Advertisement

Platelet Contributions to Trauma-Induced Coagulopathy: Updates in Post-injury Platelet Biology, Platelet Transfusions, and Emerging Platelet-Based Hemostatic Agents

  • Zachary A. MatthayEmail author
  • Lucy Zumwinkle KornblithEmail author
Hemostasis after Trauma (N Saillant, Section Editor)
  • 3 Downloads
Part of the following topical collections:
  1. Topical Collection on Hemostasis after Trauma

Abstract

Purpose

The purpose of this review is to summarize the current understanding of the role of aberrant platelet biology in trauma-induced coagulopathy (TIC), discuss the evidence for platelet transfusions in the management of hemorrhaging trauma patients, and review emerging platelet-based hemostatic adjuncts.

Recent Findings

Advances in the study of post-injury platelet biology have led to the discovery of pathways associated with altered platelet activation and aggregation observed in the context of TIC. Impaired platelet aggregation after injury has recently been associated with histone driven modifications in platelet structureand function, alterations in calcium signaling, and alterations in von Willebrand factor (vWF) platelet interactions. Furthermore, studies have identified several soluble factors in plasma which may play a role in inhibiting platelets after injury. Lastly, loss of the normal regulatory and bidirectional relationships of platelets with the endothelium and with fibrinolytic pathways may additionally play key roles in TIC. Importantly, the use of platelet transfusions as a treatment for hemorrhage control is not “one size fits all”—the benefit in several circumstances may be outweighed by risks, and there is a lack of demonstrated effectiveness for certain populations. Therefore, current efforts are underway to develop platelet based and platelet mimetic hemostatic agents, and to improve the effectiveness of platelet transfusions while mitigating the risks.

Summary

Our understanding of how injury leads to altered platelet behavior contributing to TIC has grown substantially but remains incomplete. Decoding the complex biologic interface of platelets with the endothelium, fibrinolysis, and inflammatory pathways will lead to a more complete understanding of platelets and of TIC. Platelet transfusions remain the mainstay of treatment as part of balanced and goal-directed resuscitation, but through advancing knowledge of the underlying biology, safer, targeted, and more effective therapies may emerge.

Keywords

Platelets Trauma-induced coagulopathy Platelet transfusions Platelet biology Platelet aggregation 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Kornblith and Dr. Matthay have nothing to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001;85(6):958–65.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Jacoby RC, Owings JT, Holmes J, Battistella FD, Gosselin RC, Paglieroni TG. Platelet activation and function after trauma. J Trauma Acute Care Surg. 2001;51(4):639–47.CrossRefGoogle Scholar
  3. 3.
    Kutcher ME, Redick BJ, McCreery RC, Crane IM, Greenberg MD, Cachola LM, et al. Characterization of platelet dysfunction after trauma. The journal of trauma and acute care surgery. 2012;73(1):13–9.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Solomon C, Traintinger S, Ziegler B, Hanke A, Rahe-Meyer N, Voelckel W, et al. Platelet function following trauma. Thromb Haemost. 2011;106(08):322–30.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Chang R, Cardenas JC, Wade CE, Holcomb JB. Advances in the understanding of trauma-induced coagulopathy. Blood. 2016;128(8):1043–9.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Kornblith LZ, Moore HB, Cohen MJ. Trauma-induced coagulopathy: the past, present, and future. J Thromb Haemost. 2019;17(6):852–62.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Saillant NN, Sims CA. Platelet dysfunction in injured patients. Mol Cell Ther. 2014;2:37.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Gonzalez Rodriguez E, Ostrowski SR, Cardenas JC, Baer LA, Tomasek JS, Henriksen HH, et al. Syndecan-1: a quantitative marker for the endotheliopathy of trauma. J Am Coll Surg. 2017;225(3):419–27.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Moore HB, Moore EE, Gonzalez E, Hansen KC, Dzieciatkowska M, Chapman MP, et al. Hemolysis exacerbates hyperfibrinolysis, whereas platelolysis shuts down fibrinolysis: evolving concepts of the spectrum of fibrinolysis in response to severe injury. Shock. 2015;43(1):39–46.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Nachman RL, Rafii S. Platelets, petechiae, and preservation of the vascular wall. N Engl J Med. 2008;359(12):1261–70.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Brogren H, Karlsson L, Andersson M, Wang L, Erlinge D, Jern S. Platelets synthesize large amounts of active plasminogen activator inhibitor 1. Blood. 2004;104(13):3943–8.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Vieira-de-Abreu A, Campbell RA, Weyrich AS, Zimmerman GA. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol. 2012;34(1):5–30.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock. Crit Care. 2015;19:72.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Brown LM, Call MS, Margaret Knudson M, Cohen MJ, Trauma Outcomes G, Holcomb JB, et al. A normal platelet count may not be enough: the impact of admission platelet count on mortality and transfusion in severely injured trauma patients. J Trauma. 2011;71(2 Suppl 3):S337–42.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    •• Kornblith LZ, Robles AJ, Conroy AS, Hendrickson CM, Calfee CS, Fields AT, et al. Perhaps it's not the platelet: Ristocetin uncovers the potential role of von Willebrand factor in impaired platelet aggregation following traumatic brain injury. J Trauma Acute Care Surg. 2018;85(5):873–80 Identifies vWF deficiency as a novel mechanism of platelet impairment in TBI. PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Wu Y, Liu W, Zhou Y, Hilton T, Zhao Z, Liu W, et al. von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury. Blood. 2018;132(10):1075–84.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    •• Verni CC, Davila A Jr, Balian S, Sims CA, Diamond SL. Platelet dysfunction during trauma involves diverse signaling pathways and an inhibitory activity in patient-derived plasma. J Trauma Acute Care Surg. 2019;86(2):250–9 Described new mechanisms of platelet inhibition by factors in plasma. PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    •• Lee MY, Verni CC, Herbig BA, Diamond SL. Soluble fibrin causes an acquired platelet glycoprotein VI signaling defect: implications for coagulopathy. J Thromb Haemost. 2017;15(12):2396–407 Describes new mechanisms of platelet inhibition by factors in plasma. PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Yanagida Y, Gando S, Sawamura A, Hayakawa M, Uegaki S, Kubota N, et al. Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock. Surgery. 2013;154(1):48–57.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    •• Vulliamy P, Gillespie S, Armstrong PC, Allan HE, Warner TD, Brohi K. Histone H4 induces platelet ballooning and microparticle release during trauma hemorrhage. Proc Natl Acad Sci U S A. 2019;116(35):17444–9 Proposes histone released from tissue injury mediates platelet ballooning and microparticle release and development of pro-inflammatory, pro-coagulant platelets with defective aggregation. PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Sirajuddin S, Valdez C, DePalma L, Maluso P, Singhal R, Schroeder M, et al. Inhibition of platelet function is common following even minor injury. J Trauma Acute Care Surg. 2016;81(2):328–32.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Stalker TJ, Traxler EA, Wu J, Wannemacher KM, Cermignano SL, Voronov R, et al. Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood. 2013;121(10):1875–85.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    • Li R, Elmongy H, Sims C, Diamond SL. Ex vivo recapitulation of trauma-induced coagulopathy and preliminary assessment of trauma patient platelet function under flow using microfluidic technology. J Trauma Acute Care Surg. 2016;80(3):440–9 Study demonstrating defective platelet mediated clot formation in trauma patients in a microfluidics model with flow and shear stress effects. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Davis PK, Musunuru H, Walsh M, Cassady R, Yount R, Losiniecki A, et al. Platelet dysfunction is an early marker for traumatic brain injury-induced coagulopathy. Neurocrit Care. 2013;18(2):201–8.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248(3):447–58.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Holcomb JB, del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, et al. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148(2):127–36.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Holcomb JB, Zarzabal LA, Michalek JE, Kozar RA, Spinella PC, Perkins JG, et al. Increased platelet:RBC ratios are associated with improved survival after massive transfusion. J Trauma. 2011;71(2 Suppl 3):S318–28.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    •• Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471–82 Landmark clinical trial demonstrating benefit of balanced resuscitation. PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Devine DV, Serrano K. The platelet storage lesion. Clin Lab Med. 2010;30(2):475–87.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Kasotakis G, Starr N, Nelson E, Sarkar B, Burke PA, Remick DG, et al. Platelet transfusion increases risk for acute respiratory distress syndrome in non-massively transfused blunt trauma patients. Eur J Trauma Emerg Surg. 2019;45(4):671–9.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Etchill EW, Myers SP, Raval JS, Hassoune A, SenGupta A, Neal MD. Platelet transfusion in critical care and surgery: evidence-based review of contemporary practice and future directions. Shock. 2017;47(5):537–49.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    •• Cardenas JC, Zhang X, Fox EE, Cotton BA, Hess JR, Schreiber MA, et al. Platelet transfusions improve hemostasis and survival in a substudy of the prospective, randomized PROPPR trial. Blood Adv. 2018;2(14):1696–704 Identifies possible mortality benefit for early platelet transfusion in massive hemorrhage. PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    • Kornblith LZ, Decker A, Conroy AS, Hendrickson CM, Fields AT, Robles AJ, et al. It’s about time: transfusion effects on post-injury platelet aggregation over time. J Trauma Acute Care Surg. 2019. Effect of platelet transfusions on aggregation depends on time from injury- later timepoints associated with improved aggregation in vitro. Google Scholar
  34. 34.
    Henriksen HH, Grand AG, Viggers S, Baer LA, Solbeck S, Cotton BA, et al. Impact of blood products on platelet function in patients with traumatic injuries: a translational study. J Surg Res. 2017;214:154–61.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Ohm C, Mina A, Howells G, Bair H, Bendick P. Effects of antiplatelet agents on outcomes for elderly patients with traumatic intracranial hemorrhage. J Trauma. 2005;58(3):518–22.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Vulliamy P, Gillespie S, Gall LS, Green L, Brohi K, Davenport RA. Platelet transfusions reduce fibrinolysis but do not restore platelet function during trauma hemorrhage. J Trauma Acute Care Surg. 2017;83(3):388–97.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Stettler GR, Moore EE, Moore HB, Nunns GR, Huebner BR, Einersen P, et al. Platelet adenosine diphosphate receptor inhibition provides no advantage in predicting need for platelet transfusion or massive transfusion. Surgery. 2017;162(6):1286–94.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kim DY, O'Leary M, Nguyen A, Kaji A, Bricker S, Neville A, et al. The effect of platelet and desmopressin administration on early radiographic progression of traumatic intracranial hemorrhage. J Neurotrauma. 2015;32(22):1815–21.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Martin G, Shah D, Elson N, Boudreau R, Hanseman D, Pritts TA, et al. Relationship of coagulopathy and platelet dysfunction to transfusion needs after traumatic brain injury. Neurocrit Care. 2018;28(3):330–7.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    • Furay E, Daley M, Teixeira PG, Coopwood TB, Aydelotte JD, Malesa N, et al. Goal-directed platelet transfusions correct platelet dysfunction and may improve survival in patients with severe traumatic brain injury. J Trauma Acute Care Surg. 2018;85(5):881–7 Example of how implementation of goal-directed platelet transfusions based on TEG PM may improve mortality and outcomes in TBI. PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Guillotte AR, Herbert JP, Madsen R, Hammer RD, Litofsky NS. Effects of platelet dysfunction and platelet transfusion on outcomes in traumatic brain injury patients. Brain Inj. 2018;32(13-14):1849–57.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Briggs A, Gates JD, Kaufman RM, Calahan C, Gormley WB, Havens JM. Platelet dysfunction and platelet transfusion in traumatic brain injury. J Surg Res. 2015;193(2):802–6.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Holzmacher JL, Reynolds C, Patel M, Maluso P, Holland S, Gamsky N, et al. Platelet transfusion does not improve outcomes in patients with brain injury on antiplatelet therapy. Brain Inj. 2018;32(3):325–30.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Jehan F, Zeeshan M, Kulvatunyou N, Khan M, O'Keeffe T, Tang A, et al. Is there a need for platelet transfusion after traumatic brain injury in patients on P2Y12 inhibitors? J Surg Res. 2019;236:224–9.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Baharoglu MI, Cordonnier C, Salman RA, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605–13.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Naidech AM, Liebling SM, Rosenberg NF, Lindholm PF, Bernstein RA, Batjer HH, et al. Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage. Neurocrit Care. 2012;16(1):82–7.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Garraud O, Cognasse F, Tissot JD, Chavarin P, Laperche S, Morel P, et al. Improving platelet transfusion safety: biomedical and technical considerations. Blood Transfus. 2016;14(2):109–22.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Baimukanova G, Miyazawa B, Potter DR, Gibb SL, Keating S, Danesh A, et al. The effects of 22 degrees C and 4 degrees C storage of platelets on vascular endothelial integrity and function. Transfusion. 2016;56(Suppl 1):S52–64.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Bode AP, Fischer TH. Lyophilized platelets: fifty years in the making. Artif Cells Blood Substit Immobil Biotechnol. 2007;35(1):125–33.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    • Lopez E, Srivastava AK, Pati S, Holcomb JB, Wade CE. Platelet-derived microvesicles: a potential therapy for trauma-induced coagulopathy. Shock. 2018;49(3):243–8 Identification of platelet extracellular vesicles as a potential new therapy. PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    • Miyazawa B, Trivedi A, Togarrati PP, Potter D, Baimukanova G, Vivona L, et al. Regulation of endothelial cell permeability by platelet-derived extracellular vesicles. J Trauma Acute Care Surg. 2019;86(6):931–42 Characterization of regulation of endothelium by platelet derived extracellular vesicles. PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    • Dyer MR, Alexander W, Hassoune A, Chen Q, Alvikas J, Liu Y, et al. Platelet-derived extracellular vesicles released after trauma promote hemostasis and contribute to DVT in mice. J Thromb Haemost. 2019. Large animal studies demonstrating effectiveness of synthetic platelet based therapy for hemorrhage control given after injury. Google Scholar
  53. 53.
    Hickman DA, Pawlowski CL, Sekhon UDS, Marks J, Gupta AS. Biomaterials and advanced technologies for hemostatic management of bleeding. Adv Mater. 2018;30(4).CrossRefGoogle Scholar
  54. 54.
    Lee DH, Blajchman MA, Ho TWC, et al. In vitro characteristics of thrombospheres, a novel hemostatic agent. Blood. 1995;86:902a.Google Scholar
  55. 55.
    Yen RKC, Ho T, Blajchman MA. A new hemostatic agent: thrombospheres shorten the bleeding time in thrombocytopenic rabbits. Thromb Haemost. 1995;73:986.Google Scholar
  56. 56.
    Levi M, Friederich PW, Middleton S, de Groot PG, Wu YP, Harris R, et al. Fibrinogen-coated albumin microcapsules reduce bleeding in severely thrombocytopenic rabbits. Nat Med. 1999;5(1):107–11.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Takeoka S, Okamura Y, Teramura Y, Watanabe N, Suzuki H, Tsuchida E, et al. Function of fibrinogen gamma-chain dodecapeptide-conjugated latex beads under flow. Biochem Biophys Res Commun. 2003;312(3):773–9.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol. 1996;12:697–715.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Hickman DA, Pawlowski CL, Shevitz A, Luc NF, Kim A, Girish A, et al. Intravenous synthetic platelet (SynthoPlate) nanoconstructs reduce bleeding and improve ‘golden hour’ survival in a porcine model of traumatic arterial hemorrhage. Sci Rep. 2018;8(1):3118.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Shukla M, Sekhon UD, Betapudi V, Li W, Hickman DA, Pawlowski CL, et al. In vitro characterization of SynthoPlate (synthetic platelet) technology and its in vivo evaluation in severely thrombocytopenic mice. J Thromb Haemost. 2017;15(2):375–87.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    • Dyer MR, Hickman D, Luc N, Haldeman S, Loughran P, Pawlowski C, et al. Intravenous administration of synthetic platelets (SynthoPlate) in a mouse liver injury model of uncontrolled hemorrhage improves hemostasis. J Trauma Acute Care Surg. 2018;84(6):917–23 Animal studies demonstrating effectiveness of synthetic platelet based therapy for hemorrhage control. PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of SurgeryUniversity of California San Francisco, Zuckerberg San Francisco General HospitalSan FranciscoUSA

Personalised recommendations