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Anyone who works with platelets knows they are extremely sensitive cells that are activated in many ways. This sensitive nature is an integral part of platelet function. We regularly receive questions about the impact of post-donation processes like gamma irradiation, pneumatic tube delivery systems, extended shelf life, and pathogen reduction on platelet activation. While many of these stressors can play a role in increasing the level of activation in a platelet unit, the primary source of activation is the donor [1] This post provides a broad overview on the sources of activation relevant to donated platelet units.

 

Introduction

Platelet activation is a normal part of the platelet life cycle as depicted in this map. Megakaryocytes in the bone marrow produce non-activated platelets and release them into the bloodstream where they are ready to activate to fulfill their immune and hemostatic functions[2]. Many, if not all, pathological conditions involve platelets and can lead to activated platelets in a donor. Stress applied during or after the donation of platelets will add to the stress these platelets endured during circulation in the donor. Data shows that platelet units which come from donors with activated platelets are especially vulnerable to additional activation from external stressors. Conversely, platelet units that are donated by people with non-activated platelets are more robust to additional stress and will remain non-activated despite exposure to moderate levels of external stress [1].

To provide an overview of the current understanding of platelet activation, information was collected from selected publications and unpublished study data to provide a baseline understanding of the sources of platelet activation. These sources are discussed below in two groups: donor factors and external stressors. The studies referenced rely on a variety of markers or indicators of platelet activation status including microparticle content, CD62P, CD63, and platelet function assays.

 

Donor Factors for Platelet Activation

Cardiovascular Disease – Platelet microparticles, a known marker of platelet activation, are found at higher levels in patients with increased coronary heart disease [3][4]. Additionally, microparticles increase with the presence of arterial calcification in otherwise healthy individuals [5]

Hypertension – The level of microparticles, and thus platelet activation, is significantly increased in patients with essential hypertension [6].

Type 2 Diabetes – Circulating microparticles were found to be significantly higher in individuals with type 2 diabetes compared with healthy controls. [7][8].

Pathogens – Bacterial pathogens can induce platelet activation through direct interaction, through bridging molecules and by secreted bacterial products and endotoxins [9][10]. Platelets are also activated through direct interaction with viruses and some viral antigen-antibody complexes [11][12].

Autoimmune Diseases – Platelet activation has been associated with rheumatoid arthritis [13], psoriasis [14], asthma [15], Crohn’s disease [16]. Due to the platelet’s role as an innate immune cell, it is likely that elevated levels of platelet activation would be found in nearly all autoimmune conditions.

Depression – Depression has been associated with increased platelet activation as measured by circulating CD62P and CD63 positive platelets, additionally, a positive correlation was found between the level of platelet activation and the severity of depression. [17]

Inflammation – Platelet activation is a crucial part of various inflammatory processes [18]. Many of the above-listed associations with platelet activation are directly linked to the inflammatory components of these conditions. Numerous reviews have been published on the role of platelets in inflammation – one example is the review by Storey and Thomas [19].

Diet & Exercise – While many of the above factors could be asymptomatic and not prevent a person from donating platelets, a higher level of platelet activation in a person’s blood likely indicates a disease state. Studies suggest that diet and exercise impact microparticle content and platelet activation [20][21]. Various dietary factors can significantly increase or decrease platelet activation and platelet microparticle content [22] [23]. Additionally, moderate exercise can lead to a temporary increase in platelet activation and microparticle generation [24]. It is possible that healthy donors who donate shortly after strenuous exercise give activated platelets [25].

 

External Stressors for Platelet Activation

Collection Method – The collection method is the first opportunity for external stressors to increase the level of platelet activation. There is evidence that plasma recirculation combined with elutriation (Amicus) leads to additional stress compared to centrifugation in a conical-shaped chamber (Trima). [26]

Pathogen Reduction – The impact of pathogen reduction technologies on platelet activation likely depends on the technology used. It was found that Mirasol treatment leads to significantly more microparticle generation and thus platelet activation on days 5 and 7 of storage compared to untreated control platelets [1]. Interestingly, if the untreated control platelets were highly activated, their Mirasol-treated counterparts showed greater increases in activation, again supporting the idea of cumulative responses of platelets to multiple stress factors. Preliminary data on Intercept-treated platelets suggest a later onset of platelet activation and microparticle generation [*].

Gamma Irradiation – A small study investigating the effects of Gamma irradiation found no significant differences in microparticle generation before and after Gamma irradiation [1].

Transportation – As expected from previous research[27], a small study investigating microparticle generation before and after simulated truck transportation found no significant differences [1]. Additionally, pneumatic tube transport does not appear to have a significant impact on platelet activation [28][29].

Cold Storage – Platelets stored at 4°C appear to have improved hemostatic function when transfused to acutely bleeding patients compared to platelets stored at 22°C [30]. It was also shown that cold storage leads to GPIIb‐IIIa activation [31].

Excessive or Insufficient Agitation – Excessive agitation increases shear stress-induced platelet activation and insufficient agitation promotes platelet-platelet contact and aggregation in vivo as well as in vitro. Tumblers and elliptical agitators are known to cause platelet activation. Current storage conditions for platelet units were established to avoid higher expression of CD62P and poorer morphology scores when platelets are stored without agitation [21].

Aging during storage – The age of platelet units has long been a topic of interest due to the conflicting requirements of maximizing shelf life and minimizing storage lesion. Platelet activation as measured by average CD62P expression increases with platelet storage [33]. However, platelet age is a poor predictor of platelet activation status due to the high variability of donors and the effects of processing factors listed above. Microparticle content (measured with ThromboLUX) varies greatly with age (see figure).[*]

 

Moving Forward

Platelet activation is an incredibly active field of study. This overview is just a high-level summary. Please contribute to the conversation by commenting below. Any additional sources of platelet activation and additional references would be greatly appreciated.

 

References

  1. Maurer-Spurej, E., Larsen, R., Labrie, A., Heaton, A. and Chipperfield, K. (2016). Microparticle content of platelet concentrates is predicted by donor microparticles and is altered by production methods and stress. Transfusion and Apheresis Science, 55(1), pp.35-43. https://sciencedirect.com/science/article/pii/s1473050216300787
  2. Li JL, Zarbock A, Hidalgo A. Platelets as autonomous drones for hemostatic and immune surveillance. J Exp Med. 2017. http://jem.rupress.org/content/early/2017/07/17/jem.20170879
  3. Viera, A., Mooberry, M. and Key, N. (2012). Microparticles in cardiovascular disease pathophysiology and outcomes. Journal of the American Society of Hypertension, 6(4), pp.243-252. http://www.ashjournal.com/article/S1933-1711(12)00130-1/fulltext
  4. Nomura S. Microparticle and Atherothrombotic Diseases. J Atheroscler Thromb. 2016;23(1):1-9. https://www.jstage.jst.go.jp/article/jat/23/1/23_32326/_article
  5. Jayachandran, M., Litwiller, R., Lahr, B., Bailey, K., Owen, W., Mulvagh, S., Heit, J., Hodis, H., Harman, S. and Miller, V. (2011). Alterations in Platelet Function and Cell-Derived Microvesicles in Recently Menopausal Women: Relationship to Metabolic Syndrome and Atherogenic Risk. Journal of Cardiovascular Translational Research, 4(6), pp.811-822. https://link.springer.com/article/10.1007/s12265-011-9296-9
  6. Nantakomol, D., Imwong, M., Mas-Oodi, S., Plabplueng, C., Isarankura-Na-Ayudhya, C., Prachayasittikul, V. and Nuchnoi, P. (2012). Increase Membrane Vesiculation in Essential Hypertension. Laboratory Medicine, 43(1), pp.6-9. https://doi.org/10.1309/LM0AKS1ZXDR1UAYW
  7. Tripodi, A., Branchi, A., Chantarangkul, V., Clerici, M., Merati, G., Artoni, A. and Mannucci, P. (2010). Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay. Journal of Thrombosis and Thrombolysis, 31(2), pp.165-172. https://doi.org/10.1007/s11239-010-0506-0
  8. Xu MD, Wu XZ, Zhou Y, Xue Y, Zhang KQ. Proteomic characteristics of circulating microparticles in patients with newly-diagnosed type 2 diabetes. Am J Transl Res. 2016;8(1):209-20. https://www.sciencedirect.com/science/article/pii/S2214647415000872
  9. Fitzgerald, J., Foster, T. and Cox, D. (2006). The interaction of bacterial pathogens with platelets. Nature Reviews Microbiology, 4(6), pp.445-457. https://www.nature.com/articles/nrmicro1425
  10. Semple JW, Italiano JE, Jr., Freedman J. Platelets and the immune continuum. Nature Reviews Immunology. 2011;11(4):264-74. https://www.nature.com/articles/nri2956
  11. Assinger, A. (2014). Platelets and Infection – An Emerging Role of Platelets in Viral Infection. Frontiers in Immunology, 5, p.649. http://doi.org/10.3389/fimmu.2014.00649
  12. Othman M, Labelle A, Mazzetti I, Elbatarny HS, Lillicrap D. Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance. 2007;109(7):2832-9. http://www.bloodjournal.org/content/109/7/2832
  13. Pisetsky, D., Ullal, A., Gauley, J. and Ning, T. (2012). Microparticles as mediators and biomarkers of rheumatic disease. Rheumatology, 51(10), pp.1737-1746. https://doi.org/10.1093/rheumatology/kes028
  14. Laresche, C. (2014). Increased Levels of Circulating Microparticles Are Associated with Increased Procoagulant Activity in Patients with Cutaneous Malignant Melanoma. Journal of Investigative Dermatology, 134(1), pp.176-182. https://doi.org/10.1038/jid.2013.288
  15. Duarte, D. (2013). Increased circulating platelet microparticles as a potential biomarker in asthma. Allergy, 68(8), pp.1073-1075. https://doi.org/10.1111/all.12190
  16. Chamouard, P. (2005). Circulating Cell-Derived Microparticles in Crohn’s Disease. Digestive Diseases and Sciences, 50(3), pp.574-580. https://doi.org/10.1007/s10620-005-2477-0
  17. MOREL-KOPP, M., MCLEAN, L., CHEN, Q., TOFLER, G., TENNANT, C., MADDISON, V. and WARD, C. (2009). The association of depression with platelet activation: evidence for a treatment effect. Journal of Thrombosis and Haemostasis, 7(4), pp.573-581. https://doi.org/10.1111/j.1538-7836.2009.03278.x
  18. Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. 2010;327(5965):580-3. https://www.semanticscholar.org/paper/Platelets-amplify-inflammation-in-arthritis-via-Boilard-Nigrovic/ac04215a36c3bdc848e28ef46134de730aa064e1
  19. Storey, R. and Thomas, M. (2015). The role of platelets in inflammation. Thrombosis and Haemostasis, 114(09), pp.449-458. https://www.thieme-connect.com/products/ejournals/abstract/10.1160/TH14-12-1067
  20. Badimon L, Suades R, Crespo J, Padro T, Chiva-Blanch G. Diet, microparticles and atherothrombosis. Front Biosci (Landmark Ed). 2018;23:432-57. https://www.ncbi.nlm.nih.gov/pubmed/28930554
  21. Chen YW, Apostolakis S, Lip GY. Exercise-induced changes in inflammatory processes: Implications for thrombogenesis in cardiovascular disease. Ann Med. 2014;46(7):439-55. https://www.ncbi.nlm.nih.gov/pubmed/25012964
  22. McEwen, B. (2014). The Influence of Diet and Nutrients on Platelet Function. Seminars in Thrombosis and Hemostasis, 40(02), pp.214-226. https://www.thieme-connect.com/DOI/DOI?10.1055/s-0034-1365839
  23. Phang, M., Lincz, L., Seldon, M. and Garg, M. (2012). Acute supplementation with eicosapentaenoic acid reduces platelet microparticle activity in healthy subjects. The Journal of Nutritional Biochemistry, 23(9), pp.1128-1133. https://www.sciencedirect.com/science/article/pii/S0955286311002026?via%3Dihub
  24. SOSSDORF, M., OTTO, G., CLAUS, R., GABRIEL, H. and LÖSCHE, W. (2011). Cell-Derived Microparticles Promote Coagulation after Moderate Exercise. Medicine & Science in Sports & Exercise, 43(7), pp.1169-1176. https://www.ncbi.nlm.nih.gov/pubmed/21131870
  25. Chaar V, Romana M, Tripette J, Broquere C, Huisse MG, Hue O, et al. Effect of strenuous physical exercise on circulating cell-derived microparticles. Clin Hemorheol Microcirc. 2011;47(1):15-25. https://www.ncbi.nlm.nih.gov/pubmed/21321404
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  27. Dumont LJ, Gulliksson H, van der Meer PF, Murphy S, Nixon JG, de Wildt-Eggen J, et al. Interruption of agitation of platelet concentrates: a multicenter in vitro study by the BEST Collaborative on the effects of shipping platelets. Transfusion. 2007;47(9):1666-73. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1537-2995.2007.01339.x
  28. Sandgren, P. (2014). The effects of pneumatic tube transport on fresh and stored platelets in additive solution. Blood Transfusion, 12(1), pp.85-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926735/
  29. Lancé, M. (2012). Platelet concentrate transport in pneumatic tube systems – does it work?. Vox Sanguinis, 103(1), pp.79-82. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1423-0410.2011.01580.x
  30. Reddoch KM, Pidcoke HF, Montgomery RK, Fedyk CG, Aden JK, Ramasubramanian AK, et al. Hemostatic function of apheresis platelets stored at 4 degrees C and 22 degrees C. Shock. 2014;41 Suppl 1:54-61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991734/
  31. Getz, T., Montgomery, R., Bynum, J., Aden, J., Pidcoke, H. and Cap, A. (2016). Storage of platelets at 4°C in platelet additive solutions prevents aggregate formation and preserves platelet functional responses. Transfusion, 56(6), pp.1320-1328. https://onlinelibrary.wiley.com/doi/full/10.1111/trf.13511
  32. van der Meer, P. and Korte, D. (2011). Platelet preservation: Agitation and containers. Transfusion and Apheresis Science, 44(3), pp.297-304. http://www.trasci.com/article/S1473-0502(11)00060-7/fulltext
  33. Devine DV, Serrano K. The platelet storage lesion. Clin Lab Med. 2010;30(2):475-87. https://www.sciencedirect.com/science/article/pii/S0272271210000089?via%3Dihub

* Data on file with LightIntegra Technology