1. Issues of Standardization of Coagulation Assays to detect effects of hormones, including the menstrual cycle, pregnancy and hormone replacement therapy. 

Speakers included:  Dr. He discussed the OHP (overall hemostatic potential) applied to the normal pregnancy, pregnancy complications and hormone replacement therapy; Dr. Hellgren discussed the TEG (thromboelastogram) and the Sonoclot applied to pregnancy; and Dr. Eichinger discussed application of activation markers to predict TE events during pregnancy.  There is a need for a screening assay(s) to predict bleeding or thrombotic events and, potentially, to predict adverse pregnancy outcomes.

The evidence presented demonstrated a good ability of all global assays to discriminate populations, including normal pregnant women from non-pregnant control women, as well as women with complicated pregnancy from uncomplicated.  However, individual data points showed substantial overlap, and the sensitivity and specificity of these assays to predict clinical events, as well as the comparability of various assays, is of yet unknown.  

ACTION STEPS:  There was agreement regarding a need to determine the usefulness of global assays by validation and application.  Various approaches were discussed including comparison studies utilizing a specific global assay in various laboratories and patient groups, collaborative studies with assays performed in one central lab or direct comparison of more than one global assay in a single population. The goal is to develop an experimental approach with implementation ongoing prior to next year’s meeting. Working group members are encouraged to participate in the development and execution of these validation studies by e-mailing directly to the following people:

Shu He                                he_shu@yahoo.com    
Katarina Bremme                katarina.bremme@ks.se
Margareta Hellgren             margareta.hellgren@vgregion.se
Margareta Blombäck           margareta.blomback@ks.se
Sabine Eichinger                 sabine.eichinger@akh-wien.ac.at

Dr. Blombäck discussed standardization of patient and laboratory conditions for determination of coagulation factors in women.  For example, factor assays, especially factor VIII and vWF should be drawn during days 1-4 of the menses.  Women should be off OCPs for a minimal period (e.g. 2 months) prior to baseline testing or on HRT for a minimal period to determine hormonal effects. Women should be encouraged to have blood drawn in the morning prior to any vigorous exercise or stress, after sitting for 20 minutes.  

ACTION STEP: It was agreed that there are many conditions specific to accurate laboratory determination of hormonal effects on coagulation.  A short recommendation paper will be written to suggest such clinical methodologies to be used for all published reports.  Dr. Blomback will draft the report and copies, comments and collaborations can be made by e-mail to her (see address above).  Input from other relevent subcommittees including vWF committee will be solicited.  This project should be completed within six months and the results available for clinical protocols related to the global assay validation described above.

2. Issues in thrombophilia relative to pregnancy: assays and normal values.

Risk factors for thrombosis during pregnancy were reviewed by Dr. B. Brenner.  Discrepancies in the literature were highlighted and the suggestion was made that differing risk assessments result from differences in eligibility criteria of women studied as well as laboratory assays performed. Specifically, the relationship between thrombophilia and pregnancy outcome is predicted to be strongest when pregnancy complications (such as pre-eclampsia or intrauterine growth retardation) are severe in nature and thrombophilia risk (e.g. lupus anticoagulant, antithrombin deficiency or multiple trait thrombophilia) is also severe.

ACTION STEP:  A recommendation paper has been developed in conjunction with the perinatal and pediatric subcommittee regarding thrombotic risk during pregnancy and will be submitted for review and recommendation for publication in JTH.  This will be accomplished within the next month.
 
ACTION STEP:  A recommendation paper will be developed proposing definitions to standardize severity of pregnancy complications as well as thrombophilia severity to be used in future studies of maternal outcome relative to thrombophilia.  This  objective should be accomplished within the next six months.  To participate please contact:  Dr. Benjamin Brenner:        s_kamenetsky@rambam.health.gov.il    

Dr. Saskia Middeldorp discussed indications for anticoagulation in women with a history of pregnancy loss.

Dr. Barbara Konkle introduced the issue of thrombosis associated with the ovarian hyperstimulation syndrome (OHSS), seen particularly in women with polycystic ovary syndrome.  The contribution of endogenous androgens and thrombophilia to clinical VTE events is unknown.

ACTION STEP:  Dr. Konkle will establish a registry structured to collect data regarding OHSS, thrombophilia, clinical and/or biochemical evidence  of androgen excess and clinical VTE events.  Input into registry data collection form development is welcome.  The registry should be established by the next meeting.  Contact Dr. Konkle for registry development and data collection:  Barbara Konkle:    barbara.konkle@uphs.upenn.edu

Dr. Jacqui Conard presented existing data on pregnancy-associated VTE in antithrombin deficient women with provocative evidence that prognosis may differ in AT propositi relative to AT-deficient women detected with family studies, regardless of history of prior thrombosis.  AT deficiency is rare and has been considered to convey a high risk of pregnancy-associated VTE in all affected women.  To further determine the magnitude of differential risk, Dr. Conard will establish a registry.  The registry will be established and running by next year’s meeting.  Please contact her:

Dr. Jacqueline Conard        jacqueline.conard@htd.ap-hop-paris.fr

Dr. Andra James presented data regarding the poor prognosis of pregnancy in women with mechanical heart valves affected both mother and fetus.  Recommendations regarding anticoagulation in pregnant women with mechanical heart valves are considered a very high priority need.  To collect preliminary data, a registry will be established.  To participate in registry development, contact her:  Dr. Andy James    andra.james@duke.edu    

3. Issues in thrombophilia relative to hormonal therapies.

Reports were made by :  1) Dr. James. Douketis on the effects of prothrombotic  factors on DVT risk in women using hormone replacement therapy (HRT); 2) Dr. Leo Zacharski on the role of iron accumulation in cardiovascular risk in postmenopausal women; and 3) Dr. Kluft on the results of a European Consensus Conference on sex steroids and cardiovascular disease in women. Recent data was discussed that suggests cardiovascular event risk is higher in women using combined estrogen/progesterone HRT as compared with estrogen alone.  This is of concern as progestational agents alone have been prescribed to women with thrombophilia.

ACTION STEPS: In order to determine the safety of progestational-only agents in DVT risk, a registry will be developed to record the outcome of women with thrombophilia who have been treated with progestins only including women with asymptomatic thrombophilia as well as women with thrombophilia and previous symptomatic VTE.  To review the draft registry, comment and record data, contact: Dr. J. Douketis    jdouket@mcmaster.ca

4. Hormonal influences in bleeding disorders of women.

Dr. Peter Kouides presented recommendations for screening, laboratory assays and treatment algorithm for women with menorrhagia on behalf of himself, Anne Dilley, Connie Miller, Christine Lee and the working party following 2 years of developmental work.  

ACTION STEP: The recommendations will be submitted to the Chair for proposal as a recommendation paper in JTH on behalf of the working party in collaboration with the vWF Subcommittee.  This goal should be completed within 3 months.  To comment, please contact:  Dr. Peter Kouides    peter.kouides@vianethealth.org

Dr. James Bussel discussed issues in ITP during pregnancy including inadequate data regarding minimal platelet numbers during normal pregnancy, and hemostatic levels of platelets for procedures during pregnancy, such as amniocentesis or epidural anaesthesia.  Further discussion of this issues will be conducted in conjunction with the perinatal and platelet subcommittees.  To contribute to this issue contact:  Dr. James Bussel    jbussel@med.cornell.edu

5. New Business

The creation of a standing subcommittee from the working party was discussed.  This concept was approved by the attendees of the meeting and a request will be forwarded to the SSC for consideration.