Chicago, IL, August 15-18, 2022
David L. McGlasson, MS, MLS(ASCP)
The recent THSNA 2022 meeting that was held in Chicago, IL from August 15-18, 2022, was a welcome event, as attendees for the first time in a couple of years could attend the conference in person or virtually. Finally, attendees had the ability to network with other colleagues in meeting rooms, exhibits, sponsored events, and poster sessions. The good times are back. We had the opportunity to learn what everyone is doing, what they have in the planning stages, future research protocols, and clinical work.
The topics and sessions covered a wide spectrum of hemostasis/thrombosis, anticoagulation, clinical laboratory testing, and evaluation of the many currently relevant topics. Attendance was approximately 1000 total, with about 850 in person at the meeting and 150 viewing virtually.
The meeting opened on Monday, August 15 with a session hosted by NASCOLA and ISLH titled INTERESTING CASES IN LABORATORY HEMOSTASIS AND THROMBOSIS. There were some great presentations, including an interesting talk from Andrew Goodwin, MD from the University of Vermont Larner College of Medicine and the University of Vermont Medical Center. The title was Newborn Male with Hemophilia. Common occurrence we have all seen right? This one was incredibly unique. The mother is a known carrier of FVIII and FIX deficiency (X-linked); male newborn was not expected to have both Hemophilia A and B. However, the child was found to have both FVIII and FIX deficiencies. The physicians questioned the accuracy of the lab results, and the assays were repeated. The findings were confirmed by the laboratory three days later after the patient received Vitamin K supplements. The results were again confirmed on a separate specimen.
This finding brings up a lot of questions. Was this anomaly due to de novo inherited and one de novo mutation? In a previous article by V Ivaškevičius et al:
Combined coagulation factor VIII and factor IX deficiency (CDF8F9) in a patient from Lithuania. Hamostaseologie. 2016 Nov 8;36(Suppl. 2):S29-S33.. The chances of a newborn male having both deficiencies of a mother with both known FVIII and FIX carrier genetic issues are extremely unlikely. The question then became is this due to a recombination event? This had been questioned in an article by S. Siddiq et al: F8 and F9 mutations fail to co-segregate in a family co-incident haemophilia A and B. Haemophilia 2011 Jan 17(1):e230-4
This dealt with non-Mendelian inheritance of the disease associated loci through a recombination event. Was this a newborn with sex aneuploidy such as XXY Klinefelter Syndrome?
A coagulation disorder panel by next generation sequencing (NGS) profile was ordered to include:
Factors X, FXI, FXIII A1, FXIII B, FII, FV, FVII, FVIII, FIX, VKORC1, FGA, FGB, GGCX, LMAN1, MCFD2, SERPINA 1, SERPINE 1, SERPINE 2, VWF.
|Sex aneuploidy||G-Banded Karyotype||46 X,Y||Negative for aneuploidy|
|Inherited& De-Novo||NGS Coag DO Panel||F8 and F9 variants||Both inherited|
|Recombination event||NGS Coag DO Panel||F8 and F9 Variants||Recombination event|
The family pedigree shows the mother to be a carrier of both FVIII and FIX mutations. She has a daughter with normal FVIII and FIX. The son inherited both the FVIII and FIX mutations resulting in factor deficiencies in both. Genetic information present in the germ cells may be inherited by subsequent generations. This includes molecular processes in the genome germline generations. Therefore, the recombination events caused this exceedingly rare event to take place. Dr. Goodwin, like myself, had to rely on geneticists to explain this rare event.
Many of the presentations at THSNA this year seemed to be more Physician oriented. I have tried to highlight some of the ones that can be used by laboratorians and pathologists in the clinical laboratory.
An excellent one was presented by Kathleen Devreese, MD from Ghent University, in Belgium. The title was: Challenges in Laboratory Diagnosis of the Lupus Anticoagulant (LA). Previously I had written a blog post on this very subject and I noticed Dr. Devreese used many references that I had notated. She covered definitions, the laboratory diagnosis, the pathogenicity of LA, patient selection for testing for LA, the methodology used, the importance of pre-analytical procedures for specimen preparation, and the analytical procedures for the identification and classification of the presence of LAs. Her conclusion then summarized the importance of the LA presence in diagnosing antiphospholipid syndrome (APS).
See the CLOT CLUB post for a detailed discussion of the APS-LA current information..
Following up on the prior topic by Devreese was Bob Gosselin, CLS, from University of California Davis Health System, Thrombosis and Hemostasis Center Sacramento, CA. The title of his talk was PT/APTT Mixing Study Looking for Harmonization. This is a subject that the coagulation community has been debating about for at least 30 years in the study of LA testing.
The International Council for Standardization in Haematology (ICSH) in 2016 established a hemostasis committee to address guidance in the area of blood coagulation. Their first recommendation was in laboratory measurements of DOACs, then in ADAMTS13, coagulation critical values, coagulation instrument selection, and preanalytical variables in coagulation. The recommendations are all available in direct access information.
In 2018 Dot Adcock, MD addressed the controversial subject of a PT/APTT Mixing Study Lab Guidance Document.
A committee of experts put out a guidance draft in 2019. Mr. Gosselin reviewed this draft and concurred with the 1:1 mix; correction indicated a factor deficiency and a non-correction evidence of an inhibitor. The document was primarily for guidance and interpretation for identifying presence of a LA and what suggested a correction vs a non-correction. The committee then went to ICSH to suggest a PT/APTT mixing field study. This started in 2019 when a field study kit was produced for use by all participants. The kit was standardized with 25 normal donors and 22 abnormal samples and normal pooled plasma. Twenty testing sites were selected based on ability and previous experience to perform the studies to be performed. Multiple reagent/system combinations were employed in the testing. Six different countries were represented.
Twenty-two specimens from all factor deficiencies, two FVIII inhibitors, two heparinoids (UFH, LMWH), two warfarin specimens and 4 different DOACs along with two known LA positive samples were provided for testing by the individual laboratory testing sites. Eighteen laboratories in all fully participated
Specific instructions were given for the handling of the specimens and testing for the presence of the LA. The procedures for performance of the assays were specific for each individual laboratory. PT and APTT 1:1 mixing studies were performed with and without incubations. Eight different calculations were used to obtain the result.
Method and calculation:
B. Gosselin THSNA 2022 Presentation on PT/APTT Mixing Study
The data from all laboratories was evaluated. The statistical analysis showed that specific standard studies for each laboratory will still require a self-assessment using a standardized laboratory testing protocol for LA mixing studies.
A topic that is very relevant to today was presented by Damon E. Houghton, MD, MS, Associate Professor & Consultant, Gonda Vascular Center, Mayo Clinic, Rochester MN, titled On Venous Thromboembolism After COVID-19 Vaccination in Patients with inherited or Acquired Thrombophilia. Vaccine induced thrombotic thrombocytopenia (VITT) syndrome or thrombosis with thrombocytopenia Syndrome (TTS) has been seen as a complication of COVID-19vaccination. The COVID-19 vaccinations have also been seen as being associated with venous thromboembolism (VTE) but without risk of thrombocytopenia. Several protocols have been published that have shown no increased risk of VTE in different populations after receiving several distinct types of vaccine such as Pfizer, Moderna, and Johnson & Johnson. They included:
Klein et al. JAMA 2021: Data from Vaccine Safety Datalink examined BNT 162b2(Pfizer-BioNtech) and mRNA-1273 (Moderna).
Barda et al. NEJM 2021/ data from population-based study in Israel with BNT 162b2.
Houghton et al. JTH 2022 Data from Mayo Clinic Enterprise pre/post vaccination analysis examining Pfizer/Moderna and Jannsen (Johnson and Johnson) vaccines.
In the Houghton study there was no increased risk in cancer patients, no increased risk in patients with heparin-induced thrombocytopenia (HIT), and lower risk after vaccination in patients with prior VTE.
Subjects who had a previous history of inherited or acquired thrombophilia were hesitant about the elevated risk of getting a VTE from the COVID-19 vaccination despite no evidence in the current literature.
The data showed that the VTE risk with any pre-existing thrombophilia was not higher than those without thrombophilia post-COVID-19 vaccination. VTE presence in subjects with any pre-existing thrombophilia was not different in the pre-post vaccination for at least 90 days. The presence of pre-existing conditions that have been associated with VTE either inherited or acquired should not discourage patients from getting the COVID-19 vaccinations.
Effect of Three Factor Xa Inhibitors on a Subset of Common Coagulation Assays. RA Crist DA Stephens, GM Rodgers, KA Moser, KJ Smock ARUP Laboratories Institute for Clinical and Experimental Pathology, Salt Lake City, UT; Department of Pathology University of Utah School of Medicine, Salt Lake City UT, USA Division of Hematology and of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
The authors did a great job of showing how the DOACs (rivaroxaban, apixaban, and edoxaban) affected a variety of clotting and chromogenic assays on several concentrations of the mentioned factor Xa inhibitors. The assays included PT, APTT, DRVVT, DRVVC, PNP, UFH and LMWH anti-FX assays.
Pathologist-Directed Reflexive Evaluation of Prolonged Clotting Times: A National Reference Laboratory Experience. KA Moser, MV Lim, KJ Smock. Department of Pathology University of Utah, Salt Lake City, UT ARUP Institute for Clinical and Experimental Pathology, Salt Lake City UT, USA, Division of Hematology and Hematologic Malignancies, Department of Internal medicine, University of Utah, Salt Lake City, UT, USA.
The authors in this study designed pathologist directed algorithms to conduct reflexive testing on clotting assays that evaluated prolonged PT/APTT tests to cut down on excessive testing and multiple blood draws. They produced the term Clot-Ref. They then used the information to more efficiently identify the cause of the abnormal assays. They took a clinical history of each subject, to include bleeding, thromboses, anticoagulants, and ran a Clot-Ref panel of a PT, APTT, DRVVT, fibrinogen and D-dimer test. Depending on the findings they then ordered specialty testing to identify specific conditions. Using this panel, they were able to identify clinically significant abnormalities like factor deficiencies, VWF, the presence of an LA, and specific inhibitors as well as DIC. Some abnormal results reflected anticoagulants contamination or mild presence of a transitory LA.
Analysis of the safety and efficacy of direct-acting oral anticoagulants for the treatment of venous thromboembolism (VTE) in obesity. JE Sperry, AE Rose. University of Wisconsin Health, Madison, WI, USA.
Obesity has increased drastically in the United States since the turn of this century. Almost half of the population could be classified as obese. Current studies have shown as many as 42.4% have an elevated BMI. DOACs are now being suggested as an alternative to warfarin in the management of VTE. To date, the data in the original clinical trials using DOACs for treating VTE had very few subjects that had a body mass index (BMI) >40 kg/m2 or weight >120 kg in 2021. International Society of Thrombosis and Hemostasis (ISTH) recommended that the use of rivaroxaban and apixaban were preferrable in treating obese patients regardless of their body weight or BMI. The data collected was all retrospective, through professional opinion or purely observational. These authors developed a protocol that observed all subjects who were on any DOAC to include edoxaban and dabigatran. Exclusion criteria were specified such as <48-hour dosing with a DOAC or treatment for a recurring condition. The latest preliminary statistics results indicated that there are no medication issues in the bleeding events or VTE recurrence amongst the subjects with obesity.
Elevated Factor VIII and von Willebrand Factor (VWF) Activity levels in patients with a history of VTE and corticosteroid use. JR Adalf, A Chaudury.
It has been found in previous studies that patients on glucocorticoids therapy can have elevated FVIII and VWF. This can increase the risks of developing hypercoagulable states. The authors in this study measured both VWF and FVIII levels in all patients who had a thrombotic event and had received glucocorticoids in the past by oral, inhaled, or injected treatments. The findings indicate that the anti-inflammatory medications significantly raised the VWF and FVIII levels. They suggested that clinical personnel check on whether the means of administration of the glucocorticoids were an issue.
CLOSING THOUGHTS OF THSNA 2022.
It was great to attend a meeting that was back up to full strength in attendance again. The topics were top notch in quality and information. The vendors did a great job in displaying their new products to the coagulation community. The posters had new great topics that sent me to Pubmed for literature searches. If there is a criticism it was that the vendors and plenary sessions were taken down too soon. As the world gets back to normal, I am looking forward to seeing meetings like the one THSNA 2022 put on that will further the new topics, treatments and theories in the field of hemostasis and thrombosis again in live an living color.