Episode 132: VTE Series- Approach to Hypercoagulable/Thrombophilia Testing

Summary

Podcast Summary: Episode 132 - VTE Series: Approach to Hypercoagulable/Thrombophilia Testing

Released on April 2, 2025, by Rouleaux University Medical Center, "The Fellow on Call: The Heme/Onc Podcast" delves into the complexities of hematology and oncology with a focus on practical management approaches. In Episode 132, the hosts continue their Venous Thromboembolism (VTE) series by exploring hypercoagulable and thrombophilia testing alongside the discussion of anticoagulant reversal agents.

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1. Introduction

The episode kicks off with the hosts, Ronak, Vivek, and Dan, setting the stage for an in-depth discussion on VTE management, specifically hypercoagulable testing and anticoagulant reversal agents.

• Ronak [00:24]: "Today we're moving on to discussions about hypercoagulable testing and also reversal agents for our commonly used anticoagulants."

2. Case Presentation

Dan introduces a clinical case to anchor the discussion:

• Dan [03:04]: "Last episode, we were talking about our 58-year-old guy with a DVT and PE in the setting of pancreatic cancer... discussing the utility of running additional tests to determine underlying prothrombotic conditions."

3. When to Order Hypercoagulable Testing

Vivek elaborates on the appropriate timing and necessity of hypercoagulable testing:

• Vivek [03:37]: "The overwhelming majority of the time when we're asked about running testing... the answer is, let's just sit tight. Not yet."

Key Points:

• Testing during the acute phase or while on anticoagulants is often inaccurate.
• Most results do not alter immediate management, typically leading to a standard anticoagulation regimen.

4. High-Risk and Low-Risk Thrombophilias

The hosts differentiate between high-risk and low-risk hereditary thrombophilias.

• Ronak [22:29]: "Factor V Leiden and the prothrombin gene mutation are both very common in the heterozygous state and are considered low-risk mutations."

4.1 High-Risk Conditions

• Antithrombin Deficiency:

  • Dan [19:24]: "Antithrombin 3 deficiency is the highest risk condition... requires antithrombin replacement for maximal anticoagulation effectiveness."

• Protein C and Protein S Deficiency:

  • Dan [19:24]: "Production is vitamin K dependent and can be falsely low on warfarin... increases the risk for warfarin skin necrosis."

4.2 Low-Risk Conditions

• Factor V Leiden and Prothrombin Gene Mutation:
  • Ronak [22:29]: "These are low-risk and have fewer implications for therapy unless in homozygous or compound heterozygous states."

5. Acquired Thrombophilias

Ronak expands on non-hereditary causes of hypercoagulability:

• Ronak [24:03]:
  • JAK2V617F Mutation: Associated with myeloproliferative neoplasms (MPN).
  • Paroxysmal Nocturnal Hemoglobinuria (PNH): Detected via flow cytometry.
  • Inflammatory Conditions: Such as Inflammatory Bowel Disease (IBD) and Nephrotic Syndrome.
  • Malignancy-Associated Hypercoagulability: Particularly in cancers like pancreatic cancer.

6. Conditions and Tests Not Recommended

Dan emphasizes certain tests that lack clinical utility:

• Dan [25:18]:
  • Tests to Avoid: PAI1, MTHFR mutation, homocysteine levels, elevated factor VIII.
  • Rationale: Lack of high-quality evidence linking these tests to meaningful clinical outcomes. For example, elevated homocysteine levels have not proven to affect recurrence rates when treated.

7. Cancer Screening in Unprovoked VTE

Vivek addresses the common query about cancer screening in patients with unprovoked thrombotic events:

• Vivek [27:02]: "We shouldn't be fishing for or over-proceduralizing our patients with PET scans or full-body CT scans without other symptoms."

Key Points:

• Recommended Approach: Age-appropriate cancer screenings (e.g., colonoscopy, mammography) rather than extensive, symptomless screenings.
• Rationale: Low yield in finding occult malignancies without other clinical indications.

8. Clinical Implications and Shared Decision-Making

The hosts stress the importance of individualized patient discussions:

• Vivek [09:04]: "We can start labeling patients with extra diagnoses, leading to unnecessary anxiety."
• Dan [15:23]: "Most patients with hypercoagulable tests don’t have test results that change management, so excessive testing can lead to confusion and unwarranted treatments."

9. Recap and Takeaways

Dan summarizes the key points, reinforcing the appropriate use of hypercoagulable testing:

• Dan [28:27]: "Most of the time when you're asked about hypercoagulable testing, it's not the appropriate time to do it... focus on high-risk underlying conditions that require beyond anticoagulation management."

Final Takeaways:

• **Avoid testing during acute VTE or while on anticoagulants unless it will change management.
• **Focus testing on unusual clot locations, strong family histories, and young patients.
• **Exclude low-yield tests to prevent unnecessary anxiety and medical interventions.
• **Adhere to standard cancer screening protocols without overreaching in asymptomatic patients.

10. Conclusion

Ronak wraps up the episode by highlighting the practical aspects of applying these insights in clinical settings:

• Ronak [30:52]: "Ask how the test will impact management. It's critical to provide that insight to your patient because from the patient's lens, more testing feels better, but that's not always the case."

The hosts tease upcoming episodes focusing on anticoagulant reversal agents and antiphospholipid antibody syndrome, encouraging listeners to stay tuned.

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Notable Quotes:

• Vivek [03:37]: "Not yet. Because it's not going to change management."
• Ronak [22:29]: "Factor V Leiden and the prothrombin gene mutation... are considered low-risk mutations."
• Dan [25:18]: "We don't see a role for [PAI1, MTHFR, etc.] in clinical practice."
• Vivek [27:02]: "We shouldn't be fishing for... full-body CT scans on these patients."

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Closing Remarks:

This episode serves as a comprehensive guide for healthcare professionals navigating the challenges of hypercoagulable and thrombophilia testing in VTE patients. By emphasizing evidence-based practices and the importance of tailored patient discussions, the hosts provide valuable insights that align with contemporary clinical standards.

Transcript

[Ronak]

Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call, the hemonk podcast. We're coming at you from Merlot University Medical Center. I'm Ronak.

[Vivek]

I'm Vivek.

[Dan]

And I'm Dan.

[Ronak]

And in today's episode, we continue on our discussion about being venous thromboembolism and how we manage this. And this time we're moving on to discussions about hypercoagulable testing and also reversal agents for our commonly used anticoagulants.

[Vivek]

Yeah, I'm excited to get into this one. It's always the topic that comes up is, when do you send this? What do you do? And we'll walk you through some of the ways to really conceptualize that and think about it, because it's really, there's no one size fits all. It's really a shared decision making, which makes this extremely challenging.

[Dan]

Yeah, this is right up there with thrombocytopenia in terms of questions that we get asked a lot in the hospital. So hopefully pretty high yield for our listeners. Let's dig right in.

[Ronak]

All right, guys, without further ado, let's roll that show. So, guys, I'm going to save discussions about this season of the White Lotus for a few weeks down the line just in case people are catching up. But, Dan, I don't think this is normally your thing in case you decided to watch Love is Blind this time. But, Vivek, we never talked about what are your thoughts from this past season.

[Vivek]

We have abandoned Love is Blind. So this is Christine stewing. I'm not supposed to talk about her on this podcast. She's always like, why are you talking about our stuff? But here's the thing. I want to watch this season. This is too trashy for her and that's fair. So I think I'm just going to have to watch it alone. So she's actually gone this weekend, so I might just binge Love is Blind this weekend to really just catch up and see what happened.

[Ronak]

Well, then we'll have to debrief next week when you get the time to do that because I am dying to hear what your thoughts are. Dan, like I said, this is not your cup of tea. But if you decide that you also want to watch it this weekend, we can have a little book club like discussion next week.

[Dan]

No, I mean, I get what you're going through, Viveka. This is how I feel about football and basketball. I have to watch it on my own time. Not going to be watching it together with Logan. So it's a rough existence, but you do find the time for it.

[Ronak]

And then hopefully by next week I will also have more time to catch up on more of season one of Severance because we just started and Dan told us last time that we need to watch Severance if we haven't watched it. And so I took that to heart and we started watching it. So I'm about only two or three episodes into the first season, so more to come.

[Dan]

So glad.

[Ronak]

So far. Very strange, very bizarre, very different than anything I've watched.

[Vivek]

But excellent decision. Excellent decision.

[Ronak]

I'm excited. But until we have another spinoff podcast about television shows, why don't we focus this time again and follow up on our conversation on venous thromboembolism management, this time talking all about hypercoag testing, which is the thing that everyone loves to refer their patients to hematology for. And then also we'll talk touch on a little bit of reversal agents for anticoagulation. So, Dan, do you want to start us off with a case?

[Dan]

Definitely. So last episode, you know, we were Talking about our 58 year old guy with a DVT and PE in the setting of pancreatic cancer. We were meeting with him in clinic and we were talking with him about the utility of running additional tests on his blood to determine if he has any underlying prothrombotic conditions. Well, it's been a week and I think I'm finally ready to talk about this. Giving myself space to breathe and to grieve, having to deal with this question. As I alluded to before, it's something that generally makes him feel a little bit uncomfortable. Would one of you guys want to tackle explaining why that is why we get angsty with this question?

[Vivek]

We do get asked this question quite a lot. And when you really think about it, it seems like a great idea. Right? You want to know why that patient had a thrombosis. And I know in this case this patient had pancreatic cancer. Let's pretend this guy did not have pancreatic cancer. Let's switch it up. We don't have pancreatic cancer. And now we're really wondering, why did a thrombus occur? What happened? We went through our provoking risk factors. We thought about the major provoking risk factors, the transient major provoking risk factors. The minor provoking risk factors. And let's say all of that comes up null. We can't figure out why a thrombosis happens. Then we run into this issue that the tests for hypercoagulability we run are either inaccurate or impossible to perform in the setting of an acute thrombosis or for a patient on anticoagulation. So the overwhelming majority of the time when we're asked about running testing for a patient admitted with acute venous thromboembolism or even they follow up in our clinic, let's say a week later, the answer is, let's just sit tight. Not yet. Because it's not going to change management. Right now, we're going to at least anticoagulate this patient for three months at minimum if they had a thrombosis. You know, just think about how you treat just some sort of a provoked thrombosis. The same thing's going to happen here because we have to maintain blood flow to the vessel that's occluded. As we talked about in our last episode. The other problem is that this kind of testing is kind of a false promise. And most of the time the results won't change how we take care of the patient. If there's no provoking risk factors, this is an unprovoked clot, then we really think that the patient will need indefinite anticoagulation. So is it really going to change our management? And that's really, really important because we can start labeling patients with extra diagnoses, leading to unnecessary anxiety, and that becomes very challenging. Where it might be useful, on the other hand, is that some patients might be really looking for their family, right? Are my loved ones at risk for a thrombosis? Are my children at risk for a thrombosis? So in some cases, that can be informative for some situations, but it's important to counsel your patients on these issues. The coagulation system is complex enough that there are probably many more heritable and sporadic conditions that put patients at risk for developing a clot that we simply don't have a test for. And all of these negative tests aren't going to make me feel any better about stopping anticoagulation. Like we said before, and it doesn't rule out that the patient doesn't have some sort of heritable thrombosis syndrome. And that's where a family history becomes really important. Right. If there's a huge family history of thrombosis, that might tip your head that, yeah, we have something going on here and that also make you more likely to test for some of these things. On the other side of the equation, there are many conditions that we do have tests for that just don't make that much of a difference in absolute risk and just serve to increase patients. So even if we find these things, they may not be important for other family members. So when we're thinking about this, we're thinking about Factor V Leiden and prothrombin gene mutation for these, we know they can increase the risk of a first thrombotic event. But Ronak, what are the issues with that?

[Ronak]

Well, in most cases we are screening for these patients having these abnormalities after the clot has already happened. So it's like we found out you had an increased risk of having the clot in the first place, but, but now you already have the clot. So what really are we proving here? And the other thing is then patients will say, well, does this really increase my risk of recurring clots in the future? And the reality is that maybe there's some slight increase, but it's really, really not that dramatic. And so the same precautions that we would take based on the fact that, you know, whether this was a provoked or unprovoked clot, we'd probably want to have those same conversations regardless of what the testing is showing. And you know, if for instance, a patient had a provoking risk factor for a thrombotic event and had a clot that took place, and later down the line we decide to test them for something like factor V Leiden and it comes back positive and homozygous, there's no clear cut guidance on what to do in that situation. Many people would still say you have this mutation, but you had a clear provoking risk factor to develop the said clot. And so completing three months of anticoagulation is probably sufficient. But this unnecessary testing may make patients really, really Anx and Vivek. I, you know, I think you bring up a really, really important point. So this is how I counsel my patients all the time, is we have these tests that are available if you are interested. However, in a case of an unprovoked clot in the situation that you just gave the example for, no testing is going to convince me that you do not need to be on indefinite anticoagulation. So is this test really going to change management? No. And furthermore, I also remind patients that over reliance on mutational analysis, also not a good idea because of what you said about how complex the coagulation system is. Just because everything looks normal doesn't necessarily mean that everything is truly normal. And there still may be a myriad of different mutations that we don't yet know about and thus we can't test for that may have contributed to this patient's clotting phenomenon. So it is really, really needs to be an informed conversation when patients are questioning this. And it's our job as our hematologists to provide that guidance.

[Dan]

That's right. You know, the big thing is, you know, in Vivek you'd also reference testing family members if somebody is discovered to have a mutation for things like factor 5 gliadin and per thrombo gene mutation. Even though it does increase the risk of first thrombosis, it doesn't do so to the level that we can justify starting empiric anticoagulation without a VTE history. So you ask yourself what you really gain. But of course there are specific scenarios where we do send these tests and it's really important to understand where we'll find these tests useful. The most common clear cut category are patients with thrombosis in unusual locations. And so that's patients with concurrent or simultaneous arterial and venous thromboembolism, patients with dural venous sinus thrombosis. So the cerebral veins and visceral thrombosis, things like a portal vein or splenic vein thrombosis in the absence of a clear local provoking factor like cirrhosis or recent abdominal surgery.

[Vivek]

And Dan, you know, I think that's one that's really important that you mentioned. In the absence of a provoking factor, you'll see splenic vein thrombosis and portal vein thrombosis. Sometimes in a patient with severe pancreatitis or in a patient who just got a big abdominal surgery. So really wanted to highlight what you said because that's so important.

[Dan]

Yeah, we gotta, we gotta make sure that we can't otherwise explain away these clots before we go off and send a bunch of testing. But if those are coming up just out of the blue, it should give you some pause and you should wonder why it happened there because most of the time when we're seeing these dvts, they're happening in the extremities. But let's start with the concurrent venous and arterial thrombosis. There are only a few conditions that tend to do this. I tend to think about the aniphospholipid antibody syndrome, hit or heparin induced thrombocytopenia and Behcettes as the big three that can cause concurrent venous and arterial thrombosis. There's also of course paradoxical embolization. So if somebody has a patent foramen ovale and there's a connection between their right side and left sided circulation, then perhaps you could explain away a concurrent venous and arterial thrombosis that way. But, but in terms of underlying conditions so hit obviously that's going to require other features like heparin exposure and thrombocytopenia. And so that testing is usually happening in the acute setting when the clinical suspicion is high enough. Behet's that's more complicated sort of systemic vasculitis syndrome. There are other diagnostic criteria there. And so if there's concern for that, rheumatology should really be involved to help guide that workup and management. And as far as antiphospholipid syndrome, we will have a whole episode devoted to a deep dive on this very important subject. But for now, suffice to say this is one type of hypercoagulable testing that we send off pretty regularly as it does have implications for risk of recurrence and for anticoagulation management.

[Vivek]

And listeners remember to check out our hit episodes that we had. We really outlined how to work this up, really how to think about it. For basettes I always think about the pathology test that basically if somebody has an inflammatory response, if you just stuck them with a small needle then that's a sign of Behet's. But again, you know, sometimes you see mucocutaneous involvement and these are reasons refer to the rheumatologist and the antiphospholipid antibody syndrome. Really, really excited to get into that episode which we're going to release very soon in this series. So for the cerebral venous thrombosis or visceral thrombosis. Ronak, what do you, how do you think about working those up?

[Ronak]

Yeah, absolutely. Again, these are weird places for people to get clots and so that should set off our spidey senses that something underlying may be at play here. So here you're thinking about primary disorders of the bone marrow that may increase thrombotic risk. So this includes things like NMPN. So specific JAK2V617F is something that we frequently test for in this setting. Another important can't misdiagnosis, pnh, paroxysmal nocturnal hemoglobinuria. Both of these conditions may initially present with unusual thrombosis and there may not be evidence of disease on the cbc. So it's something that you just have to be sort of on the lookout for. JAK2 mutations can be detected by molecular testing on the peripheral blood. And PNH testing involves flow cytometry to detect a loss of complement regulatory proteins. Genes then Pig A or CD 56 and 59 are the buzzwords that you may have seen in your reading. Another situation that always warrants testing is when we see thrombosis in really young patients. And for some of these patients with these super high risk conditions like antiphospholipid antibody syndrome and antithrombin deficiency, the first VTE is often seen in adolescence. And so again should tell you that something strange here is going on. We often see testing sent by colleagues in obstetrics in the setting of recurrent pregnancy loss. And when tests come back positive, the patient will often get referred to hematology for assistance with management too. So just something to be aware of that there may be referrals that come in that way as well.

[Vivek]

All of this is really, really important when you think about it. Let's say you found a JAK mutation, for example, and the patient ends up getting a bone marrow biopsy and everything looks normal. Well, that's still a major provoking risk factor that isn't going to go away. And that's why it's so important, because it informs your for lifelong anticoagulation, that PNH testing, if you've got that clone there, even if you're not having hemolytic anemia or issues with that complement mediated hemolytic anemia issue, you still need to put that patient on anticoagulation because you have this major provoking risk factor that's not gonna go away. And Dan, I really liked what you said because I started out the episode saying that when you think about hypercoag testing, there's some things about testing the family members and things like that. But what you said was spot on. If you have a factor V Leiden or prothrombin gene, which we're gonna get to here in a second, the penetrance isn't necessarily such that everyone's going to get a thrombosis and it only really predicts the first thrombosis and subsequent thrombosis after that, doesn't really predict where they're going to have that in a provoked setting. So that's what's really, really important from what you mentioned, is that just because somebody is a heterozygote carrier for factor V Leiden doesn't mean that all Family members are going to get thrombosis all of a sudden, and that's really, really, really important. Again, the shared decision making comes into play with that. So these all seem like reasonable situations where testing will change management or lead to a diagnosis of another underlying condition that's going to require beyond just anticoagulation. For this DVT episode for, let's say, three months, what are some of the more borderline indications where you'll still find yourself setting off this testing?

[Dan]

I tend to have a more detailed discussion of hypercoagulable testing with patients who don't have a clear indication for either indefinite anticoagulation or limited duration anticoagulation. So for those folks who are kind of in the middle, this is folks with minimally provoked first VT el or with recurrent provoked VT el who are either reluctant to remain on indefinite anticoagulation or who have a higher risk of bleeding. So patients where even a small increase in risk of recurrent thrombosis could potentially push me towards recommending indefinite.

[Vivek]

And Dan, can you give us an example of a minimally provoked VTE?

[Dan]

Sure. I mean, this is like your patient who comes in with a pulmonary embolism or a DVT after a flight from Australia or after having a vasectomy or some, you know, outpatient procedure. These are things where you really wouldn't expect that that should be a strong enough provoking risk factor to set off a thrombotic event. But it's something. And so how do you deal with those patients? What should I be looking for? Is there anything that can push me one way or another on duration of anticoagulation? And so ultimately, if the patient does feel strongly about choosing a limited course of anticoagulation and they fully understand the risk of recurrent thrombosis in one of these borderline cases, I won't push them to do testing if they aren't interested. But I do think that it can be helpful to try and better understand the risk profile. I'll usually also send testing in young patients with a strong family history of thrombosis, These patients are more likely to have one of the high risk thrombophilias. And even if they are found to have a low risk thrombophilia, like factor V Leiden or per thrombin gene mutation, we know from their family history that there must be something about their family's genes that sets them up for being a higher risk for vt.

[Vivek]

So, Dan, one thing that you're maybe implicating, there that if we have a patient with a strong family history of VTE, that that might be a situation that they may have had an unprovoked event and they're just wondering in their children, what do I is maybe that's a situation where you might be pushed towards ending the testing. Is that kind of what you're getting at?

[Dan]

Yeah. And you know, also just you have a young patient who's got a clot, even if it was provoked, but all their aunts and uncles on their mother's side also have thrombosis history that's really strongly suggestive of, of a clinically relevant heritable condition. And so I think that it just can be helpful to try and delineate that.

[Vivek]

All right, so we've talked about high risk and low risk conditions a few times at this point. What are these conditions and what conditions are you generally not testing for in any patients when we're thinking about hypercoagulable testing?

[Ronak]

Well, I can start with what is worth testing for. And so the main inherited thrombophilias, where there is a role for testing in the appropriate clinical context would be things like antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, and the prothrombin G2210Amutation or the prothrombin gene mutation for short of these. I think of antithrombin 3 deficiency as by far the highest risk condition. The average age of 1st VT EL is 14 years. So in the adult hematology clinics, patients may already come to you with this diagnosis. For this testing involves sending an antithrombin 3 activity level, which we know will be reduced in patients who are on anticoagulation, especially those with heparin or Lovinox in their system. And so levels can be falsely low in these situations. Levels can also be falsely low for patients with acute thrombosis as well. So patients who do have this condition can be treated with anticoagulation. And in fact, Lovenox or Enoxaparin seems to work very well. But some patients may need antithrombin replacement for it to be maximally effective, or they can even get injections of recombinant antithrombin. So the key takeaway from this is, yes, you can test for it, but do not test for it in the acute setting of a clot and be weary about what anticoagulants they're currently taking before sending off this testing. Dan, I mentioned protein CNS deficiency. What are your thoughts on those two?

[Dan]

Yeah, and you Know, I'll just also mention there is technically an acquired form of antithrombin deficiency. So it's hepatically produced. And if patients have been treated with asparaginase as a part of some of these protocols, for all acute lymphoid leukemia, they may develop an antithrombin deficiency. So it's something to keep in mind. It can happen in certain weird clinical scenarios. As far as protein CNS deficiency, I do think of these as the next most impactful heritable conditions. The diagnosis here can be a little tricky. Remember that production of both protein C and S is vitamin K dependent and therefore is suppressed by warfarin. So whenever I see a patient with history of both protein C and S deficiency, I am immediately suspicious that somebody ran their testing while they were on warfarin. These factors also change during pregnancy. Protein S levels can decline by as much as 50% from baseline. And so if any patient has been diagnosed with deficiency during pregnancy, they also need to have repeat testing at least six weeks postpartum to confirm that that was a true deficiency. Acute illness, like severe infection or critical illness in the icu, that can also deplete protein CNS levels. So, again, this is just another example of why we don't like to do this testing on inpatients. The big treatment implication here is how we manage thrombosis in folks with protein C deficiency. And this is because there's an increased risk for warfarin skin necrosis. I usually avoid warfarin for these patients, but if for some reason I absolutely have to use warfarin, I start at a low dose and I keep them on their bridging anticoagulant for a longer period of time. I like to see at least two consecutive INRs in the goal range before I'm comfortable pulling off that added protection just because of that high risk for warfarin skin necrosis.

[Vivek]

And Dan, one thing I wanted to ask you about the protein CNS deficiency, there's a lot of different ways you can send this testing. There's antigen levels and activity levels. Can you tell us a little bit more about that?

[Dan]

Yeah, definitely. So there are a few things to look out for here. There's a test called activated protein C resistance. That's actually a screening test for factor V Leiden. Factor 5 is inactivated by protein C and factor 5 Leiden is a mutation that makes factor 5 less able to be digested by protein C. So it's one of these things where that is not a relevant test. You're looking for a protein C activity level. And you're right. On protein S, we have both protein S activity and protein S antigen. This is because being on even a drug like apixaban or non warfarin anticoagulants can impact the protein S activity level assay. So protein S antigen can be a useful tool there, where if you're seeing somebody has a low protein S level but they're on a blood thinner, you want to run that antigen and just see, okay, was this really. Is this protein really low or is the assay just being impacted by the presence of the anticoagulant?

[Vivek]

Got it. It makes so much sense. And let's keep moving along here and let's talk about the one that we see the most on tests. I feel like the factor 5 Leiden and the prothrombin gene mutation. On all these internal medicine board exams, there's all these random questions. Nobody knows how to answer them. They're guessing C for every time. So, Rona, tell us about factor V Leiden and prothrombin gene mutations.

[Ronak]

Yeah. And so factor five Leiden and the prothrombin gene mutation are both very common in the heterozygous state and they are in fact considered low risk mutations. There's a higher risk of clotting with the compound heterozygosity. So that's heterozygous for both the prothrombin gene and factor V Leiden mutations. Pseudohomozygosity, where you have one mutated copy and one loss of function gene copy. And then of course, with true homozygosity, where you have two abnormal copies of either factor V Leiden or prothrombin gene mutation. But all in all, this is still a lower risk situation with fewer implications for therapy. So this includes patients with a history of recurrent pregnancy losses. Unfortunately, the evidence suggests there is not a significant decrease in the risk of pregnancy loss if we use prophylactic anticoagulation for patients with these lower risk mutations. However, for patients who have a history of thrombosis during pregnancy, that's another story. And I do generally put these patients on anticoagulation for pregnancy and for six weeks postpartum. But other than that, there's really no role for anticoagulation here.

[Vivek]

And the important thing that you mentioned there about that is that this is. You'll see antepartum and postpartum prophylaxis. That's what this means if you've got homozygous factor V Leiden or homozygous prothrombine or a compound heterozygous condition you're going to be doing through pregnancy and six weeks after because there's still a high risk of thrombosis. So, Ronick, why don't you continue on the conversation with the acquired thrombophiles? Thrombophilias, yeah.

[Ronak]

And I sort of alluded to some of these just a little while ago. But the acquired thrombophilias that we're thinking about includes, once again that JAK2V617F mutation looking for an MPN. Also PNH, paroxysmal, nocturnal hemoglobinuria. We have alluded multiple times already, but we're not going to talk about in too much detail the antiphospholytic antibody syndrome. Just wait. We've got a good episode for you planned, I promise. Other things to consider include things like ibd. There's also hypercoagulability of malignancy. Patients with underlying cancers are hypercoagulable just given the nature of the malignancy. And then we also have to be weary of nephrotic syndrome. Remember that anticoagulant proteins, cns, are smaller, and so they're more readily filtered through a very leaky glomerulus than the factors of the coagulation cascade. And so as we know, in nephrotic syndrome there is is protein loss. Right. So if you're preferentially losing your anticoagulants, this can increase risk of patients having thrombosis. And unfortunately, this does result in many patients presenting with things like renal vein thrombosis.

[Vivek]

And so, Dan, what are things that you just don't test for? So we kind of talked about the things to test for in certain circumstances. But what are the no gos that you'll just never test for?

[Dan]

I almost didn't even want to talk about this in this episode, but I do think it's important to mention some of these things because you're probably going to see them on folks that get referred to you in the clinic. And they may have this panel of tests that was sent by someone else who didn't listen to this podcast and still didn't know that these weren't things that we necessarily considered clinically relevant. These are things that include PAI1, so plasminogen activator inhibitor mutations, the MTHFR mutation, and homocysteine levels. These things kind of go together. I do not send those. I don't look for elevated factor VIII levels either. And the story with all these is basically, which is that there was A time when we thought there might be some clinically significant risk for VTE associated with the results of these tests. But as we've gotten larger amounts of data reanalyzed or older studies, the picture has become actually less clear. And we don't have any high quality evidence to suggest that these tests give us any clinically valuable information. Let's take homocysteine as an example. We re examined that early data that initially suggested a connection between high homocysteine levels and VT and that revealed that the link was very likely confounded since the studies did not control for things that we know to strongly be associated with vt, elike smoking and elevated bmi. Beyond that, studies that looked at interventions to lower homocysteine levels in patients with VTE and high homocysteine didn't find any difference in recurrence rate between folks who were treated and untreated patients. So these tests, the MTHFR mutation, homocysteine level, elevated factor VIII PAI1 mutations. I don't see a role for them in clinical practice. In the research world, if you're doing a study on whether or not these things do have any clinical relevance, great. But we don't know what to do with them in the clinical world.

[Vivek]

And I think this is a really, really great episode. I'll kind of cap us off with the big question that people always ask. If a patient comes in with an unprovoked clot, for example, let's say they had some sort of VT EL event. Do I need to look for cancer? And this is an important thing to consider because people think, okay, maybe I should do that. The reality is that that's not really something that we should be doing. We shouldn't be fishing for over proceduralizing our patients and just getting PET scans or full body CT scans on these patients. What we do recommend is age appropriate cancer screenings like colonoscopies, mammographies, lung cancer screening in patients with smoking history, all of those are going to be critically important.

[Ronak]

But.

[Vivek]

But in the absence of other symptoms, they had GI bleeding, they had hematemesis, they had a pathologic fracture. In the absence of those other symptoms that might make you think about a cancer, there's no actual evidence that fishing to find a cancer is going to help the patient in any way. If anything, it's going to cause increased anxiety, unnecessary medical costs, increased proceduralization without improving outcomes. And we know that the patients who have unprovoked VTE were rarely finding an occult malignancy. In that case, in the absence of other symptoms. So just wanted to finish off the episode with that little bit because I know that comes up a lot. And Dan, can you just take us home here, give us a recap of what we talked about today, some of the high yield points when you think about hypercoagulable testing.

[Dan]

Absolutely. And I'm glad that you mentioned that. Right. Like if a patient's coming in with a bunch of unexplained symptoms and a clot, like, yeah, work those symptoms up like you would for any other patient whether or not they had a VT El. That's how I deal with it. And like you said, age appropriate cancer screenings stay up to date on that again, like any other patient. So, yeah, I agree. Agree with you. No fishing expeditions here. So to wrap things up, most of the time when you're asked about hypercoagulable testing, it's not the appropriate time to do it because by and large, these questions are coming when a patient has just had their clot. And we know that our tests, except for the genetic tests, are going to generally be inaccurate at that time or hard to run because the patient's on a blood thinner. Once you are a little bit further out from the acute event, so the dust has settled and it's appropriate to run that testing. We think about doing it in situations where it's really going to change our management. We're looking for high risk underlying conditions that require management beyond just anticoagulation or things that truly do change our course of treatment. In folks who have clots in unusual locations, a strong family history and initial diagnosis at a young age, and for folks who are sort of borderline between needing a short course or indefinite anticoagulation. That's the group of folks that I like to test. As far as things we're looking for, there are five main heritable antithrombid deficiency, protein, CNS deficiency, factor V Leiden and prothrombin gene, and a handful of acquired mutations and other conditions that might provoke a clot. We have a lot of tests that we don't send. If you see PAI1MTHFR, Homocysteine Elevated Factor VIII, you're going to have a lot longer clinic visit explaining why we don't need to do those tests and why we don't find them clinically relevant. So I just don't send them in the first place. But again, if you have a patient come to you with those tests now, you'll at least have some good information as to why they aren't considered clinically relevant. So hopefully this gives you a good idea of why we get so uncomfortable when we're asked about this.

[Vivek]

Yeah, Dan, I thought that was really great. And you know, one of the things that I think always sticks in my head from what you said is that just because somebody had a factor V Leiden mutation doesn't mean that their family member is going to have a clot. Even if they have that factor V Leiden mutation, the penetrance isn't just completely there, it's not. The family history is really important. So taking a clinical history is super important in these cases.

[Ronak]

Yeah, I thought this was great. And I hope that our listeners can feel comfortable when they walk into clinic and inevitably have a patient that's going to have this exact same question and referral. And I give the caveat that there aren't clear cut guidelines about when it's appropriate and when it's not. But what I hope you all take away from this is essentially a real world look into what's going through hematologists minds when they discuss this exact question. And most importantly asking the question of how will this impact management. And it's really, really, really critical for you as the doctor to provide that insight to your patient because from the patient's lens in their eyes more testing is always better. It's often our job to remind them that that's not always the case case. So guys, next time we continue on this, this conversation we'll talk in the episodes to come about reversal of anticoagulants. We'll talk all about of antiphospholipid antibody syndrome which we keep alluding to. We've got a lot in store so make sure you guys check in again with us next week. We'll talk to you then. Until next time, we'll see you all later.

[Vivek]

See you later.

[Dan]

Peace.

[Vivek]

Sa.