Current Tasks:

The Chairman welcomed the participants and outlined the Programme. On this occasion the Subcommittee has been allocated two complete sessions. A report was received from the Working Party on the Preparation and Use of Calibration Plasmas for INR Determination (T. Barrowcliffe, Chair) and recommendations from the Working Party on LMW Heparin Monitoring (A. Giles, Chair). Reports were also received from E. Gray and A. Tripodi on Unfractionated Heparin Replacement of WHO International Standard and WHO/oral anticoagulation respectively.

Report from Working Party on Preparation and Use of Calibration Plasmas for INR Determination (T. Barrowcliffe, Chair)

Dr. van den Besselaar presented results of a collaborative study on INR calibrated plasmas. The purpose of the study was to evaluate different types of lyophilized plasmas for local calibration. Significant INR differences were demonstrated for the lyophilized plasmas between the prothrombin time systems. The differences were relatively small for the deep-frozen coumarin plasmas and three lyophilized coumarin plasmas from one manufacturer.

Professor Poller summarized 1998 results from the European Concerted Action on Anticoagulation (ECAA). He stressed the following important points:

In thromboplastin calibration, artificially depleted and fresh coumarin plasmas give reasonable differences from conventional plasmas but these are acceptable in clinical terms.

Although a minimum of 20 abnormal plasmas are ideally required for ISI calibration it may be possible to achieve this with ten.

Fresh plasmas give reliable ISIs when calibrating human and rabbit reference reagents across species, but freeze-dried plasmas needed to be certified in terms of a similar species reagent.

INR correction by local ISI assignment appears successful with the ECAA human reagent but not with the rabbit reagent.

Dr. Houbouyan reported that substantial improvement of interlaboratory variability of INR determination could be achieved by the use of plasma calibrants. She demonstrated that at least three calibrants are required to cover the therapeutic range and that in respect of unproved interlaboratory variability AVK calibrants were superior to ART (artificially depleted) calibrants.

Dr. Taberner reported on the preparation and practical use of calibrated plasmas. He particularly highlighted the practical difficulties of preparing calibrants and discussed different methods of analysis.

Dr. Johnston reported the results of a local calibration exercise using Immuno reagents and Thromborel S. She reported apparent lot to lot variability of the calibrants and she expressed the view that international validated reference plasmas were required for calibration.

Dr. Yetsuka presented results from Japan of a comparison of manual and instrument-derived INR results using NIBSC control plasma. The study confirmed recognized problems associated with instrument use.

Dr. Fischer (Organon Teknika) presented the company strategy in respect of calibration plasmas for INR determinations.

Dr. Jaklitsch and Dr. Lang (Immuno) presented the results of a study in which target values of AK calibrants were compared with those of European Reference Plasmas.

Dr. Barrowcliffe summarized the good progress made in this area and concluded by indicating that the group will continue to work together toward developing draft guidelines in respect of the preparation and use of calibrated plasmas for consideration by the Subcommittee.

Dr. Mackie reported that lupus anticoagulants have no effect on INR determination if low instrument-specific ISI thromboplastins are used. A minority of patients may have potent antiprothrombin antibodies and prolonged prothrombin times.

Dr. Moll presented data to support his view that lupus anticoagulants can influence the PT and lead to INR values in warfarinized patients that do not reflect the true level of anticoagulation.

Dr. Houbouyan presented results of a French study designed to address the influence of the lupus anticoagulant in INR determination. She concluded that the use of calibrants reduces and abolishes the LA effect on INR.

Prof. Tripodi presented details of a current collaborative study designed to investigate the influence of LA on INR determination.

Prof. Machin (Co-Chair, Lupus Anticoagulant Subcommittee) suggested a joint exercise involving this Subcommittee and the Lupus Anticoagulant Subcommittee to explore further the clinical impact of LA on INR determinations.

Dr. Gray reported on the Collaborative study to establish the 5th International Standard for Unfractionated Heparin. Twenty-four laboratories from 14 countries participated. Materials included two candidates, the 4th IS, the USP reference standard and the EP reference standard. After WHO consultation on June 17-18, 1998, it was agreed that sample A, 97/578 will be proposed to the SSC of the ISTH and the ECBS of WHO as the 5th International Standard for UFH.

Prof. Tripodi provided a detailed account of the long standing collaboration between the SSC of the ISTH and WHO. He reviewed the situation of currently available WHO International Standards for thromboplastin and summarized the main issues discussed in the WHO Guidelines.

Dr. van den Besselaar described the effect of sodium citrate concentration and collection systems on prothrombin time and INR determinations. He reiterated the WHO recommendation for 109 mmol sodium citrate concentration.

From the ensuing discussion it became clear that this recommendation is not always adopted and Prof. Tripodi recommended that the Subcommittee prepare a recommendation in respect of this.

Prof. Fareed described the pathophysiology of heparin induced thrombocytopenia and reviewed the methods of detection. He gave a detailed account of thrombin inhibitor monitoring.

Dr. Massicotte presented a report on behalf of Dr. Andrews on LMW Heparin monitory in lldsen. She stressed critical pediatric issues which included weight, age, dependency of pharmacokinetics and the necessity of monitoring during long term therapy. Detailed information is available for two LMWHs. Monitoring should be undertaken with anti Xa assays 4-6 hours after a subcutaneous dose. If unexplained thrombocytopenia occurs HIT should be considered. Two relevant international clinical studies are underway and should help clarify the issue of LMW heparin monitoring.

Prof. Samama considered LMW heparin monitoring in adults. He discussed the clinical indication for treatment with LMWH and stressed that dose responses were unreliable in obese patients, in the elderly, and in those with impaired renal function. He indicated that monitoring with anti Xa could be of value in these categories of individual and possibly in those at high risk of bleeding or postoperative thrombosis. Additional monitoring should be considered in pregnant women receiving long-term LMW heparin. Platelet count monitoring is strongly recommended.

Prof. Giles concluded by indicating the despite limited available information the Group will continue to work together towards developing draft guidelines in respect of recommendations relating to LMW heparin monitoring in children and adults.

 S. Kitchen reported clinically important differences in anti Xa results obtained with different assay systems on samples from patients receiving LMW heparin.

L. Mitchell reported results of an in vitro study which showed that conventional chromogenic heparin assays are influenced by the patient's plasma AT level.

Dr. Kovacs described a series of studies of LMW heparin monitoring. He concluded that present methods of monitoring are inadequate in that there is poor comparability between different assay systems.

Prof. Harenberg discussed therapeutic ranges for new anticoagulants. He considered the use of heptest for LMW heparin monitoring and the ecarin clotting time for hirudin/PEG-hirudin.

Prof. Jespersen reported an ECAA multicentre randomized study on computerized anticoagulant dosage. Results using the DAWN system were presented. The computer dosage programme gave significantly better INR control than that obtained by clinical staff.

Dr. Palareti discussed factors which influence the risk of bleeding in oral anticoagulated patients. He emphasized differences in published definitions of bleeding classifications and suggested that the Subcommittee should provide recommendations in respect of this. He further indicated a need for guidelines in reversal of oral anticoagulant therapy.

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