Great, thank you all for having me as a hematologist at your conference. I'm gonna talk about treatment of pediatric venous thromboembolism, particularly in the ICU. I have no personal disclosures, but I am gonna talk about the use of anticoagulation and anticoagulants that are off-label in children. So we're gonna talk about the options for anticoagulation with a brief review with some subjects and hopefully some new data on other drugs. We'll talk about thrombolysis for VTE as well as DVT and pulmonary embolism and a brief introduction or maybe review for some about pulmonary embolism response teams. So delving into the options. Unfractionated heparin, I'm sure you're all very familiar with, as you can see here with the coagulation cascade. You can't invite a hematologist without a picture of the coagulation cascade. Unfractionated heparin works by potentiating antithrombin, mostly on factors 10A and thrombin 2A, but also the minor effect on 11 and 12A. It can be challenging to titrate. As you all know, we monitor with a PTT and or an anti-10A and it is reversible with protamine and has a short half-life. So it's a good drug in patients who might need to go to the operating room or have a high risk of bleeding. Low molecular weight heparin also works through antithrombin, predominantly by potentiating the inhibition of factor 10A. It has relatively predictable pharmacokinetics. We can often get patients therapeutic relatively quickly with the anti-10A monitoring. It is partially reversible and does require dose adjustment in renal disease. So it does have some limitations in certain populations. Bivalirudin is a direct thrombin inhibitor, works on factor 2A and has increasing popularity in pediatrics. It's not reversible technically, but has a really short half-life. It does have some renal clearance and so it's important to monitor that if you have patients who are in renal failure. And monitoring really depends on your institution. Some will use a dilute thrombin time or a PTT and that's really institution dependent. It doesn't require antithrombin, so it can be a good drug in patients who have antithrombin deficiency, whether that's a congenital deficiency or due to their comorbidities like nephrotic syndrome or a lymphatic disorder. And the clinical utility is really expanding for this drug. Initially, it's been very useful for heparin-induced thrombocytopenia for obvious reasons. It's now used in Berlin hearts. It can be used in patients with thrombotic storm who clot despite their anticoagulation with heparins. And then there's increasing potential utility in pediatric ECMO at certain centers, so that's an evolving topic as well. Direct oral anticoagulants are relatively new in pediatrics, although we have the most randomized trial evidence for these drugs and it's a really exciting time. They are either direct 10A inhibitors, so apixaban and rivaroxaban being the most common that we think about in pediatrics, or direct thrombin inhibitors, so 2A inhibitors with dabigatran. They're oral. They have really relatively predictable pharmacokinetics. They don't technically require monitoring and there's fewer food or drug interactions than with vitamin K antagonists like warfarin. So they're a great option for our outpatients on anticoagulation who need long-term anticoagulants. But they do have potential limitations, so they require stable eneral, and really this is gastric intake. The way the studies were designed for VTE treatment, they require five days of a parenteral agent prior to starting. They have limited periprocedural evidence in pediatrics, and we'll talk a little bit about the half-life being much shorter, and so extrapolating adult data may be challenging for this. There's no reversal agent dosing for pediatrics, and they're contraindicated in antiphospholipid antibody syndrome and mechanical heart valves due to an increased risk of thrombosis. So these are the common drugs that have pediatric evidence. Dabigatran has an FDA label in pediatrics for VTE treatment and secondary prevention. It's the most renally excreted of the DOAC, so important to note that. The dose is both weight and age dependent, so just to pay attention closely if you're prescribing that. Rivaroxaban has an FDA label for VTE treatment, prevention, and post-Fontan prophylaxis as well. The dose varies by weight and is much more frequent in the younger patients who have a much shorter half-life. Apixaban and Adoxaban don't have FDA labels. They both have recently published evidence for prophylaxis in pediatric cardiac patients. Apixaban, the VTE treatment trial, is not quite finished, and there was recent evidence for pediatric acute lymphoblastic leukemia and lymphoma for primary prophylaxis. That's been published. Adoxaban has the cardiac publication, but again, not an indication yet, and their VTE treatment trial is recently completed, but not yet published. So what about bleeding? Bleeding was relatively low in the clinical trials for these drugs, with 2% in Dabigatran and everything else zero to less than 1%. There's a study that's using observational data out of 15 pediatric centers that recapitulated the really low rate of major bleeding, with overall bleeding being around 14%. Of note, there was worsening menstrual bleeding with these drugs, which does mimic the adult data where Rivaroxaban showed increased rates of menstrual bleeding compared to Warfarin or Apixaban as well. So just to note when you start this drug to think about who you're starting it for. And then what do you do if your patient is one of those rare patients who does experience major life-threatening bleeding? There are drug-specific reversal agents that are approved for adults. Idaricizumab is a humanized monoclonal antibody fragment that binds to Dabigatran and is the approved agent for reversal of Dabigatran. The pediatric evidence that's published is limited to a case report of a 15-year-old nearly adult-sized child who received Idaricizumab for Dabigatran overdose and did well. And dexanet-alpha is the 10A inhibitor reversal agent that's approved in adults. And the pediatric literature, again, is limited to a case report out of my institution where a four-year-old 20-kilo patient received an empiric 25% adult dose after an intracranial hemorrhage on Rivaroxaban. So we don't know what dose to use for these patients when they're lower. PCCs have been used off-label in adults, but there's not published evidence for their use in pediatrics, again, so the dosing for reversal is really limited. So what does that practically mean if you have a patient in the ICU? Should you be starting a DOAC? Should you have the patient stay on their DOACs? They need to have, if you're treating VTE, five or more days of a parenteral agent before. They need gastric nutrition. That's pretty stable. They can have a G-tube or an NG-tube or eat by mouth, but they can't have J-feeds. No upcoming procedures is sort of a vacillating topic. The adult data is based on the PAWS study, which was looking at adults with atrial fibrillation. They held one day for low-bleeding risk procedures and two days for high-bleeding risk procedures, and they defined those in the paper. You can extrapolate that data, but as I showed you, the half-life of rivaraxaban in young children is much different than older children, and we don't have great evidence for how long we need to hold those drugs in the young children, and we may be putting them at increased risk of thrombosis if we hold them the same way we would hold for an adult. Stable renal function, and again, that depends on the drug that you're using. And then while the drug-drug interactions are much lower for these compared to warfarin, there are some drugs like antiepileptics or antifungals that you guys are using in the ICU that may be interacting. And then again, you can't use it in patients with APS or a valve. So for us, practically, that means we transition patients at or near discharge. We know that some people are using these drugs in the ICU, but I think there's variability in practice, and we just wanna make sure as we gain more experience with these drugs, we're using them in the right populations. And then just to note, while we do have a lot of great randomized trial evidence for these drugs, infants and patients with catheter-associated VTE, which you just heard are the highest risk populations, are actually underrepresented in the trial. So we still use these drugs in these populations, but the observational post-marketing data will be really important because it was hard to enroll these patients in the randomized trials. Okay, so what do you do when thrombolysis isn't enough, or when anticoagulation isn't enough? So thrombolysis is really indicated for lifelong or organ-threatening thrombosis, which I listed the indications here. There is some sort of expansion of these indications depending on the patient, but you should always think about the contraindications, which are really based on bleeding. So any major surgery, any active bleeding, CNS injury that's recent, thrombocytopenia or hypofibrinogenemia that you can't correct, and then prematurity, which the age limit is a little varied, but I wrote 32 here, just really you're trying to prevent major intracranial hemorrhage. The ASH adult guidelines recommend, or suggest actually against thrombolysis and say anticoagulation alone for lower extremity DVT, so this is non-limb or life-threatening. However, they do say that there may be select younger patients with a low bleeding risk for whom it might be beneficial, and this is a lot of our patients who come in adolescents with a lower extremity DVT and a big swollen leg. And this is really based on data from the ATTRACT trial, which is an adult trial that looked at acute femoral, common femoral, and iliac DVTs, randomized to anticoagulation alone versus anticoagulation with pharmacomechanical thromboprophylaxis. And they saw no difference between post-thrombotic syndrome and they saw an increased rate of major bleeding in the thrombolysis arm. However, they did a post hoc analysis that looked at just the more proximal clots, so the iliofemoral DVTs, and there was a greater reduction in PTS, and there was no change in major bleeding in these patients. And so that's sort of where this qualifier in the ASH 2020 guidelines for adults come from. So what do the pediatric data say? These are the 2018 guidelines. The pediatric guidelines are actually currently being rewritten, so it'll be exciting to see what new data and information we get from that. But these also suggest against thrombolysis for patients who have a lower extremity DVT that's not life or limb threatening, although this is based on zero randomized trials and 15 observational studies that overall included less than 500 children. So again, practically, what does that mean? What do we do? So I consider catheter-directed thrombolysis for an iliofemoral DVT in an otherwise healthy adolescent patient who has a significant symptoms. And I really do that with shared decision-making with the family, acknowledging that they may have some improvement in their risk of post-thrombotic syndrome if I think they're a low bleeding risk patient. How do you practically do thrombolysis? So they should be in an ICU. Concomitant anticoagulation we think is likely important. So that does increase their bleeding risk. Some centers will use 10 units per kilo per hour of an unfractionated heparin. We've experienced using low molecular weight heparin even at a therapeutic dose intensity. And really this is important because when you stick the catheter in, if there's any mechanical thrombectomy in addition to the thrombolysis, you're getting a local prothrombotic effect and you wanna prevent recurrent thrombosis in there while you're lysing the patient. Neonates often need FFP for plasminogen supplementation in order to get a fibrinolytic effect while you're running the TPA. And all patients should have lab monitoring both to make sure that they're getting a fibrinolytic effect with a rising D-dimer and a falling fibrinogen, and then for safety with CBC and fibrinogen monitoring. Avoiding procedures seems pretty obvious, but even, you know, you think about arterial sticks, line placements, LPs, but also urinary catheters, rectal temperatures to try and just prevent any risk of bleeding while the TPA is running. And then if your patient experience is bleeding, obviously stopping the infusion, stopping anticoagulation, and if there's severe life-threatening bleeding, consider reversal of anticoagulation. And while there's no true reversal agent for TPA, you can give cryoprecipitate or antifibrinolytics to help with hemostasis. Okay, so transitioning to PE and PE response teams. When you see a patient with pulmonary embolism, you always wanna do a risk assessment, which seems obvious. You'll look at their hemodynamic stability, which you all are very good at, and you also wanna assess the right ventricle, both with imaging with CT, echo, as well as cardiac biomarkers. And then think about their bleeding risk and their renal functions while you pick their anticoagulant and their therapy. And we really take all these data and we extrapolate them into a risk stratification system. There's no validated risk stratification for PE in pediatrics, so this is extrapolating the European Society of Cardiology guidance, as well as a risk stratification system extrapolated to pediatrics in a paper by Catherine Ross. Low-risk patients are hemodynamically stable. They don't have RV dysfunction. They don't have signs of abnormal cardiac biomarkers, and really, these patients should get low molecular weight heparin and quickly transition to an oral anticoagulant and hopefully do well. Intermediate-risk patients are not hypotensive. They're stable hemodynamically, but they do have signs of RV dysfunction, either on imaging or cardiac biomarkers or both. And these patients are really challenging to determine how to treat, and a lot of this has patient and center-specific decision-making, which we'll go through. High-risk patients are the patients who come in hypotensive and shock or with arrest, and these patients should really get reperfusion therapy, whether that's systemic TPA, surgical embolectomy, or gopher ECMO. And the majority of patients will do well with low molecular weight heparin. There's adult data that showed that the majority of adult patients who came in with PE, who got started on unfractionated heparin, were still not therapeutic 48 hours after diagnosis, and we know that, as we've talked about, low molecular weight heparin can be very challenging to get therapeutic, and so low molecular weight heparin is really your friend when these patients come in with PE. It's easy to give in the ED, it's easy to direct an outside hospital to give prior to transport, and most patients will do well even if they proceed to need a catheter-directed intervention or even systemic thrombolysis with low molecular weight heparin. So what about thrombolysis for PE? So this is a table of different guideline statements from ASH, the European Society of Cardiology, and the PERT Consortium, which is an adult organization of PE response teams. For high-risk or massive PE, most organizations recommend reperfusion therapy or suggest thrombolysis. For intermediate-risk patients, they actually mostly, their guidance suggests against thrombolysis, although there's some consider this, consider that, and really there's variable clinical practice for these intermediate-risk patients with PE, and that's in adults and in pediatrics, and the adults obviously have way more evidence than we do. And this depends on the availability of catheter-directed interventions at your institution, it depends on the bleeding risk and the anesthesia risk of the patient. And there's multiple sort of pathways, guidance statements, this is the ESC, this is the PERT Consortium, this is out of that pediatric paper by Dr. Ross, and you'll see the intermediate-risk have a sort of consider all these different options and really to do that through multidisciplinary decision-making, and that's really led to the implementation of PE response teams or PERTs. So adult PERTs are gaining popularity with a lot of centers now having them, they're multidisciplinary groups of people, including intensivists, interventionalists, hematologists, and the data in adults have shown that these groups have increased utilization of advanced therapies, they've shortened hospital stays for patients with PE, and some of the data have demonstrated a decrease in mortality, although that outcome is a bit mixed in the data. We've started a PERT at our institution about a year ago, it's run by hematology, we have our ICU colleagues, our cardiologists, and our interventional cardiologists, as well as the primary team taking care of the patient, meet for anyone who has an intermediate or a high-risk PE. We have a brief virtual call, they last less than 10 minutes, mostly. We're able to come to consensus and then implement care quickly for the patient, and so it's a low-frequency event, but it does allow for, with these low-frequency events, to get all the right people together on the same call to help with decision-making, and overall it's going well, and I think there are other pediatric institutions who've started to build these, and so we're all sort of learning together how to implement these in pediatrics. So I hope I've shared some new information about anticoagulants or therapeutic approaches. As we gain more information about these new drugs or these new data, we'll need to figure out which patients or which populations are the right ones to use them in, and then it'll require multidisciplinary collaboration in order to improve our outcomes. So with that, I want to thank you for inviting a hematologist, and I'd be happy to take questions. Thank you.

pediatric venous thromboembolism

anticoagulants

direct oral anticoagulants

thrombolysis

Pulmonary Embolism Response Teams