2012 Cheat Sheet

From an inquirer to the ASCLS Consumer Forum (with permission): “I have a titanium aortic valve and  sometimes experience afib. I take 5 mg daily of warfarin and my cardiologist wants my PT/INR to be 2.5-3.5. I also take a baby aspirin (81 mg) daily. Today my PT was 2.8 (perfect for me and it is usually pretty steady). My question relates to changes in altitude, as in a trip to Colorado, and the possible effects on PT/INR in staying at high altitude, 8-10,000, feet for a week. Will this raise or lower my PT/INR ? What will happen to the value upon return home? I also consume beer and wine. The last time we went to Colorado, we were there for one week and consumed beer at the various breweries. When I came home, I was working in the yard and developed a hematoma on my wrist. When I sought treatment, my PT/INR was 5.8! Do you think the PT/INR elevation was attributable to alcohol consumption, going up in altitude for a week, or coming down, or a combination of all of the above?

George answered, short-term high altitude (several hours’ exposure) has no effect upon the PT/INR , as shown in several studies conducted using hypobaric chambers. These studies were mostly concerned with the possibility of thrombosis subsequent to prolonged air travel or the conditions that affect mountain climbers, high-altitude neurological or pulmonary edema (HANE, HAPE). There are no studies that employ several days’ exposure, though it is probably safe to generalize from the short-term hypobaric chamber studies.

Alcohol is a more likely culprit, although George does not conclude from your message that you are either a chronic or binge drinker. Chronic long-term alcohol consumption at a level that can damage the liver is a known cause of bleeding, as liver damage reduces the production of the coagulation factors. This can be verified by repeating the PT/INR and simultaneously testing for the liver enzymes. Binge drinking, by comparison, tends to suppress platelet function, which also leads to bleeding such as the hematoma you experienced, however platelet suppression is not reflected in the PT/INR.

Responses to our May, 2012 quick question: When using point of care testing, at what INR does your anticoagulation clinic require a confirmatory plasma-based (conventional) PT ?

a. 4.0: 34 (65%); b. 5.0: 9 (17%); c. 6.0: 4 (8%); d. Never: 5 (10%)

Our responses closely parallel our April 24 and May 7 discussions; it looks like the majority of us prefer caution, knowing the risk of bleeding rises rapidly as the INR exceeds 4.0.

Most of us have maintained separate calibration curves for our chromogenic anti-Xa heparin assays, one each for UFH , LMWH , and fonda.

Dave McGlasson (Wilford Hall USAF Medical Center) has published two articles on the use of a hybrid curve that may be used for either UFH or LMWH , thus eliminating the need to inquire which formulation we are testing, and some have even extended the curve mathematically to use it for monitoring fonda.

At least two hemostasis assay distributors, Aniara and Stago, now make hybrid curve calibrators and advocate for this approach to heparin monitoring, however an informal poll at the recent Thrombosis and Hemostasis Summit of North America reveals that most of us are still using individual curves. Consequently, our current quick question asks us which approach we are taking.

Laura Paterek asks, are you sure the following statement is correct? “When a lupus anticoagulant is present, SCT Confirm becomes prolonged beyond the SCT Screen. Normalization renders the SCT insensitive to warfarin.” Doesn’t the confirm step decrease when LA is present?

George thanks Laura for locating this misstatement in his May 15, 2008 description of the Instrumentation Laboratory HemosIL Silica Clotting Time assay. The statement should say, “When a lupus anticoagulant is present, the SCT Confirm step produces a shorter clotting time than the SCT Screen.” George asks how many labs are using the SCT.

Dr. Kathryn Doig, Michigan State University writes: “Hi George. We have a grad student who is doing a project related to hemostasis. Along the way, she used the term “thrombokinase” which I had not heard in quite some time. Just thought I would verify that it is not used anymore.

George replies that factor X was first described in the 1950s as the Stuart factor and the Prower factor, named for the families in which the factor’s absence caused bleeding. Some time after, activated factor X was named “prothrombinase” because its substrate is prothrombin. Xa also somehow got assigned the term “thrombokinase,” coined by Morawitz in the 1920s, who postulated four related coagulation factors, a seminal event in coagulation understanding. We’ve almost universally dropped the descriptive names (also eponyms like Stuart-Prower) in favor of the Roman numerals these days.

Ginger Weeden, Bio-Rad Laboratories asks what heparin-induced thrombocytopenia with thrombosis (HIT ) testing is available in the US?

George responds that all the C14 serotonin release assay methods (washed platelets) available from reference labs are laboratory-developed tests. Here are the manufacturers who provide immunoassays designed to detect anti-platelet factor-4 (PF4 )-heparin antibodies that are associated with HIT :

Akers Biosciences PIFA Heparin/PF4 Rapid Assay (Two-minute lateral immunoassay)
Gen-Probe LIFECODES PF4 (formerly GTI Laboratories)
HYPHEN BioMed Anti-(h)-PF4, available through Aniara
Instrumentation Laboratory HIT-Ab (PF4-H, RUO)
Sekisui Diagnostics (formerly American Diagnostica) IMMUCLONE Platelet Factor 4 ELISA (RUO)
Stago Asserachrom HPIA (ELISA )

A question from Farah Quresh in follow-up to a presentation on antithrombotics that George made May 24 during “Bioconference Live”: What are the conditions in which Pradaxa is preferred over warfarin?

George equivocates that this is a clinical judgment call that a physician may use based on economics, ability of the patient to comply, and availability. In the USA, dabi is cleared only for prevention of stroke in atrial fibrillation. From anecdotes, it seems that most physicians retain their patients on warfarin if they are using home-testing or have ready laboratory access and are having no trouble remaining within the therapeutic INR of 2-3. If they are encountering difficulty staying in range, dabi may be the answer. Also, physicians appear to be starting all their new afib patients on dabi.

Posted Wednesday, May 23 on Pat Letendre’s Medlab list: We have a patient with lymphoma and an IgG peak. The antibodies are interfering in the coags: INR &gt ;5.0, clinical challenges cause no bleeding. Is there any way to remove IgG from samples? I am currently trying a heterophile blocking tube (HBT) hoping that it will neutralize the antibodies. Does anyone know of any other method to remove unwanted IgG from a sample, but have it remove little else? Thanks in advance for any suggestions. Linda Stang MLT, University of Alberta Hospital.

She later adds the HBT tube did correct the INR somewhat, but only from 4.9 down to 3.9 (3.4 if I were to use 2 HBT tubes), and the appropriate controls did not vary much with the HBT treatment. The INR is consistently 4.8-6.0 with different reagents/analyzers; PTT is 48 or 80, depending on the PTT reagent. I am considering purchasing a protein G column, but am a little scared of how the coag will be affected. Surgery is on hold, with us trying to verify that the underlying coags are normal.

May 30: Have you tried mixing studies with normal pooled plasma (NPP) to rule out factor deficiency/liver impairment? Running serial dilutions of the patient sample in NPP with and without pre-incubation will tell you if fast or slow reacting antibodies exist against coagulation factors (parallelism/non-parallelism rule). Removing normal human IgG from plasma per se doesn’t significantly affect coagulation result. I have done it before. However, if we are dealing with Ab against targets involved in coagulation, then you have to make sure other than Ab no active pro/anti-coagulant proteins remain on the column.Dr. Ali Sadeghi-Khomami, PrecisionBioLogic

May 30, “Jlow:” What is the lupus anticoagulant status? Some thromboplastins may give anomalously high results, for instance, Innovin and other recombinant thromboplastins with some patients only. Could be IgG or IgM in our experience. Is this a paraprotein? What is the thrombin time?

June 5, “Sidsham:” Lymphomas with IgM antibodies are more common than IgG-secreting lymphomas; unless you are talking about plasma cell neoplasms where IgG secretion is common. IgM lymphomas manifest like any other cold agglutinin disease. So how about trying the conventional method of incubating the sample at 37 degrees for 15 minutes before performing the test to see if there is any correction?

George referenced our article, Fritsma GA, Dembitzer FR, Randhawa A, Marques MB, Van Cott EM, Adcock-Funk D, Peerschke EI. Recommendations for appropriate activated partial thromboplastin time reagent selection and utilization. AJCP 2012 137:904–8. It appears that some of us are using lupus anticoagulant-sensitive PTT reagents for our routine coagulopathy screening or heparin monitoring.
Chris Ferrell (Seattle) added this comment: Your recommendations were thought provoking. I remember back to the 70s and 80s when we had quite a selection of high- and low-LA responsive PTT reagents in the marketplace. It was confusing to the smaller labs as to which PTT reagent to use. Many of them were using an inappropriate reagent for their patient population, sometimes because their purchasing department wanted them to use the cheapest and not necessarily the best reagent. That practice still goes on today. When I worked for Sigma Diagnostics, I got to meet the research scientist who invented Innovin, Pamela Harker. She was the grand dame of coagulation reagents. She told me something that I’ve always remembered: there are only three things that go into making a PTT reagent. One controls the factor sensitivity, another controls the lupus sensitivity and the third controls the heparin sensitivity. If you change one of the three, it always changes the other two. So, no matter how hard you try, you can’t make the perfect PTT reagent.

Jack” asked, “Has any research been done on how long a patient with a positive HIT test stay positive before turning negative?” George replied that the HIT antibody remains 50–80 days after it is first detected, and provides two references to HIT expert Ted Warkentin MD publications on this topic.

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