Can we prevent venous thromboembolism in our sick patients, particularly in our pediatric patients? So I'm presenting today on behalf of Dr. Vince Vestino, who couldn't be here today. Here are our disclosures. And so I think many of us, from a clinical standpoint, have been in this situation. So we have a new patient who's maybe been admitted or newly has a central line. We examine them one day, and we see unilateral swelling of the extremity with redness and congestion. And we go on to diagnose them with a venous thromboembolism, or DVT. And we've probably also been in this situation, although hopefully less commonly, where that thrombus embolizes, travels up the venous system into the lungs, and causes tissue ischemia, and potentially cardiopulmonary compromise. On the left, you can see a schematic of the potential path of the embolus. And on the right, you can see where it might land. This is a saddle embolus that's sitting at the bifurcation of the pulmonary arteries. So together, we talk about these entities as venous thromboembolism. And this is the slide that Michelle showed in her talk. But importantly, this entity is not only prevalent in our population, but it's on the rise. So this is when you look overall at patients, you see this increase. And you see this also across ages, and importantly, sort of profoundly in the adolescent age group. So we know this is a problem. How can we prevent it? So the American Society of Hematology, or ASH, came out with guidelines around this in 2018. They did not say anything specifically around thromboprophylaxis in pediatric patients, but they did use adult data to make recommendations. Specifically, they say in critically ill medical patients, they recommend using unfractionated heparin, or low molecular weight heparin, over no pharmacologic prophylaxis. In acutely ill medical patients, so less sick patients, they suggest using unfractionated heparin, low molecular weight heparin, or Fondoparanox over no pharmacologic prophylaxis. And in both groups, they suggest using either mechanical or pharmacologic prophylaxis, but not both combined. So we have these recommendations. Is it possible that we can apply these to our pediatric patients? Well, it turns out that pediatric patients behave differently than adults. So this is a study comparing adults greater than age of 40 with adolescent patients. So this is a series of studies. And you can see that adults were more likely to be diagnosed with asymptomatic DVTs, more likely to have clinically apparent VTE, more likely to have a DVT leading to PE, a PE resulting in death, whereas our adolescent patients were more likely to have catheter-associated DVTs, particularly in the lower extremity. Another way of assessing whether we can use adult data to try to take care of our pediatric patients was looked at in this study. So this group took adult risk assessment models, specifically the Geneva, the Padua, the improved VTE and the improved bleed, and applied them to critically ill adolescents to see if they could predict VTE. So this is sort of small, but you can sort of get a sense here of the different factors and definitions that were used in the models. But what we saw, what these investigators saw, was that they actually weren't able to predict VTE well in this patient population. So these are medical patients. Is there something that we can use in our surgical or trauma patients? So this was taken from a systematic review of pediatric trauma patients where they looked through the data and they come up with guidelines around surveillance and prophylaxis. They end up conditionally recommending for pharmacologic prophylaxis to be considered, so kind of a lot of qualifying language here, for those who are greater than 15 years old or younger that are post-pubital and who have an injury severity score of greater than 25. So these are severely injured patients with injuries affecting multiple sites. So they recommend that above, they recommend using pharmacologic prophylaxis and against routine pharmacologic prophylaxis in all younger patients. They also recommend mechanical prophylaxis in that same patient population versus no prophylaxis or in addition to pharmacologic prophylaxis. And they don't recommend active surveillance with imaging above just a regular physical exam. So we have these recommendations, but in the article, in my mind, one of the take home points is that there's really a lack of high quality data to guide what we're doing. In fact, they were able to identify 14 studies, but ended up using adult data to really extrapolate these recommendations. So up until recently, there's really a lack of high quality data to guide us. Another barrier was discussed with the CLOT randomized trial. So in this trial, there was an automated prognostic model that was able to predict hospital-acquired VTE in patients. And they randomized patients' medical charts to have this algorithm to predict hospital-acquired VTE versus not. But interestingly, even though this was a validated model, there was no difference between the intervention and the control group in terms of identifying hospital-acquired VTE. And there were also no difference in secondary outcomes. The authors postulate that this was because there were barriers to actually implementing prophylaxis when indicated by the model. So in addition to having evidence, there's also some barriers around implementation. And then this, I just wanted to mention this to sort of frame the rest of the discussion, which is really gonna be focused on catheter-associated DVT. So this is data from Solutions for Patient Safety, which is a sort of collaborative group that looks at quality and safety metrics. And this is the report of non-CVC-associated VTEs from 2017 to 2021. You can see that there's not a change in the incidence across these six years. And so the first point is that we're not making an impact on that. So that's one villain piece of it. But the second is that if you remember the data where the incidence overall is increasing, we think that's primarily related to catheter-associated events. So that's really where sort of most recently a lot of the research has been, including a lot of work that Dr. Fasino has done. So this is from a prospective study, just working to describe some of the epidemiology around catheter-associated clots. And what you can see is that in this study, which was of 11 tertiary PICUs, 41 out of 53 or 77% of the identified clots were catheter-associated. They also were more likely to be seen in the lower extremities. And then this is a little small, but a meta-analysis. So putting together all of the studies that were cohort studies or trials, looking at the incidence of catheter-associated clots by active surveillance. And the overall incidence that was identified here was around 20%. So one in five patients who has a clot, a catheter is at risk of having a clot. So to take a step back, it's helpful in understanding some of the sort of pathophysiology that happens after we place a catheter in our patients. So after the catheter is placed, really starting almost immediately, we see deposition of platelets and fibrin. And then this in some patients progresses. We think that this is in part related on hypercoagulability, endothelial injury and stasis, so essentially a Virchow's triad, but maybe related to other factors, platelet activation, that kind of thing. But in some percentage of patients, this progresses. By day four, you see infiltration of smooth muscle cells. And after day seven, there's collagen deposition resulting in a fibrous sleeve. So really when we're thinking about prevention in these patients, you wanna sort of hit the patients around before day three. So again, timing is critical in sort of preventing catheter-associated DVT. This is from a study that looked at patients who had catheters inserted, followed them with active surveillance daily and looked for incidence of DVT. You can see that there's a drop in the initial three days after catheter insertion, and then kind of a plateau. So there's really an opportunity within those first days to prevent these clots. The PROTEX study was one of the first studies to try to prevent this. They used prophylactic reviparin, targeted an anti-10A level of 0.1, but ended up with a risk ratio of 1.1, so really no clear benefit of this prophylaxis. The CRETE trial, which was run by Dr. Faustino, attempted to start prophylaxis a little bit earlier. So in the prior trial, the average initiation of prophylaxis was 2.5 days prior after insertion of the catheter. But in the CRETE trial, they started prophylaxis within 24 hours of the catheter placement. And you can see that with prophylactic anoxaparin and an anti-10A targeted at between 0.2 and 0.5, there was a risk ratio of 0.55. The aggregate data is not statistically significant, but there's clearly a trend, and we'll come back to this figure in a minute. So it turns out that prophylaxis also might be better earlier on just in the course of the hospitalization. This is from a trial looking at pediatric trauma patients and looking at rate of VTE by hours after admission. It's comparing unfractionated heparin with low molecular weight heparin. And the two things are to note are that the low molecular weight heparin seems to perform better than the unfractionated heparin, but the low molecular weight heparin only performs better in the first 72 hours after admission. Another study that suggested this was looking at factors of venous thromboembolism on, sorry, factors of treatment failure with prophylactic anoxaparin. So there are two factors that increase the risk of treatment failure. Those were being an infant, which we'll talk about more in a sec, and previous VTE. But there were two factors that decreased your risk of treatment failure. And the first was being enrolled in the second half of this study. That's significant because patients in the first half of the study, they just had sort of a standard dose of anticoagulation, where in the second half of the study, they had a targeted anti-10A level of between 0.3 and 0.5. And then having anoxaparin administered within three days after admission was also a factor that decreased your risk of treatment failure. This is just to bring back to the age point. So this, again, I was looking at the CREIT study, but looking at patients by age. So when you pull out the infant patients, they have a risk ratio of essentially one. So there's no benefit of prophylactic anoxaparin for these patients. But in the older children greater than age one, there was with a risk ratio of 0.24, and that's statistically significant. So maybe we need a different dose for our infants. So this is from a study looking at post-cardiac surgery infants. And what they found, which is illustrated in the graph on the left, is that there was a decrease in incidence of VTE with therapeutic anoxaparin compared to sub-therapeutic anoxaparin. They also looked at bleeding risk in these patients. And essentially, if you look through all of their data, they showed that there's no increase in bleeding with therapeutic administration of anoxaparin. We just put this graph up because it's kind of interesting because they actually saw a increase in red blood cell transfusion need in the sub-therapeutic patients, which is sort of an interesting finding. So putting this all together, Dr. Faustino and others have put forward the CRETE studies, which are ongoing right now. The first aim is to confirm the efficacy and safety of prophylactic dose anoxaparin in reducing catheter-associated DVT in critically ill older children. The second is to determine the efficacy and safety of higher therapeutic dose anoxaparin in critically ill infants. And the third is to probe the mechanisms that underlie age-dependent heterogeneity in the efficacy of anoxaparin. So a couple of other studies to know just to sort of round this out. So this was a study that looked at how to treat, how to anticoagulate to prevent recurrence of a catheter-associated DVT. And what they found was a decreased odds of recurrence using secondary anticoagulation at the full dose. And they didn't see a decreased odds when only a prophylactic dose was used. They also saw a couple of risk factors that might contribute to recurrence, namely the addition of an additional CVC, TPN dependence, and congenital heart disease. And then finally, whenever you're thinking about clotting, you also often think about bleeding. And so bleeding can potentially complicate matters. This is from a study that's not thrombus-focused, just looking at the incidence of bleeding in critically ill pediatric patients, and looking at a couple of different studies. Really the take-home is that around 10% of all comers in the ICU are at risk of having clinically relevant bleeding. Factors that are associated with bleed, this probably won't surprise folks, but it includes a higher pediatric index of mortality, bleeding history, gastric ulcer, and vasopressive support. So this has started to be looked at in patients who are anticoagulated. So this is from a meta-analysis looking at low molecular weight heparin in children. This is looking at prophylactic dosing, and they were able to identify sort of a cumulative risk of bleed of around 2.3% of patients. This is from the same meta-analysis looking at therapeutic dosing, and they identified a higher risk of 5%. So it seems that bleeding risk increases with a level of anticoagulation. And then finally, some food for thought. So we often talk about bleeding and thrombosis together, but actually the process of hemostasis and the process of thrombosis are different. So this is a schematic looking at the coagulation cascade in hemostasis and thrombosis, as well as looking at the vessel itself. And in the hemostasis process, it's really about if you have vessel injury, sort of trying to sort of clot off that area of injury. With thrombosis, it's actually formation of clot that's intraluminal. And so there may be ways to sort of leverage the differences between these two pathways to better treat our patients for clot without increasing their risk of bleed. In particular, factor XI is much more active in the thrombosis pathway, and so that may be sort of a future direction for these patients. So there are a lot of sort of aspects to this. So to kind of put everything together, a series of questions. Should we prevent VTE? Likely yes. Future studies might interrogate the significance of treating or prophylaxing against asymptomatic catheter-associated DUTs. Should we, can we prevent VTE? Probably yes. The ongoing CREIT studies will help us to answer this question. Future studies will focus on prophylaxis against non-catheter-associated DUT. Who should we target? Well, it's a balance between the risk of having a VTE and risk of bleeding, and so we need to understand that balance. So future studies really should focus more on sort of individualized understanding of a patient's risk of bleeding in addition to an individualized risk of clotting. When should we start prophylaxis? So probably less than three days after insertion of a line or potentially less than three days after hospital admission in critically ill patients. Future studies might explore what we do if we're not able to initiate early prophylaxis. Who should receive therapeutic dosing? Likely infants and those who have a history of VTE. Again, future studies might focus more on assessing individualized risk. And then finally, what should we use for prophylaxis? So currently we're using anoxaparin, which is anti-TEN-A directed over heparin. But again, future studies might look at alternative therapies to really uncouple bleeding from thrombosis. And with that, I'd like to thank you very much. Thanks, Vince, for putting together this wonderful slide deck. I hope I did it justice. And thank you all for listening. Thank you.

venous thromboembolism

pediatric patients

catheter-associated DVTs

low molecular weight heparin

CRETE studies