Traumatic Brain Injury

Early Platelet Dysfunction Following Traumatic Brain Injury

In the United States alone, 52,000 deaths occur due to traumatic brain injury (TBI). As a result of TBI, there are 275,000 hospitalizations and 1.365 million emergency department visits per year. TBI is a contributing factor to a third of all injury-related deaths in the US.

Acute coagulopathy is a serious complication of TBI, and is of uncertain etiology due to the complex nature of TBI. However, recent work has shown a correlation between mortality and abnormal hemostasis due to early platelet dysfunction. The goal of the current study is to develop and characterize a rodent model of TBI that mimics the human coagulopathic condition, so that mechanisms of the early acute coagulopathy in patients with TBI can be more readily assessed. Studies in rats demonstrate a strong correlation with important post-injury pathological changes that are observed in human TBI patients, viz., diminished platelet responses to agonists, especially ADP, while platelet counts remain in normal ranges, and subarachnoid bleeding. Additionally, administration of a direct thrombin inhibitor, pre-injury, recovers platelet functionality to ADP stimulation, indicating a direct role for excess thrombin production in TBI-induced early platelet dysfunction.

Currently, collaborative efforts between the W.M. Keck Center and Memorial Hospital are in the process of correlating observations from the rodent model and human TBI patients. Both human and rodent samples are being used to further our understanding of the mechanisms of platelet dysfunction. The clear dysfunction of ADP-induced platelet activation in severe head trauma patients has led to a greater defined clinical point-of-care approach. This has enabled physicians at Memorial Hospital to improve patient prognoses both short and long term.

Platelet mapping expressed as percent platelet response induced by (A) ADP; (B) AA; (C) P AR-4 agonist; (D) summarized values
Platelet mapping expressed as percent platelet response induced by (A) ADP; (B) AA; (C) P AR-4 agonist; (D) summarized values. Statistical analysis was performed using an unpaired t-test by comparing a specific post-injury time to the control.

Subarachnoid blood pools 1 hr post-injury in TBI-induced rats
Subarachnoid blood pools 1 hr post-injury in TBI-induced rats. Representative 4 ìm coronal sections of control (A,C) and 1 hr post-injury (B,D) rat brains. Arrows indicate bleeding in the subarachnoid space of the injured brain. Images were scanned at 40X magnification and zoom magnified at 1.2X for A, B and 4.5X for C, D.

Links: Traumatic Brain Injury; Brain Injury Association of America (BIAA); TBI Treatments; Platelet Dysfunction

References

Davis PK, Musunuru H, Walsh M, Cassady R, Yount R, Losiniecki A, Moore EE, Wohlauer MV, Howard J, Ploplis VA, Castellino FJ, Thomas SG. Platelet dysfunction is an early marker for traumatic brain injury-induced coagulopathy. Neurocrit Care. 2013 Apr;18(2):201-8. doi: 10.1007/s12028-012-9745-6. PMID:22847397

Davis PK, Musunuru H, Walsh M, Mitra R, Ploplis V, Castellino FJ. The ex vivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: mechanistic implications for clinical medicine. Thromb Haemost. 2012 Sep;108(3):586-8. doi: 10.1160/TH12-04-0222. Epub 2012 Jul 10. PMID:22782135

Wohlauer MV, Moore EE, Thomas S, Sauaia A, Evans E, Harr J, Silliman CC, Ploplis V, Castellino FJ, Walsh M. Early platelet dysfunction: an unrecognized role in the acute coagulopathy of trauma. J Am Coll Surg. 2012 May;214(5):739-46. doi: 10.1016/j.jamcollsurg.2012.01.050. PMID:22520693

Walsh M, Thomas SG, Howard JC, Evans E, Guyer K, Medvecz A, Swearingen A, Navari RM, Ploplis V, Castellino FJ. Blood component therapy in trauma guided with the utilization of the perfusionist and thromboelastography. J Extra Corpor Technol. 2011 Sep;43(3):162-7. Review. PMID:2216445

Castellino FJ, Chapman MP, Donahue DL, Thomas S, Moore EE, Wohlauer MV, Fritz B, Yount R, Ploplis V, Davis P, Evans E, Walsh M. Traumatic brain injury causes platelet adenosine diphosphate and arachidonic acid receptor inhibition independent of hemorrhagic shock in humans and rats. J Trauma Acute Care Surg. 2014 May;76(5):1169-76. doi: 10.1097/TA.0000000000000216. PMID:24747445

Ploplis VA, Donahue DL, Sandoval-Cooper MJ, MorenoCaffaro M, Sheets P, Thomas SG, Walsh M, Castellino FJ. Systemic Platelet Dysfunction Is the Result of Local Dysregulated Coagulation and Platelet Activation in the Brain in a Rat Model of Isolated Traumatic Brain Injury. J Neurotrauma. 2014 May 21. [Epub ahead of print]. PMID:24605991

Donahue DL, Beck J, Fritz B, Davis P, Sandoval-Cooper MJ, Thomas SG, Yount RA, Walsh M, Ploplis VA, Castellino FJ. Early platelet dysfunction in a rodent model of blunt traumatic brain injury reflects the acute traumatic coagulopathy found in humans. J Neurotrauma. 2014 Feb 15;31(4):404-10. doi: 10.1089/neu.2013.3089. Epub 2013 Nov 21. PMID:24040968

Mamczak CN, Maloney M, Fritz B, Boyer B, Thomas S, Evans E, Ploplis VA, Castellino FJ, McCollester J, Walsh M. Thromboelastography in Orthopaedic Trauma Acute Pelvic Fracture Resuscitation: A Descriptive Pilot Study. J Orthop Trauma. 2016 Jun;30(6):299-305. doi: 10.1097/BOT.0000000000000537. PMID: 27206253 [PubMed - in process]

Yasui H, Donahue DL, Walsh M, Castellino FJ, Ploplis VA University Of Notre Dame. Early coagulation events induce acute lung injury in a rat model of blunt traumatic brain injury. Am J Physiol Lung Cell Mol Physiol. 2016 May 17:ajplung.00429.2015. doi: 10.1152/ajplung.00429.2015. [Epub ahead of print]  PMID: 27190065 [PubMed - as supplied by publisher]

Walsh M, Fritz S, Hake D, Son M, Greve S, Jbara M, Chitta S, Fritz B, Miller A, Bader MK, McCollester J, Binz S, Liew-Spilger A, Thomas S, Crepinsek A, Shariff F, Ploplis V, Castellino FJ. Targeted Thromboelastographic (TEG) Blood Component and Pharmacologic Hemostatic Therapy in Traumatic and Acquired Coagulopathy. Curr Drug Targets. 2016;17(8):954-70.  PMID: 26960340 [PubMed - in process]