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2016 Annual Minutes
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6/23/2016 at 6:27:40 PM GMT
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2016 Annual Minutes

Plasma Coagulation Inhibitors

26 June 2016

14:15 – 18:45


Chairman: Richard A. Marlar (USA)

Co-Chair: Ian Jennings (UK), Jun Teruya (USA), Hiroko Tsuda (Japan), Cecilia Guillermo (Uruguay)


Working Session #1: On-going Projects

Project: Investigation into discrepancies in Protein S activity assays results- I. Jennings (UK).

The protein S (PS) activity assay has been shown in External Quality Control studies to have significant variation among laboratories and these issues extend to patient results as well. This study will attempt to elucidate the causes of the variation observed in the clinical PS activity assays. Up to 40 laboratories will participate in this study. The design of the study has been completed. The difficulty was obtaining the appropriate samples for distribution to the participating laboratories. However, normal and protein S deficient individuals have been identified and obtaining sufficient plasma for the proposed studies is in progress. Both lyophilized and frozen plasma will be distributed in the fall of 2016. The results will be analyzed during the spring of 2017. It is anticipated to have the data by the next meeting in Berlin.

Project: Investigation into racial differences in genetic risk factor (AT, PC, PS) for venous thrombosis- H. Tsuda (Japan).

The design for the study is developed and request for specimens is on-going. At this time, the East Asian samples and some European and South American samples have been received and tested. Preliminary data from both plasma and genetic polymorphisms have been analyzed. It is anticipated that the collection of specimens and the analysis of data will be continued and more countries and regions will be recruited. Enough data will be available for a final presentation at the next meeting.

Working Session #2: Guidance Manuscripts for Clinical Testing.

Project: Manuscript on Guidance for Clinical Testing for Antithrombin, Protein C, Protein S and APC-Resistance.

Clinical laboratory assessment of plasma levels of AT, PC, PS and APC-Resistance is difficult and associated with many problems and pitfalls. The working groups are producing four manuscripts on the state-of-the-art clinical assessment of plasma levels of the common thrombophilic risk factors. The manuscript progress for these four thrombophilic factors was presented:

Antithrombin: P. Meijer (The Netherlands)- Presented the preliminary outline and basic data to be included in the manuscript. The major AT assays types were discussed as to their sensitivity and specificity. There are three major types of AT deficiency which were discussed in relationship to the molecular mechanisms and effect on the various assay types. The manuscript is approximately half completed at this point.

Protein C: P. Cooper (UK)- Recommendations for protein C (PC) assays for plasma assessment using either the clotting based assay or a chromogenic based assay and the antigenic assay was presented. In addition the genetic deficiencies of PC testing was summarized. The manuscript has been written and is in final editing for submission.

Protein S: R. Marlar (USA)- The biochemistry and coagulation physiology for PS was presented as this molecule is difficult to assay because of the complexity of PS interaction with other plasma molecules. The pitfalls of the PS activity assays were discussed. The recommended initial or screening assay for PS is Free PS antigen assay using monoclonal antibody assay. The lack of useful information from the Total PS antigen assay was also discussed. Various parameters that affect the reference range such as gender differences was also discussed. The manuscript is about half completed (writing portion) but should be completed and edited by the December, 2016 deadline.

APC-Resistance: G. Moore (UK) - The concept of APC Resistance was presented. The various modifications of the APC-R assay were reviewed. Discussions about the relationship with the genetic mutations and the assay results was also presented. Other causes (non-genetic) of APC-Resistance were reviewed. The initial writing of the manuscript has been done and final editing will be completed this summer and fall for the deadline of December, 2016.

The writing of these manuscripts will be completed by December, 2016 and final review, editing, harmonization will be completed by spring, 2017 with submission to the Journal of Thrombosis and Hemostasis as SSC reports planned for June, 2017.

Working Session 3: Thrombophilia Testing Schemes.

Thrombophilia Testing Schemes- I. Jennings (UK), P. Meijer (The Netherlands), E. Favoloro (Australia), C. Guillermo (Uruguay):

Thrombophilia testing schemes vary by country and/or region. This session reviewed the thrombophilia testing schemes from two different European perspectives (based on External QA studies), and Australia and South America. Testing variations occur for a variety of reasons, including mandated testing or restricted testing (from national health services), racial differences, and clinician decisions or test availability. The information presented showed that there are multiple approaches to thrombophilia testing with no unified approach to testing schemes. The criteria for who to test and when the patient should be tested are not consistent. Further studies into the variability are necessary. To round out the evaluation of thrombophilia testing schemes, other countries and regions will also be presented at the next meeting. The major areas of the world will be covered and a summation of the testing methods will be presented and possibly submitted for publication.

Working Session #4: Coagulation Inhibitor Interference by DOACs and Protein S Cleavage.

Effect of New Anticoagulants on Thrombophilia Assays- R. Gosselin (USA)

The oral anticoagulant drugs pose significant issues with clinical testing of the plasma coagulation inhibitors. The DOAC drugs when present in the specimen appear to increase the thrombophilic factor values giving the potential for a false normal test. The impact of these inhibitors on the different testing methods was presented. Significant problems are associated with clotting assays for protein C, protein S and APC-Resistance. Some inhibitors can specifically affect antithrombin assays based on the enzyme used for the test. However some tests are not affected by the DOAC drugs (PC chromogenic assay or immunologic assays). Recommendations are not to test when a patient is on a DOAC drugs but rather wait until the patient has been off of the drug for at least 4-5 days. The genetic tests are not affected by the DOAC drugs.

Protein S cleavage- H Brinkman (The Netherlands)

Protein S is cleaved and inactivated in a region known as the thrombin sensitive loop. Thrombin and other enzymes can cleave protein S in this region and subsequently inactivate the PS activity. There at least 3 specific sites that can be cleaved in this specific loop by different enzymes. Work was presented showing the mechanism and parameters of this cleavage by the various enzymes. This work may have clinical significance for assay performance. 

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