The working group will meet in the fall and spring and consists of M. Blombäck, I. Bokarew, C. Dempfle, K. Hoots, M. Levi, S. LaRosa, A. Schorer, F. Taylor, C.H. Toh, and H. Wada. The work of this group will be submitted for review by critical care physicians, clinical trialists, and hemostasis experts not on this committee during the preparation and rewriting of this draft proposal.

The first topic covered was overt DIC chaired by Dr. K. Hoots. In his opening remarks he emphasized that DIC was one of the manifestations of a dysfunctional reticuloendothelial/microvascular organ and that DIC was to this organ as azotemia was to the kidney or hypoxia was to the lung. He emphasized that there were at least two categories of DIC. The first is characterized by a simple override of the normal endothelial anticoagulant factors by foreign procoagulant factors such as occurs in transfusion reactions or envenumation. The second is characterized by an override combined with a degradation of regulatory factors such as occurs in sepsis, SIRS following trauma, etc.

Drs. Hoots and Blombäck then reviewed studies by Drs. Gando, Bredbeck and Gramander in which trauma and leukemia patients were evaluated for DIC using global coagulation tests and clinical criteria combined with evaluation of the underlying disorder using criteria developed for assessing sepsis, SIRS, MOF, ARDS, and head trauma. The DIC and criteria for underlying disorder correlated almost exactly supporting the hypothesis that disorder of the microvasculature/hemostatic systems as reflected by DIC scores were closely linked to and possibly contributed to initiation or amplification of the underlying disorder of the RES/microvascular organ. The contribution of molecular markers of endothelial injury (sTM) and thrombin cleavage of fibrinogen (sFM) to the global coagulation test data also was reviewed.

The second topic covered was non-overt DIC chaired by Dr. Toh. In his opening remarks he emphasized that definitions of useful criteria for diagnosing impending DIC or non-overt DIC was critical for patient care because it would provide the opportunity to intervene under more favorable circumstances. He stressed that though global coagulation tests (that were useful in evaluation of overt-DIC) were not as useful in diagnosing non-overt DIC, there still could be a place for them together with molecular markers. These comments were based on his analysis of prospective studies by Dr. Woda of 40 patients who progressed from non-overt to overt DIC. He also stressed the importance of keeping the laboratory aspects of the diagnosis of both overt and non-overt DIC as simple as possible because of cost and availability throughout the world. Finally, Dr. Toh introduced data concerning whole blood or plasma function in DIC as measured using thrombelastography, wave form analysis of whole blood and plasma, respectively. In contrast to the ELISA assay of molecular markers, the assessment of whole blood or plasma clotting in patients could be done almost immediately. The technology and understanding of abnormal wave forms or clotting signature of whole blood or plasma samples may advance to the point where they could be used.

Drs. Wada and Taylor reviewed primate models of E. coli sepsis and peritonitis. They observed a dose response of global coagulation markers and molecular markers. Special interest centered on soluble fibrin which in human and non-human primate studies exhibited a second very large peak 24-48 hours after sublethal E. coli or endotoxin respectively. This second peak coincided with a fall in Factor VIII and rise in tissue factor and was unexpected as these events occurred long after mediators had returned to normal and after complete clinical recovery. They emphasized that these late procoagulant events probably reflected an opening up or reperfusion of the microvascular beds 24 to 48 hours following the initial insult. sTM also remained elevated even though all clinical and global coagulation tests were normal. These observations were important, for they increased our understanding of the characteristics of non-overt DIC and the settings in which it occurs.

These findings led naturally to the observations of Drs. Bokarew and Dempfle on continuous low grade, non-overt DIC and soluble fibrin as a potential marker of these more subtle forms of DIC. Dr. Bokarew reviewed the history and offered data showing elevated concentrations of thrombin fibrin products in patients with hemophilia, arthritis, and coronary occlusion ischemia. Dr. Dempfle reviewed the chemistry of soluble fibrin and the challenge of validating and standardizing assays of soluble fibrin such that they could be used reliably.

The third and final topic covered was treatment of DIC chaired by Dr. Levi. In his opening remarks he emphasized how important an adequate, useable set of criteria for defining overt and especially non-overt DIC is to those conducting clinical trials. He reviewed studies done in primates using molecular markers which, if made available at the bedside, would aid in the selection of patients to be treated.

Drs. Kessler and LaRosa who have been conducting clinical trials of antithrombin and activated protein C (APC) reviewed their experiences. Dr. Kessler emphasized the need for infusion of antithrombin (AT) in concentrations sufficient to raise AT levels above normal. He spoke of AT anti-inflammatory properties. The response to AT therapy in studies remains to be fully evaluated. Dr. LaRosa emphasized the effect of APC on coagulant factor generation and activation in patients with sepsis. He spoke of treatment of patients with meningicoccal sepsis. Again, the response to APC therapy in ongoing trials remains to be fully evaluated. Both emphasized the need for updated, more sophisticated criteria for diagnosis of non-overt DIC.

The attendance was in excess of 300 people. There was adequate discussion opportunity the first session. What was of interest was that in spite of the session lasting the full four hours allotted, the audience remained at about 300 throughout the session.