Hello, this is Dr. Joshua Meadow along with Dr. Christopher Zacco here to discuss coagulopathy reversal and DBT prevention for patients with traumatic brain injury. We would like to frame it first with a case and then go over the general principles of coagulopathy development and reversal strategies that may be incorporated, realizing that many of the strategies that may be incorporated may be anecdotal. At the University of Wisconsin, an 86-year-old female presented who was otherwise healthy and very active, but developed a headache and presented to the emergency department. She had this cerebellar hemorrhage, her PTT was abnormal, everything else was normal. She did not have any evidence of a vascular lesion. She was observed in the neuro ICU, the hematology service was consulted immediately and they were not terribly concerned about the PTT elevation. The workup for the coagulopathy problem, however, was started and she was clinically doing well for a day, but she became confused with nausea and emesis, progressing to lethargy. The patient and family were already prepped for possible surgical decompression and ventriculoscopy placement. She had the ventriculoscopy placed first and then was brought to the operating room for a suboccipital craniectomy for evacuation of the blood. There was no obvious hemorrhaging at the end of the completion, but the surgical bed took a long time to dry prior to closure. We spent approximately 45 minutes until we did not see any subtle ooze from the surgical bed. The patient returned to the neuro ICU. She was awake, alert, and following commands, but we left her intubated overnight because of her posterior fossa hemorrhage and our concerns about either swelling or bleeding. Six hours later, the patient acutely stopped following commands. She had a cushioning response and within 15 minutes blew both her pupils. Hypertonic sodium was given because of concern for posterior fossa hemorrhage or malignant edema and a CT scan was obtained and it demonstrated hemorrhage at the ventriculostomy site and also significant hemorrhage above the region of the suboccipital decompression. To be clear, when looking at this image on the right side, we did not show the suboccipital decompression, which was not nearly to the level of the torcula, but allowed for, but was basically about 50% larger than what we would do for a standard Chiari decompression. As it turns out, this ended up being the first reported case of a factor VIII inhibitor related intracranial hemorrhage. This patient had developed a factor VIII inhibitor in her later years and this was not known. This case was published, I believe, in Neurocritical Care. So how do you work up a patient like this and the most important thing is history. As this patient suddenly had bruising that started in the last couple of weeks, the last couple of months, the last couple of years, getting routine labs is a good start. Finding out what medications they're on, if they're able to tell you, and considering some other measurements of clotting, such as a factor Xa, an ACT, which is an activated clotting time, or a thromboelastogram, otherwise known as a TEG. This is the coagulation cascade. This was something that we all had to memorize in medical school and learn for our USMLE exam or NBME exam, depending on when you studied for them. Either way, this cascade is very important for us to determine what points bleeding can occur. What failure points in this cascade can we significantly locate and reverse the patient's coagulopathy. So we'll start with the factor II and factor Xa inhibition and when we think of something that actively affects both, we think of antithrombin 3. We think of heparin, which activates antithrombin 3 and which can be reversed using protamine. As it turns out, low molecular weight heparins have very little activation with antithrombin 3 in the same manner, and so protamine may have a very limited amount of effect. Some people have recommended the use of activated factor VIIa to stop low molecular weight heparin related hemorrhages. Pure factor Xa inhibitors, such as Fondoparanox, cannot be reversed at all with protamine. As a consequence, factor VIIa may be the agent of choice. There are others that may have indicated that depending on the time frame from when the patient started bleeding and the time at which the inhibitor had been given, the patient may also or could potentially benefit instead using either tranexamic acid or aminocoproic acid, which work on preventing fibrinolysis. The direct thrombin inhibitors, such as dabigatran or gatraban, herudin, leperudin, people have suggested factor VIIa or prothrombin complex concentrate reversals. Other people have suggested, again, as with the Fondoparanox group, that if there has been somewhat of a delay from the time the patient got the drug to the time they started hemorrhaging, that fibrinolysis inhibition with amicar or tranexamic acid may be beneficial in place of factor VIIa or PCC. Herudin and leperudin would come from leeches. They are direct thrombin inhibitors and they've been around for quite some time. Our gatraban has been around for a while, has been using cardiac surgery. Gatraban is relatively new to the market. Patients that have TPA may benefit from amicar or tranexamic acid directly because TPA causes plasminogen to become plasmin. It then activates the fibrinolysis portion of the cascade, so the removal of clot. If they are removing clot too much, the use of amicar or tranexamic acid can help prevent that from occurring. It is very important to note that patients that have DIC, in other words, that patients that have a consumptive coagulopathy, need that plasminogen activation to plasmin to cause fibrinolysis. Otherwise, they will clot off all sorts of places. So giving patients with active DIC, tranexamic acid, or amicar is absolutely contraindicated because of the risk of massive thrombosis. There is a small group of patients that have an indolent, low, kind of slow DIC with malignancies that may benefit from amicar or tranexamic acid, but we would respectfully suggest that you refer to a hematologist or your oncologist for determination if that group should use these two drugs for that purpose. In patients with acute DIC, i.e., terrible trauma or infection, we would recommend replacing the consumed agents, including the use of FFP, cryoprecipitate, and platelets, and absolutely treating the underlying cause of the DIC in the first place. The vitamin K related factors are very important. Coumadin and its activity can be measured using the INR. These vitamin K factors, which are 2, 7, 9, and 10, are best treated with the now available four-factor PCC or the three-factor PCC along with FFP and should also be reversed by adding vitamin K because the effect of PCC or Factor 7A, if it's used in place of that, is relatively short-lived, and the vitamin K epoxide reductase inhibitor, warfarin, can be overwhelmed by giving additional vitamin K and allow the liver to then re-synthesize the appropriate factors. The shortest circulating time factor, Factor 7, is also the one that is generated the fastest, and so the three-factor PCC, which was available currently and was only the one available up until about a week and a half ago, meaning early May of 2013, did not have Factor 7 associated with it, but the addition of FFP would generate oftentimes enough Factor 7 to be able to overrun the inhibition provided that vitamin K was given concomitantly. Patients with liver failure typically can have their INR dropped, usually into the range of about 1.5 to 1.7 with FFP plasmapheresis without the use of albumin. Liver failure patients may also benefit from amicar or tranexamic acid, and there's a question as to whether or not PCC or Factor 7A would be useful in these patients given the fact that they are relatively short-acting with PCC acting until the factors wear down and Factor 7A acting for approximately two hours. Platelet inhibitors are very difficult. If you are looking for cyclooxygenase inhibitors such as aspirin, you can measure a PFA-100 or a CDP collagen epi test, but they're not consistent. NSAIDs typically are with the PFA-100 alone. Plavix is an ADP platelet inhibitor, and you can oftentimes measure it with a TEG or AGM, and then there's antibody-mediated antiplatelets activity or platelet inhibition, and we think of Agristats, which you can use your ACT, activated clotting time, for PFA-100, Reapro using the same things, or Integralin using PFA-100 alone. So in conclusion, liver failure is a difficult one. Generally speaking, you try to replace all those factors that are given, I'm sorry, that are made by the liver, so every factor except for Factor 8, and they will obviously, or almost always, need platelets because their spleens are enlarged, you can find yourself in a pinch using amicarotranexamic acid, and possibly considering PCC. Factor 7a, probably less useful, except for the sudden hemorrhage, but again, its length of activity is only approximately 2 hours. For Coumadin reversal, we recommend either PCC or Factor 7a, and Vitamin K. You might have to re-dose and give FFP, depending on if the patient is able to correct enough with the presence of Vitamin K. Factor 7a alone will only reverse you for 2 hours, and then the INR will creep right back up again, so it is exquisitely important to continue the correction process, otherwise the coagulopathy will return in short order. For unfractionated heparin, we recommend reversal with protamine, there's good literature to support that. For low molecular weight heparin, maybe 20% of it is reversible by protamine in the best case scenario, but you may find yourself needing to use Factor 7a, PCC, or some people recommending based on time frame, Tranexamic acid or Aminocoproic acid, which is also known as Amicar. Fondoparanox, which is a Factor 10a inhibitor, again, we'd use Factor 7a, or PCC potentially, or again, based on timing, potentially Tranexamic acid or Amicar. For anti-platelet agents, we recommend that patients are given platelets, but the effect may be mitigated by the presence of drugs, so if the drug has not cleared the system yet, giving them platelets may not be a successful endeavor. For patients that have direct thrombin inhibitors, again, bets are off. Factor 7a may have some benefits, PCC may have some benefits, and possibly Amicar or Tranexamic acid may be used in place of those two drugs to try to help stem hemorrhaging. The use of all of those drugs together may lead to massive thrombosis. For patients that receive TPA, we recommend the use of Amicar or Tranexamic acid since that directly hits the issue at hand. For patients with DIC, we do not recommend the use of Amicar, but instead treating the underlying cause of DIC and then replacing the various factors that have been consumed. We've included eight tables here that show the anticoagulant, the half-life, the duration of action, the reversibility, the reversal agent, the dosing for the reversal agent, and the reversal agent half-life, as well as labs that can be measured to try to treat a coagulopathy or identify a coagulopathy. The first table are the Factor 2 and Factor 10 inhibitors. Table 2 are the direct Factor 10a inhibitors alone. Factor 3 are the direct thrombin inhibitors, many of which are problematic. Factor 4 are those relating to fibrinolysis or plasminogen activation and their treatment. Factor 5 is for patients that either are on Coumadin or have liver failure. Factor 6 is platelet inhibition and the medications associated with that, as well as labs, which have a certain minimal value in determining the extent of antiplatelet effect. Table 7 shows the platelet maldevelopment and dysfunction syndromes with reversal strategies. And Table 8 demonstrates inhibitor-related coagulopathies with reversal agents and labs. We hope that these tables prove to be useful to you in a pinch should you need to try to reverse a patient with a significant coagulopathy. Recognize that when the FDA does approve a drug for coagulopathy, they don't necessarily approve the reversal agent along with it, and that is problematic. As a consequence, there are many times that you will find yourself in a position that you're making a decision or a judgment as to how to improve the patient's current coagulopathy status and you may find that that circumstance is fairly poorly written about and that your approach may be somewhat anecdotal. Many of the things in this table are anecdotal because there haven't been proven reversal agents for many of the new drugs that are coming out. The only thing that we can hope is that this will serve as a table, a series of tables for possible options, and that by no means are these guidelines or strong recommendations in any way, but when something new comes through your door, this may be a means by which to help try to stem the bleeding that will inevitably occur with the patients who have these various coagulopathies. There was a lot of research on our end involved in trying to find the data to put in these tables, time that you would not otherwise have on your own in an emergent circumstance. There's approximately 1.6 million people a year who suffer a traumatic brain injury or hemorrhagic stroke. The risk of DVT in those populations is 30% and 18% respectively. The CDC considers DVT a preventable disease, and although we're not entirely certain that it is always preventable, there may be certain times when, in fact, it is. And patients may actually benefit from DVT chemoparapheralysis in addition to sequential compression devices, thromboabolic deterrent hose, otherwise known as TED hose or TED stockings. And the things that we wonder in our practice is whether or not chemoprophylaxis is valuable, safe, and is our intravascular devices, such as the Greenfield filter or removable filters of similar origin, practical and safe. In February of 2012, a series of guidelines from CHEST were released, and specifically those things that are of interest to us were those pertaining to the extracorporeal mechanical devices, including TEDs and SCDs, intravascular devices, such as filters, which are either removable or non-removable, and anticoagulation agents, including antiplatelets and heparanoids. The strategies in the talk that we are going to be speaking of come from these CHEST guidelines, as well as a homegrown protocol that we developed at the University of Wisconsin. These do not gear themselves towards patients with orthopedic injuries. The methodology from the CHEST guidelines are listed below. When we talk about the grading system, this is where it comes from, for the level of evidence from the literature. For patients with low risk for venous thromboembolism, the guidelines, and again, these are not for brain, this is specifically at this point for abdominal surgery. We will get to the brain stuff a little bit later. For those with abdominal pelvic surgery patients, there is no specific pharmacologic or mechanical prophylaxis, other than early embolation. For patients with low risk, that is higher than the lowest possible score, so instead of a Caprini score of 0, a Caprini score of 1 to 2. Mechanical prophylaxis, such as with SCDs, may be better than no prophylaxis at all. For patients with moderate VTE risk and abdominal pelvic surgery, with a Caprini score of 3 to 4, low molecular weight heparin is indicated, or unfractionated heparin is indicated, along with mechanical prophylaxis, as opposed to no prophylaxis at all. Patients who are at high risk for major bleeding complications after their surgeries, or those in whom the consequences of bleeding are thought to be particularly severe, should have mechanical prophylaxis alone, as opposed to no prophylaxis at all, but they do not recommend chemoprophylaxis in those patients. For patients that are at high risk for developing DBTs or PEs, that are not at high risk for major bleeding, pharmacologic prophylaxis with low molecular weight heparin, there is good evidence to support its use. For patients with high risk for venous thromboembolism, but are also at high risk for major bleeding, mechanical prophylaxis is preferred, but they do recommend starting pharmacologic prophylaxis as soon as possible when the risk of substantial bleeding diminishes. Now, for trauma patients, not specific to the head just yet, there is some data. For major trauma patients at high risk for venous thromboembolism, they recommend mechanical prophylaxis being added to pharmacologic prophylaxis as long as there is no contradiction to its use. For major trauma patients in whom the use of prophylactic heparinoids is contraindicated, they recommend mechanical prophylaxis over no prophylaxis, and they also recommend the use of mechanical prophylaxis not in areas where there is an affected limb, i.e. a substantial fracture of a lower extremity, etc. In general, IBC filters should be avoided for VTE prevention. That is not the same as to say if a patient has developed a large DVT, should you not use an IBC filter, because that would be incorrect. In patients that do have a DVT of substance, an IBC filter may be beneficial, but for those patients that do not have a DVT and are just being considered for VTE prophylaxis with the device, the device should not be used, and there is a great 2C event for that. For general trauma patients who do not have any clinical suspicion for a DVT, they should not be getting routine ultrasounds to prove or disprove the presence of a DVT. If you have a clinical suspicion, they do recommend obtaining venous duplex ultrasounds, but otherwise they do not recommend it as being evidence-based for proving DVT or for doing so in a cost-effective manner. Now, using the same guidelines for spine surgery patients, for patients undergoing spinal surgery, mechanical prophylaxis is preferred over no prophylaxis, and fractionated heparin or low molecular weight heparin is recommended if it is deemed safe, once the risk of bleeding has substantially decreased, but no one really defines what that risk of bleeding must be or how it should be decreased. Something that is very interesting along these lines is that there is a black box warning label for the use of low molecular weight heparin in patients that have an epidural venous catheter, and the real question is can this black box warning label be extrapolated to patients that have had spinal surgery or have evidence of a spinal hemorrhage of sorts. So, when considering your options for chemoprophylaxis at some point, keep in mind the black box warning label for low molecular weight heparinoids, as there is some data in the anesthesia literature that suggests that it should not be used in patients receiving an epidural. The guidelines also talk about craniotomy patients, and again they use the same sort of vague terminology, recommending mechanical prophylaxis over no prophylaxis for craniotomy patients, but suggesting adding pharmacologic prophylaxis to mechanical prophylaxis once adequate hemostasis has been established and the risk of bleeding decreases. Again, there are no specifics as to how to address that sort of issue. At the University of Wisconsin, we wanted to see if we could provide pharmacologic prophylaxis or chemoprophylaxis using either unfractionated heparin or low molecular weight heparin in sub-q fashion. We noticed that in the literature that there is a significant increased risk of bleeding if you start the heparin prior to the injury or the surgery, but that started after the surgery, the rate of hemorrhage was similar to patients, I'm sorry, the rate of DBT was similar to patients wearing STDs and TEDs alone without having an increased risk of hemorrhage. But the data was somewhat mixed. So we embarked upon a quality improvement initiative using a more physiologic approach to blood clotting. The patients must all have normal coagulation, and it was based on a time point when bleeding had been determined to have stopped using CT imaging. The protocol used the physician's individual CT scanning practices. So there would be the initial head CT, which would demonstrate a hemorrhage. If another subsequent head CT was done that showed no hemorrhage, and it was at least three hours, no additional hemorrhage rather, and it was at least three hours after the first CT scan, then 24 hours later, we would then start chemoprophylaxis using low molecular weight heparin or sub-q heparin. A 24-hour CT was not necessarily performed, but the key was that you had a stable head CT that was at least three hours after the first head CT. This gave us a better idea that the patient was no longer having any evidence of hemorrhage, and since it was thought to be more than 24 hours since the last hemorrhage, we then would start the chemoprophylaxis. All patients received STDs and TEDs within four hours of admission as per our routine protocol. The dose of low molecular weight heparin was 5,000 units of Dalteparin delivered once daily, or unfractionated heparin, 5,000 units delivered twice daily. The inclusion criteria were ages 18 and above, remaining more than 48 hours in the neuro-ICU, so we wanted to grab the sick patients that were not going to be ambulatory right after their surgery. The exclusion criteria were patients that were pregnant, patients that were coagulopathic, patients that had continued bleeding, i.e. GI bleeds, or a history of heparin-induced thrombocytopenia. Now, we were not able to get all neurosurgery faculty to participate, even though we had collected data on all the patients through the neuro-ICU. Approximately 30% of the patients were not given heparinoids via the protocol because of a predetermined practice by the neurosurgical faculty. It is very important to note that no exclusion was based on hemorrhage type, so it did not matter if the patients had contusions, subdural hemorrhages, etc. Regardless, the other 70% of patients had their chemoprophylaxis delivered to them, regardless of the type of hemorrhage that was present. We did our data mining through our electronic medical record, and we also cross-referenced it along with the pharmacologic databases, the M&M proceedings, and any surgical procedures that were performed, as well as any evidence of the low molecular weight heparin or unfractionated heparin being stopped would also trigger an alert to us. So, between January 1st and December 31st, 2009, there were 1,143 neuro-ICU patients. Of these admissions, 475 had NICU stays greater than 48 hours. 70% of the patients received chemoprophylaxis an average of 2.37 days after admission. 87 of those patients had traumatic brain injury, and 69 patients received prophylaxis an average of 3.4 days after admission. And again, this was based on if there was any evidence of continued bleeding. This is the population of trauma patients. You can see that the subdural patient population was the largest, but we also had contusions as the primary diagnosis, and traumatic subarachnoid hemorrhages, epidural hematomas, and other intracranial hemorrhages as well. Now, when we say subdural hematoma making up 44% of the patients, we do want to be very clear that these patients that had subdural hematomas could have also had contusions, but specifically this was the primary diagnosis for their presentation. We found that there were 32 operative cases after chemoprophylaxis, 4 of which were cranial cases. One was a cranioplasty, one was a depressed skull fracture, one was an epidural evacuation that was unchanged on head CT. In other words, the hemorrhage size was not any different, but because there was a concern of clinical decline rather than a change in size of the hemorrhage, the patient underwent decompression. And there was one patient who did have an acute to chronic subdural evacuation that happened 45 days later. We show that particular image here on this next slide. What we were able to find was that there were no acute hemorrhages after initiating chemoprophylaxis, that in fact the patient that did have a chronic subdural hematoma that developed had that develop over a 45-day period, and we personally believe that it was likely related to natural history and that the sub-q heparin that had been given likely did not cause the chronic subdural hematoma, but we cannot say that with certainty, and so we present it to you in this talk for you to be able to determine on your own. This paper was also published in Neurocritical Care in April 2013 under Nicoli et al. What we did find was that the drug administered in the control year versus the intervention year, there was a higher percentage of patients in the intervention year receiving chemoprophylaxis, and this was statistically significant, and we found that the time to delivery of chemoprophylaxis was almost statistically significant. What we did find was that the DBTs that were present were in patients that had more than four days of time between their presentation and the starting of chemoprophylaxis. None of the patients had symptomatic PEs. What's important is that there are many limitations of this quality improvement initiative, and specifically that not all of the neuro-ICU faculty participated, and the fact that our DBT rates were not necessarily high in the neuro-ICU could also be in part a function of the fact that we only got ultrasound studies on patients that had symptomatic clots. If they did not have any symptomatic clots or edema, we did not recommend the use of venous duplex ultrasound, and so you could be concerned that the DBT rates could be artificially lower because small DBTs would be missed. So in conclusion, the CDC does consider DBT preventable. It may or may not be entirely preventable in our patient population, especially in the trauma patient population who is inflamed already systemically and does have many reasons to develop clot. Nevertheless, we will be held accountable for DBT and PE regardless of how it occurs. We do personally believe that if it's possible to prevent DBT and PE, it's much better using a small dose or a prophylaxis dose of anticoagulant than using a full anticoagulation in the vicinity of a recent trauma as a consequence of a significant pulmonary embolism. Perhaps an ounce of prevention is worth a pound of cure, especially in these patients because the risk of intracranial hemorrhage could be substantial. IVC filter placement to prevent DBT is not indicated, but if a DBT is present, it may be useful. Pharmacologic prophylaxis with class I data is nonexistent at this point for cranial or spinal injury patients, but we do believe that prophylaxis can be done safely when applying a protocol that considers when hemorrhaging has stopped. It is our responsibility to try our best to prevent DBT and secondary injuries. Our biggest goal is to try to change behavior towards DBT pharmacologic prophylaxis to better optimize prevention since treatment of a pulmonary embolism is likely more dangerous than the prevention strategies mentioned before. Thank you very much for listening to our talk today. I'd like to end the talk with a quote. Excellence is the result of caring more than others think is wise, risking more than others think is safe, dreaming more than others think is practical, and expecting more than others think is possible. Thank you very much. Thank you.

coagulopathy reversal

deep vein thrombosis prevention

traumatic brain injury

cerebellar hemorrhage

PTT levels

coagulation cascade

reversal strategies