For several years, most coagulation specialists have supported using the chromogenic anti-Xa assay in place of the PTT for monitoring unfractionated heparin therapy. We contend the anti-Xa is more accurate and reproducible as it is less prone to interference. Many medical center laboratories have converted to the anti-Xa as their primary means for monitoring UFH, and can also use it to measure low molecular weight heparin and synthetic pentasaccharide therapy. These institutions still offer the PTT as a coagulopathy screen and many surgeons and physicians insist on using both the anti-Xa and the PTT for monitoring UFH.
A pathologist colleague recounts that surgeons at his institution have encountered a few patients whose anti-Xa values were below the therapeutic range limit, 0.3–0.7 units/mL while the PTTs from the same specimen were prolonged beyond the upper limit of the therapeutic target range in seconds. Increasing the drip rate to achieve the anti-Xa therapeutic target resulted in serious hemorrhaging.
In a single instance, the patient’s PTT was prolonged to within the therapeutic target range but the anti-Xa was below the limit, and the antithrombin level was 30%. When the patient was given antithrombin concentrate, the PTT remained nearly the same but the anti-Xa value rose to within the therapeutic target range.
I don’t have a good answer for my friend, however I know there are many who consider the anti-Xa, a primary measure, to be inferior to the PTT, a secondary measure, because the PTT is a surrogate for the outcome of UFH therapy and not merely UFH concentration. They say the PTT more closely reflects the patient’s clinical condition. I’d like to get some comments from colleagues who have similar experiences and who can both explain anti-Xa–PTT discrepancies and who can advise which of the measures to rely upon in the clinic or surgery.
Excellent comments from JO
From Bob Gosselin: Excellent comments from JO and EF–however, lest we forget, that unlike other disciplines, we usually have the capacity to measure 1) is it there, and 2) is it working? For heparin, there are still methods that can assess “is it there” (LC-MS/MS) along with other anti-Xa DOACs (and dabigatran) which may be different from “is it working” (functional based assays such as anti-IIa/anti-Xa). While I am not suggesting that most places would even think about ordering a mass spec for a heparin sample, hopefully our future docs get more edified about coagulation. I am skeptical, as the duration of medical school is the same as it has been for over 40 years. With the exponential amount of information that is being taught from 40 years ago, something has to be given up, so it appears that something is often the basic stuff, including coagulation.
From Dave McGlasson: Dr.
From Dave McGlasson: Dr. Olson brings up some great point about the names of the test Anti-Xa. I know the institution of which he speaks and the idea for the hybrid curve that we published came out of a conversation with a health care provider arguing that they wanted a factor X level when they really wanted a UFH level.
From George: I know this is off-topic, but we seem to have several lab assay naming problems. For instance, we get orders at least once a day for a “Factor V,” when the unit clearly wants a factor V Leiden mutation. Also, the letter C gives us trouble, is protein C, activated protein C resistance ratio, or C-reactive protein. There are at least 25 names for vitamin D. As we develop narrative clinical laboratory results, we need to also address nomenclature confusion.
From Dr. John Olson:
From Dr. John Olson:
Hello George, I have little to add to the comments that you have received but I have a couple of minor points.
Donna raises the well known issue that the aPTT and heparin assay are two entirely different measurements and do not correlate with each other and, frankly, we shouldn’t expect them to correlate. The shift to the Xa inhibitory method presents an interesting problem for a clinical lab. If you change the assay for another drug, e.g. digoxin, when the change is made, the prior assay is removed from the menu and all clinicians adapt to the new assay. Some will grump about it but there is no choice. When the heparin assay is instituted, there are obvious reasons that the aPTT cannot be removed. Many clinicians continue to use the aPTT even though it is not recommended by the Laboratory and Pharmacy. The greater problem is that many cannot resist ordering both tests, frequently leading to confusion. Attempts to prevent aPTT orders in patients on full dose UFH meet with great resistance.
The other issue that does not go away is whether AT is added to the assay or whether, as in your clients case, the assay relies on the AT in the patient specimen. In the most recent CAP proficiency testing survey, 13% of over 850 laboratories report UFH assay were using an assay with AT added to the assay. In the majority of cases I suspect that the clinician receiving the data does not know the type assay used or the pro/con of each type of assay. Sadly, there are probably laboratories that are also confused about this.
Finally, my little plea, a battle that will not be won, but I’ll bring it up anyway. We should refer to this assay as a Heparin Assay, Low Molecular Weight Heparin Assay, etc., not the Anti-Xa or Xa Inhibitory Assay. Xa inhibition is the method, the assay is for the drug level. When we order a Sodium level, we don’t order a flame photometry or an ion selective electrode, we order a sodium. For some years we had much confusion with people ordering factor X, thinking that they would get a heparin level, generating phone calls, inappropriate tests and the like. Our test menu no longer lists the method, only the drug level to be requested, i.e. Unfractionated Heparin, Low Molecular Weight Heparin, Fondaparinux. It works well.
From Ali Sadeghi-Khomami,
From Ali Sadeghi-Khomami, Precision BioLogic Inc.
Great comments from participants here. To answer your pathologist friend’s question: “When the patient was given antithrombin concentrate, the anti-Xa value rose to within the therapeutic target range.” I think they used a kind of anti-Xa kit in market that comes without excess antithrombin (AT) in its reagent. Unfortunately, results produced by this kind of kit will vary with the level of patient’s own AT level. Typically, anti-Xa activity of heparin potentiates with increasing level of AT and in this case AT administration to the patient did potentiate heparin inhibitory effect of Xa, hence final chromogenic result rose to the therapeutic level in vitro.
In terms of assay selection in general, functional clotting assays will represent clinical situation better than chromogenic assays but instead they suffer from poor analytical performance. Regardless, the lack of clinically relevant calibrator will partially offset some of these differences.
From Dr. Thomas Exner,
From Dr. Thomas Exner, Haematex Research, Sydney NSW. Hi George, Thanks for asking.
Clearly APTTs are affected by many plasma factors whereas anti Xa methods are more specific. Both tests are warranted in difficult cases. An anti Xa method not supplemented with ATIII should probably be preferred as being more clinically relevant but this is precisely where differences with APTT are probably more common. It might be interesting to know which APTT reagents have the biggest discrepancies as there are major differences in composition these days (and not just in choice of contact activator). We now know that APTTs are more sensitive to thrombin inhibitors such as dabigatran than to inhibitors of factor Xa (rivaroxaban, apixaban, etc) for equal clinical effect. Also that heparinoids have little effect on APTTs at therapeutic levels. Thus it is likely that APTT is mainly measuring the thrombin inhibitory activity of heparin which is dependent on heparin cofactor II rather than on ATIII. APTT might be a better indicator for risk of bleeding whereas anti Xa (without ATIII supplementation) is a better indicator for therapeutic benefit.
Here is a comment from our FF
Here is a comment from our FF technical advisor, Donna Castellone.
“Another thing to consider would be the sensitivity of your reagent. Some reagents will cause a high prolongation of the aPTT at 0.4 units of heparin. Also, remember there is no dose response relationship due to biological patient variables. This is seen when you perform a heparin therapeutic range. One year the results were all over the place- the computer program I used couldn’t draw one best fit line, it drew 2!
Most important is to understand how the tests perform using your instrument, reagent combination. Know the reagent and test that you use!
Here is a comment from Dr.
Here is a comment from Dr. Emmanuel Favaloro, who is, among other things, Editor In Chief of Seminars in Thrombosis and Hemostasis:
“I would agree there are advantages and disadvantages for both approaches (APTT vs anti-Xa). There is a great review on this topic: Cuker A. Unfractionated heparin for the treatment of venous thromboembolism: best practices and areas of uncertainty. Semin Thromb Hemost. 2012;38:593–9.
We also see occasional failures of both test systems in practice. For the APTT, a global test system, you will get falsely short APTTs on heparin with high acute phase coagulation proteins such as FVIII and fibrinogen. You will also get falsely elevated APTTs on heparin with the presence of lupus anticoagulant and FXII deficiency. On the other hand, the anti-Xa assay is also not impervious to problems, and is more costly to run, and not available at all sites that monitor heparin therapy. In addition, the evidence base for ‘superiority’ of one process over another is very weak. There will always be anecdotal evidence driven by personal experience that places individuals into one or other camp, but the literature does not provide compelling evidence to support one process over the other, or indeed over the case of ‘no monitoring’ at all.”
Dorothy M. (Adcock) Funk, M.D
Dorothy M. (Adcock) Funk, M.D., Medical Director, Colorado Coagulation asks, “What about PF4 neutralization of heparin in the evacuated tube?”
Here’s a message from Dave
Here’s a message from Dave McGlasson, Wilford Hall, Lackland AFB, San Antonio. Dave is also a FF Technical Adviser.
“I have seen what Mr. Gosselin has referenced, and for the exact same reasons he has listed, but I had seen the APTT affected by low AT levels years ago. I refer to a study we accomplished in 2005 that looks at the pre-analytical variables that affect the APTT and the anti-Xa assay: McGlasson DL, et al. Effects of pre-analytical variables on the anti-activated factor X chromogenic assay when monitoring unfractionated heparin and low molecular weight heparin anticoagulation. Blood Coagul Fibrinolysis 2005;16;173–6. We found that the anti-Xa test was almost impervious to any pre-analytical conditions that would affect the APTT with the exception of elevated plasma hemoglobin.”
Thanks, Dave. It seems in my colleague’s case that the opposite has happened: the anti-Xa was suppressed by a reduced antithrombin activity level, but the PTT was nevertheless prolonged. Geo.
George received this comment
George received this comment from Fritsma Factor Technical Adviser Robert Gosselin, UC Davis: “We often see APTT treatment ‘failures’ with UFH. The reason is not usually AT deficiency, but rather, marked increases in factor VIII and FBG, which bias the APTT low. Often the anti-Xa is within therapeutic target, but the drip rate keeps getting increased in order to meet the APTT target.”