Control of Anticoagulation

7 August 2005
8:30 to 12:00
Ballroom 2
Sydney Convention and Exhibition Centre

Chairman:  S. Schulman, Sweden
Co-chairs:  M. Greaves, UK; J. Harenberg, Germany; C. Kearon, Canada; M. Laposata, USA; J. Olson, USA; G. Palareti, Italy; A.M.H.P. van den Besselaar, The Netherlands

As a novelty, it had been decided to conduct the first half of our meeting as a joint session with the Subcommittee on Perinatal and Pediatric Haemostasis, the reason being that representatives from each committee felt that there were many topics of common interest, that there are needs to learn from each other and that in case of separate sessions there is a difficulty to fit that into the itinerary. The joint session was designed to contain educational components as well as updates on subcommittee activities of potential mutual interest.

New anticoagulants for pediatric use; lessons from adults

Jeff Weitz gave an overview of the development of new anticoagulants over the past few years, with emphasis on the lessons learnt and possible implications for the pediatric population. He described the development of heparins towards lower molecular weight with problems regarding decreased clearance in case of renal impairment, lack of specific antidotes and long half-life. New, selective anticoagulant agents have usually rapid onset and offset, a wide therapeutic window and no or reduced need for monitoring, but pediatric data is lacking as well as specific antidotes. A comment from the audience was that argatroban and bivalirudin, both approved drugs, are in clinical trials in the pediatric population.

Recommendation: It is important to ensure that some of the new anticoagulants will fit the needs of the pediatric population, for example with parenteral (subcutaneous) administration, no need for monitoring, not contraindicated in case of hepatic failure etc.

Towards a unified definition of major hemorrhage in clinical trials.

I. Non-surgical studies

Report S. Schulman
The process from discussion at the previous SSC in Venice 2004 was recapitulated briefly. The recommendation was published as a full length paper in JTH in April 2005. The European regulatory authority, EMEA, has been contacted and expressed interest in possibly adopting the recommendation but preferred to have the complete set, including recommendations for orthopedic and general surgery studies. Informal contacts have also been taken with FDA, and there is a growing interest there for possible issues of harmonization.

Plan: Encourage the process for similar recommendations in surgical studies and to further develop the contacts with EMEA and FDA.

II. Surgical studies – orthopedic.

Update. G. Raskob
The Working Party on Bleeding Complications in Orthopedic Studies has identified a large variety of definitions used in their field by performing a systematic literature review. Traditional measures of severity of bleeding have limitations in the early postoperative period. There is a definite need to include the surgeon’s assessment of the surgical site bleeding.

Recommendations (preliminary): 1) There is a need for explicit reporting for the surgical site, which must be distinguished from other bleeding. 2) A blinded assessment should be done by a surgeon regarding the clinical importance of the bleeding at surgical site. 3) Bleeding index and clinically important bleeding should be reported independently as separate outcomes. 4) A clinically important bleeding at the surgical site if it leads to wound dehiscence, infection, re-operation, prolonged hospital stay or contributes to myocardial infarction, stroke or death, as assessed by an independent adjudication committee. The WP will accelerate their pace of development of the recommendations and will endeavor to get this published within the next 12 months.

III. Surgical studies – general.

Update . D. Bergqvist.
This issue is even more complicated than the orthopedic procedures, since the surgical procedures are less standardized in general surgery and the severity of the procedures vary greatly. Gynecologic procedures may differ a lot from other general surgery. The transfusion requirements are influenced by more or less conservative policies.

Recommendations (very preliminary): Major bleeding is tentatively defined as 1) leading to death, 2) leading to transfusions or endovascular hemostatic procedures, or 3) occurs in critical organs.

Plan : To form a working party within the next few months to continue the development of a unified definition.

The Use of Heparin in Children. P. Monagle

Unfractionated heparin (UFH) is the anticoagulation of choice in infants and children who are at high risk of bleeding (peri surgery, trauma, chemotherapy) because of ease of reversibility (protamine sulfate) and short half life. During cardiopulmonary bypass and extracorporeal membranous oxygenation, UFH is currently the anticoagulant agent of choice. However, infants and children do not respond to UFH in the same way as adults. The activated partial thromboplastin time (aPTT), a surrogate measure of UFH level, does not correlate to increasing levels of heparin in the same fashion as in adults. In fact, if comparing therapeutic anti factor Xa levels to corresponding aPTT levels, in infants and young children the therapeutic aPTT ranges are much high than those in older children and teenagers. This difference may relate in part to developmental haemostasis differences, but there may be other different mechanisms of interaction compared to adults.

Recommendations: The difference response to unfractionated heparin between adults and children will be determined. A subgroup lead by Dr Monagle will determine how best to monitor UFH in neonates and children. This will be submitted as a position paper to the SSC.

HIT in children A. Greinacher

The literature in adults with HIT was summarized. In neonates and children, heparin induced thrombocytopenia is rare (2.4% of those exposed). Most infants who develop antibodies have underlying cardiac disease. In children and teens, most who receive heparin have deep venous thrombosis. The testing for HIT in children has not been standardized and cut off values for abnormal must be established.

Recommendations: A standardized approach to the diagnosis of HIT in children must be established. Dr Greinacher will lead a subgroup to develop a diagnostic approach in children which will be submitted as an SSC position paper.

European Concerted Action on Anticoagulation: A multicentre calibration study of WHO International Reference Preparations for thromboplastin, rabbit (RBT/90) and human (rTF/95).

Recommendation: It is important to continue to monitor the stability of thromboplastins.

International collaborative study for calibration of two candidates international standard for thromboplastin, rabbit, plain.

Report. A. Tripodi and A.M.H.P. van den Besselaar
The rabbit brain thromboplastin RBT 90 has been depleted, unfortunately to the extent that nothing remained for calibration versus a successor. Instead, two other rabbit standards were made available for this study and they have in turn been calibrated against RBT 90. Two new candidates for the international standard for thromboplastin rabbit plain have been thoroughly evaluated regarding a) within laboratory precision of calibration, b) between laboratory precision of calibration, c) conformity with the WHO model and d) stability. Important results were, regarding
a) percent of calibrations with a Cv of the slope of <3%: 84% with 04/106 and 94% with 04/162. The distribution of ISI values were overall close to 1.2;
b, c) The overall Cv was 5% and the percent of calibrations with a deviation of normals from patients line: 14.3% with 04/106 and 11.1% with 04/162, which shows the adequacy of the model. Between laboratory precision, measured as Cv of the ISI was 5.0 for both candidates.
d) The stability of the candidates underwent accelerated testing at 45ºC for 3 months demonstrated a minor increase of the PT after storage, equal to what previously was reported for another reference material for thromboplastin, rabbit, plain. Candidate 04/162 was marginally better than 04/102.

The results of this study had been circulated to the co-chairmen (M. Greaves, UK; J. Harenberg, Germany; C. Kearon, Canada; M. Laposata, USA; J. Olson, USA; G. Palareti, Italy; A.M.H.P. van den Besselaar, The Netherlands) before this SSC meeting and the selection of the 04/162 candidate was approved, with the exception that one co-chair suggested that both candidates be approved.

Recommendation and decision: It was proposed to the subcommittee that 04/162 should be selected, and this was confirmed by show of hands with an overwhelming majority supporting this candidate. Thus, 04/162 will be recommended to WHO as the new standard for thromboplastin, rabbit, plain. An SSC communication in the JTH is expected within the next year.

Working Party on Thrombin Generation Test: Survey on current practices and in vitro study on suitability of a general method for the thrombin generation test.

Plan: An international study on fluorogenic methods for TGT will be carried out and invitation goes out in mid-September. Analysis is planned by the end of December with report to SSC 2006. A suggestion was made to compare samples that are microparticle-free by high speed centrifugation.

(A Boehringer-Ingelheim representative took at this point the opportunity to announce a lunch meeting not found in the program)

Validation of a thrombin generation test.

Thrombin generation as a test for all types of anticoagulants?

Report. H.C. Hemker, R. Al Dieri and S. Béguin
Heparins, direct thrombin inhibitors (DTIs), direct FVIIa and Xa inhibitors and vitamin K antagonists (VKA) were tested. Heparins, including pentasaccharides, affect all parameters of the Thrombogram. Hirudin prolongs particularly the lag-time due to decreased feed-back activation, but melagatran gives a different result. Direct FVIIa and Xa inhibitors affect all parameters. ETP and ETP-inhibition have lower variability to different heparins than to FVIIa and Xa inhibitors. VKA gives increased lag-time. Aspirin has a significant effect on mainly the lag-time (with PRP used in the system). Thus, all anticoagulants diminish the thrombin generation, as measured in this TGT. However, the influence on the test is not necessarily equal to the clinical effect and further investigations with each anticoagulant agent will be needed.

Overview of the NCCLS (CLSI) document: Procedures for Verification of INR and Local Calibration of PT/INR Systems.

Prothrombin-induced Clotting Time (PiCT) in the monitoring of low-molecular-weight heparins.

Standardization of methods to monitor fondaparinux.

Plan: Submission of manuscript for SSC approval in the near future. The next phase of this study is to receive ex-vivo plasmas form clinicians on patients treated with fondaparinux and if possible with direct Xa inhibitors and to compare in different anti-Xa tests such as PiCT, Heptest, chromogenic anti-Xa.

Monitoring of the direct thrombin inhibitors argatroban, angiomax and hirudin. Discordance between the anticoagulation and dosing.

Importance of quality control of vitamin K antagonist therapy during the initial period.

Recommendation: Efforts have to be made to improve the quality of anticoagulation, especially during the first 3 months of treatment, perhaps by more frequent monitoring and dose adjustments and/or bridging with LMWH.