Two Steps Forward, One Step Back: The Questionable Practice of Reversal of Anticoagulation to Facilitate rt-PA Administration for Stroke


In the process of caring for patients suffering from acute ischemic stroke (AIS), a cognitive bias shifts the focus of our typical approach to drug therapy selection. Rather than approach a problem and determine whether a drug is going to help, in the case of alteplase for AIS, we often look for reasons not to give this drug (contraindications) and fail to ask whether the given patient will benefit. Fewer still will ask, what is the patient oriented benefit? This shift in clinical reasoning is highlighted in this case report describing the reversal of heparin in order to facilitate alteplase administration.(1) This cognitive bias is further reflected in framing of the issue of whether or not we are treating enough patients with alteplase, as described by the authors quoting epidemiologic data. This bias can be remedied by reflecting on the evidence to support the use of alteplase for AIS.


The only supporting evidence for alteplase in AIS comes to us from the NINDS-2 (NINDS 1 & 2, two studies published in one manuscript) and ECASS-3.(2,3) In these studies, the benefits observed were improvement in functional neurologic outcomes at 90 days.  These improvements are not to be confused with a return to baseline function or a curative intervention. Furthermore, NINDS-1 failed to demonstrate superiority of alteplase in improving NIHSS by at least 4 points or neurologic recovery at 24 hours. If you continued to line up the studies where alteplase failed to show improvement in primary outcomes or was stopped early due to futility you have a list including: ECASS-1, ECASS-2, ATLANTIS-A, ATLANTIS-B.(4-7) Not to mention the curious results of the uncontrolled, analysis of registry data ITS-3 study.(8)  However, pause to consider the risk versus benefit: reduction in disability versus intracranial hemorrhage (fatal or not).  Furthermore, these potential harms are the best case scenario given the strict inclusion and exclusion criteria from these studies. In practice, each time we venture outside, we increase the risk of harm without proven increase in potential benefit.(9,10,11,12,13)


When faced with almost certain peril, Dr Ian Malcolm asked “[you] scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should.”(14)  While this quote refers to the genetic engineering and creation of dinosaurs in a fictional story, it cuts through to the core of the issue described in this case. Stroke care has been rapidly advanced in recent years and the patient population exposed to alteplase continues to increase. While we continue to see the strict inclusion and exclusion criteria for this drug slip away, we must remember to stop and think although we can treat this patient with alteplase, should we?


I read with great interest the case report presented by Drs. Fontaine and Smith where a patient was treated with protamine sulfate to reverse unfractionated heparin in order to administer alteplase for AIS following a percutaneous coronary intervention (PCI). It is worth noting that the prasugrel, aspirin and tirofiban that were administered during PCI were not attempted to be reversed. An analysis of 965 patients treated with alteplase found that dual antiplatelet therapy was associated with a significantly increased risk of symptomatic intracranial hemorrhage.(15) In this case, the patient experienced what the authors’ described as a favorable outcome with a modified rankin score of 3 at three months follow up. This outcome would not be included in the primary endpoints of favorable neurologic outcome in either the NINDS-2 or ECASS-3, as scores of 2 or greater were considered “unfavorable” in these trials. While a modified rankin score improvement from 5 to 3 at three months is a positive finding, one should not attribute this outcome to alteplase without acknowledging the improvements made in the totality of stroke rehabilitation care.


This trend in reversing anticoagulant therapy in order to administer alteplase for acute ischemic stroke is troubling given the lack of evidence to support safety and efficacy. Given the minute clinical patient oriented outcome benefits with alteplase for AIS, using reversal strategies to facilitate thrombolytic therapy should not be conducted outside of research settings.


Craig Cocchio, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
CHRISTUS Trinity Mother Frances Health System


Kyle DeWitt, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
The University of Vermont Medical Center


Scott Deitrich, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
Poudre Valley Hospital




  1. Fontaine, G. V. and Smith, S. M. Alteplase for acute ischemic stroke after heparin reversal with protamine – a case report and review. Pharmacotherapy. Accepted Author Manuscript
  2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995 Dec 14;333(24):1581-7
  3. Hacke W, Kaste M, Bluhmki E, et al.Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29
  4. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995 Oct 4;274(13):1017-25.
  5. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.Lancet. 1998 Oct 17;352(9136):1245-51
  6. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke 2000 Apr;31(4):811-6
  7. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.JAMA. 1999 Dec 1;282(21):2019-26.
  8. IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012 Jun 23;379(9834):2352-63.
  9. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke. 2003 Dec; 34(12):2847-50.
  10. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. March 1 2000;283(9):1145–1150.
  11. Lopez-Yunez AM, Bruno A, Williams LS, et al. Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke. January 2001;32(1):12–16.
  12. Tsivgoulis G, Frey JL, Flaster M, et al. Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke. November 2009;40(11):3631–3634.
  13. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med. 2002;162:1994–2001.
  14. Cucchiara B, Kasner SE, Tanne D, et al. Factors associated with intracerebral hemorrhage after thrombolytic therapy for ischemic stroke: pooled analysis of placebo data from the Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II Trials. Stroke. 2009 Sep;40(9):3067-72.

What I Bring When Attending A Code

Pharmacists have been shown to improve adherence to advanced cardiovascular life support (ACLS) guidelines (1,2), and pharmacist involvement adds instant drug expertise during intense situations. Not to mention, the multidisciplinary team wants us there at the bedside. Nurses and providers surveyed have overwhelmingly (97%) believed that having a pharmacist present during a medical resuscitation enhances their ability to deliver safe, quality care to patients.(3) The large amount of code cart drugs suffering from national shortages has added an additional spotlight to pharmacists attending codes.

First things first, you should know your code cart inside and out. Inside and out being very much figurative and literal. Take the time to go through each drawer, medication, piece of supply, and refresh your memory on how to use the defibrillator.

Knowing your code cart like the back of your hand allows the code to run smoother and other team members to focus on emergent procedures, compressions, IV/IO placement, recording, etc. This includes knowing where supplies is located and what each one is used for (e.g. Bougie, blade differences, endotracheal tube sizes, 3-way stopcock, defibrillator pads, pressure-bag). Since I know which drugs and equipment are unavailable in the code cart, bringing supplies is imperative to my emergency medicine (EM) game.

Syringes, Needles, Flushes

While all are in our code cart (except an appropriate 20 mL syringe for some odd reason), restocking a code cart is a pain for the emergency department (ED), sterile processing, materials management, and pharmacy staff. Most would prefer not to “crack” the code cart open if it can be prevented and this is generally good news for the patient. By having these available ahead of time, if it is determined we need “x” drug STAT, such as rapid sequence intubation (RSI) medications or push dose pressors, we are ready to go. I will usually bring a 3 mL, 6 mL, 10-12 mL (x2), and a 20 mL syringe.

When the time comes for medication infusion a smart pump should be available (a pole as well if your patient bed does not have a built-in or if the area is overcrowded). This is a great opportunity to ask somebody outside the room for retrieval while you focus on other pressing issues if these are not readily accessible. Personally, I often use the volunteer onlookers or a curious looky loo for this purpose.

*Our code carts are stocked with 3-way stopcocks [20 mL syringe is handy for SVT] and transfer devices; if yours is not, consider bringing these devices, as they will especially be useful for pediatric codes.

RSI Kit 

Often the patient is being bagged by EMS and/or has a laryngeal mask airway (LMA) placed and will still require proper intubation. Standing there with your syringes and needles, along with your institutional RSI kit, you are ahead of the game and ready to go. This will prevent having to rush to the Pyxis/Omnicell/random-box-in-the-corner to retrieve the medication.

Alteplase 50 mg Vial

Having this stocked in your ED, you can prevent a wasted 50 mg from the 100 mg vial ($3900 saved!). Give a blast of alteplase if the cause of cardiac arrest is thought to be secondary to pulmonary embolism or ST-elevated myocardial infarction with no access to the catheterization lab or for some reason the catheterization lab cannot be ready in an appropriate amount of time.(4) We prefer the 50 mg bolus dose during a code situation, which can be followed by another 50 mg if necessary 30 minutes later. A lot can happen in 30 minutes during a code. Here’s a 2013 ALiEM post on the tPA code dosing.


Esmolol 

EMPharmD has previously discussed the utility of esmolol after ACLS measures have failed in refractory ventricular fibrillation and pulseless ventricular tachycardia. As a reminder, since you should be doing the defibrillations (you are ACLS-certified after all, right?), after 2 shocks have been given (don’t forget EMS defibrillations), consider using esmolol and how you plan to dose and prepare after a third shock. You will likely be the only one in the room that knows how to dose and prepare and esmolol infusion for this indication.

Lazer-Focus 


When walking into a room for a resuscitation be ready to anticipate the team and patient needs, listen to everything, prepare epinephrine/norepinephrine infusions, and cycle in your head the appropriate ACLS algorithm and H’s & T’s (Hypovolemia, Hypoxia, Hydrogen ion, Hyper-/hypokalemia, Hypothermia, Toxins, Tamponade,Tension pneumothorax, Thrombosis) and how to treat. Since every patient is different, often with limited information, numerous challenges are faced during cardiac arrest. Having a pharmacist who is prepared and can anticipate the needs of the team serves the patient well and puts the pharmacy profession in a positive light.

Short-Term Amnesia 

Bring this to a limited extent, as you should review what could have been done differently and what can be learned from the code, but the stark reality is that you were bedside with a human being just pronounced dead. This can be a heavy burden and have found that short-term amnesia helps to continue moving forward for the next patient. Remember, this patient was going to die without your help, but with it, they had a better shot. 

It should be mentioned that formal debriefing implementation after a code has been found to increase the feeling of support among peers and leaders, pay homage to the patient that has passed, and give a brief pause to reflect prior to resuming normal activities within the ED (5).

If your facility does not have a formalized process, the debriefing or lack thereof, will be provider-dependent. As a pharmacist training students and residents, if the provider does not offer a debriefing, I believe it is in our due diligence to offer our trainees one such session. If you are on your own, consider speaking with fellow team members, and more often than not, they will debrief with you.

Leave the Ego 

There will be times when the team does not know you (responding to a code on an unfamiliar floor or new to the department). The crystal-baller approach can work wonders in these scenarios. In addition, you already brought additional supplies you may need to the code. It is not unreasonable that the team has never had a pharmacist attend a code before and members may be unsure of what role you can play. Introduce yourself to the team and state that you are available. Sometimes you may be late to the party, but in this case, I would recommend introducing yourself to the person at the code cart and offer to help. At this point, if you are pushed away, consider making infusions and on-the-ready for anything called out that is unavailable in the code cart. During the debriefing (if applicable), introduce yourself again to the team and what role you could play in the future. After a few saves and anticipatory wins, you will likely have gained the team’s trust; try not to lose it.

Being forceful and arrogant in situations already intensified with stress and high-stakes often leads to defensive nurses and providers. When the team may be annoyed by your presence, even if you are the best pharmacist in the world, the patient care you can contribute will be significantly diminished. Consider this impact and be highly cautious of the 'guns a’ blazin’' approach with a new team.

Conclusion 

Undoubtedly, the first codes an inexperienced pharmacist attends will be scary, uncomfortable, and likely involve the “deer-in-the-headlights” look. However, with appropriate preparation and a repertoire of experience, the pharmacist becomes an integral and highly appreciated code team member. Make the profession proud!

Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner University Medical Center
Phoenix, Arizona

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

Sample of our institution’s medication tray in the Adult Code Cart - WITHOUT SHORTAGES

6
Epinephrine 1mg/10ml SYR
4
Atropine 1mg/10ml SYR
2
Calcium Chloride 10% 1gm/10ml SYR
2
Lidocaine 100mg/5ml SYR
1
Etomidate 40mg/20ml SYR
1
Sodium Bicarbonate 8.4% 50ml SYR
1
Dextrose 50% 50ml SYR
1
Flumazenil 1mg/10ml
1
Vecuronium 10 mg
5
Adenosine 6mg/2ml
2
Vasopressin 20units/ml
2
Naloxone 0.4mg/ml
1
Epinephrine 30mg/30ml MDV
4
Magnesium Sulfate 1gm/2ml
4
Norepinephrine 4mg/4ml
4
Amiodarone 150mg/3ml
1
Lidocaine 2% 5ml Jelly
1
Epinephrine 1mg/ml SubQ Administration Kit
1
Dopamine 400mg/250ml

References:

1. Draper HM, Eppert JA. Association of pharmacist presence on compliance with advanced cardiac life support guidelines during in-hospital cardiac arrest. Ann Pharmacother. 2008;42(4):469–74.
2. Hashemipour Z, Delgado G, Jr, Dehoorne-Smith M, Edwin SB. Pharmacist integration into cardiac arrest response teams. Am J Health Syst Pharm. 2013;70(8):662, 664, 666–7. 
3. Fairbanks RJ, Hildebrand JM, Kolstee KE, et al. Medical and nursing staff highly value clinical pharmacists in the emergency department. Emerg Med J. 2007;24(10):716–9.
4. Böttiger B, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet. 2001;357(9268):1583-1585.
5. Copeland D, Liska H. Implementation of a Post-Code Pause: Extending Post-Event Debriefing to Include Silence. J Trauma Nurs. 2016;23(2):58-64.

TXA Isn’t For Everyone: Fibrinolysis Shutdown in Traumatically Injured Patients

Tranexamic acid (TXA), an antifibrinolytic agent used to prevent clot breakdown in hemorrhaging trauma patients, has been shown in the CRASH-2, MATTERS, and PED-TRAX trials to reduce overall mortality in adult and pediatric patients.1-3 Additional mortality benefits were seen in the MATTERS trial among patients who received a massive transfusion protocol (MTP) with a number needed to treat (NNT) of 15 in the overall cohort compared to a NNT of 7 in MTP cohort.2 Although CRASH-2 is not without its criticism,4 TXA has been widely recommended for the treatment of traumatically injured patients.5 However, recent trials in mature trauma systems have shown conflicting results for mortality and increased rates of venous thromboembolism (VTE) with TXA.6-8


table 2.pngViscoelastic assays, such as thromboelastography (TEG) or rotational thromboelastometry (ROTEM), are becoming increasingly popular tools to guide resuscitation compared to older, less helpful tests, such as aPTT and PT/INR. Both Taming the SRU9 and LITFL10 have excellent reviews of TEG, but briefly, TEG measures the dynamics of clot development, stabilization/strength, and dissolution providing a glimpse into a patient’s real-time hemostatic state.10 Emerging research utilizing TEG has identified 3 distinct fibrinolysis phenotypes among traumatically injured patients: hyperfibrinolysis, physiologic fibrinolysis  (i.e., normal), and fibrinolysis shutdown.11,12 These phenotypes are based on the Ly30 which measures the percentage of clot lysis 30 minutes after maximum amplitude (see Table 1).11



Hyperfibrinolysis patients have high levels of circulating endogenous tissue plasminogen activator (tPA) compared to fibrinolysis shutdown patients whose majority of tPA is complexed with plasminogen activator inhibitor 1 (PAI-1) resulting in undetectable free tPA levels.13  Moore et al completed a bi-institutional study of two Level 1 Trauma Centers who analyzed rapid TEGs drawn within 1 hour of injury in severely injured patients, defined as an Injury Severity Score (ISS) of greater than 15, in attempts to identify a fibrinolysis spectrum and determine effects of fibrinolysis phenotypes on post-injury outcomes.12 Patients were excluded if they were on anticoagulant therapy or received antifibrinolytics prior to TEG. A total of 2,540 patients were analyzed with a median ISS of 25 and an overall mortality of 21%. Fibrinolysis shutdown was the most common phenotype seen in 46% of patients, followed by physiologic fibrinolysis in 36%, and hyperfibrinolysis in 18%.  Mortality was highest in hyperfibrinolysis patients (34%), followed fibrinolysis shutdown (23%) and physiologic fibrinolysis (15%). Hyperfibrinolysis patients were more likely to expire early from hemorrhage compared to either other group. Fibrinolytic shutdown patients on the other hand, tended to have delayed mortality secondary to traumatic brain injury or organ dysfunction.12


Meizoso et al completed another study comparing TEGs drawn upon ICU admission to results drawn 1 week later among 182 traumatically injured patients. They also identified fibrinolysis shutdown as the most common phenotype (58%) compared to only 4% of patients with hyperfibrinolysis. After 1 week, 78 patients had an additional TEG drawn showing 44% of patients were in “persistent shutdown” and 56% had an improvement in their Ly30 and were categorized as “transient shutdown.” Both persistent and transient shutdown groups has similar ICU and hospital length of stays, but the persistent shutdown group experienced significantly higher mortality (21% vs 5%).14


Meizoso et al’s results echo those of Moore et al in that fibrinolysis shutdown was the most common phenotype seen amongst severely injured trauma patients. However, Meizoso’s much lower proportion of patients with hyperfibrinolysis is likely attributed to the time in which the TEGs were drawn. Moore’s were drawn within 1 hour of injury compared to Meizoso’s drawn at the time of ICU admission. A TEG drawn at ICU admission reflects post-resuscitation hemostasis, and combined with the potential for survivor bias (as we know hyperfibrinolysis patients are at increased risk for early mortality due to exsanguination) likely resulted in the much lower incidence of hyperfibrinolysis seen in Meizoso’s cohort compared to Moore’s (4% vs 18%).


So where does TXA fit into current trauma resuscitation? If we assume almost half of all trauma patients coming to our trauma bay are in fibrinolysis shutdown, the subsequent empiric administration of TXA without a TEG result seems risky.  Data from mature trauma systems have shown TXA to only be of benefit in shocked patients8  but based on the work by Moore et al, patients in shock can be hyperfibrinolytic or in fibrinolysis shutdown.11,12 Data are still conflicting regarding injury mechanisms predisposing patients to one particular phenotype.12,14 Per Moore et al, it “remains unclear why patients with a similar degree of shock and injury severity could have substantially different levels of fibrinolysis.”13 Rapid TEG is the only way to reliably identify patients who may potentially benefit from the administration of TXA (i.e., hyperfibrinolysis; currently unknown if physiologic fibrinolysis would benefit) and which patients may potentially be harmed (fibrinolysis shutdown).


This raises the question, should all TXA be withheld until after TEG results are available? Pre-hospital TXA administration is increasing.15 Are we doing our patients a disservice by administering a therapy which will potentially further worsen their hemostasis? Or does early administration of TXA offer more benefit (and therefore outweigh the risk of administration to patients in fibrinolysis shutdown) than if given later when TEG results have been drawn and resulted? The PATCH Study16and STAAMP Trial17 are currently recruiting patients in attempt to answer this question. Additionally, the COAST Score18 is a prehospital tool under study in Queensland, Australia which seeks to identify patients more likely to develop acute traumatic coagulopathy. The score ranges from 0-7 with points based on blood pressure, temperature, vehicular entrapment, presence of major chest injury, and potential for intraabdominal or pelvic injury.  A score of > 3 is “a good predictor of patients requiring TXA.” However, as stated above, patients with similar injury patterns and shock can still have different fibrinolysis phenotypes so this tool may not be completely accurate.


There is unfortunately little data regarding the use of TXA based on in-hospital TEG results. The best so far was a retrospective review completed by Harvin et al which identified traumatically injured patients with an admission Ly30 > 3% (i.e., hyperfibrinoloysis) stratified by the administration of TXA or not. Similar to Meizoso’s study, only 6% of the total trauma population was found to be in hyperfibrinolysis on admission and was included for analysis (1,032 of 17,629 patients). Although the TXA group was more severely injured, had a lower GCS and BP, received more blood products, and were more likely to go immediately to the operating room, after multivariate adjustment there was no difference in in-hospital mortality between groups. Additionally, there was no difference in the repeat Ly30s between TXA and non-TXA treated patients (repeat Ly30 median 0.0% vs 0.4%, respectively, p=0.096). Even in the population most likely to benefit from TXA (as all patients were hyperfibrinolytic), TXA therapy did not improve outcomes and the non-TXA treated patients had similar resolution of their hyperfibrinolytic state based on repeat Ly30s. As a result, the authors conclude that “the effectiveness of TXA in mature Level 1 trauma center[s] with rapid prehospital transport, access to early blood products, and a ready operating room is unclear.”19


Also, does the 3-hour window of time of injury to TXA administration from the CRASH-2 exploratory analysis still apply?20 We know patient’s fibrinolysis phenotype can change during the course of their resuscitation and hospital stay.14,19 Would a prolonged state of hyperfibrinolysis beyond 3 hours from time of injury exclude them from a potentially life-saving therapy? CRASH-2 patients were a different population compared to Moore and Meizoso’s patients, so can you extrapolate those results to these populations?


Additionally, does the dosing protocol from CRASH-2 (1 g bolus followed by 1 g over 8-hours) still make sense? As stated, patient’s fibrinolysis phenotypes change during resuscitation. Patients who present to the ED in one phenotype may soon be in fibrinolysis shutdown in the ICU and an 8-hour infusion of TXA would not be wise. A recent “Commentary and Conversation: Interactive Social Media Discussion about Persistent Fibrinolysis Shutdown” was held by the Journal of the American College of Surgeons and published online21 on April, 25 2017. Dr. Karim Brohi himself had this to say: “Regarding the necessity of a second TXA dose, probably not. No published studies, but our local data suggests [an] initial 1 g bolus sufficient in [the] vast majority of cases.”


Or, is all this over-exaggerated? Should we base our therapeutic decisions for TXA on the results of a trial with over 20,000 patients instead of studies with one-tenth (or less) that number? Obviously additional studies are needed with prospective, randomized, TEG-driven protocols, but unfortunately, at this point we may have more questions than answers. Maybe the most important question now is whether or not this data will result in any change in how you think about TXA in your trauma patients? I know it has for me.



Scott Dietrich, PharmD
@PCC_PharmD
Emergency Medicine Pharmacist
University of Colorado Health – North




References:
  1. CRASH-2 Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusions in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial. Lancet. 2010;376(9734):23-32
  2. Morrison JJ, Dubose JJ, Rasmussen TD, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERS) study. Arch Surg. 2012;147(2):113-119
  3. Eckert MJ, Wertin TM, Tyner SD, Nelson DW, Izenberg S, Martin MJ. Tranexamic acid administration to pediatric trauma patients in a combat setting: the pediatric trauma and tranexamic acid study (PED-TRAX). J Trauma Acute Care Surg. 2014;77(6):852-858
  4. Binz S, McCollester J, Thomas S, Miller J, Pohlman T, Waxman D, Shariff F, Tracy R, Wash M. CRASH-2 study of tranexamic acid to treat bleeding in trauma: a controversy fueled by science and social media. J Blood Transf. 2015;2015:874920
  5. SMACC “Karim Brohi on tranexamic acid in trauma.” https://www.smacc.net.au/2015/10/karim-brohi-on-tranexamic-acid-in-trauma/ [accessed 5/4/2017].
  6. Swendsen H, Galante J, Utter G, Bateni S, Scherer L, Schermer C. Tranexamic acid use in trauma: effective but not without consequences. J Trauma & Treatment. 2013;2(4)
  7. Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, livingstone AS, Namias N, Schulman CI, Proctor KG. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76(6):1373-1378
  8. Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg. 2015;261(2):390-394
  9. Hill J. Thromboelastography aka The TEG. Aug, 16 2015.  http://www.tamingthesru.com/blog/grand-rounds/teg
  10. Nikson C. Thromboelastogram (TEG). July, 11 2014. https://lifeinthefastlane.com/ccc/thromboelastogram-teg/
  11. Moore et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown - spectrum of post-injury fibrinolysis and relevance to TXA therapy -- J Trauma. 2014;77(6):811-817
  12. Moore et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality -- J Am Coll Surg. 2016;222(4):347-355
  13. Moore HB, Moore EE, Gonzalez E, Hansen KC, Dzieciatkowska M, Chapman MP, Sauaia A, West B, Banerjee A, Silliman CC. Hemolysis exacerbates hyperfibrinolysis, whereas plateolysis shuts down fibrinolysis: evolving concepts of the spectrum of fibrinolysis in response to severe injury. Shock. 2015;43(1):39-46.
  14. Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg. 2017;224(4):575-582
  15. Napolitano LM. Prehospital tranexamic acid: what is the current evidence? Trauma Surg and Acute Care Open. 2017;2:1-7
  16. Clinicaltrials.gov, “Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH Study).” https://clinicaltrials.gov/ct2/show/NCT02187120
  17. Clinicaltrials.gov, “Study of Tranexamic Acid During Air Medical Prehospital Transport Trial (STAAMP Trial).” https://clinicaltrials.gov/ct2/show/NCT02086500
  18. Clinical Quality & Patient Safety Unit. “Clinical Practice Procedures: Assessment/COAST score.” October, 2016. https://www.ambulance.qld.gov.au/docs/clinical/cpp/CPP_COAST%20score.pdf
  19. Harvin JA, Pierce CA, Mims MM, Hudson JA, Podbielski JM, Wade CE, Holcomb JB, Cotton BA. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015;78(5):905-909
  20. CRASH-2 Collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomized trial. Lancet. 2011;377(9771):1096-1101
  21. Commentary and Conversation: RAS-ACS and JACS Hosted Interactive Social Media Discussion about Persistent Fibrinolysis Shutdown. April 7, 2017. http://www.journalacs.org/RAS-ACS-discussion-2017-04