedical Advanced Research and Development Authority
Biomedical Excellence for Safer Transfusion
Coronary artery bypass grafting
Center for Biologics Evaluation and Research
Cluster of differentiation 41a (GPIIb/IIIa)
Cluster of differentiation 42b (GPIb)
Current Good Manufacturing Practice
Cryopreserved Platelets Versus Liquid Platelets Trial
Cryopreserved platelet product
Defense Advanced Research Projects Agency
Department of Defense
Food and Drug Administration
Fresh frozen plasma
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Lyophilized platelets stabilized with paraformaldehyde
Lyophilized platelets stabilized with trehalose
Medical treatment facilities
North Atlantic Treaty Organization
National Institutes of Health
Netherlands Armed Forces
New Zealand white rabbits
Platelet additive solution
Room temperature, 20–24 °C
Funding for some research studies reported here was from the US Army Medical Research and Materiel Command. The views, opinions, and/or findings contained in this report are those of the authors and should not be construed as an official Department of Defense position, policy, or decision unless so designated by other documentation.
Funding for some research studies reported here was provided in whole or in part with federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No. HHSO100201300021C.
- 41.Esber EC. FDA MEMO: reduction of the maximum platelet storage period to 5 days in an approved container. https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/UCM063013.pdf. FDA; 1986. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/UCM063013.pdf.
- 43.Mulcahy AW, Kapinos KA, Briscombe B, Uscher-Pines L, Chaturvedi R, Case SR, et al. Toward a sustainable blood supply in the united states: an analysis of the current system and alternatives for the future. Santa Monica: RAND Corporation; 2016. Available from: https://www.rand.org/content/dam/rand/pubs/research_reports/RR1500/RR1575/RAND_RR1575.pdf.
- 50.Valeri CR, Feingold H, Melaragno AJ, Vecchione JJ. Cryopreservation of dog platelets with dimethyl sulfoxide: therapeutic effectiveness of cryopreserved platelets in the treatment of thrombocytopenic dogs, and the effect of platelet storage at −80 degrees C. Cryobiology. 1986;23(5):387–94.PubMedCrossRefPubMedCentralGoogle Scholar
- 53.Khuri SF, Healey N, MacGregor H, Barnard MR, Szymanski IO, Birjiniuk V, et al. Comparison of the effects of transfusions of cryopreserved and liquid-preserved platelets on hemostasis and blood loss after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1999;117(1):172–83; discussion 83–4.PubMedCrossRefPubMedCentralGoogle Scholar
- 59.ARC. Frozen Platelets Clinical Trial. https://www.donateblood.com.au/research/frozen-platelets-clinical-trial. Australian Red Cross Blood Service; N/A [Web page briefly describing ARC collaboration with the CLIP Trial]. Available from: https://www.donateblood.com.au/research/frozen-platelets-clinical-trial.
- 60.Authorities TCoA. The factors affecting the supply of health services and medical professionals in rural areas. http://www.aph.gov.au/DocumentStore.ashx?id=bdccdbb5-bfcd-4440-ac8a-ee4f8ae8c157. Submission to the Senate Standing Committee on Community Affairs 2011 [cited 2018 5/8/2018]. Available from: http://www.aph.gov.au/DocumentStore.ashx?id=bdccdbb5-bfcd-4440-ac8a-ee4f8ae8c157.
- 69.Collaborative BEST. Platelet radiolabeling procedure. Transfusion. 2006;46(Suppl):59S–66S.Google Scholar
- 72.Read MS, Reddick RL, Bode AP, Bellinger DA, Nichols TC, Taylor K, et al. Preservation of hemostatic and structural properties of rehydrated lyophilized platelets: potential for long-term storage of dried platelets for transfusion. Proc Natl Acad Sci U S A. 1995;92(2):397–401.PubMedPubMedCentralCrossRefGoogle Scholar
- 83.Joshi NV, Raftis JB, Lucking AJ, Hunter AH, Millar M, Fitzpatrick M, et al. Lyophilised reconstituted human platelets increase thrombus formation in a clinical ex vivo model of deep arterial injury. Thromb Haemost. 2012;108(1):176–82. https://doi.org/10.1160/TH12-02-0059.CrossRefPubMedGoogle Scholar
- 84.Getz TM, Bode AP, Hale AS, Stanton M, Johnson M, Fitzpatrick GM. Safety evaluation of lyophilized canine platelets in a model of coronary artery bypass graft (CABG). Transfusion. 2017;57(Supplement S3):21A.Google Scholar
- 86.Fitzpatrick GM, Vibhudatta A, Agashe H, Dee J. Trehalose stabilized freeze dried human platelets, thrombosomes, reduce blood loss in thrombocytopenic rabbit ear bleed model by as much as 89.5%. Vox Sang. 2010;99(Suppl 1 P-0452):261.Google Scholar
- 91.Dyer C, Alquist CR, Cole-Sinclair M, Curnow E, Dunbar NM, Estcourt LJ, et al. A multicentred study to validate a consensus bleeding assessment tool developed by the biomedical excellence for safer transfusion collaborative for use in patients with haematological malignancy. Vox Sang. 2018;113(3):251–9.PubMedCrossRefPubMedCentralGoogle Scholar