2013 Cheat Sheet

From Robert Löfvenmark, MediRox AB, Nyköping, Sweden “I am curious about the international differences in the use of PT. Most parts of the world use PT Quick except Scandinavia, where we use the Owren method. Owren seems better in all aspects. It utilizes a buffer to pre-dilute the sample giving a final dilution of 21:1 and has a thromboplastin reagent with bovine factor V and fibrinogen. This gives full focus on vitamin K factors; is insensitive to factor V and fibrinogen levels so old samples are not a problem; lacks fibrinogen sensitivity; high INR in mechanical systems is not a problem; it is insensitive to optical disturbances owing to 1:21 dilution; it is suitable for capillary testing of whole blood after pre-dilution, can be used with plasma or whole blood, and has less variation among manufacturers. The only negative sides of PT Owren are that it adds a buffer and is a corner of a penny more expensive. Why do a majority prefer the Quick?”

George checked with Cindy Johns, who had written the following in a 1981 textbook: “The Thrombotest reagent contains an optimal concentration of calcium with adsorbed bovine plasma as a source of factor V and fibrinogen, and a tissue thromboplastin of bovine brain origin. This reagent gives longer coagulation times than those recorded with the standard one-stage Quick PT test and, according to Owren, reflects sensitivity to intrinsic-system factors, particularly to factor IX. This test system is also extremely sensitive to the concentration of factors VII and X. Since the method is designed primarily for the control of therapy with anticoagulants and not the diagnosis of hemorrhagic disorders, its accuracy is highest with activity levels below 50%. A therapeutic range for anticoagulant therapy is 5-15%.

Cindy and George speculated that perhaps the Quick PT may have seemed more useful in 1981 because it functioned as a coagulopathy screen as well as a warfarin monitor. It is likely the PT has since become less often applied as a coagulopathy screen, and the Owren PT could see a comeback.

Rob responded the next day, “I was not around with the Thrombotest, but I have heard that it was the use of bovine thomboplastin that had some set backs. It was slower, more imprecise, but I think mad-cow disease was a topic of discussion as well? Owren brands used here in Scandinavia use rabbit thromboplastin. And beside MediRox which is a small local firm it is produced by global hemostasis companies like Stago and Axis Shield, so it should be available for the rest of the world if you wanted it.

So what can it be? Coagulopathy screening? Possibly, but I think teaching clinicians to order a PT Quick for those < 10% tests should easily balance the advantages for the remaining 90% OAT patients. Do you agree? Owren is slightly slower, that is true. Normal clotting time is 20-22 sec vs 10-14 for Quick. But again, there are many smart people out there that would figure out a faster Owren reagent if that was required. For example with a 1:15 dilution you would still avoid interference problems yet gain all the Owren pros. And as a parenthesis on speed; many automatic systems-like US market leader IL ACL TOP-have fixed analysis times on the tests, and are not at all optimized for speed, so the general lab can´t be in that hurry. it just the tradition? Opinions from opinion-leaders? Has a less good method won because of tradition and possibly marketing efforts? That would be kind of sad-I am really hoping that you could tell me different.”

George also received this reply from Dr. John D. Olson, Director of Pathology, University of Texas Medical Center: “I have had no experience with the Owren method. I suspect that there is little advantage of one over the other and your hypothesis makes sense to me. The Quick method is easy to automate and it is likely that once there was a marketing foothold, laboratories saw little reason to make a change. With INR gaining a very strong acceptance, I think the Quick method will remain dominant.”

And finally, George had a follow-up email from Flo Newlin, retired co-president (withGordon Ens) of Colorado Coagulation Consultants. She, like Cindy Johns and Dr. Olson, considers the choice of the Quick over the Owren PT to be mostly driven by historical and perhaps economic forces. Likewise George spoke with Dr. Larry Brace of Edward Hospital, Naperville, IL reaching the same conclusions, and with Dave McGlasson, Wilford Hall USAF Medical Center in San Antonio, who advocates for the chromogenic X assay for its accuracy and reproducibility.

Dee McMichael comments, a recent CAP survey revealed an inconsistency when reporting factor assays in the presence of an inhibitor. In your opinion, what is the highest dilution that should be tested when an inhibitor is suspected? Is it appropriate to report the value of the highest dilution with a comment indicating inhibitor activity? We recently had a patient with a Bethesda titer of 14. Factor VIII results from the regular curve were: 1:10 = 1%; 1:20 = 2%; 1:40 = 4%; 1:80 = 6%; 1:160 = 12%. All values were below the linearity of the curve. From the low curve the value was <1%. What would have been the appropriate value reported: <1%, linearity of the low curve; <7% linearity of the regular curve; or 12%, highest value obtained but extrapolated from the curve?
George responded that Dr. Larry Brace asserts there is no reason to carry dilutions past the linearity limit. He advises that <7% is an appropriate report. Further, presuming the physician is attempting to achieve stable coagulation using large factor VIII doses, or perhaps with NovoSeven or FEIBA , the best approach is to test for stability using the PTT and follow with periodic new Bethesda titers.

On March 15, “conchi0607” added, I believe the CAP specimen is CGE-B 2012, sample CGE-04, normal plasma with rivaroxaban.

Per Michael Huang, An 80 YO male on warfarin was admitted for shortness of breath. There was an INR of 15 on admission. Just 8 hours before, the POC instrument his doctor used to monitor his INR showed a reading of 2.6. The patient died of pneumonia. Why did the INR of the patient increase from 2.6 to 15 in 8 hours? POC not accurate? Lab not accurate? Patient medical condition changed?
George speculates that acute DIC consumed coagulation factors rapidly between collections, as the patient could have gone rapidly septic. Of course, a short draw or clotted specimen could result in a falsely prolonged PT as well.

In follow-up to Dee McMichael’s March 2 question, Dr. John Olson comments, “We discussed factor assays at our consensus conference. The CLSI document on assays recommends dilution up to 1:160; I believe that it was a consensus opinion.” An in-depth response from Russell Higgins, MD, colleague of Dr Olson and current chair of the Coagulation Resource Committee of the College of American Pathologists (CAP) was attached as a PDF.

We highlight Marianne Thawley’s March 11 question that appeared as a comment in the March 8 post,  “What are some causes for decreased PTT results?” George asserts that only technical artifacts shorten the PTT to below the lower limit of the RI. These could include partial activation of the coagulation cascade through a specimen collection error, specimen chilling, excessive incubation with the initial PTT reagent prior to adding CaCl2 solution, incorrect reagent formulation, or wrong incubation temperature. Elevated factor VIII, while it does not shorten the PTT , renders the PTT less sensitive to heparin, thus the assay may underestimate plasma heparin.
George’s comment attracted this March 27 comment from Dr. Emmanual Favaloro: I would suggest the following review: Lippi G, Salvagno GL, Ippolito L, Franchini M, Favaloro EJ. Shortened activated partial thromboplastin time: causes and management. Blood Coagul Fibrinolysis. 2010;21:459–63. Although most cases of shortened APTTs are due to preanalytical events, a proportion are due to in vivo events associated with prothrombotic tendency. “Japgi” also added this question on March, “Thanks for the list of answers to this often encountered lab result. Why does chilling the sample shorten the PTT ?” George failed to answer this question, but will post an answer on April 23.

Prof. Bernadette Rodak of Indiana University forwarded this question from the ASCLS Consumer Web Forum: “What should the INR be when on simultaneous aspirin and clopidogrel for PCI stent placement and Coumadin for DVT and PE ?” Prof Rodak and George responded, the INR is unaffected by clopidogrel and aspirin, so the usual limits of 2–3 apply. However, the combination of Coumadin with aspirin and clopidogrel may raise the patient’s bleeding risk, so the patient should be told to watch for easy bruising, nosebleeds, or lengthy bleeding from cuts.
The questioner asked this follow-up: “The patient has decided to discontinue aspirin for safety. Is this a good choice?” We responded with a somewhat inconclusive quote fromHylek EM, Palareti G, Ageno W, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed : American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: 44S–88S:  “Although there are no randomized controlled trials that have compared bleeding rates in patients receiving “triple therapy” with either warfarin alone or with “dual therapy,” a systematic review identified 12 reports involving 3,413 patients treated with oral anticoagulants who underwent PCI with stent insertion and subsequently received the combination of aspirin, clopidogrel, and warfarin. The rates of major bleeding in patients receiving triple therapy ranged from 0% to 21% (mean 7.4%) during up to 21 months of follow-up and 0% to 5.9% (mean 2.6%) during 30 days of follow-up. In a Danish nationwide registry of patients with AF , all combinations of warfarin, aspirin, and clopidogrel were associated with an increased risk of nonfatal and fatal bleeding, whereas dual or triple therapy carried a more than threefold higher bleeding risk than warfarin alone.”
The article provides no therapy recommendations for someone requiring both anticoagulant and antiplatelet therapy, however, a March 6 Heart.org post, “A Dangerous Cocktail, Aspirin and Anticoagulants,” addresses this question and makes reference to the WOEST study, conducted in the Netherlands, that addresses the bleeding risk of aspirin in triple therapy. In particular, the linked audio comment by Dr. Samuel Goldhaber seems to settle the argument in favor of eliminating aspirin.

From Dr. Larry Brace, Edward Hospital, Naperville, IL : “We should no longer have to do a normal range for the PT in seconds. We know that the general consensus is that the INR is considered normal to at least 1.2 (or 1.25). I think that the PT in seconds should be eliminated and we should view the INR in the same way we view cholesterol. We don’t do normal reference intervals for cholesterol; we just adopt them based on ATP guidelines because cholesterol is a “standardized” assay. Isn’t the INR a “standardized” assay? We say it is, and that every laboratory that reports INR should match every other laboratory that reports INR. If someone really needs a normal reference interval for the PT in seconds (and I don’t know why they would), the upper end could be the PT in seconds that correlates to an INR of 1.2 and the lower end would be the PT in seconds that corresponds to an INR of 0.9.
If you adopt as normal an INR of 0.9–1.2, but determine independently the reference interval for the PT in seconds, you invariably get situations in which the INR is normal but the PT in seconds is not, or vice versa. This causes no end of grief because it is almost impossible to explain to clinicians why one result is flagged as normal and the other as abnormal.
I bring this up because during my most recent CAP inspection, the inspectors had a fit about the upper end of our normal range in seconds, which corresponded to an INR of 1.25. (Yes, we still report both, but I don’t know for how much longer). BTW, the upper limit of 1.25 was based on clinician input because they were unhappy chasing clinically irrelevant “abnormal” results. Personally, I would be just as happy with an INR upper limit of 1.2 and will lobby for that with the newest lot of reagent (see below). When we did our last normal range verification, it comes as no surprise that our normal range in seconds did not match the upper and lower limits based on the INR. I simply adjusted the PT in seconds to match the INR. We just completed our evaluation of a new lot of PT reagent. We have 3 Stago instruments in 2 locations – the Satellite is at an off-site. Here are the results of the reagent validation:

Compact range: NEW LOT PT = 11.9–13.5, INR 0.92–1.08; OLD LOT PT = 12.2–15.4, INR 0.93–1.26
Evolution range: NEW LOT PT = 12.2–13.4, INR 0.94–1.06; OLD LOT PT = 12.2–15.4, INR 0.93–1.26
Satellite range: NEW LOT PT = 11.6–13.6, INR 0.90–1.10; OLD LOT PT = 12.4–15.7, INR 0.93–1.26

What would you do? There is no way that an INR upper limit of 1.1 would ever work.

George stubbornly hews to “conventional wisdom,” asserting that the INR was developed only for monitoring Coumadin. To screen for extrinsic pathway coagulopathies, we must use and report the PT in seconds compared to our locally developed PT normal range. However, it is true that most clinicians who have entered the profession in the past 20 years only know the test by “INR ,” and, in fact, the INR is no more than a ratio computed directly from the PT in seconds, so why not just use it? This provocative post attracted six lengthy comments both pro and con.

Kathleen Finnegan, MS MT (ASCP) SH, asked, “In cardiac catheterization, what is the standard length of time to wait to check the ACT after a heparin bolus is given?”
George contacted friend and colleague Derek Webber, University of Alabama at Birmingham, a surgical physician assistant. Derek checked with two friends and learned: From a chief anesthesia resident: “Before we go on bypass, we draw a sample for ACT and notify the surgeons two minutes after we give a bolus of heparin. A second message is from a PA who works in CV surgery: We give our heparin as a bolus, weight based, 30–40K. Usually we check ACT ~3 min after the bolus. Half life is 1.5 h so it’s about 6 h before it’s all out. Anesthesia will re-dose as needed based on ACT throughout the case as directed by perfusion. We really only care about ACT before we go on pump or after protamine, rarely will the surgeon want to know what’s the ACT during the pump run.

Linda Stang asks, “Does anyone have experience with apixaban interference in LA panels, clot-based C or S assays or APCR ? Rivaroxaban seems obvious in our LA panel as the DRVVT 1:1 mix samples are usually 75 seconds or above. I am not sure if any samples containing apixaban have come in, and just ‘slid under the radar.’

George says, “I’ll suggest that apixaban will have the same effects on clot-based assays as rivaroxaban, considering that both are direct anti-Xa anticoagulants, but I’ll ask for comments from those who have actually encountered apixaban in practice.”

Linda commented on April 4: If you run hybrid curve anti-Xa from a patient on rivaroxaban you get a high value (&gt ;2.0), whereas apixaban reads about where LMWH/UNFH would read. Also, if you take a sample that reads 0.75 U/mL on a hybrid curve anti-Xa and then try to run that sample on the Aniara rivaroxaban assay, it is hardly a blip on the radar. The Aniara assay requires a large dilution–1/50 or close to it. I think rivaroxaban needs a whole pile of little anti-Xa soldiers to do its job, while the apixaban army seems to need a whole lot less. In other words, I don’t think the assay interference from apixaban is going to be quite as obvious as rivaroxaban.

George has joined an LMBP panel whose purpose is to review patterns of preoperative coagulation screening profile usage, in particular, PT and PTT. We accept the premise that screening PTs and PTTs fail to consistently predict intraoperative hemorrhage in unselected patients, and that the volume of screens could be reduced by taking a patient history without sacrificing patient safety. The LMBP panel requests unpublished data; If you have any data on screening PT and PTT volumes and outcomes that you would like to share with the panel, please email it to george@fritsmafactor.com. This post generated a comment from Brad Ertz supporting screens and from Dave McGlasson and Dr. Emmanual Favaloro (both citing references), supporting history over screening.