Hello, this is Dr. Gretchen Brophy, and I will be speaking with you today on is it bloody confusing timing of anticoagulation prophylaxis and reversal for intracranial hemorrhage. These are my disclosures. The objectives of my presentation are to describe the anticoagulation agents that we currently use and some of the reversal strategies for those in patients that come in with intracranial hemorrhages. Also, we're going to determine when to utilize these reversal agents and also when can we restart or start venous thromboembolism prophylaxis safely in our neurocritical care patients that come in with life-threatening bleeds. Let's first start with our coagulation cascade. We have vitamin K antagonists that we use for anticoagulation, usually warfarin here in the US, and this inhibits factors 2, 7, 9, and 10, and also protein CNS. Then we have our direct thrombin inhibitors that inhibit factor 2A, which is dabigatrin, which is the oral agent, bivalirudin, and argatropin as IV agents. And finally, our factor 10A inhibitors, which are rivaroxaban, apixaban, edoxaban, enfamdaparinox, and batrixaban was available but is no longer available on the market. In our patients that come in on warfarin, we need to think about reversing their bleeds because we know that the factors that warfarin inhibits, 2, 7, 9, and 10, are going to have an extended period of time in which they are going to be inactive until we replace those factors. And so we do that through various ways. In order to reverse warfarin in a life-threatening bleed, we have a couple different agents we can use, IV, vitamin K, FFP, PCC, and recombinant factor 7A. Now the pharmacokinetic differences between these are something to consider as you want something that you can give quickly and reverse warfarin quickly. IV vitamin K is slower than any of these other agents, but it is replacing vitamin K, which is needed to stimulate the vitamin K-dependent clotting factors that were inhibited by warfarin. So you always want to give this in addition to either FFP or PCC. PCC is our general drug of choice in this situation just because you can give it quickly, you can get it on board quickly, and the reversal of warfarin, again, is quick when you give the PCC. Factor 7 is also able to be given quickly in this in patients that do not accept human blood products as an option. If you can't give the PCCs or FFP, you can give it quickly, and it's only reversed in factor 7. In patients that are on dabigatrin, we use idariocizumab as the reversal agent. This is an antidote for dabigatrin as it actually binds much greater to dabigatrin than dabigatrin binds to thrombin, and therefore, inactivates dabigatrin, which is our factor 2A inhibitor. For our 10A inhibitors reversal, we have one drug that's currently on the market, indexinet alpha, and one, seramparentag, that's currently in development that may come a little bit later down the road. These factor 10A inhibitor reversal agents are actually imitations of factor 10A that actually bind to the 10A inhibitors so that they cannot bind to factor 10A themselves, therefore inactivating these drugs. Seramparentag is also designed in a similar fashion in that it will bind to our targets, which include DOACs, the 10A and 2A inhibitors, unfractionated heparin, and low molecular weight heparin. It's currently in phase 2 and 3 trials, so we might see this in a couple years. An important feature of our anticoagulants are the pharmacokinetic characteristics and monitoring that we can do for these agents. When a patient comes in with a life-threatening bleed, knowing the kinetics of each of these drugs and whether or not there's a way to monitor them will help us determine the need for a reversal agent. Knowing the half-life of the anticoagulants the patient came in on is very important because this will help you determine when or if you need to give a reversal agent. These drugs are generally renally cleared, so looking at the creatinine clearance is very important. You can see here that based on dabigatrin or the 10A inhibitors, looking at their half-lives, you'll know that 50% of the drug is cleared in these half-lives, and it generally takes four to five half-lives to eliminate these drugs from the body. A very important question then to ask your patients when they come in or ask the family members is when was the last dose of their anticoagulant. If it was greater than 24 hours and the patient has normal renal function, this patient may not need a reversal agent at all. And knowing that 50% of the drug is eliminated in one half-life, drugs that have shorter half-lives, such as rivaroxaban, may not need a reversal agent after one or two half-lives because it might not be clinically effective at that point. So knowing these half-lives of the different agents will help determine whether or not that patient needs a reversal agent in order to decide if benefit outweighs the risk. Body weight is a characteristic that also may be helpful as the volume of distribution does change in patients with low and high body weights. So this study shows you some of the different agents that we have available. And in those patients with low body weight versus those that are obese, there is a change that can be seen in the concentrations that are achieved with these different agents, which also may affect the amount or extent of anticoagulation in our patients. In addition to our pharmacokinetic parameters and the importance of knowing those for each individual agent, it's also important to know if there's a monitoring parameter for the agent that the patient is receiving. There are different laboratory tests that can be done for the different agents. However, most of us don't have the actual assay that is needed for the 10A inhibitors at our institutions. Therefore, a lot of these are qualitative and not quantitative type assays that we can sometimes use to help us determine if drug is on board, but not how much drug is on board. So this just lists for you a couple of the different tests that could be done in order to determine whether or not there may or may not be drug on board when patients come in on these newer DOACs. Another way to monitor the effects of the anticoagulant on the patient when they arrive at the hospital is a thromboelastography, or TAG. This will tell you how fast the patient clots, how strong the clot is, and how long it takes for that clot to dissolve. Using the TAG is sometimes good because it's a point of care test that you can get back pretty quickly. And if your patient needs to go to surgery, this could tell you whether or not you feel safe enough to go to surgery with or without a reversal agent. There are guidelines out there that actually recommend the TAG as a point of care test to be utilized to assess and optimize coagulation function during interventions in these life threatening bleeds. And including sometimes our ICP probe insertions to, again, make sure the patient is clotting efficiently. A recent study used TAG to look at a retrospective group of severe traumatic brain injury patients and evaluated the differences between those patients with and without progressive hemorrhage. And what they found was that the K time, or the time to maximum clot formation, actually was different in those patients that bled versus those that did not. The authors went on to determine some cut points for TAG. Using the values that they found in this study, and you can see them here on this slide. So TAG may be something we can use that is rapid that will help us predict the pathophysiologic changes that are occurring in our patient and may be contributing to progressive hemorrhagic injury. As we're evaluating our patient that comes in with intracranial hemorrhage and is on an anticoagulant. Using the pharmacokinetic parameters and also some of our monitoring techniques may give us some ideas as to what we need to do to help prevent progressive hemorrhage in these patients. And then the question is still whether or not to give that reversal agent. So when is a reversal agent indicated? Some guidelines that have been set out in the literature include life-threatening bleeding, which would be all of our traumatic brain injury patients with intracranial bleeds. But also those with any bleeding into critical organs or closed spaces, prolonged bleeding despite local hemostatic measures, high risk of recurrent bleeding because of overdose or delayed clearance of our DOACs, as we talked about with Half-Life, a need for urgent intervention associated with high risk of bleeding, such as our emergency neurosurgical procedures, as well as any of our lumbar drains, cardiac or vascular surgeries, and hepatic or other major organ surgery. A probably more important question to ask yourself is when do I not use a reversal agent in these patients? And this would be in those patients that are coming in for elective surgery where you have plenty of time to hold the agents prior to coming in, if the bleeding is managed with local hemostatic measures or it has stopped completely on its own, or if you can delay any interventions for eight hours or more to permit clearance of that anticoagulant in those with normal renal function. And we might limit the effects of this anticoagulant and therefore not need a reversal agent. So again, the most important question you should ask your patients or their families is when was the last dose of the DOAC administered? So now that we know that when a patient comes in with an intracranial bleed, we do need to stop the bleeding, but we need to consider the timing of the drug, the last dose of the drug, as well as thinking about how we can monitor the effects of that drug to help us make a good decision. Once we get that patient stabilized and we know they have achieved hemostasis, we have to consider the fact that they were on an anticoagulant for a reason, and if they're in our ICU, they're probably at high risk for venous thromboembolism just from the immobility and other factors of being in the ICU. So we do need to consider VTE prophylaxis, but when do we start that in these patients with life-threatening bleeds? A quick look at some of the statistics for VTE in our critically ill patient shows us that it is frequent that VTEs occur, and despite our prophylaxis that we do use, mechanical or pharmacological, there are still patients that have clotting issues. These patients that are on an anticoagulant may have a VTE or other issues prior to coming into our ICU, so they are probably at even more risk. So we really have to think about what else is happening to the patient that can increase that risk. For our traumatic brain injury patients, we know that there's TBI-related coagulopathies that can occur. There's generally some delay in initiation of prophylaxis because of the bleed and where the bleed is. These patients also have immobility that will lead to increased clotting, and they could have concomitant injuries such as polytrauma that will also contribute to their higher risk of clotting. So without DVT prophylaxis, most TBI patients, greater than 50% of them, will probably have a DVT if we don't do something to help prophylaxis against that. So we do need mechanical, which we should start probably immediately, but we probably need something in addition to that, too. And again, assessing the stability of the bleed, the stability of the patient, and knowing when the last dose of those DOACs were and if or when we gave the reversal agent, it's going to be key as to when we're going to start this DVT prophylaxis. As we all know, we have to always weigh the benefit and risk of giving VTE prophylaxis to those patients that come in with bleeds. So this study looked at VTE prophylaxis within the first 72 hours after a TBI and compared to those that had a later initiation of VTE prophylaxis. And as you can see here, early prophylaxis was favored as well as seeing that there was no difference between the pharmacologic prophylaxis and the mechanical prophylaxis in regards to safety events. So by giving VTE prophylaxis early is probably more effective than late, and there was no hemorrhagic progression within 24 hours of injury in those that received pharmacologic prophylaxis. And again, there were no significant differences in safety in this patient population that was evaluated. There was a recent study done as well looking at the TQIP database from 2013 to 2017 in a matched cohort of patients that had traumatic subdural and subarachnoid hemorrhages, and looking at the timing of VTE pharmacologic prophylaxis. What they found was that patients that received early intervention, less than 48 hours, had significantly less DVT and VTE. Their ICU admission rate was less, and length of stay in the hospital and ICU were less than those that had it prolonged, extended, or late prophylaxis. And also those discharged to home were more frequent in those that had early prophylaxis. So basically signifying effectiveness and safety by giving it within 48 hours in these traumatic brain injury patients. Now, what about the type of prophylaxis given? Early versus late, between unfractionated heparin and low molecular weight heparin, there was no difference in these two agents. So again, most of us probably tend to use 5,000 Q8 of unfractionated heparin or 30 Q12 of low molecular weight heparin. But generally, with the kinetic differences between these two agents as well, thinking about timing and possible procedures, the low molecular weight heparins could stay around a little longer and could be problematic. So unfractionated heparin might be something that you choose in your unit due to that fact. In 2016, the Neurocritical Care Society actually put out guidelines for VTE prophylaxis in critically ill patients with intracranial hemorrhage, subarachnoid hemorrhage, and traumatic brain injury. And these are listed here. So what they recommend is obviously IPCs or intermittent pneumatic compression devices for all patients beginning at their hospital stay, as long as there's no contraindications. And then for intracranial hemorrhage, to use either unfractionated heparin or low molecular weight heparins within 48 hours of hospital admission. And then for subarachnoid hemorrhages, they shorten that to at least 24 hours after the aneurysm has been secured for unfractionated heparin, thinking again about the kinetics of the drugs that was chosen. And then for traumatic brain injury, again, either agent, low molecular weight or unfractionated heparin within 24 to 48 hours of presentation or 24 hours after a crani. So again, thinking about when the patient has achieved hemostasis is a good marker for when to start the pharmacologic prophylaxis, and knowing that earlier is probably better without a risk of bleeding. The traumatic brain injury guidelines from the Brain Trauma Foundation in 2017 also suggested either low molecular weight heparin or unfractionated be used with mechanical prophylaxis and initiated, again, early, within a day to two days once the patient is stabilized. So to summarize everything we've talked about in regards to timing of reversal and timing of VTE prophylaxis in our patients with traumatic brain injury and intracranial hemorrhage, we know that anticoagulant reversal agent selection is dependent on the specific anticoagulant the patient is receiving and that the indications for reversal should be identified before we give any reversal agent. Some things that will help us with that include determination of the time of the last oral anticoagulant dose, which would be essential to assess the benefit and make sure it's greater than the risk for the anticoagulant reversal. Also looking at the pharmacokinetics and some monitoring tests that we can do to help us determine the risk of bleeding and if a reversal agent is needed is very key to what we do as we assess our patient. And then finally TAG can be considered as an assessment tool because it's going to tell you whether or not the patient has coagulation and platelet function in these patients that had previously bled or bled due to trauma and possibly indicate whether or not their risk is high or higher for continued progressive hemorrhage. So in these patients that bleed, that come in, we know that they are at risk as well for VTEs, so we need to think about mechanical and pharmacological prophylaxis in these patients and the mechanical prophylaxis should start immediately with pharmacologic prophylaxis initiated once the clot is stabilized and this is generally within 24 to 488 hours of the bleed.

anticoagulation prophylaxis

reversal

intracranial hemorrhage

anticoagulation agents

venous thromboembolism prophylaxis

VTE prophylaxis