Plasma Coagulation Inhibitors

July 12, 2003
09:00 to 13:00
Hall 9
The International Convention Center, Birmingham

Chair- F. Church, USA
Co-chairs:  F. Bernardi, Italy; C. Jackson, USA; D. Lane, UK; K. Suzuki, Japan

The meeting this year was held to a very large audience, perhaps the largest ever for this subcommittee, and we had some lively conversations and dialog during the talks, and around the coffeepot.  We divided our meeting into 4 sessions: Endogenous Thrombin Potential (ETP); Heritability of Plasma Levels of Coagulation Inhibitors from Family and Twin Studies; Anticoagulant Proteins- Characterization and Clinical Use in Disease Therapy; and Other Topics of Interest to SSC on Plasma Coagulation Inhibitors.

Dr. Hemker presented the rationale behind the EPT in that thrombin begets thrombin and the complexity of platelet-poor and platelet-rich plasma for devising assays.  There was much conversation dealing with this presentation, especially related to tissue factor sensitivity, effect of thrombomodulin, standardization of the assay, and the influence of circulating tissue factor/phospholipid particles.  Dr. Giesen then focused his presentation on an automated form of the ETP, using a fluorophore that thrombin cleaves, and the need for an internal "calibrator" to take into account the color of the plasma and to help standardize the assay.  Dr. Tans then focused his talk on the use of the EPT in assessing APC resistance and the thrombotic effects of oral contraceptives.  The role of a2-macroglobulin to bind thrombin was addressed and issues related to measuring free versus bound thrombin were mentioned.  He summarized recent work with transexuals to highlight the different effect of male and female hormones on APC resistance, and devoted some time to the notion that ethinyl estrodial is prothrombotic and that the progestagen in oral contraceptives is antithrombotic.  Dr. van Hylckama Vlieg summarized her work with EPT on the Leiden Thrombophilia Study, focusing again on APC resistance.  Her observations focused on the EPT being related to APC resistance with and without the occurrence of Factor V Leiden, and that APC resistance was increased in women on oral contraceptives.  Dr. de Visser then directly compared the traditional APTT assay to the ETP, again focusing on APC resistance.  A ratio comparing activity plus and minus the addition of APC to both plasmas was compared using over 200 patient samples and 200 control samples.  Her work highlighted differences in sensitivities to the APTT to prothrombin and factor VIII and to free TFPI and free protein S for the ETP.   Dr. Kakkar finished this session with a summary of his work comparing heparin and low-molecular weight heparin in combination with oral anticoagulants using various clinical parameters and assays, including the ETP.  At the end of this session, Dr. Elaine Gray spoke briefly about a need and attempt to standardize the ETP, and has suggested that our subcommittee might be able to help implement plans to establish a standard.  There are, as would be expected, lab to lab differences, actual methods are slightly different, and it is important to organize a "working group" for this interesting assay, and we would work to have something ready for our next meeting in 2004 in Italy.
The second session was a presentation with Dr. Souto, who had an interesting presentation on the heritability and genomic mapping of modified plasma coagulation proteins.  He work is focused on quantifying the genetic trait analysis.  He was the GAIT study to highlight some features of a wide genome scan of protein S levels, TAFI, protein C, and antithrombin where data was presented to relate genetic components to plasma levels.  

The third session focused on key anticoagulant proteins that are currently being used clinically to treat various thrombotic/inflammatory diseases.  Dr. Grinnell began by describing the biology of Drotrecogin alfa (activated) recombinant human activated protein C.  He described the effect of APC to modify genes of NF-kB, and the ability of APC to be much more than an anticoagulant protease.  Dr. Joyce then summarized the success of APC in treating severe sepsis, noting the survival rate of patients receiving a single dose, notably the improvement in morbidity, especially related to cardiovascular and respiratory functions.  Dr. Heinrichs then summarized the recent antithrombin data for treatment of severe sepsis, and summarized the data showing that antithrombin, like APC, has both antithrombotic and anti-inflammatory actions.  He described the KyberSept study, wbere high doses of antithrombin was given with either unfractionated heparin or low molecular weight heparin.  In these studies, there was no benefit shown for the use of antithrombin; however, when the groups were analyzed for those without heparin, there was a significant reduction in death.  There was much discussion that suggested that it was too early to conclude that antithrombin was not effective, that additional studies should be performed, especially in light of the information found for antithrombin in the absence of heparin.  Even suggestions that combination of proteins, APC and antithrombin and TFPI be considered.  Dr. Levi summarized his work on all of the above areas, including APC, antithrombin and tissue factor pathway inhibitor (TFPI).  The TFPI data was recently made public, and its use in severe sepsis seemed to mimic the antithrombin data, that there was no major reduction in death for patients treated with TFPI in the presence of additional heparin.  Like antithrombin, the TFPI patients who did not receive heparin had a more successful course during their severe sepsis.  The final conclusion was that there is significant cross-talk between coagulation and inflammation.

The final session was devoted to other issues of our sub-committee, and Dr. Gray summarized initial studies to prepare a reference genetic panel of genomic DNA for factor V Leiden.  She presented numerous methods that have been suggested to prepare the samples, and a survey of users preferred gDNA (genomic DNA).  Dr. Jackson updated us on his progress for the SSC Working Group Report on Antithrombin, where numerous scientists and clinicians from around the world have agreed to study and test this protein, using kinetic methods of analyses.  The final speaker, Dr. Moll, was delayed in transit to Birmingham, but he stresses the need to continue the International Collaboration Group to study "Combined Thrombophila", and urges members of the SSC and ISTH to contact him with patient information for collaborative work.

After running over by 40 minutes due to the stimulating discussions generated by the first 3 sessions, we adjourned our meeting.  All sub-committee co-chairs were in attendance, and were all active participants in chairing sessions and interacting with the audience in attendance.