WORKING PARTY ON DURATION OF ANTICOAGULANT THERAPY IN VENOUS THROMBOSIS
S. SCHULMAN and C. KEARON, Chairmen

L.PINEDE
Three months vs. 6 months for first DVT (DOTAVK Study)

A report was presented on a study published in the May issue of Circulation. This was an open label, randomized, controlled trial of duration of anticoagulation for objectively confirmed first VTE. Calf DVT subjects were randomised to 6 and 12 weeks of warfarin and proximal DVT/PE to 3 vs 6 months. Enrollment ceased after patient 736, 539 patients were included with proximal DVT/PE. In this group the recurrence rate was similar in the two arms at around 8%. Serious bleeding occurred in around 2% in each arm. Higher recurrence rates were noted in those with idiopathic events than temporary risk factors. It was concluded that for proximal DVT/PE there was no advantage of 6 months of OAC over 3 months.

G. RASKOB
Oklahoma Optional Duration Studies

These studies report that patients with a first episode of idiopathic DVT have an annual recurrence rate of around 12% per year for years 1-3 after stopping OAC at 6 months. Extended treatment is effective but the annual risk of major bleeding during years 1, 2 and 3 was around 6%, 2%, and 0%, respectively, offsetting at least some of the benefit. It was concluded that indefinite treatment may be of benefit for those patients at low risk of bleeding who prefer to continue therapy.

C. KEARON
Recurrence rate after 27 months of OAC therapy.

A follow-up to the study published in the New England Journal of Medicine was reported. 3 months of OAC was compared with 27 months after first episode of proximal DVT. Extended follow-up of those treated for 27 months (n=116) and untreated for 10 months was reported. Recurrence occurred in 13%, this being lower than in the cohort stopped after 3 months. (It is noted that the recurrence rate was unusually high in that group, however.) It is concluded that long-term treatment after a first idiopathic event is an option, but the significant risk of bleeding must be considered.

G. AGNELLI
WODIT DVT and WODIT PE studies.

In the DVT study, the initial advantage of 12 over 3 months of OAC treatment was lost eventually as the recurrence rate caught up in the longer treatment arm. In PE there was no difference in recurrence rates between those treated for 6 and 12 months (around 7% in each arm). A lower recurrence rate was again noted in those with temporary risk factors.

Dr. Kearon summed up the results of studies to date. Although OAC therapy is very effective at preventing recurrence, there is an average 10% per annum recurrence rate after discontinuation, regardless of the duration of therapy (3 months treatment in his own study giving an unusually high recurrence rate compared with 3 other studies). It was concluded that the minimum duration of therapy to achieve the lowest recurrence rate is 6 and possibly 3 months. This lowest achievable rate of recurrence may be as high as 10% per year.

During discussion the question of use of less intense anticoagulation for longer periods was raised. Dr Kearon reported that a study of target INR of 1.75 vs. 2.5 had just completed enrollment.

The Chairman congratulated the speakers on their excellent efforts to provide an evidence base for the management of venous thromboembolism.

WORKING PARTY ON NEAR-PATIENT TESTING AND SELF-MANAGEMENT OF ORAL ANTICOAGULANT CONTROL
F.E. PRESTON, Chairman

S. KITCHEN
Proficiency testing of near-patient devices.

It was reported that although there is a spread of INR results in QA exercises in near-patient testing, this spread is no broader than that in hospital laboratories. Some outlying results are due to inappropriately handled QC materials. It was demonstrated that improved performance could be achieved in centres by continuing enrollment in external QA exercises. Results of health care providers improved with time, as did those of patients using self-management.

It was concluded that external assessment of near-patient testing is achievable and that appropriate EQA materials equivalent to whole blood can be developed for use with near-patient devices.

J. ANSELL
Clinical Trials.

Results of 13 clinical trials of PST/PSM (Patient Self Testing/ Self Management) were reviewed. In each case outcome was at least equivalent to comparator (usually a hospital-based clinic). Time in therapeutic range averages 77% in PSM studies compared with 72% in the anticoagulant clinic and 50% in unstructured anticoagulant management.

It was hypothesized that the improved outcomes with PST/PSM are due to increased access to and more frequent testing as well as improved consistency (use of the same equipment for each test) and better understanding and empowerment of the patient in their own care.

Barriers to adoption of PST/PSM were considered to be lack of physician awareness, unfounded concerns regarding safety and efficacy, lack of training opportunities and funding difficulties.

M. SPANNAGL
Update on ISO TC212

The properties of ISOs were described and a report given of a meeting held in Dublin earlier this year. Common issues between self-testing for blood glucose and INR were identified, including performance, validation, QA and training issues.

H. JOIST
NCCLS Update

An update of the programme of the NCCLS (National Commission on Clinical Laboratory Standards) on both heparin and warfarin monitoring was presented.

WORKING PARTY ON CALIBRATED PLASMAS FOR INR DETERMINATION
T. BARROWCLIFFE, Chairman

It was reported that the guideline is close to completion. There was a continuing debate over use of linear or orthogonal regression for setting of calibration curves. The chairman reported that statistical expert advice had been solicited but no consensus had been achieved. A meeting of the working party will be scheduled during the ISTH 2001 meeting in order to resolve this issue. Progress is essential here.

WORKING PARTY ON LABORATORY MONITORING OF LOW MOLECULAR WEIGHT HEPARIN
M. GREAVES Chairman

H.C. HEMKER
The ETP Test as a global method for anticoagulant control.

The extensive laboratory validation of this approach was reviewed. It was emphasised that all antithrombotics tested influence the ETP. The relationships between APTT and ETP during heparin therapy and INR and ETP on warfarin were illustrated. Professor Hemker highlighted the technical simplicity of this approach as well as its sensitivity to all antithrombotics and to mixed treatments.

J. FAREED
Monitoring of high dose LMWH heparin and newer agents.

New data on monitoring of the anticoagulant effect of high doses of LMWH, such as those used in unstable coronary syndromes, were reported. It was concluded that there are clear limitations of anti óXa assays and that the ACT correlates with anticoagulant efficacy and bleeding. It was also suggested that the global anticoagulant effect can be assessed using a standardised APTT method.

J. HARENBERG
Relationships between anticoagulant effect and Marder score.

It was reported that, in two studies, the anti-Xa level by chromogenic assay was higher in those subjects treated with LMWH in whom the Marder score improved, compared with the level in those with no improvement in Marder score. The D-Dimer level was also lower at day 12 in those with improved Marder score. Use of UFH was associated with comparable D-Dimer results but not anti-Xa results. These data are important as they are one of the few reports of a relationship between anticoagulant efficacy of LMWH and anti-Xa level.

P. MASSICOTTE
Status of paediatric guidelines

The special considerations in relation to anticoagulant therapy in infants and children were emphasised. The higher doses needed in infants of less than 3 months of age than older children were noted. The presenter favoured the use of anti-Xa assay for monitoring of LMWH dosage in paediatric practice but acknowledged the need for the performance of randomised trials to assess the safety and efficacy in relation to anti-Xa level.

In relation to UFH use, it was reported that over 70% of APTT values do not match with anti-Xa levels. A plea was made for clinical studies of standard doses of UFH compared with lower doses in paediatrics as there is a perception of an unacceptably high rate of bleeding using standard doses.

M. GREAVES
Status of adult guidelines.

It was confirmed that these had reached an advanced stage and the principal contributors had agreed on the content. The limitations of anti-Xa assay in the assessment of antithrombotic efficacy and bleeding risk in treatment with LMWH had been conceded. These limitations relate largely to the role of other mechanisms in the antithrombotic effect, variation between heparin preparations, the poor standardisation of assays and calibration issues. The chairman confirmed that the final version should be approved imminently. He also urged caution in relation to promoting the routine use of anti-Xa assays in any situation of monitoring of LMWH and suggested that the major limitations of this approach to monitoring be borne in mind.

ORAL ANTICOAGULANT MONITORING
7^th July, 08:00-13:00
A.H.M.P. van den BESSELAAR & L. POLLER, Chairmen

A.H.M.P. van den BESSELAAR
A method for citrated plasma samples on CoaguChek and TAS whole blood PT monitors

Calibration of 3 near patient PT devices for whole blood according to WHO ISI procedures is not practicable because it would require parallel samples of blood and citrated plasma from a large number of subjects. A new procedure is required, therefore. Plasma would be preferable but it must be demonstrated that plasma recalcified with a suitable concentration of calcium chloride gives satisfactory results. A study was conducted to show this. Mean plasma PT was higher than mean whole blood PT for all calcium concentrations tested. Further work is needed in deriving a procedure which will allow ISI calibration of individual instruments and permit expression of results as INR.

A. TRIPODI
A method for determination of ISI of 2 whole blood PT monitors using citrated plasmas.

Calibrant plasmas have been developed by the ECAA, but it is important to validate these for PT monitors which use whole blood. In 3 centres whole blood and plasma were used to calibrate using three home PT monitors: CoaguChek Mini test strip, CoaguChek Low ISI test strip and TAS PT-NC test cartridge. CV of slopes and test lines were <5%. ISI on plasma were less than those on blood but there was reasonable comparability with two of the three systems. A further study is in progress to investigate the greater difference with the TAS system.

M. KEOWN
An assessment of PT and INR variability of CoaguChek Home and TAS Near-patient testing PT monitors.

A QA study of 28 instruments of two different manufacturers (Brands A and B) was performed. The same operator and samples were employed. The samples were 2 pooled coumarin plasmas, 3 lyophilised depleted plasmas and blood and plasma from 3 normal adults. The results demonstrated problems of instrument variability, largely due to duplication problems with both brands of monitor, giving cause for concern in terms of patient care and oral anticoagulant dosage.

L. POLLER
The European Concerted Action on Anticoagulation (ECAA) Computerized Dosage Clinical End Point Study

The ECAA performed a randomized prospective study of dosage using Dawn AC to compare the results of computer dosage with those of experienced medical staff at 5 centres. With all INR ranges over the whole period the time in range was 72% for computer and 59% for medical staff dosing.

Professor Poller reported on a clinical end-point study being conducted at over 40 European centres. Dawn AC and Parma 4 are to be employed. Target recruitment over the 4 year period after induction will be 16,000 patients.

J. HARENBERG
Preliminary results on a quality of life questionnaire.

A non-randomised study of patients using self-testing and INR control who had been on OAC for 5 to 6 years at enrolment demonstrated that there was improved independence, organisation of vacation time, self-assurance and plans and prospects.

0RAL ANTICOAGULANT REVERSAL
FE. PRESTON, Chairman

M. MAKRIS
Use of factor concentrates and FFP

The relative merits of use of FFP and factor concentrate to reverse of the effect of OAC in subjects with life-threatening bleeding were discussed. In those with INR >5 the factor IX concentration is generally < 10%. In serious bleeding it is necessary to correct this to normal levels. This would require 3000 mls of FFP in a 70 kg individual. This dose is difficult to administer and cannot be delivered rapidly. It is concluded that factor concentrate (II, IX, X, {VII}) must be administered, along with vitamin K, for anticoagulant reversal in life-threatening bleeding. Centres responsible for the management of OAC therapy should have appropriate material available. Although there is a risk of thrombosis associated with use of these products, in the situation of life-threatening bleeding this is more than balanced by efficacy. Dr. Makris suggested that a reporting system for thrombotic complications should be established.

H.G. WATSON & M. CROWTHER
Oral and intravenous vitamin K

Dr. Watson reported on a 3 centre non-randomised study of intravenous versus oral vitamin K for OAC reversal in non-life threatening situations. In 64 subjects with INR above the therapeutic range there was clear evidence for more rapid reversal in those given intravenous vitamin K. Factor levels and INR showed a significant response after 4 hours with IV but not oral vitamin K. There was also some evidence for differences in responses to various oral formulations. It was concluded that vitamin K should be administered intravenously when reliable and rapid response is required.

Dr. Crowther reported on a study in which 114 subjects with INR >6 were followed for 2 weeks without intervention. 11 sought attention for bleeding and there were 5 major bleeds with 2 fatalities (Arch. Int. Med. 160:1612, 2000). The OVVAL I study was also reported. In 92 subjects with INR 4.5-10 given 1mg Vitamin K or placebo orally, the INR was 1.8-3.2 in 56% and 20% on the following day, respectively. Finally, preliminary data on subcutaneous administration of vitamin K were presented. In 51 subjects, by the next day the proportions in therapeutic range were 58% versus 24% for oral. These data suggest that the subcutaneous route is less efficient.

WORKING PARTY ON STANDISATION OF METHODS TO DETERMINE DIRECT THROMBIN INHIBITORS.
J. HARENBERG, Chairman

E. GRAY
Analysis of data from the thrombin inhibitor study

A preliminary analysis was presented. Seven methods were examined on 4 sets of plasmas. Sensitivity and robustness of methods were examined. Using most methods clotting times differed between the same concentrations of hirudin and argatroban. A more detailed analysis will follow.

J. WALENGA
Developments in the monitoring of direct thrombin inhibitors

Results of detailed studies were presented. It was concluded that the APTT is not reliable for monitoring of all thrombin inhibitors due to variable sensitivity. New methods, such as ECT and celite ECT are being developed but individual calibration curves are required. Also, drug interactions between thrombin inhibitors and other antithrombotics occur and should be measurable by the assay used for monitoring.

REPORTS ON WHO WORKING GROUP ACTIVITIES ON UNFRACTIONATED HEPARIN AND LOW MOLECULAR WEIGHT HEPARIN.
T. BARROWCLIFFE, Chairman

E. GRAY
A pilot study of comparability of LMWHs

8 LMWH are now licensed, with anti Xa:anti IIa of 1.5-10. A report was given on the relationships between these LMWH and UFH and a search for candidates for a new LMWH standard. 10 coded samples, including the first IS for LMWH and the 5^th IS for UFH, were distributed to 9 laboratories. Each laboratory performed 4 independent assays. The 2 standards generally assayed well against each other but there was wide inter-laboratory variability. Four of the 8 LMWH were identified as potential standards to replace the 1^st LMWH standard. It was concluded that UFH should not be used as a calibrator for anti-IIa/Xa activities of LMWH due to non-parallelism and poor reproducibility.

A. PADILLA
Anti-IIa chromogenic assay protocol and assessment

An outline protocol was presented

HEPARIN-INDUCED THROMBOCYTOPENIA
H. BOUNAMEAUX, Chairman

S. AHMAD
Endogenous factors contributing to generation of heparin-PF4 antibodies

Some clinical observations were reported. It was noted that IgG antibodies, rather than other species, were associated with thrombosis. A high rate of anti-PF4 antibodies in knee surgery patients was noted, possibly due to activation by thrombin generation. The possible role of various inflammatory markers in HITT was reviewed.

B. CHONG
Report on a survey on testing for HIT & Essential criteria for diagnosis

Dr. Chong indicated the need for standardisation in view of the wide range of assays in use. He presented results of a survey of the tests used by 42 expert laboratories and 23 routine laboratories. The laboratories were asked to investigate 6 sera (2 neg, 2 weak and 2 strong positives) by their usual methods. Expert laboratories were correct in 86-90% of cases. Many routine laboratories failed to detect weak positive antibodies.

In expert laboratories both ELISA and functional assays were used. ELISA performed well, but 1 gave some false positives. Aggregation tests performed well when selected donors were used, but not random donors. Overall ELISA and functional assays had equal specificity, but the ELISA was a little more sensitive. In the routine laboratories ELISA results were good but aggregation tests were unreliable and insensitive.

Dr. Chong also discussed criteria for diagnosis of HITT and proposed a new scoring system which included both clinical and laboratory parameters. This provoked considerable discussion and should form the basis for standardization of diagnosis.