SCCM Resource Library-Anti-Xa Monitoring for UFH: Benefits and Pitfalls

Video Transcription

Welcome. As we move through the potential advantages and pitfalls of anti-tendon monitoring for  unfractionated heparin, note this discussion will focus on an adult patient population and for non-extracorporeal uses and more traditional indications as the rationale  for anticoagulation. I have no disclosures financial or otherwise.  By the end of this discussion, I hope you will come away with a brief history of unfractionated heparin, an overview of how a chromogenic anti-tendon assay is processed  by the lab, the potential benefits of anti-tendon monitoring as compared to APTT,  and finally some disadvantages or pitfalls to be aware of before implementing anti-tendon guided  strategies. It is just over 100 years since the discovery of heparin in the early 1900s, leading to some of the first therapeutic uses in the 1930s and expanded use in the 40s, 50s,  and 60s for treatment of VTE, and a common theme emerges, namely the history of heparin is the  history of monitoring of heparin, which becomes more apparent with the attempt to optimize  outcomes in patients with acute VTE. Most notably were Basu and colleagues who in 1972 determined  that an APTT goal of 1.5 to 2.5 times the control resulted in decreased VTE recurrence.  While the anti-tendon assay was developed in the mid-1970s, UFH monitoring almost remained  entirely APTT, including in the 1990s where the use of weight to guide dosing was established, along with reports that delays in time to achieving therapeutic anticoagulation  was associated with negative clinical consequences.  Over the past 20 years, the advantages to anti-tendon monitoring have become more apparent, with studies reporting improved time to therapeutic anticoagulation, decreased dose  adjustments, including after therapeutic anticoagulation has been achieved, and decreased likelihood of the potential swings and oscillations between non-therapeutic values.  There are also many studies reporting discordance with APTT labs when an anti-TEN-A is concurrently  drawn. In addition, the landscape for oral anticoagulation has been completely upended with the increased use of the DOACs, which include factor TEN-A inhibitors, which complicate  the common chromogenic anti-TEN-A assay when used for patients on UFH.  Moving on to the variability of UFH, recall it's a high-risk, neurotherapeutic window medication with unpredictable pharmacokinetic and pharmacodynamic  properties. This is because UFH involves large and negatively charged plasma proteins, and in critically ill patients or patients with infections, inflammation, this results  in more variability in the heparin requirements as acute phase proteins may be elevated. When heparin molecules bind to these acute phase proteins, this results in fewer heparin  molecules and the potential for increased variability of the PKPD properties. But wait, there's more! Heparin also binds to endothelial cells, platelet factor IV, and along with a  highly variable molecular weight, where about one-third of heparin molecules administered produced anticoagulant activity, this all contributes to the need for accurate monitoring  of heparin. The two most common labs used for heparin include APTT and anti-TEN-A. APTT has the  benefit of being the more widely used test over many more decades and may have greater provider familiarity and decreased direct lab cost. However, the determination of therapeutic  APTT ranges is often based on internal lot conversion studies performed at each individual hospital lab because it is recommended that the therapeutic APTT ranges be used for the  lab because it is recommended that the therapeutic APTT references are defined according to a more direct measurement of heparin activity, such as anti-TEN-A concentrations.  As for the anti-TEN-A assay, since anti-TEN-A measures the inhibition of a single enzyme, it is a more direct measure of heparin activity, with values that are reproducible across  institutions with minimal recalibration with differing reagents. However, this comes at an increased cost.  Moving on to discuss the process for quantitative determination of anti-TEN-A levels, the sample  begins with a standard blue top, 3.2% sodium citrate tube, and centrifugation lasts 15 minutes, resulting in platelet-poor plasma. Note this centrifugation should occur within  60 minutes of sample collection to avoid PF4 activation, which could result in neutralization of the heparin activity, as PF4 is a potent inhibitor of UFH.  Next, a fixed amount of Factor-10A is added to the plasma, which includes a chromophore attached. The added Factor-10A will bind to antithrombin if heparin is present in the  sample, and the chromophore allows for detection of a potential color change, which can be measured as follows.  Starting with an example where there is an absence of heparin. Due to a lack of heparin  in the plasma, there is minimal binding or formation of an antithrombin-10A complex,  and thus more of that fixed amount of Factor-10A that was added earlier is available to cleave  the chromogenic substrate. More cleaving results in more color that can be detected as a photometric measurement by a spectrophotometer.  In contrast, when there is heparin present in the plasma sample, there is in fact binding of an antithrombin-10A complex, since the fixed amount of Factor-10A that was added  combines with antithrombin molecules from heparin. Therefore, the amount of 10A complex that is available to cleave the chromogenic substrate is reduced, and there is less cleaving.  Less cleaving results in less of a color change that can be detected as a photometric measurement.  The color change is inversely proportional to the concentration of heparin in the sample.  After the light measurement by the automated analyzer is complete, the absorbance value is placed on a curve that is correlated to an anti-10A concentration.  For example, a hybrid curve may be used for both UFH and low-molecular weight heparins versus a single calibration curve, which would just be for UFH.  When discussing anti-10A levels and sample processing, it's important to know the types  of variables that will affect the final reported lab result. The use of anti-10A as compared to  APTT reduces pre-analytic and biologic variables overall, and the influence of underfilled tubes  or blood sampling differences, a lot of this becomes less of an issue with anti-10A samples. But there are a few caveats with anti-10A monitoring, which include delayed analysis  from the time of sample collection. Recall it should be processed within 60 minutes. And of course, recent exposure to factor 10A inhibitor,  low-molecular weight heparin, or FONDA paranox therapies, which we will be discussing shortly.  Beginning with the benefits of anti-10A monitoring as compared to APTT.  Starting with time to therapeutic anticoagulation. In general, a more expeditious time to therapeutic anticoagulation occurs when utilizing anti-10A monitoring, as compared to APTT.  While the reduction in number of hours is variable, depends on the institution, the defined therapeutic target, the protocol, the nomogram that's utilized,  up to a 20-hour reduction in time to achieve a therapeutic range has been reported.  Here are the same data with time represented on the y-axis and hours to achieve therapeutic anticoagulation in a bar graph, where the reduced number of hours consistently favors  the orange anti-10A bars. When looking at percent therapeutic at a certain interval,  such as 24 hours, the number are as high as 92% for anti-10A, and when compared directly to APTT,  anti-10A has been reported to have a higher percentage of patients at a therapeutic target.  When evaluating the dose adjustments required for patients on UFH, there are fewer dose adjustments for patients on APTT than for anti-10A.  However, there are fewer dose adjustments per 24 hours that are required when utilizing  anti-10A monitoring, as compared to APTT. We found, for example, that use of anti-10A monitoring resulted in one fewer adjustment per every 2.5 patient days of heparin.  The reduction in dose adjustments is fairly consistent across studies over the last several  decades. The general theme is there is one fewer dose adjustment per every two to three patient days, and there are fewer resources for phlebotomy, lab, and nursing.  Moving on to discordance. Discordance is the disagreement between what would be considered non-therapeutic or therapeutic values. For example, this often involves an APTT that  is super therapeutic, but the underlying anti-10A level when obtained is actually a therapeutic value. Overall, discordance between anti-10A and APTT is highly prevalent  in physicians and labs, and it ranges typically between 40% to 60%. Let me repeat, there is a 40% to 60% disagreement between APTT and anti-10A.  The prevalence of discordance is consistent among many studies, and not surprisingly, also includes patients with COVID positivity. To expand on one example, in the Whitman-Perve  within their 49% discordance rate, they found the APTT was therapeutic only 35% of the time that the anti-10A was also therapeutic. When discussing heparin therapy, monitoring  often reveals fluctuations and swings similar to a sine wave, with many of these oscillations  occurring between non-therapeutic values. One goal within the realm of heparin monitoring is to decrease these oscillations and decrease or shrink the amplitude of those swings  to increase the time spent in a therapeutic window.  While there are limited data describing these oscillations, I wanted to share data we found with likelihood of having consecutive non-therapeutic values between anti-10A and APTT.  For example, if a super therapeutic level is drawn, what is the likelihood that the next value would also be elevated? We found it was 3.7 times more likely to occur  with APTT as compared to anti-10A monitoring.  And what about going from a super therapeutic value to a sub therapeutic value? We also found it was 3.7 times more likely to occur with APTT versus anti-10A monitoring.  Next, we found a 5.5 times increased likelihood of going from a sub therapeutic value to a super therapeutic value when using APTT as compared to anti-10A monitoring.  And finally, we found patients were twice as likely to have consecutive sub therapeutic values with APTT monitoring as compared to anti-10A.  Overall, the likelihood of having two consecutive non-therapeutic values two consecutive non-therapeutic values, including those on the opposing side of the  therapeutic window, was significantly increased with APTT monitoring. It does appear that the  intensity of the heparin rollercoaster ride is directly related to the monitoring parameter  utilized. The overall summary of the anti-10A benefits include improved time to therapeutic anticoagulation, fewer dose adjustments that are required, reduced oscillations between  non-therapeutic values or consecutive supra or consecutive sub therapeutic values,  anti-10A has reduced impact on pre-analytic, analytic, and biologic variables, and arguably most importantly, it removes the significant discordance concerns.  Note that recalibration with varying batches of reagents is minimal. Despite these advantages,  the data to support decreased risk of bleed or thromboembolism with anti-10A monitoring has yet to be demonstrated. Moving on to the anti-10A pitfalls.  First, we all probably know about the significant elevations that can occur with anti-10A levels in  the presence of recent oral factor 10A inhibitors and Fonda Paranox. These elevations can persist  for 72 or 96 hours or greater, and this really confounds the monitoring and introduces the  potential for under-anticoagulation. For example, a patient with new NSTEMI on a PIX band for history  of AFib, it started at 12 units per kilo per hour of UFH with repeated anti-10A levels greater  than 1.1, resulting in infusion interruptions and down titrations, and the patient soon ends up on three units per kilo per hour. If we think back to the anti-10A chromogenic assay,  the prolongation that occurs is directly related to the steps involved with the cleaving by factor  10A. Normally, in the presence of a usual intensity of heparin, the known or fixed amount  of factor 10A that is added to the sample binds with antithrombin, thus less is available to cleave the substrate, which may result in a level such as 0.3, for example.  However, when the factor 10A inhibitor is present in the sample, this results in inhibition of the  factor 10, thus less is available to cleave the substrate, and results in a faux sky-high level  of greater than 1.1. Because this process is inherent in the standard approach of how the  chromogenic assay is performed by the instrument, the influence of these medications significantly  complicate anti-10A monitoring, which is not a concern with APTT. What you may want to watch out  for is how this influence due to the chromogenic assay also applies to low molecular weight heparins,  but potentially in a different manner. While an anti-10A level may be greater than 1.1 from  just a whiff of an oral factor 10A inhibitor, for low molecular weight heparins there may be more  of an apparent dose-dependent relationship. We found that prophylaxis dose low molecular weight heparins prior to UFH did not significantly influence the initial anti-10A levels.  However, treatment dose low molecular weight heparins preceding UFH will likely significantly  elevate initial anti-10A levels. For example, a patient with a new DVT diagnosis receives 120  milligrams of inoxaparin, is then admitted and transitioned from inoxaparin to UFH, a VTE  nomogram, with apparent repeated anti-10A levels greater than 1.1, resulting in infusion interruptions  and down titrations during a critical time to be therapeutic, and again potential under anticoagulation occurs.  Represented with a figure, we found that prophylactic dose inoxaparin within 24 hours of UFH had no significant impact on initial super therapeutic anti-10A levels. However, for  treatment dose inoxaparin, the median anti-10A level was greater than 1, similar to what is  seen with oral factor 10A inhibitors, which appear to indicate the potential dose-dependent influence  of low molecular weight heparins on the likelihood of having a super therapeutic anti-10A level for  UFH. This is important because the monitoring parameter for UFH may not just be an influence by simply the presence of inoxaparin administration prior to UFH, but rather the dose.  One of the major downsides or barriers for anti-10A implementation has been the cost. In general,  anti-10A will be more expensive, at least in terms of direct costs, but this may be offset by the  decreases in phlebotomy, lab, and nursing resources. For those institutions who have yet to transition  to anti-10A monitoring in the U.S., anticipate that a $2 PTT may be $4 or $5 for an anti-10A  level, but the several extra dollars spent for each lab test is likely quite reasonable given  heparin is a high-risk, narrow therapeutic window medication, and given the hundreds and hundreds  of dollars spent on daily labs for critically ill patients. In summary, the overall disadvantages  and pitfalls to be aware of include prolongation of the anti-10A level due to exposure of factor  10A inhibitors and Fondoparanox, and don't forget about loma like the weight heparins, especially treatment dose. Note the anti-10A assay, if it's opaque, gonicteric, lipemic,  and hemolyzed samples, this can impair the light detection and complicate monitoring in patients  with hypertriglyceridemia and hyperbilirubinemia. Note the sample should be processed within 60  minutes to avoid neutralization of the sample, and the direct cost of the assay is more expensive  as compared to APTT. Some implementation keys that I will mention for institutions who may be  considering a change to anti-10A, you may want to integrate clinical decision support for the choice of monitoring, and from a provider perspective, the choice to anticoagulate a  patient does not just involve the decision about using heparin, but about the monitoring parameter  utilized by the nurse, as many protocols are nurse-driven. It is now imperative for providers  to utilize the pertinent patient medical history to guide the monitoring decision tree. The anti-10A  lab meant for heparin should be clearly designated such that a low molecular weight heparin calibration  curve is not utilized. Also, if keeping APTT nomograms, ensuring that these are clearly  differentiated from anti-10A, and to consider a standardized process for transitioning from APTT to anti-10A after an appropriate period of time.  With a final summary, the benefits of anti-10A monitoring include faster time to therapeutic  anticoagulation, fewer time spent with oscillations as well, fewer adjustments, avoidance of discordance,  but it is complicated by factor 10A inhibitors, von der Paranox, or low molecular weight heparins.  But unless a patient has one of these complicating scenarios, APTT should likely be avoided in the  vast majority of situations, and an APTT value should be viewed with healthy skepticism,  considered highly variable, discordant, and a poor surrogate marker of intensity of anticoagulation  that is outdated. It is time for widespread adoption of anti-10A monitoring. Note that the biologic variables and increased lab costs should be considered prior to implementation,  along with having the capability to ensure that the samples are processed within 60 minutes.  The increases in direct lab costs are likely offset by decreases in other resources and the clinical benefits.

Video Summary

The video transcript discusses the advantages and pitfalls of anti-10A monitoring for unfractionated heparin (UFH). It explains that UFH has been used for over 100 years, and monitoring of heparin has always been important in optimizing patient outcomes. The two most common labs used for monitoring heparin are activated partial thromboplastin time (APTT) and anti-10A assay. The anti-10A assay is a more direct measure of heparin activity, with reproducible values across institutions. It has several advantages over APTT, including improved time to therapeutic anticoagulation, fewer dose adjustments, and reduced oscillations between non-therapeutic values. Discordance between APTT and anti-10A is common, with disagreement rates ranging from 40% to 60%. However, anti-10A monitoring is complicated by the presence of factor 10A inhibitors, Fondaparinux, and low molecular weight heparins. Cost and processing time are factors to consider before implementing anti-10A monitoring. Despite the disadvantages, the transcript concludes that anti-10A monitoring should be widely adopted due to its clinical benefits.

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 Anticoagulation

Tag Quality and Patient Safety

Year 2022

Keywords

anti-10A monitoring

unfractionated heparin

activated partial thromboplastin time

heparin activity

therapeutic anticoagulation

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