Dr. M. Mosesson chaired the first portion of the meeting dealing with fibrin sealants as chair of the fibrinogen subcommittee. Drs. M. Blombäck and F. Taylor chaired the second portion of the meeting dealing with soluble fibrin assays as chairs of the DIC subcommittee. The subjects reported and discussed by this subcommittee were as follows:

1. Fibrinogen Subcommittee

   There was a wide ranging discussion concerning the characterization and rationale for standardization of fibrin sealants including present and past formulations, delivery devices, clinical applications. Discussants included Dr. D.L. Amrani (session moderator), Dr. U. Martinowitz, Dr. T. Seelich, Dr. M. Weinstein, Dr. M. MacPhee, Dr. M. Nowartarski. Approximately 120 persons were in attendance.

   There is currently a broad range of formulations for fibrin sealants, which vary greatly with respect to the concentration of fibrinogen, factor XIII concentration, fibronectin concentration, and the presence and amounts of a number of other plasma constituents and/or additives. Specific issues that were raised included 1) the need for high fibrinogen concentrations; 2) the need for standard assay of mechanical strength and standardization of in vitro methods for measuring fibrin sealants; 3) the role of factor XIII; 4) the inclusion of antifibrinolytics and other agents. There is no accepted or preferred basis for such formulation, or objective criteria by which preparations are measured.

   The discussants agreed by consensus that it would be valuable to develop a rationale and establish criteria for standardization and calibration of fibrin sealants. A working party was formed which will exchange written communications among interested participants and develop criteria for characterizing fibrin sealants as outlined above. Dr. Michael Mosesson will head up the working party. It is anticipated that information will be solicited and collected over the next six months, disseminated for consideration, and be ready for discussion at the next meeting of the SSC in 1998.

   Dr. F. Dati (Behring Diagnostics) reported on a study of criteria for establishing a High Concentration Fibrinogen Standard. Dr. Dati presented a detailed analysis of the need for a high fibrinogen standard, problems in the measurement of fibrinogen, and standardization of testing methods. He made specific recommendations for a high fibrinogen plasma standard. It is expected that Dr. Dati will submit a written summary of his report for further consideration by the Fibrinogen Subcommittee.

2. DIC Subcommittee

   1. Immediate, Practical Issues

      1. Definition of DIC

         In 1994-95, Drs. Müller Berghaus and Margareta Blombäck oversaw the development of a definition of DIC by the subcommittee: DIFF (DIC), Disseminated Intravascular Fibrin Formation, is an acquired process associated with disseminated soluble fibrin formation within the microvasculature.

      2. Assay of Soluble Fibrin Formation

         In 1996-97, Dr. Charles Francis enlisted the assistance of the DIC subcommittee and of Drs. F. Taylor and M. Blombäck in the development of a protocol for the assessment of the clinical relevance of assays of soluble fibrin using four different commercially available ELISA assay kits. A protocol was agreed upon which included collection of samples from patients with DIC (i.e., patients with culture positive sepsis or with specified trauma within 12 hours of injury) as well as from patients following myocardial infarction (Thrombo Study). During the first year (1996-97) of this two-year study, 12 members of the DIC subcommittee agreed to participate. Four members provided samples from 17 sepsis patients and Dr. Owenings provided samples from the 44 trauma patients. The results are summarized as follows:

         PERCENT OF RESULTS WHICH WERE ELEVATED (SOLUBLE FIBRIN)

         SOLUBLE FIBRIN ASSAY #	THROMBO (275-892)	TRAUMA (44)	SEPSIS (17)
         1	30	48	60
         2	21	95	75
         3	55	70	94
         4	90	73	81

         The biochemical/immunologic rationale explaining the differences between these four tests, although of importance, is secondary to simply collecting data on the overall incidence of elevated concentrations of soluble fibrin in these three arbitrarily defined clinical conditions. It was agreed with Dr. Francis that at least 20 additional sepsis DIC samples be provided by Drs. Blombäck and Bredbecka (Sweden), Bokarew (Russia), and Sakuragawa and Wada (Japan) as well as possible additional samples from Drs. Levi (Netherlands), Brenner (Israel) and Falanga (Italy).

      3. Assessment of Markers of Pre DIC

         The remainder of the meeting was taken up by presentations by Dr. Hoots concerning his experience with anti-thrombin concentrates in neurotrauma patients and by Dr. Wada concerning his experience with assays of the pre DIC state in patients who went on to develop DIC (114 leukemia, 126 non-leukemic patients). Dr. Wada observed that hemostatic markers such as PAP (PIC), TAT, D-dimer and soluble fibrin that were already elevated began a further significant rise two to three days before the onset of DIC. On the other hand, protein C, protein S, and tissue factor levels did not change. It was agreed that continued examinations of markers of increased but compensated hemostatic activity (pre DIC) might be as important as evaluation of a definitive marker of DIC or decompensated hemostatic activity such as soluble fibrin. In line with this, Dr. Ten Cate and Dr. Taylor suggested that a controlled study using primates (baboons) also be considered as a means of evaluating assays of soluble fibrin and enzyme/inhibitor complexes as markers of decompensated and compensated responses of the hemostatic system, respectively. Accordingly, Drs. Taylor, Wada, and Sakuragawa agreed to run assays for soluble fibrin and for enzyme/inhibitor complexes including PAP (PIC), TAT, APC/PCI, TFPI/Xa, and for Factor VIIa on blood of baboons infused with very low (102 CFU/kg), low (105 CFU/kg), medium (10-7 CFU/kg), and high (1010 CFU/kg) concentrations of E. coli. The question is whether the above markers are of value in discriminating between a stressed but compensated hemostatic system (pre DIC) and a stressed and decompensated system. In theory, enzyme/inhibitor complexes consisting of regulators and mediator components might appear under conditions where the hemostatic system is stressed but compensated before markers of DIC such as soluble fibrin, DD dimers, or FDP appear. These studies will be done this year.

   2. Less Immediate, Conceptual Issues

      Assuming these studies described above are informative, Dr. Bokarew raised the serious question of whether we can provide a picture or concept which could be used 1) to interpret these studies, and 2) to connect the various clinical conditions in which we will find evidence of DIC (soluble fibrin) with the molecular and cellular events unique to each condition which can be understood and used by the practicing physician. It was agreed among the chairs of the subcommittee to draft a preliminary report on this issue by the 1998 ISTH-SSC meeting in Slovenia. jwd/6/10/97

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