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How to Establish the PTT Therapeutic Range

Hi, George,

We survived the validation and are very pleased with our new Beckman-Coulter TOP, but I have an issue with the new PTT therapeutic range we established for unfractionated heparin (UFH).

We collected many specimens over time, made sure they were double-spun and froze them at –70°C. Once we had the PTT validated and a reference range established, we started running chromogenic anti-Xa heparin assays and PTTs. We are still performing our anti-Xa assays on the MDA using the Stago Stachrom kit as we are waiting on the all-liquid heparin kit from IL. We had over 100 specimens but our range looked pretty flat! So we re-evaluated the results, and pulled out the ones that did not make sense (high PTT with little or no heparin) and threw in several fresh specimens. We came up with a range that (1) is much shorter and narrower than our previous range but (2) matched other TOP/Synthasil users so we felt comfortable.

We have had nothing but grief! We seem to be seeing many super-high PTTs right after bolus that we were not seeing before and it is difficult for the surgeons to hit that more narrow target. To make things worse, we are now being told our pharmacy is switching from Baxter heparin, due to the recall, to another brand and we will have to repeat! The pharmacy wants a range before they switch, which I have explained we cannot do since we do not have any patients to collect on the new heparin.

What would you recommend to the pharmacy? Should they stick with our current range and monitor with anti-Xa assays when needed until we can check the new range?

Sorry this is so long…cheers!
Kim Kinney, Clarian, Indianapolis

Kim, thank you for your question. We’ve used the activated partial thromboplastin time (APTT, PTT) to monitor UFH therapy for many years, though knowing it loses validity in a variety of circumstances. It cannot be used when there is a coagulation factor deficiency or a circulating inhibitor, and its sensitivity is reduced during inflammation when the fibrinogen or factor VIII levels rise. We also know about heparin resistance, in which the PTT fails to measure heparin when the antithrombin activity level is decreased, as may happen in chronic inflammation, liver disease, or long-term heparin therapy.

Following CAP guidelines, we establish the PTT therapeutic range for UFH using the Brill-Edwards ex vivo method. We collect a minimum of 50 specimens from patients receiving all levels of UFH but not receiving Coumadin (established by a normal prothrombin time result). We also collect a minimum of ten normals. Large busy institutions like Clarian typically collect 100 or more. A PTT and anti-Xa heparin assay is performed on each and the pair-wise results are graphed. The PTT therapeutic range is established as the equivalent of anti-Xa assay heparin values 0.3–0.7 heparin units (U)/mL.

When you examine the Brill-Edwards curve closely, you notice the scatter. There are always a number of points with a prolonged PTT and low heparin value. Likewise, you will find some short PTTs associated with therapeutic heparin levels. This further illustrates the variability of the PTT.

A handful of institutions has moved to using exclusively the anti-Xa assay, though most of us retain the PTT for its relatively low cost. Those who have changed use these justifications:

 UFH usage is declining as physicians turn to low molecular weight heparin (LMWH, Enoxaparin, Lovenox) and to pentasaccharide (Fondaparinux, Arixtra).
 Several distributors offer a hybrid anti-Xa heparin curve. The assay may be used for both UFH and LMWH without changing curves.
 At least one distributor, Aniara, offers an Arixtra curve.
 While the cost of the anti-Xa assay exceeds the PTT, the lowered risk for adverse events generated by assay instability makes the new assay cost effective.
Dan Kaczor and others at Stago have been assisting with this upgrade, and may be able to point you to the institutions that have made the change. Meanwhile, you have little choice but to offer the anti-Xa assay to monitor UFH patients during the switch away from the Baxter product. You may be able to switch back once you have collected enough UFH patients, or you may use this opportunity to recommend moving permanently to the anti-Xa assay.

The PTT won’t completely go away, of course. We still use it to monitor the direct thrombin inhibitors Argatroban and Bivalirudin, and we will continue to need it to detect coagulopathies and circulating inhibitors.

Given the problems Baxter has had with their heparin, I wonder how many other institutions are having to change heparin and how they are managing the change.

For more on establishing therapeutic ranges, go to our educational module, Method Validation in Hemostasis.


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