David L. McGlasson, MS, MLS(ASCP)
The recent THSNA meeting that was supposed to held in Chicago, IL from October 27-30, 2020 was held in a virtual meeting setting. This seems to be the theme this year for all of the professional events that have been affected by the world-wide COVID-19 pandemic. The one thing I have heard from all of my colleagues is that they miss the ability to network with each other in the meeting rooms, exhibits, events. That is where you really find out what everyone is doing, what they have on the horizon, what their plans are for future research and clinical work. I hope next year we can get back to normal, because even though we can exchange ideas in a virtual setting, it just isn’t the same as face to face.
Still the topics and sessions covered the wide spectrum of hemostasis/thrombosis, anticoagulation, and clinical laboratory testing and evaluation of the myriad disorders that are relevant.
The meeting opened with Plenary Session 1: Embracing Change: From New Discoveries to New Treatments to Improved Practices. All the sessions were 3-part topic related presentations. This one discussed Anticoagulant Stewardship in the Era of Novel Therapeutics, was presented by Allison Burnett, Pharm D, the incoming President of Anticoagulation Forum. She stressed the need for stewardship over the DOACs in these times by the pharmacy working in conjunction with the clinicians, nursing staff, and the laboratory. She cited publications that stressed how to implement a DOAC screening service at a large academic medical center, the establishment of a pharmacy managed anticoagulation clinic, and expansion of antithrombotic stewardship efforts. Evaluation of a pharmacist led outpatient direct oral anticoagulant service was presented. A pharmacist checklist for direct oral anticoagulant management: Raising the bar and Antithrombotic Stewardship: assessing Use of computerized Clinical Decision: Support Tools to Enhance Safe Prescribing of DOACs in Hospitalized Patients. It was stressed that the medical community has a critical need for anticoagulation stewardship now, given the choices of 11 anticoagulants, 6 reversal agents, and 8 antiplatelets meds. With DOAC use alone we need advice on extended prophylaxis, extended treatment, obesity, and renal issues for dosing. COVID-19 dosing and effects has caused a whole new set of issues and questions on treatment plans. The speaker stressed the following goals: secure administrative commitment; establish professional accountability and expertise; engage multidisciplinary support; perform data collection, tracking and analysis; facilitate transitions of care; federal recognition of pharmacists as providers, telehealth clinics for remote patient care, post-acute and long-term care facilities, and the recognition and use of more novel therapies such as: osocimab, ciraparantag, and others.
The second presentation was Building from Basic Biology to improve Diagnosis and Care. This was given by Dr. David Ginsburg MD, from Howard Hughes Medical Institute and University of Michigan. Dr. Ginsburg, who is a very breezy presenter gave a great talk on that entailed venous thrombosis (VT) and basically whether or not to test for hypercoagulable states and what things to test for. Factor V Leiden, elevated FVIII levels, Prothrombin 20210, and deficiencies of Proteins C and S, and Antithrombin (AT) make up about 40% of known causes of VT cases with the other 60% caused by unidentifiable causes. Genetic testing for thrombophilia now can be used for establishing risk factors for thrombosis.
Factor V Leiden (FVL) is found in 5% of population: primarily European ethnicity; Prothrombin 20210 mutation-1%; Protein C and S about 1 in 500; AT deficiency 1 in 2500; the possibility of elevated FVIII levels (and FIX and FXI)-5-10%; dysfibrinogenemia in rare cases. These make up the primary cases for VT. Most people don’t test for Homocysteine or MTHFR gene variants or plasminogen Activator I (PA-I) anymore because they do not increase the risk for thrombosis. However, when doing a full panel Thrombophilia workup, one could include an antiphosoholipid antibody syndrome test panel.
Then you have the problem of what do you do when you find a patient who is either symptomatic or asymptomatic with a finding of FV Leiden marker. Approaches were discussed.
|Treatment of Venous Thrombosis|
|Indication||Rx with FVL||Rx without FVL|
|Asymptomatic Patient||No treatment||No treatment|
|Acute Thrombosis||Heparin/Warfarin/DOAC||Heparin/Warfarin /DOAC|
|Prophylaxis after VTE||?indefinite oral anticoagulant||?indefinite oral anticoagulant|
|Oral contraceptive-estrogens||?? May or may not be contraindicated (? Or not)|
|Other special cases||??????? case by case||??????|
So as you can see, there are a lot of questions and interpretations for thrombophilia treatments for positive tests for FVL and other thrombophilia mutations. To treat or not to treat depends on the situation. If you find a FVL that is heterozygous and no personal or family history would your treat this person? If you find as FVL that is homozygous would you treat them any different than you would any other thrombophilia. Future treatments should be evidence based, not personal opinion, says Dr. Ginsburg, who cited Coppens et al: JTH 2008,6:1474 Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. He then quoted Rosendaal. “Thrombophilia testing in mainly of psychotherapeutic value…I’m not sure for whom, the patient or the doctor.”
The final speaker of the session was Dr. Rajiv Pruthi, MD from the Department of Hematology at Mayo Clinic. His Topic was Adapting to New Therapeutic Options: Implications for Clinical Services and Coagulation Laboratories. He opened with a great table that discussed the Evolution of treatment of bleeding disorders. This started with the use of whole blood from 1900 to the 1940s. Then the use of Plasma from 1950-1960s which in the mid-1960s switched to use of cryoprecipitate. Then in the late 1960s the use of plasma derived FVIII leading to purified/viral inactivation processing in the 1980s. During this time the labs came up one the one stage factor assays for FVIII and FIX (OSA), shortly followed with Von Willebrand factor (VWF functional assays and Ristocetin cofactor) assays. In the 1990s came the recombinant FVIII and FIX products. The early 2000s brought pdVWF and initial (ongoing) gene therapy trials along with chromogenic factor assays (CFA). In 2014 we saw the production of extended half-life factors and in 2015 recombinant VWF with alternate vWF functional assays. In 2017 the non-factor therapeutic option Emicuizumab was FDA approved for hemophilia A. We now have clinical trials going on for Fitusiran, Concizumab, BAY 1093884, PF-06741086. As the saying goes, we have come a long way baby.
He discussed adaptions that have come about such as the extended half-life concentrates and individualized pharmacokinetics as well as the non-factor therapies, such as emicizumab. He stressed a laboratory adaptation that needs to be addressed. Reagent dependency and variability will have to addressed for accurate measurement of factor levels with these new treatments. Gene therapy is still in clinical trials but shows great promise. For a review on this, I would suggest reading the first Clot Club Issue about the Update on Hemophilia A and B. This has a lengthy discussion of the testing and new products available.
In particular, Dr. Pruthi discussed how the difference in factors influencing the OSA factor assays—especially the activators, phospholipids, and instruments—that can influence the testing for new products. He talked about the comparison of clotting vs chromogenic factor assays and photo-optic vs mechanical instrumentation result differences.
Most OSA provide acceptable results of factor measurement with some exceptions. Chromogenic assays provide consistently acceptable estimations of factor levels. Be sure to follow the individual manufacturer package inserts for the assay and when in doubt contact with special coagulation reference laboratories.
When performing FVIII inhibitor Bethesda assays, there are technical issues that may affect the test results. When using the OSA and CSA with human substrates, you may see false negatives when detecting lower values of Bethesda titers. If the lab is using a CSA FVIII method, a bovine substrate is required for accurate estimations of results when measuring results on emicizumab.
In one-to-one discussions, both Dr. Ginsburg and Dr. Pruthi noted that for FVL testing, an activated Protein C resistance assay is performed showing aberrant results before a FVL mutation test can be ordered in their institutions. I like that stand-up approach.
There were several submissions that I would like to mention the authors and topics that caught my eye as being relevant in today’s coagulation world. The following were displayed at the THSNA 2020 virtual poster event:
Evaluation of Anticoagulation Regimens in patients with COVID-19. L Forouzan, A Pagliaro, V Colomy, R Wright, t reinaker, J Knorr. Einstein Medical Center, Philadelphia, PA, USA
Standardization of direct oral anticoagulant management across a health system J Burdick, C Patterson, A Rose. University of Wisconsin Hospital and Clinics, Madison, WI, USA
Hepatic Disorders Contribute to Platelet Dysfunction. A Faroqui, C Bacher, F Siddiqui, B Darvath, D Hoppensteadt, O Iqhal, J Fareed, M George D VanThiel. Loyola University Medical Center, Maywood, IL, USA
Trends in D-Dimers and Thrombosis among patients evaluated for COVID-19. F Rollin, BB Adhyaru, A Idrees, S Tekwani, MY Akbashev. Emory University School of Medicine, Atlanta, GA, USA
Performance Characteristics of a Chromogenic Factor VIII Method on the STA-R Evolution XP (Chromogenic Coamatic Factor VIII kit). RA Crist, Da Stephens, GM Rodgers, J Corean, KA Moser, KJ Smock. ARUP Institute for Clinical and Experimental Pathology, Sal Lake City, UT, USA. Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. Division of Hematology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Recognizing reasons of unwarranted coagulation testing in medical il patients- a sneak peek. S Assad Ali, A Khan, S Noor. Patel Hospital, Karachi, Pakistan.
Differences in the clot based and amidolytic anti-XA assays between the neutralization profile of apixaban, betrixaban, edoxaban and rivaroxaban. F Siddiqui, A Tafur, D Hoppensteadt, E Bontekoe, W Jeske, B Lewis, O Iqbal, J Fareed. Loyal University Medical Center, Maywood, IL, USA. Northshore Health Systems. Skokie, IL, USA.