LAtest News

  • 07/20/2017 11:32 AM | Deleted user

    Dear Colleagues,

    To encourage the support of professional development for pathology educators, the Group for Research in Pathology Education (GRIPE) is again offering the John H. Holliman Resident Scholarship to a pathology resident who is sincerely interested in pursuing undergraduate or graduate teaching of pathology as part of their career planning. GRIPE is a national/international organization of institutions, interest groups, and individuals who are dedicated to improving the quality of pathology education in allopathic and osteopathic medical, nursing, dental and allied health schools.

    The scholarship covers registration expenses (travel and lodging are not included) for the annual GRIPE Winter meeting will be in Las Vegas, Nevada, January 25-27, 2018. Further details of the meeting can be found online at www.gripemeeting.org.

    Please encourage any of your residents who are interested in Pathology medical education to apply before October 31, 2017.

    Download the application here.

    E-mail the completed form along with the resident’s one-page statement emphasizing his/her interest in teaching along with a curriculum vita that demonstrates past teaching experiences to Danielle Inscoe at danielle@gripeadmin.org. You may also fax your completed forms to 304-523-9701.

    The resident will also be asked to prepare a poster on a topic of his/her choice and give a 10-minute presentation summarizing the poster at the 2018 meeting. The scholarship will be awarded by December 15, 2017 at which time the recipient and all applicants will be notified.

    Thank you,
    GRIPE Admin Team


  • 07/17/2017 4:48 PM | Deleted user

    Doctor Day 2018 has been set for Tuesday, January 30.  The event will again be held at the Monona Terrace in Madison and is hosted by over 20 medical societies.

    The event provides physicians an opportunity to meet with their legislators, and have input on important health care issues. The day will conclude with a reception in downtown Madison.

    Registration is available online (link).


  • 07/10/2017 9:20 AM | Deleted user

    July 6, Wisconsin Health News"I would call it 5 percent justice instead of 100 percent justice," he said. 

    An appeals court struck down a state law Wednesday capping the amount of money that injured patients can receive for some malpractice claims.

    The 1st District Court of Appeals ruled that a state law capping awards for noneconomic damages at $750,000 was unconstitutional. Noneconomic damages are intended to compensate for pain and suffering.

    Judge Joan Kessler, who penned the majority opinion, wrote that the law imposes "an unfair and illogical burden only on catastrophically injured patients, thus denying them the equal protection of the laws."

    The case involves Ascaris Mayo, who lost her limbs after she wasn't notified she had an infection after visiting a Milwaukee-area emergency room in May 2011. Mayo and her husband sued, and a jury awarded them $16.5 million for noneconomic damages. 

    The state's Injured Patients and Families Compensation Fund, which is funded by hospitals and doctors and covers large medical malpractice claims, moved to reduce that amount to the $750,000 limit. The Mayos challenged that.

    Hospitals and doctors in the state were concerned about the Wednesday's ruling. Wisconsin Hospital Association CEO Eric Borgerding expects the state's Supreme Court to review the decision. 

    "We believe the court will uphold the well-supported and bipartisan public policy balance set by the Legislature to help ensure accessible healthcare in Wisconsin," he said in a statement.

    A spokeswoman for the Office of Commissioner of Insurance, which provides administrative staff to the 13-member board, didn't respond to a request for comment on whether the state would appeal the decision.

    Dr. Noel Deep, Wisconsin Medical Society president, said the decision"endangers the long-term solvency of the Injured Patients and Families Compensation Fund and its ability to adequately compensate patients." He warned that it could incentivize "attorneys to file questionable cases in hopes of astronomical jury awards seen in other states without caps."

    Dan Rottier, an attorney for the Mayos, called the society's claim regarding fund's solvency "ridiculous." The fund reported a net position of $879 million as of June 2016, according to an annual report.

    Rottier said that pursuing such cases are difficult because "they're extremely expensive...these cases are not taken lightly.

    Rottier said the court's decision has "implications for a few cases every year where there's horrendous injuries...it's those cases where the inequity is the most severe." He noted that applying a cap in this case would have reduced the jury award by more than 95 percent.

  • 06/27/2017 3:57 PM | Deleted user

    An IVM interpretation seminar designed for pathologists

    When: Saturday, September 16, 2017
    Where: The James Hotel, 55 E. Ontario Street

    Chicago, Illinois
    Sponsor: In Vivo Microscopy Committee

    This is a complimentary workshop but has limited space.To reserve your seat, register today at surveymonkey.com/r/IVMWorkshop17.

    For more information, click here

    Pathologists and pathology residents interested in establishing their presence in IVM and GI specialists wanting to collaborate with their pathology colleagues on IVM may want to attend.


  • 06/26/2017 11:09 AM | Deleted user
    Doctor Day 2018

    Doctor Day 2018 has been set for Tuesday, January 30.  The event will again be held at the Monona Terrace in Madison and is hosted by over 20 medical societies.

    The event provides physicians an opportunity to meet with their legislators, and have input on important health care issues. The day will conclude with a reception in downtown Madison.

    Registration is available online (link).


  • 06/05/2017 7:40 AM | Deleted user

    HEMATOPATHOLOGY FOR THE GENERAL PATHOLOGIST
    November 3-4, 2017
    Fluno Center, Madison, WI

    New Conference Details Now Available!

    EXHIBITING: $500

    • Exhibit space includes 8' skirted table with two chairs.
    • Non-competitive exhibitor viewing times.
    • Roster of attendees distributed at the time of the meeting.
    • Complimentary meals and refreshments during exhibit hours.
    • Inclusion in the exhibitor listing on the WSP website.
    REGISTRATION INFORMATION
    Register by October 4, 2017 to ensure that your company will be recognized in printed materials. Registrations received after October 4 are not guaranteed to be included in printed materials.

    Space is limited, Click here to register



  • 06/01/2017 10:48 AM | Deleted user

    Hi All –

    Attached, please find our current letter to HHS Secretary Price raising grave concerns about suggested changes to Medicare Part B that will harm patient access to medications or limit treatment options. A two-page background summary is also attached for your reference, with all current signers listed in the email below.

    The letter will remain open to signers through Monday, June 5, at COB Pacific time to accommodate our friends on the West Coast. The text and sign-on form can be found here: https://goo.gl/forms/WFYYEsa8q7lp6FSG2

    Please let me know if you have any questions of or if you need any additional information.

    • ADAP Advocacy Association (aaa+)
    • Advocates for Responsible Care (ARxC)
    • AIDS Response Seacoast
    • Alabama Society for the Rheumatic Diseases
    • Alliance for the Adoption of Innovations in Medicine ("Aimed Alliance")
    • Alzheimer's and Dementia Alliance of Wisconsin
    • American Autoimmune Related Diseases Association (AARDA)
    • American Behcet's Disease Association
    • American Urological Association
    • Arthritis and Rheumatology Clinics of Kansas
    • Association of Northern California Oncologists (ANCO)
    • Association of Women in Rheumatology (AWIR)
    • BioNJ
    • Brain Injury Alliance of Nebraska
    • California Academy of Eye Physicians and Surgeons
    • California Life Sciences Association (CLSA)
    • Caregiver Action Network
    • Caregiver Voices United
    • Charleston Parkinson's Support Group
    • Coalition of State Rheumatology Organizations (CSRO)
    • Community Access National Network (CANN)
    • Community Health Acton Network
    • Community Health Charities of Nebraska
    • Community Liver Alliance
    • Cutaneous Lymphoma Foundation
    • Delaware BioScience Association
    • Easter Seals Massachusetts
    • Epilepsy Foundation of Greater Chicago
    • Health Coalition, Inc.
    • Hematology Oncology Associates, PC
    • Hepatitis Foundation International
    • iBio - Illinois Biotechnology Industry Organization
    • Indiana Health Industry Forum (IHIF)
    • International Cancer Advocacy Network (ICAN)
    • International Foundation for Autoimmune & Autoinflammatory Arthritis (IFAA)
    • Iowa Biotechnology Association
    • Kentucky Life Sciences Council
    • Life Sciences Pennsylvania
    • Lupus and Allied Diseases Association, Inc.
    • Lupus Foundation New England
    • Lupus Foundation of America
    • Lupus Foundation of Florida
    • Maryland Society for the Rheumatic Diseases (MSRD)
    • MassBio
    • Matthew25 AIDS Services
    • Medical Alley Association
    • Medical Oncology Association of Southern California, Inc. (MOASC)
    • Medical Society of the State of New York
    • Mental Health America of Louisiana
    • Metro Denver Oncology Nursing Society
    • Metropolitan Milwaukee Association of Commerce
    • Michigan Biosciences Industry Association (MichBio)
    • Michigan Rheumatism Society
    • MidWest Rheumatology Society
    • Multiple Sclerosis Resources
    • National Alliance on Mental Illness New Mexico (NAMI)
    • National Alliance on Mental Illness North Carolina (NAMI)
    • National Association for Rural Mental Health
    • National Association of County Behavioral Health & Developmental Disability Directors (NACBHDD)
    • National Grange
    • National Infusion Center Association (NICA)
    • National Minority Quality Forum
    • New Jersey Association of Mental Health and Addiction Agencies, Inc. (NJAMHAA)
    • North Carolina Rheumatology Association
    • Ohio Association of Rheumatology
    • Ohio Hematology Oncology Society
    • One in Four Chronic Health
    • Prevent Blindness Texas
    • Psychosocial Rehabilitation Association of New Mexico
    • RetireSafe
    • Rheumatology Association of Iowa (RAI)
    • Rocky Mountain Health Network
    • Rush To Live
    • South Carolina Rheumatism Society
    • StopAfib.org
    • Suicide Awareness Voices of Education
    • Texas State Grange
    • The US Oncology Network
    • The Wisconsin Society of Pathologists
    • Veterans Health Council
    • Vietnam Veterans of America
    • Wisconsin Association of Osteopathic Physicians & Surgeons
    • Wisconsin Rheumatology Association
    • Wyoming Epilepsy Association
    Thank you for your continued support. We will be in touch as the list of signers grows over the next few days.

    Best,

    Shannon Finley
    The Part B Access for Seniors and Physicians (ASP) Coalition


  • 06/01/2017 8:36 AM | Deleted user

    The 2017 WSP Annual Meeting will feature a number of continuing education sessions, networking opportunities, vendors and more!

    Early conference registration is now available. Make sure your membership is in good standing so that you receive the member discount. 

    "HEMATOPATHOLOGY FOR THE GENERAL PATHOLOGIST"

    November 3-4, 2017

    The Fluno Center
    Madison, WI

    • CAP presentation and legislative updates;
    • Overview of WHO updates in Hematologic Disease;
    • New technologies in diagnosis of heme malignancies and how to use, focusing on molecular/next gen sequencing;
    • Approach to diagnosis of hematologic disease in small biopsies/FNA;
    • Talking with the clinical team – how the clinical story can drive the diagnosis, and how the diagnosis can drive treatment;
    • Resident presentations.
    Full conference details coming soon!

    Register today


  • 05/01/2017 10:52 AM | Deleted user

    Anne Ford

    March 2017—Some modified recombinant factor VIII and IX products for hemophilia prophylaxis show significant reagent-dependent recovery in the one-stage assay, while recovery in the chromogenic assay appears to be more consistent, especially for modified recombinant factor IX. The variable results can lead to over- or underestimating the factor level, warn Stefan Tiefenbacher, PhD, of Colorado Coagulation, and Rajiv K. Pruthi, MBBS, of Mayo Clinic.

    They spoke in a recent webinar, hosted by CAP TODAY and sponsored by Novo Nordisk, on the laboratory diagnosis of hemophilia and the pitfalls associated with monitoring factor VIII and IX replacement therapy.

    Dr. Tiefenbacher

    Dr. Tiefenbacher

    Dr. Tiefenbacher reviewed the status of five modified recombinant factor VIII products: Bax 855 (full length), rFVIII-Fc (B-domain deleted), and CSL627 (B-domain deleted), which have been FDA approved; and N8-GP (BDtrunc PEG­ylated) and BAY 94-9027 (B-domain deleted), which are in late-stage development.

    “Approaches to extend the half-life and to decrease the immunogenicity of these factor VIII products include changes to the protein expression systems, such as, for example, the use of human instead of animal cell lines as well as modifications to the actual therapeutic protein, such as pegylation or Fc fusion,” said Dr. Tiefenbacher, who is technical director and vice president of Colorado Coagulation, Englewood, Colo., a member of the LabCorp Specialty Testing Group.

    Three of the products—Bax 855, N8-GP, and BAY 94-9027—use attachment of hydrophilic polyethylene glycol chains to increase the molecular site or mass of the therapeutic protein, thereby reducing glomerular filtration and hepatic clearance through the LRP receptor. The Fc-fusion product uses recombinant DNA technology to link a therapeutic protein such as a recombinant factor VIII to the Fc region of IgG1, allowing the therapeutic protein to bind to the neonatal Fc receptor and thereby protecting the protein from the lysosomal degradation pathway.

    “Last but not least, there is also a protein sequence modification in which a covalent bond is introduced between the heavy and light chain of factor VIII, resulting in a single chain circulating factor VIII molecule that demonstrates improved affinity to von Willebrand factor and therefore is thought to demonstrate improved stability compared to native factor VIII,” Dr. Tiefenbacher said. The half-life extensions that these modifications achieve vary from 1.2-fold for the single chain modification (when compared with a recombinant full-length factor VIII) to 1.5- to 1.6-fold for the pegylated and Fc-fusion modifications.

    On the factor IX side, there are three new modified products: rFIX-Fc and CSL654, both of which are approved in the United States; and N9-GP. “Similar to the factor VIII side, modifications to extend the half-life of the IX protein include Fc fusion utilized in factor IX Fc, or pegylation—in this particular case, glycopegylation of recombinant factor IX, which is utilized in N9-GP,” Dr. Tiefenbacher said. Referring to the CSL654 product, he added, “Here we, in addition, have a recombinant factor IX protein that is genetically fused to recombinant albumin, which results in half-life extension due to [the] size and long half-life of the albumin.” That effect is related to albumin’s interaction with the neonatal Fc receptor, “protecting the therapeutic protein from the lysosomal degradation pathway, similar to the mechanism of halfway extension for Fc fusion.”

    Whereas factor VIII’s half-life is largely determined by von Willebrand factor, the half-life extension achieved with these modifications is much greater for factor IX. That extension ranges from 2.4-fold for the recombinant factor IX Fc-fusion protein to fivefold or more for the glycopegylated and albumin fusion protein.

    Dr. Tiefenbacher presented his own laboratory’s in vitro data to demonstrate the aPTT-reagent dependent recovery that occurs when measuring some of these modified recombinant factor proteins in commonly used IVD approved one-stage factor assays. The laboratory compared the recovery of four recombinant factor IX replacement products, one of which was the established recombinant factor IX product BeneFIX. Recovery was compared over the reportable range of the factor assay between 80 and one percent factor IX activity, and the samples were created by spiking the recombinant factor into congenital factor IX deficient plasma.

    The results showed that, consistent with the existing literature, glycopegylated factor IX (N9-GP) is significantly overestimated (recovering at around 1,000 percent from expected) when tested using a silica-based aPTT reagent. In contrast, “the other modified factor IX product recovers appropriately in this reagent,” Dr. Tiefenbacher said. “If a laboratory uses this particular silica-based reagent [to measure N9-GP], it will greatly overestimate the activity, and this would likely result in significant under-dosing and mismanagement of the patient.

    “On the other hand,” he continued, “when glycopegylated factor IX is tested in one of the commonly used ellagic acid-based aPTT reagents, the product under-recovers at around 50 percent of expected.” This underestimation, he said, “would likely result in unnecessary use of additional product that is not needed.”

    The lesson in all this: The recovery for at least some of the modified recombinant factor IX products can vary greatly according to the aPTT reagent used for factor activity determination, and that can result in both over- and underestimation of factor level, depending on the factor IX replacement product and the particular aPTT reagent used.

    “On the other hand,” Dr. Tiefenbacher pointed out, “when we look at the recovery of the same recombinant products in a chromogenic factor IX assay, you can immediately see that the modified and the undisclosed, as well as the established recombinant product [BeneFIX], all recover within about 25 percent of each other.” The two modified recombinant factor IX products recovered within established limits across the entire concentration range tested, while BeneFIX, in accordance with other reports in the literature, “slightly under-recovered” across all the concentrations tested.

    Dr. Tiefenbacher mentioned, too, that all of the recombinant factor IX products that the laboratory tested in this study recovered at 100 percent at the one percent factor activity level. “This might actually have been an artifact of the assay setup and protocol for this particular factor IX chromogenic assay on this specific coagulation analyzer,” he said. “Additional testing will have to be performed to determine whether the values at the one percent factor activity levels are valid or not.”

    Regarding the recombinant factor VIII product, most products—including the B-domain deleted and some of the modified recombinant factor VIII products—recover within about 25 percent of expected in the silica activated PTT reagent. That said, one of the modified recombinant VIII products under-recovers at 50 percent of expected in the silica activated PTT, but recovers appropriately in the ellagic acid-activated PTT.

    He pointed out that the B-domain deleted recombinant factor VIII products in the two aPTT reagents shown did not show reagent dependent under-recovery, as previously reported for Refacto, and thus could be expected to be found for both modified and unmodified recombinant B-domain deleted factor VIII. “Also, the established full-length recombinant factor VIII product slightly over-recovers in the ellagic acid-activated PTT used in our study,” he added.

    Meanwhile, recovery of the recombinant factor VIII products in the factor VIII chromogenic assay was more variable, with both of the modified recombinant products demonstrating over-recovery across the factor activity concentration range tested. That’s in contrast to some of the existing published data that suggest all modified recombinant products can be measured adequately in the chromogenic assay.

    “I should also point out,” Dr. Tiefenbacher said, “that the over-recovery observed for the two modified products could be related to the over-recovery that was observed for the SSC standard, which is the secondary standard to the WHO 6 international standard that was run as a control to verify the assigned value of the plasma calibrator.”

    Dr. Tiefenbacher reviewed the challenges clinical laboratories face when using the existing factor activity assays to measure some of these modified recombinant factor products. One of those challenges pertains to the difference between potency assays (those used to assign potency to a factor product) and the clinical factor activity assay used in the laboratory to measure the product.

    Factor potency assays commonly use a product-specific standard, a calibrator, that has been verified against the WHO concentrate international standard, whereas clinical laboratories often use a pooled normal plasma standard that the manufacturer has verified against the WHO plasma international standard. With a product-specific standard—but not with a pooled normal plasma standard—any potential nonlinearities for a modified product in a particular reagent system are likely to be masked.

    For factor VIII products, potency assignment in accordance with recommendations of the European Pharmacopoeia is commonly performed using the factor VIII chromogenic assay. To date in the U.S., factor product activity in clinical laboratories is still performed predominantly using a one-stage aPTT-based assay. To account for that potential difference, Dr. Tiefenbacher advises, it’s important to make sure that the factor assay used for post-infusion monitoring aligns with either (or both) the assay used to assign the potency to the product or the assay used to demonstrate clinical efficacy of the product in clinical studies. “This is often easier said than done,” he pointed out, “as it is often not common knowledge what assay system and/or reagent was used during registration of a particular product.”

    A second challenge is the inherent variability that exists for one-stage factor VIII and IX activity assays between different clinical laboratories, as demonstrated in CAP Surveys and other proficiency testing. Significant interlaboratory variability (for example, around 30 percent at normal factor levels, with up to 70 percent at factor levels below 20 percent) for both the factor VIII and IX one-stage assay has been observed.

    In a recent CAP Survey, he said, “a normal plasma sample with an anticipated value of 100 percent yielded results ranging between 72 and 161 percent,” depending on the aPTT reagent used and the laboratory performing the testing. That inherent variability in the one-stage factor activity assays only makes it more difficult to evaluate and interpret factor activity data for the modified products when generated across different one-stage assay systems and laboratories.

    Yet another challenge: Data are limited regarding the behavior of some of the modified recombinant factor replacement products in the one-stage and chromogenic factor assay reagents commonly used in U.S. clinical labs. In fact, such data are currently available for only two of the five modified recombinant factor VIII products, namely, Bax 855 and factor VIII Fc, and for only one of the three modified recombinant factor IX products for factor IX Fc. Ideally, information regarding whether a modified replacement product demonstrates aPTT reagent dependent recovery would be addressed before the product is launched so it can be included on the product label as required.

    Finally, although the medical and scientific advisory council of the National Hemophilia Foundation recommends the use of chromogenic factor activity assays for monitoring the modified products, factor VIII and IX chromogenic assays are still infrequently used in clinical laboratories. “Only three of the five available factor VIII chromogenic assays—more specifically the Coatest SP, the Coamatic, and the Siemens factor VIII chromogenic assay—are currently IVD approved for clinical use in the U.S.,” Dr. Tiefenbacher said. “Of these three, only the Siemens [assay] is IVD approved for use on an automated coagulation platform. The remainder of the factor VIII chromogenic kits are currently IVD approved for manual plate-based use only.”

    On the factor IX side, only two chromogenic assays are currently marketed in the U.S., neither of which the FDA has evaluated and both of which are thus RUO-labeled. Furthermore, for the factor IX chromogenic assays, only limited validated instrument applications and/or coagulation instrument protocols are currently available, restricting their use to what he called “more expert-level labs.”

    Dr. Rajiv Pruthi, director of Mayo Clinic’s Comprehensive Hemophilia Center in Rochester, Minn., used two case examples to illustrate potential issues that laboratories may encounter when monitoring the new modified recombinant factor concentrates. Prophylaxis via scheduled administration of concentrates has become the standard of care for hemophilia management, and patients are generally taught to self-administer factor concentrates at home.

    Dr. Pruthi

    Dr. Pruthi

    “The half-life of the current generation of unmodified factor concentrates varies,” said Dr. Pruthi, who is also an associate professor, Mayo Clinic College of Medicine, and co-director of Mayo Clinic’s special coagulation laboratory. For factor VIII, the half-life is between eight and 12 hours, whereas the half-life for factor IX is between 18 and 20 hours. “Based on this, the typical practice is to infuse the unmodified factor VIII concentrate about three times weekly, and the factor IX concentrate is typically administered two times weekly.”

    The target trough factor level is usually greater than one percent. “Typically, we like to target between one and five percent,” Dr. Pruthi said. “Targeting that level completely changes the frequency of bleeding that severe hemophilia patients experience.” However, there’s wide variability between patients in the half-life of these factors. To provide the most cost-effective therapy, individualized pharmacokinetic studies are usually performed so the dosing can be tailored to each patient.

    He shared a slide illustrating the results of a typical pharmacokinetic study for an unmodified and a modified factor VIII concentrate. In this trial, the half-life of the standard factor VIII was compared with that of a modified factor VIII. The data illustrate the time it takes for the factor levels to decrease from a post-infusion level of about 100 percent to a trough of between one and three percent. For the unmodified concentrate, it takes about three days to reach that level; for the modified factor VIII concentrate, it takes about five days. It takes about four days for the standard factor IX concentrate to get down to between one and three percent, but with the modification of the factor IX molecule, the time to a trough level of one to three percent is extended to about 10 days.

    “There is a wide inter-individual variability,” Dr. Pruthi reminded the audience. “One of the consequences of inaccurate measurements is that with under-dosing of the factor concentrate, you may increase the risk of bleeding. However, if you over-dose the factor concentrate, you may increase the risk of thrombosis. You certainly will be increasing the cost of care.”

    He presented the case of a 20-year-old male with severe hemophilia A who was switched to a modified factor VIII concentrate, and whose pre-infusion baseline factor level was less than one percent (normal range, 55 to 200 percent). “We calculated the dose he would require to target a peak factor VIII level of approximately 60 percent,” Dr. Pruthi explained. “However, when we measured his post-infusion level, it was actually only measured at 30 percent using the one-stage assay. So when this happens, there are several questions one has to address.” For example: Were the sample collection and transportation done correctly? Was the assay the right assay for this concentrate? Did he receive the ordered dose?

    “Once the preanalytic and analytic aspects of the assay have been investigated and the assay’s result is not felt to be erroneous, the typical next step is to increase the dose of the recombinant factor concentrate and recheck the pharmacokinetics,” he continued. “Now, if that result was inaccurate and we would be increasing the dose, then definitely we would be increasing the cost of care and potentially putting the patient at a higher risk of thrombosis.”

    His team realized the reagents used for the one-stage assay performed on this plasma sample underestimated the true factor level by about 50 percent for this modified factor concentrate. In fact, the package insert for the modified concentrate recommends that the one-stage assay result be multiplied by a factor of two. In other words, the patient was on the right dosage—it was just that the one-stage assay result had to be multiplied by two. The result of a chromogenic factor VIII assay confirmed such.

    In the second case, a 12-year-old male with severe hemophilia B was referred to Mayo Clinic’s hemophilia center for help switching to the new modified recombinant factor IX concentrate. His dosing was calculated to achieve a trough level of five percent, and indeed his pre-infusion factor IX was five percent. An hour post-infusion, he reached a peak level of 80 percent.

    “So the patient was referred back to his local care provider with the advice that the pharmacokinetics should be rechecked at some point, and between going back to his provider and coming in for a recheck of his pharmacokinetics, the patient experienced no bleeding events since initiation of the prophylaxis,” Dr. Pruthi said.

    But when the pharmacokinetics were rechecked at one point, the results—obtained in a local laboratory—demonstrated that his pre-infusion or trough level was less than one percent, while his post-infusion peak level was only 40 percent.

    The patient’s primary care provider had planned to increase the dose of the modified factor IX concentrate but contacted the Mayo Clinic hemophilia center for advice. The center determined that the local laboratory was using an aPTT reagent based on a kaolin activator for the one-stage assay, and this kaolin activator was known to underestimate the true factor IX level for this particular product. A sample was mailed to the laboratory affiliated with the hemophilia center, which confirmed the results of the original pharmacokinetic study.

    “So the underestimation of the true factor level has a significant consequence,” Dr. Pruthi stressed. “You may be increasing the dose of factor infusion, overdosing the patient, increasing the cost, and putting the patient at risk for thrombotic complications. Whereas if you overestimate the true factor level, the potential consequence is you would reduce the dosage of the factor concentrate and potentially increase the risk of bleeding.”

    This is a complex situation with multiple potential solutions, some more practical than others. For example, each laboratory could have an individualized calibrator for each concentrate for which it will potentially perform assays. However, the information regarding which concentrate the patient is on might not be communicated to the laboratory. And maintaining assays with different calibrators poses special challenges to both low- and high-volume laboratories.

    “What about chromogenic assays?” he said, referring to Dr. Tiefenbacher’s outline of the available factor VIII kits. “There are no currently FDA-approved factor IX kits. And so each lab would have to validate a kit as a laboratory-developed test, which poses unique regulatory challenges and is very time-consuming and expensive.” Finally, one could multiply the one-stage assay result by a correction factor, as one of the cases showed. “However, each hemophilia care provider would have to be aware of such recommendations to ensure that the correct correction factor is being applied.”

    Dr. Pruthi concluded by stressing again that exclusively using one type of assay may lead to misclassification of non-severe hemophilia or even a missed diagnosis, and when monitoring factor concentrates, may lead to over- or underestimating factor levels. “Hemophilia care providers should be made aware of these assay-related issues,” he said, so as to avoid risking incorrect dosage adjustments of the factor concentrates.

    Anne Ford is a writer in Evanston, Ill. See the March 2017 issue for the guidance of Dorothy M. Adcock, MD, on the initial evaluation of non-severe hemophilia A.


  • 04/25/2017 10:23 AM | Deleted user

    William Check, PhD

    Numerous preanalytical and analytical factors affect the results of these assays.
    Will she be able to reproduce that activity at the University of Kentucky Medical Center? And how realistic is it to think DMTs can become more commonplace?

    April 2017—For decades, Michael Laposata, MD, PhD, chair of pathology at the University of Texas Medical Branch in Galveston, has touted the value of diagnostic management teams, and in February he led the first conference dedicated to such teams, referred to as DMTs. There, Alison Woodworth, PhD, told the story of how and why she created a DMT for primary hyperaldosteronism, what it achieved, and where her DMT focus is now.

    “Primary hyperaldosteronism is a complex disorder that is challenging to diagnose,” she said at the conference, held in Galveston. Interpreting the screening test for primary aldosteronism, or PA, is one of the main difficulties. “We in pathology are really needed to assist clinicians in understanding what the laboratory tests mean and in understanding the limitations of laboratory tests,” said Dr. Woodworth, an associate professor of pathology and laboratory medicine and director of the core clinical laboratory and point-of-care testing at the University of Kentucky Medical Center.

    A few years ago, when Dr. Woodworth was director of esoteric chemistry at Vanderbilt University Medical Center, she established a diagnostic management team for PA and evaluated its clinical utility. The DMT assisted in the diagnostic workup for PA. “We reduced the number of unnecessary tests and helped with more efficiently diagnosing the patients,” Dr. Woodworth said. Before the DMT, four of 32 patients had unnecessary testing or procedures and eight had potential delayed or missed diagnoses. After the team was implemented, there were no perceived unnecessary tests or procedures and no delayed diagnoses.

    At the University of Kentucky, Dr. Woodworth is going through the process of implementing a DMT for PA in a more sophisticated format that includes implementing aldosterone and renin assays with fewer preanalytical interferences. She plans to institute a DMT for yet another challenging endocrine condition: measurement of thyroid function in pregnancy.

    Dr. Woodworth embarked on her journey into the world of DMT at Vanderbilt when Dr. Laposata was Vanderbilt’s vice chair of pathology.

    “When Mike came to me at Vanderbilt and said, ‘Implement a diagnostic management team in chemistry,’ I think you all can appreciate how overwhelming that seemed at the beginning,” she said at the conference.

    Overwhelming, for one, because the breadth and volume of a clinical chemistry and core laboratory make it a huge task to select a condition for which to set up a DMT. “At the University of Kentucky, and probably at most of your hospitals, the clinical core laboratory is the largest laboratory by far, in terms of volume and in terms of employees,” she said. Annual test volume is about five million. “It’s a huge scope and obviously we can’t do a diagnostic management team and interpret the 20,000 laboratory test results that come into the clinical laboratory every day,” Dr. Woodworth said.

    The core clinical lab serves the highest acuity patients, and rapid turnaround times are often required. It’s a complex, high-paced, fast-throughput, and automated area with a lot of volume, she said: “How do we determine just what to implement in a diagnostic management team?”

    Dr. Woodworth listed three main steps in choosing which area to develop into a DMT: talk to clinical peers, choose an area with a manageable volume, and look for an application with a clinical guideline in which interpretation of laboratory data supplements results.

    She began at Vanderbilt by consulting with endocrinologist Andrea Utz, MD. “At the beginning she really wasn’t sure that we in pathology could contribute to the patient care team,” Dr. Woodworth said. “It took some time and negotiation, but we did get to a point where we were able to communicate and have reasonable discussions about what might be important to implement.”

    Dr. Woodworth

    Dr. Woodworth

    For test volume, “we have to have a test that’s of a manageable volume,” Dr. Woodworth said, “because we only have so many residents and fellows,” who do much of the interpretive work.

    Third, “There needs to be a clinical practice guideline or some sort of evidence that we can base our interpretive reports on and not just expert opinions.”

    For endocrinologists, a DMT raises concern because their job is to interpret esoteric laboratory test results. “I clarified to Dr. Utz that I wouldn’t be telling her how to interpret lab tests,” Dr. Woodworth tells CAP TODAY. “I told her I would be addressing my interpretations to an audience that has a huge volume of tests to interpret—primary care physicians and nonspecialists.” Dr. Utz eventually embraced the whole process. “She could see there could be a benefit to her service.”

    Dr. Woodworth asked Dr. Utz, “How often do you get consults in which the laboratory tests were misinterpreted? How often do you see patients who are walking around out there who are not diagnosed but who have an endocrinopathy you are concerned about? Where do you most experience inappropriate lab testing—underutilization or overutilization?”

    Dr. Utz named three areas that fit these criteria: thyroid disease, Cushing syndrome, and primary aldosteronism. In many cases, she said, the primary care physicians will see these patients first and they’re often confused about what tests to order and how to work up these patients. And when the results come back, they are often misinterpreted.

    “The good news,” Dr. Woodworth said, “is that all three of these conditions have clinical practice guidelines that help guide the clinician’s workup for potential disease.

    “I think what really drove our decision was daily test volume,” she said. “Thyroid function tests in a laboratory, particularly TSH, are about 500 a day. At Vanderbilt that was the volume, and I think that’s typical for academic medical centers of similar size. Cortisols were about 50 to 100 per day. But the screening tests for primary aldosteronism, which are plasma renin activity and aldosterone, were about 10 per day, so that was a manageable test volume that would allow our residents to identify and interpret these test results in a meaningful way.”

    Setting up a DMT can be overwhelming not just because of test volume but because of the large number of people in diverse disciplines that it takes to make the team function successfully. In addition to the physicians and other medical personnel, “we also had to have people who knew the business side of things,” Dr. Woodworth said, and for this the dean’s office provided project management support. “We also had support from IT for the different aspects of programming, the EHR and/or the LIS, depending on how we wanted the results to end up in the medical record.”

    Also “crucial,” she said, was a knowledge-based management resource called the Center for Knowledge Management, centered in the university library. She found clinical practice guidelines somewhat lacking in references to the primary literature. Center for Knowledge Management staff would fill that gap. “We would say, ‘Well, the guidelines say you shouldn’t measure aldosterone in the presence of this hypertensive med; please go back to the primary literature,’” Dr. Woodworth recounts. “And they would come back with a beautiful evidence-based summary that helped guide our decision-making.”

    Finally, “No diagnostic management team can happen without the input of the clinical chemistry fellows and pathology residents.”

    To help understand better the value of a DMT for PA, Dr. Woodworth explained the normal physiology of aldosterone and renin in blood pressure regulation and the pathophysiology of PA.

    “Blood pressure is regulated in huge part by the renin-angiotensin-aldosterone system [RAAS],” she said. Low blood pressure and low sodium concentration lead to upregulation of renin from the juxtaglomerular membrane cells in the kidney, which signals conversion of angiotensinogen ultimately to angiotensin 2. Angiotensin 2 in turn acts on the adrenal glands to upregulate aldosterone secretion, which then acts on the distal tubule of the kidney to retain sodium at the expense of potassium excretion. Water follows sodium, so blood pressure goes up and sodium concentration in the blood goes up as well.

    Autonomous secretion of aldosterone by the adrenal glands that is not suppressed by high blood pressure and high sodium causes dysregulation of the RAAS, which defines primary aldosteronism. “Primary aldosteronism is actually one of the more common forms of secondary hypertension,” Dr. Woodworth said. “It is the most common form of endocrine-mediated hypertension.” It has three main etiologies: aldosterone secreting tumors of the adrenal gland, bilateral adrenal hyperplasia, and, in rare cases, a familial form. Up to 15 percent of hypertensive patients may have PA.

    The long-term effects of autonomous secretion of aldosterone are hypokalemia, severe hypertension, and damage to the cardiovascular system, along with sodium retention and suppressed renin activity. Because of its impact on the cardiovascular system, there have been numerous studies on how to work up primary hyperaldosteronism, Dr. Woodworth said. The Endocrine Society published practice guidelines for this workup in 2008 and updated them in 2016.

    With aldosterone and renin central to this homeostatic system, it is logical that screening begins with measurement of the aldosterone-to-plasma renin activity ratio. In patients who have two abnormal screening tests, a confirmatory test is done. Typically, a confirmatory test is something that will challenge the RAAS. “The most common is a saline suppression test,” Dr. Woodworth said. “When we infuse saline, it will ultimately result in downregulation of aldosterone. However, in a patient with primary hyperaldosteronism, aldosterone will remain autonomously secreted and elevated.” But among the most important aspects of the workup is a strong screening test.

    Who should undergo a screening test for PA? “The Endocrine Society practice guidelines state that we should only screen those at high risk for primary hyperaldosteronism,” Dr. Woodworth said. High-risk candidates include those with sustained high blood pressure on three different measurements over the course of several days; hypertension that is resistant to at least three hypertensive drugs; a patient who has controlled hypertension but only on four or more antihypertensives; or a patient with hypertension plus hypokalemia or hypertension plus sleep apnea. An indication of a genetic component also calls for screening, such as a person with hypertension who has a first-degree relative with primary hyperaldosteronism or a patient with hypertension with a family history of early-onset hypertension or stroke.

    The aldosterone-to-plasma renin activity ratio can be measured in two ways. “Typically, in the United States, we use an aldosterone immunoassay and we measure the activity of plasma renin activity through an activity assay,” Dr. Woodworth said. In many of these cases renin activity is suppressed because of the RAAS. (Renin secretion is downregulated in the presence of high blood pressure and/or elevated sodium.) “When you have suppression of renin, the aldosterone-to-renin ratio will be high inherently,” she noted, “and so the new guidelines suggest that we shouldn’t just use the ratio of aldosterone to renin, but we should also use aldosterone concentration.” An aldosterone-to-plasma renin activity ratio, or ARR, greater than 30 with a plasma aldosterone concentration above 15 ng/dL are cutoffs most commonly cited as diagnostic for primary aldosteronism.

    Most patients with PA have hypokalemia; low potassium leads to altered results for aldosterone and ARR. Sodium status is critical for maintaining the RAAS. As a result, there will be different results for plasma renin activity, aldosterone, and the ratio, depending on the patient’s diet. Posture is also a factor: Patients who are sitting upright have a higher ratio than those who are supine. And diurnal variation affects aldosterone and plasma renin activity, with both highest in the mid-morning.

    Numerous medications affect the RAAS. Most prominent among them are antihypertensive medications, such as direct renin inhibitors and ACE inhibitors.

    In the revised 2016 Endocrine Society practice guidelines on diagnosing PA are evidence-based recommendations for how and when to measure aldosterone and plasma renin activity. “They say you should correct the hypokalemia prior to performing these tests,” Dr. Woodworth said. “Also that you should liberalize sodium intake and discontinue many antihypertensive medications for two to four weeks. Specimens should be collected mid-morning and the patient should be awake and sitting upright for a certain amount of time because of diurnal and postural effects on aldosterone and renin.

    “I’m sure that you’re sitting there thinking about how difficult it is to take patients off of these medications,” Dr. Woodworth said to the conference audience. “And that’s exactly what my endocrine partner said when I told her we had to take everybody off the medications prior to measuring these things. Sometimes it’s actually not safe for the patients. The side effects associated with going off these antihypertensives are severe, and in some cases it’s not possible. So one of the things we did was to look at how often our clinicians were measuring renin and aldosterone in an appropriate and an inappropriate way.”

    Dr. Woodworth and Vanderbilt clinical chemistry fellow, Joesph Wiencek, PhD, studied 200 patients who had been worked up for PA by having aldosterone and plasma renin activity measured and the ratio calculated. “We defined suboptimal sampling conditions as samples with at least one interfering medication, those that were collected at the wrong time of day, those without known potassium status or with abnormal potassium concentration, or specimens with unknown or abnormal renal function,” Dr. Woodworth said. What they found was alarming: 85 percent of specimens were collected in a suboptimal manner. Only 15 percent were collected correctly.

    “If you can’t have optimal conditions for collecting these specimens, what should you do?” Dr. Woodworth asked. The 2016 Endocrine Society practice guidelines suggest that laboratory results for aldosterone and renin be interpreted in the context of confounding factors. How can laboratorians ensure that? “The diagnostic management team,” she replied. “We were pleased with our efforts because we had implemented the diagnostic management team about two years prior to the Endocrine Society recommendations.”

    Dr. Woodworth showed an example of how the team interprets results in light of the clinical history and confounding factors. “The true definition of a diagnostic management team is one that meets regularly,” she noted. “Our diagnostic management team [at Vanderbilt] met twice a week because we performed testing for renin and aldosterone twice a week. Our residents and fellows looked up clinical histories relevant to all the factors that affect test results and looked for risk factors for primary aldosteronism.”

    The interpretations included insight into what these test results might mean in the context of interfering medications, comorbidities, or clinical history. “And then we provided evidence-based recommendations to help the clinicians understand what the test results mean. We included risk factors, uncontrollable hypertension, hypokalemia, and then potassium and renal function status. We talked about the drugs that the patient was taking”—in this case lisinopril and amlodipine—“and we talked about how those are known to decrease the aldosterone-to-renin ratio.” (See “DMT-driven interpretation of high-risk hypertensive patient,” page 18.)

    Despite that, the aldosterone-to-renin ratio was 102, and, as mentioned, the cutoff for a potential positive for primary aldosteronism is 30. “So this was probably primary aldosteronism, but because this was a screening test, we advised that the patient seek an endocrine consult for confirmatory testing.” Two links were appended: one for more information on the effects of the different drugs and comorbidities on aldosterone and renin, and the aldosterone-to-renin ratio, and another for information on collection requirements.

    Dr. Woodworth and colleagues conducted a study to determine the clinical utility of the endocrine DMT. They studied four primary care practices in two periods—one year before and a little more than one year after implementing the DMT.

    “Before, we had 32 patients who had been worked up for suspected primary aldosteronism,” Dr. Woodworth said, “and after we had 27. We reviewed the electronic medical records for how the patients were worked up, the diagnoses, the outcomes, and whether we were able to save unnecessary tests. We looked to see how quickly the diagnosis occurred, whether we thought the diagnosis occurred efficiently, or was delayed.”

    Before implementation, four patients had unnecessary procedures, either imaging or lab tests. Potential delayed or missed diagnosis was “quite common,” Dr. Woodworth reported, “because physicians did not understand how to interpret the results of the aldosterone-to-renin ratio in the context of the medications the patients were taking. Eight patients were deemed to have either delayed or missed diagnosis.” Post-DMT, there was close adherence to the Endocrine Society practice guidelines and no perceived unnecessary testing or imaging procedures. Moreover, the five patients who were advised to have an endocrine consult did have the consults and follow-up care was appropriate.

    “I got really great feedback” from clinicians about the DMT, Dr. Woodworth said. “In fact, every time Dr. Utz would get a consult as a result of the diagnostic management team, she would call me, very happy that we had provided care for the patient and that they were able to see the endocrinologist quicker.”

    PhD scientists can’t bill for these consults. “Why don’t we care about billing?” Dr. Woodworth asked. The answer: Because DMT consults are good for the patient, and they are a value-added practice. “We’re providing a quicker diagnosis and fewer unnecessary tests,” she said, “so we feel like it’s a win-win for the patient.”

    hypertensive“We are instituting DMTs at UK. I just presented the concept of lab utilization bundled with DMT to the CFO, CMO, and CEO. They were overwhelmingly supportive. We have support from the dean’s office and the pathology department.” Her biggest challenge will be working through necessary IT upgrades, “which was also true at Vanderbilt.”

    One of Dr. Woodworth’s Vanderbilt colleagues, Jeremy Hart, MD, is also now at UKMC. She and Dr. Hart are on what Dr. Woodworth calls “an evangelical campaign to convert people to DMT.” They are showing data from Vanderbilt to build support among clinicians.

    Dr. Woodworth will be moving one step beyond the institutional implementation of DMTs. She will propose a grant looking at how to implement DMTs. It is a targeted NIH proposal that studies the barriers to implementing processes beneficial to patients.

    As for wider dissemination of DMTs, Dr. Woodworth said, “A lot of pathologists are doing something like this informally.” Dr. Laposata’s formal definition of a DMT says it must meet regularly and its interpretation must go into the patient’s chart and contain clinical information, be incorporated into the electronic health record, and be specific to that patient and relevant to patient care. “Maybe they don’t have all of these elements,” she said. “A lot of times it’s just about formalizing the process and collecting data showing its benefits.”

    Can the DMT concept be extended to higher-volume tests, like the thyroid function test or workup for Cushing syndrome? Dr. Woodworth is optimistic. “In the age of informatics and big data and all the things we’re doing with next-gen sequencing, I feel like we could get to the place where we could provide personalized medicine for some of these higher-volume tests. But it would require powerful informatics tools and algorithms that we had developed ahead of time.”

    The next step for the endocrine diagnostic management team is to help physicians understand the context in which they should collect the specimen and measure it. “We can’t fix all of the suboptimal conditions but we can fix many of them,” Dr. Woodworth said. She also wants to expand to other areas of endocrinology that are ripe for developing DMTs, such as thyroid function testing in pregnancy. “This is an area in which the volume would be manageable and there are lots of problems in test ordering and interpretation.”

    At Vanderbilt Dr. Woodworth studied ordering patterns for thyroid function testing in pregnancy to see whether clinicians were adhering to clinical practice guidelines. “Guidelines say you should screen pregnant patients at high risk for thyroid dysfunction by measuring TSH. That wasn’t what was happening. Some practices were screening everyone,” she says. Another error was that obstetricians were measuring TSH with free T4. “So they were not screening the right population, and they were not ordering the right test. Also, when results were abnormal, they were not following up correctly.”

    She did a root-cause analysis to understand the problem and found that practices doing universal screening had new obstetric patient order sets that included both TSH and T4. So the order set drove universal screening and use of the wrong test. “With regard to follow-up, they couldn’t easily see trimester-specific reference intervals in the EMR,” she said.

    Building on these findings, Dr. Woodworth is working at UKMC to improve thyroid function testing ordering in pregnancy. “I am working with the endocrinology fellows here to do a similar study. We are going to put in place a diagnostic management team to mitigate the problems of misordered tests and improper workup.”

    William Check is a writer in Ft. Lauderdale, Fla. The second Diagnostic Management Team Conference will take place Feb. 6–7, 2018 in Galveston, Tex.


 
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