REVIEW OF TRANEXAMIC ACID IN TRAUMA At the bottom of this article are the links to a couple of pretty good recent reviews about the current state of TXA. But first a bit of background. Coagulopathy in trauma It has long been accepted that coagulopathy is frequent in severe trauma. Traditional explanations for this have included: Dilution of clotting factors and platelets (secondary to IV fluid) Hypothermia (the clotting factors are temperature sensitive enzymes that function optimally at 37 degrees, and decrease in efficacy by approximately 10% for every degree below 37 degrees) Hypocalcaemia (due to the citrate added to stored blood) Impaired liver perfusion and synthesis of new clotting factors. These mechanisms are part of the explanation. It is for this reason we have recently developed Massive Transfusion Protocols (which ensure all the required ingredients for a massive transfusion are ordered, made available, and administered in a timely fashion). It is also one reason for the recent drive to avoid hypothermia in the setting of trauma cold patients don t clot. Acute Coagulopathy of Trauma (ACoT) Recent work by Karim Brohi has demonstrated another important mechanism. He has termed this Acute Coagulopathy of Trauma. In essence, the trauma and associated shock induces a coagulopathy. The coagulopathy is NOT due to dilution or hypothermia. Brohi is a great thinker and a clear speaker. Get to his presentation if he is ever speaking at a conference. His paper is heavy going, but the reference is here for those interested Brohi, K; Cohen, M J; Ganter, M T; Schultz, M J; Levi, M; Mackersie, R C; Pittet, J F (2008). Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. Journal of Trauma, 64(5):1211-1217. ACoT is due to a number of direct actions of shock on the coagulation system. The exact details are fairly complicated (like most of coagulation). They include Increased thrombomodulin levels. Thrombomodulin binds with thrombin, and prevents it from converting fibrinogen to fibrin the final step in the cascade. This means there is little fibrin (clot) production irrespective of clotting factor activity earlier on in the coagulation cascade. Thrombomodulin also activates protein C, which inactivates the active forms of factors V and VIII (i.e. factors Va and VIIIa) Release of tissue Plasminogen Activator (tpa) from the vascular endothelium The net effect of ACoT is anticoagulation and hyperfibrinolysis hardly what you would want in severe trauma!
ACoT is common it is present in up to 25% of patients with significant trauma upon ED arrival. ACoT is very acute. In Brohi s study of 208 patients, the mean prehospital time was 28 minutes and ACoT was present on ED arrival. The mean volume of prehospital IV was only 150ml that didn t dilute anything, and this fact alone confirms other mechanisms. How do you know if your patient has ACoT? Well, standard clotting tests (INR and APPT) don t help in addition to being slow to perform, they don t measure the part of the coagulation system relevant to ACoT. Fortunately, we have a very rapid and readily available blood test that indicates whether ACoT is likely to be present.base deficit. ACoT is very rare with a base deficit < 6. It is much more common (perhaps 20%) with a base deficit > 6. Note that an elevated base deficit does not confirm ACoT, but a normal base deficit virtually excludes ACoT. So do a blood gas ASAP on all serious trauma cases in two minutes you know whether you may have a clotting problem. What do you do about ACoT? Unfortunately the answer is not 100% clear at this time. As ACoT is due to shock per se, the treatment would seem to be to correct shock ASAP and turn off the stimulus for ACoT. Quite how we balance this with the earlier drive for minimum volume resuscitation (hypotensive resuscitation) requires further work. All would agree with ASAP stopping ongoing hemorrhage (internal or external). The best blood to give the patient is the blood they have not lost yet. So control of hemorrhage is a priority. Splint fractures. Apply pressure or pack or suture wounds quick stitches with a large suture are just fine, plastics can tidy up later. Interventional radiology. Theatre. With regard to fluid resuscitation, the current trend is to: 1. Use blood early (rather than after lots of saline) 2. Give more and earlier clotting factors and platelets that previously. So activate the massive transfusion protocol. Note that ACoT represents a block in the final stage of coagulation and also the initiation of fibrinolysis, so administration of clotting factors may not help. ACoT is not due to lack of clotting factors. Despite this, you should activate the massive transfusion protocol. When all you have is a hammer Avoiding hypothermia is important. The last thing to consider is minimizing fibrinolysis. And that brings us to TXA.
Tranexamic Acid and fibrinolysis Our body has its intrinsic fibrinolysis (clot breakdown) system. Key components of fibrinolysis include TPA (from which we derived recombinant TPA), antithrombin, thrombomodulin, protein C, protein S, and plasminogen. Clotting is a delicate and complicated balance between coagulation (fibrin formation) and fibrinolysis. Normally these 2 processes are in equilibrium. Fibrinolysis is initiated by coagulation, and is thus a form of negative feedback to prevent excessive clotting. The overall picture is of rapid and effective clotting (due to the amplification of the clotting cascade), but with self-initiated negative feedback (via fibrinolysis) to prevent excessive and unopposed clotting with depletion of clotting factors. It s a bit like driving with one foot on the accelerator and the other on the brake not necessarily great for the car, but does allow precise control of speed. So a degree of fibrinolysis is essential. And derangements of fibrinolysis (such as protein C deficiency) are associated with excessive rates of thrombosis (eg DVT). As discussed above, part of ACoT is excessive fibrinolysis. Clots are broken down prematurely and bleeding resumes. This is a clinical picture dreaded by surgeons hemostasis is achieved in one area of the abdomen, attention turns elsewhere, and shortly thereafter the first area starts bleeding again. When you see this, you almost certainly have ACoT and fibrinolysis. You almost certainly also have a hypothermic acidotic patient it is time to get out quickly, take the patient to ICU, optimize the patient, and come back and fight another day. This is termed Damage Control Surgery and has been a major advance in trauma management over recent years. Anyway, how can we reduce fibrinolysis if it is excessive? TXA. This is a synthetic analog of lysine. It works by blocking the conversion of plasminogen to plasmin. Plasmin is what breaks down fibrin (to FDPs fibrin degradation products). TXA is an old drug, first used > 50 years ago. However two recent studies have given new insights into the role of TXA in trauma. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) 20,211 patients, prospective RCT, multinational study (mostly developing countries). This showed TXA led to an absolute all cause reduction inn mortality from 16.0 to 14.5% (NNT 67). This means one live saved if you give TXA to 67 patients. That is pretty good for a very cheap drug accessible to all countries. However there were many concerns raised about CRASH2: 1. This reduction in all-cause mortality was attributable to a reduction in death due to bleeding. Rates of other causes of death were same in both groups. 2. However this TXA group didn t receive fewer units of blood, and didn t seem to have higher rates of thromboembolic problems. Hence TXA didn t actually seem to be doing much of anything to the clotting system. Some people have speculated that the benefit of TXA may be as an anti-inflammatory rather than
effects on fibrinolysis. 3. Very large study, but most patients were in developing countries. Lots of important things were not measured - injury severity, presence of fibrinolysis, administration of clotting factors. were not recorded. 4. Questions were also raised whether follow up was really as good as claimed (almost 100%) and hence whether there was under-reporting of complications such as DVT. 5. US researchers in particular doubted the benefit would exist in 1st world settings with ready access to advanced definitive hemorrhage control. Maybe TXA was only useful in a resource poor setting. 6. Many patients were not seriously injured, and only 50% received any blood at all. So we are looking at difference in mortality despite many patients not being critically injured. The other really odd thing about CRASH was that is was pretty good if given < 1 hour after injury and still fairly good if given 2-3 hours after injury. However it was bad if given > 3 hours after injury - the TXA group had a higher mortality due to bleeding if they received TXA > 3 hours. MATTERs (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study) US/UK retrospective military study, 896 patients, 293 got TXA based on physician discretion (not randomized). Guess what? TXA in a first world setting was actually much better than the CRASH- 2 results. The authors suggested this was perhaps because TXA was given to many well patients in CRASH-2, and so the beneficial effect was diluted out. Results: 1. Overall, TXA was associated with a reduction in mortality from 23.9% to 17.4% (absolute reduction 6.5%, NNT = 15). This was despite the TXA group having a higher average ISS (25.2 compared to 22.5). 2. In the most severe group (i.e. those patients requiring massive transfusion), TXA was associated with a reduction in mortality from 28.1% to 14.4% (absolute reduction 13.7%, NNT 7). This seems almost too good to be true. 3. There were higher rates of thrombotic events in the TXA group, although the authors suggested this difference disappeared when they controlled for different ISS (i.e. the TXA group were more seriously injured and hence would be expected to have a higher rate of DVT/PE). Remember, you only get associations from retrospective reviews. You can t prove causality. One theoretical concern about TXA is that it may promote excessive clotting, clinically manifested by increased rates of DVT. We know that trauma patients with multiple operations and prolonged immobilization and at times sluggish blood flow are at risk of DVT. Hence we need to look at DVT rates in studies of TXA. CRASH-2 and MATTERs did not show increased rates of DVT, but there is still some concern about this.
Current recommendations regarding TXA 1. Give to adult trauma patients with severe hemorrhagic shock (systolic BP <= 75 mmhg), with known predictors of fibrinolysis (high base deficit), or with confirmed fibrinolysis (i.e. measured by thromboelastography). Note this is much more restricted than the study group in CRASH-2 (where patients only had to be believed to be at significant risk of bleeding, and many patients did not even require a blood transfusion). However people are concerned about the potential risks of TXA, and hence its use is not recommended unless there is significant hemorrhage. That is, there must be the potential to do good before exposing the patient to the risk of harm; 2. Only administer TXA if less than 3 hours from time of injury. The 3 hour transition from good to bad seems odd, but that is the best data we currently have; 3. TXA administration: 1g intravenously over 10 minutes, then 1g intravenously over 8 hours. 4. MATTERs (military) and CRASH-2 (developing world) both had relatively young patients. Given thromboembolism is generally a disease of the elderly; there is some concern about extrapolating from these studies to the older patients often seen in 1st world civilian trauma centres. The thromboembolic potential of TXA may become apparent in our setting. Watch this space. Review papers http://emcrit.org/wp-content/uploads/2012/02/txa-in-trauma-how-should-we-useit.pdf https://www.mja.com.au/journal/2013/199/5/trauma-and-tranexamic-acid Steve Walker May 2014