SCCM Resource Library-Case-Based Integration: Discordant aPTT Versus Anti-Xa Values

Video Transcription

I'm Dipali Dixit and I'm a clinical associate professor at Ernest Mario School of Pharmacy at Rutgers in the state of New Jersey.  So as Dr. Anthes nicely discussed the anti-TENA unfractionated heparin monitoring for acute care patients that benefits in pitfalls, I have been tasked to go over a few cases that  highlight the discordant of APTT and anti-TENA values. As nicely discussed by the previous speakers, we've already learned that discrepancies in  APTT and anti-TENA values are well-documented phenomena in hospitalized patients. Despite frequent discordant values, controversy still remains over which test to use.  Should we be using APTT or anti-TENA based algorithms for monitoring and dosing unfractionated heparin?  We also know that inadequately dosed unfractionated heparin can result in severe clinical consequences such as thrombolic disease or hemorrhagic events.  So now I will go ahead and share a patient case that we recently had in the medical ICU that we took care of.  So SM is a 48 year old gentleman with end stage liver disease who was admitted to medical ICU for a change in mental status and hypertension.  SM's past medical history is where he has diabetes, history of hypertension, alcohol use disorder, portal hypertension, and esophageal varices.  Of note, per family, he did not have a history of any bleeding or any other issues.  Day two into his ICU when he sedated on propofol, some of the reports that came back that basically showed that SM developed a femoral DVT.  So as a result, he was initiated on unfractionated heparin using our nomogram and targeting the normal anti-TENA range, which is 0.3 to 0.7.  And we also decided to get his APTT as well. Of note, prior to initiating heparin, we did get all the laboratories, including his baseline  APTT, CBC, hemoglobin, and so on and so forth. This is, of course, according to our protocol that we use in-house.  24 hours following the initiation of hospital protocol, a PTT was reported to be greater  than 300 seconds, whereas the anti-TENA level was 0.7, which is the upper end of the therapeutic range.  So, of course, this case ended up having us to scratch our heads and try and figure out what is going on and why are these two tests so different from each other.  So why are the tests discordant? And then, of course, we were thinking about, given that his elevated PTT, is he going to be at increased risk of bleeding?  Should we continue SM on M anticoagulation? And what target should we be using for range of the APTT? And whether we should go with anti-TENA or should we continue APTT?  So, you know, we did go back and recheck all the numbers and it continued to show us the same thing, basically, that APTT was still elevated and the anti-TENA was with the normal  limit, except it was on the higher end of the range.  Before I further discuss the patient case, I just want to quickly review a couple of important points.  So we know that there are several complicating factors that can make APTT difficult and perhaps unreliable at times.  So as you see this table, it basically goes over some of the physiologic limitations that are commonly associated with APTT and well documented as well.  So let's quickly go over some of those potential reasons. So we know that when we see our patients that have a concomitant systemic anticoagulation that's ongoing.  So for example, on concomitant warfarin, we can see that there is a potential for under anticoagulating with APTT if we use that test and it's really because it can falsely elevate  PTT. Similar situation with antiphospholipid antibodies. We also know that patients with lupus anticoagulant may also have a very prolonged APTT at baseline  and this can of course affect the sensitivity of the assays as well. We also know that patients with inherited or acquired factors deficiencies can also have falsely elevated APTT.  Similarly, in the setting of liver disease, we know that there is decreased synthesis of coagulation factors. So that can also be falsely elevated for that reason.  On the flip side, we can have patients that can potentially over anticoagulate with activated  PTT, meaning that we will see a baseline activated PTT that could be low and it's actually falsely reduced APTT. So when would we see that kind of a scenario?  So we know that acute phase reactants specifically where there's an increase in factor VIII or an increase in fibrinogen, we can have that kind of impact.  Similarly, we can see this in our antithrombin deficient patients as well. I'd like to highlight a couple of other things as related to anti-TENA and PTT, especially  in our COVID-19 patients. So we know that both of these tests are prone to monitoring inaccuracies.  In fact, recent studies have documented poor correlation of anti-TENA and APTT in patients with COVID receiving unfractionated heparin.  So for example, patients with elevated fibrinogen and elevated factor VIII, APTT is falsely reduced, whereas patients on propofol in the ICU where they're critically ill, if their  triglycerides are elevated, then the anti-TENA level will be falsely increased as well.  So the key thing to take away from this slide is how is this going to impact heparin monitoring in our COVID-19 patients?  Honestly, I think the jury's still out, but I would say that a lot of experts are saying that perhaps anti-TENA is likely more accurate at this time, but I think there's a lot more  research that is needed to really have a definitive answer. Coming back to our patient case, why are these two tests discordant?  Recall that the baseline APTT was prolonged and we did additional testing, and the bottom line was that we found that this was consistent with coagulation factors deficiency due to  his underlying liver disease. And just to back up a little bit, I do want to share that in a certain patient population  that are complicated in nature, our hematology group likes to approach them with testing both anti-TENA factor as well as APTT, as we did for this particular case.  So APTT certainly cannot be used reliably to estimate heparin effect in this particular population, as illustrated by this particular case.  The other thing that we carefully considered is, is this patient at increased risk of bleeding?  Certainly because, you know, given his underlying liver disease with hepatic synthetic dysfunction  and portal hypertension, we deemed that this patient should be considered at increased bleeding risk.  The next thing that we thought about was, well, he definitely has a high risk of bleeding. So should we even anti-coagulate him?  And if we do anti-coagulate him, what test should we use and what range is appropriate to target for this particular patient?  So the decision to anti-coagulate or not anti-coagulate a patient depends on the clinical  assessment of risk of extension of the clot and pulmonary embolism versus his risk of bleeding.  One thing that we did consider was that maybe we can go ahead and just get a vena cava filter to decrease the risk of pulmonary embolism if we think that the anti-coagulation is too  risky for him. Well, the team did end up deciding to move forward with the continuation of anti-coagulation with unfractionated heparin.  However, we decided to use the anti-10A assay with a target of a lower end of the therapeutic range.  So instead of a usual 0.3 to 0.7, we ended up choosing to do a lower end at 0.3 to 0.5 units per ml.  And this may represent the best balance of the need for anti-coagulation with risk of bleeding for our patient.  So finally, with regard to the question, well, which test is really better? Well, as discussed, the APTT or the anti-10A assays both have their strengths and weaknesses.  However, in some scenarios, these tests can somewhat be complementary to each other and maybe we can use both, especially in our complex hospitalized patients.  So generally speaking, what we do is that we obtain a baseline coagulation test before obviously initiating any anti-coagulation therapy.  If these tests are abnormal, then we certainly try to figure out, well, what is the reason behind it? And the risk-benefit equations are reconsidered.  If the anti-coagulation with unfractionated heparin is indicated, then the first three assessments of heparin include both, APTT and 10A.  And if these are coordinated, then subsequent heparin monitoring is performed with just the APTT. Next, meet Tia.  Tia is a 51-year-old obese woman with a history of hypertension, hyperlipidemia, bipolar depression, and anxiety.  Tia presented to the ED because she's been experiencing shortness of breath. But this time, her shortness of breath was really bad and she was just really very uncomfortable.  In the ED, she was diagnosed with submassive bilateral pulmonary embolism.  She denies a history of any past DVT, but there is a family history of DVT where her sister has a recent DVT.  She denied smoking, use of oral contraceptives, recent travel, or any surgery. In the ED, because she was short of breath, she was placed on nasal cannula, which was  then transitioned to non-invasive ventilation. Patient was eventually intubated because of her persistent shortness of breath, after  which she was admitted to the medical ICU on sedation and the team wanted to initiate unfractionated heparin.  Her past medication history is consistent or significant for losartan, Lipitor, aspirin, her antipsychotic, lorazepam, two milligrams every eight hours.  In the MICU, her sedation regimen was as follows. She was initiated on propofol at 30 mics per kilo per minute, which was increased to 65  mics per kilo per minute, and she also needed fentanyl infusion. So listed here are her pertinent physical examination as well as some pertinent laboratories.  So she weighs 124 kilos, she is 60 inches tall, her BMI is 53, her renal function is normal, triglyceride is 550, and she has an elevated D-dimer.  Now because she's in the ICU, we prefer to use heparin for our intubated patients, so then the question came up, well, what would be the best recommendation for dosing her  heparin as well as how should we go about monitoring her unfractionated heparin? So then the question was, well, which weight should we be using to appropriately dose  unfractionated heparin in a lady who has a BMI of 53? Well, we use total body weight at our institution, and I think it's generally well accepted to  use total body weight, although I think there is not a clear consensus as to which weight should we use, but we did proceed with using total body weight.  So once we established the dosing scheme for our patient with the total body weight, the next question that came up was, well, are we going to use APTT or anti-TEN-A levels  to monitor heparin therapy? Well, I would preface by saying that regardless of which assay we use, I think it's important  that we diligently monitor our obese patients very carefully and make adjustments according to the numbers that we get from either APTT or anti-TEN-A.  What we ended up doing was that we chose to monitor her heparin therapy with APTT, and our rationale was really because, if you recall, that her triglycerides were quite  elevated, so we know that there's really no interference with APTT with triglycerides, whereas with the anti-FACTOR-10A, it can falsely increase your anti-FACTOR-10A in light  of elevated triglycerides. So that was really our rationale for using APTT for this particular patient.  So as illustrated by the couple of cases that we briefly covered, what we've learned is that certainly there is no ideal laboratory method to monitor and adjust our unfractionated  heparin, whether it's APTT or anti-TEN-A. However, I think it's critical that we stop and think about the reasons why one could be supertherapeutic versus subtherapeutic.  So we know that anti-TEN-A levels are a lot more sensitive, so why are they subtherapeutic? Is it because the specimen was drawn at the incorrect time?  Was the transportation longer than two hours? And was the dosing appropriate or not? And then, of course, there are reasons for supertherapeutic as well, certainly, such  as renal failure, whether the lower doses are needed, specimens, again, drawn from the wrong line, and so on and so forth.  So the point I'm trying to make is that it's critical to stop and think and figure out what are the reasons why one may have these abnormal numbers.  And certainly, several papers have documented that there's discrepancies between the two tests.  But again, it's just trying to be vigilant and figure out what are the reasons and which test is the best for patients, given their histories and so on and so forth.  So again, this slide essentially summarizes the various biologic factors that are known to influence APTT and anti-TEN-A levels.  So in summary, I would just emphasize that there is plenty of data that has highlighted that the high number of discordant values between simultaneous anti-TEN-A and APTT can  have a significant impact on our patient outcomes. Additionally, this is something that is underappreciated by many clinicians.  It's important to keep in mind that it's not just always the laboratory error that is at issue, but it could be the biologic phenomena that must be considered.  We certainly need more data in a critically ill population, and we've definitely established that there is indeed a clinical relevance in our COVID-19 patients.  I thank you for your attention and for the invitation to come and speak with you today. If anybody has any questions, please feel free to email me at ddixit at pharmacy.ruckers.edu.

Video Summary

In this video, the speaker discusses the issue of discrepancies between APTT (Activated Partial Thromboplastin Time) and anti-10A (anti-10 factor) values in monitoring and dosing unfractionated heparin for patients in the ICU. Two patient cases are presented to illustrate the challenges posed by these discordant values. Several factors can contribute to these discrepancies, including concomitant systemic anticoagulation, antiphospholipid antibodies, factor deficiencies, liver disease, acute phase reactants, and triglyceride levels in critically ill patients. It is important to correctly interpret these values and consider the individual patient's risk of bleeding and clot extension when making decisions about anticoagulation therapy. While both APTT and anti-10A assays have their strengths and weaknesses, they can be used in a complementary manner in complex hospitalized patients. It is crucial to monitor and adjust heparin therapy carefully and to consider the reasons for abnormal values in order to optimize patient outcomes.

Asset Subtitle

Pharmacology, Quality and Patient Safety, 2022

Asset Caption

Anticoagulation strategies and monitoring vary by institution. Laboratory monitoring protocols and applications in a variety of situations, including extracorporeal membrane oxygenation, will be reviewed. Quality assurance for this high-risk medication with continuous evaluation of protocols and areas of practice improvement will be highlighted though clinical cases.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Quality and Patient Safety

Knowledge Level Advanced

Membership Level Select

Tag Pharmacokinetics Pharmacodynamics

Tag Quality and Patient Safety

Year 2022

Keywords

discrepancies

APT

anti-10A

unfractionated heparin

ICU

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