Clinical implications and future perspectives

Research in the field of coagulation disorders in severe sepsis has come to the end of an era. Recent years have clearly demonstrated that coagulation is not a separate

‘island’ among the other systems, and a close interaction between inflammatory

cellular dysfunction are beyond the scope of this thesis, several confluences with coagulation disturbance should be mentioned.

Taking into account the multifactorial nature and extreme complexity of severe sepsis, it is hardly surprising that large multi-centre trials investigating the usability and treatment effect of recombinant anticoagulants AT, aPC and TFPI failed to show any benefit in reducing mortality in a heterogeneous patient groups with severe sepsis syndrome.^309,22,160 Interestingly, later subgroup analyses have demonstrated that in more precisely defined subgroups, mostly those with disturbed coagulation and high risk of mortality, the treatments may have proven efficient.^58,59 According to a recent consensus recommendation of ISTH, none of the treatments despite routine thromboprophylaxis have been strongly recommended.⁸⁹ A large phase III trial on the effect of recombinant human soluble thrombomodulin in patients with severe sepsis-related DIC is ongoing. Also, promising results from a meta-analysis combining the data from all clinical studies on thrombomodulin encourage the continued development of treatments that simultaneously target both coagulation and inflammation.^310,311

Despite the lack of globally accepted and registered treatment for DIC at the moment, it is, however, even more important to learn to recognize patients with developing coagulation disorders early, so that these patients can be selected for future studies from a large, heterogeneous population of severe sepsis patients.

Although development of multiple organ failure, with a great certainty, is multifactorial in origin, coagulation is shown to be one strong contributor. Therefore, one could speculate that those patients with developing organ dysfunction with coagulation disorder may benefit from new ‘tailor-made’ therapies most.

Use of any score (ISTH, JMHW, JAAM)^7,87,88 for diagnosing DIC is an obvious improvement as compared with older times, when DIC was defined purely on the basis of well-known alterations in coagulation tests and clinical picture. In the future, however, the scientific community should pursue one globally accepted score for DIC instead of several local scoring systems. This study showed that ISTH score for overt DIC with local modification found those patients with higher morbidity and 28-day mortality. Fibrinogen had no value in DIC diagnosis in our patients, although in some other patient group it may have had more importance. Implication of AT either in the score or as a separate indicator of DIC is challenging, as its availability may be limited.

Since the original suggestion in 2001, Scientific and Standardization Committee has strongly encouraged the evaluation of new diagnostic tools, preferably based on easily accessible point-of-care methods. This study showed that TEM has a potential in the early and definite diagnosis of overt DIC. However, before introducing TEM in clinical practice in assessing degree of coagulopathy in patients with severe sepsis, several shortcomings must be addressed. Most importantly, results from two commercial assays using different methodologies and reagents

require validation regarding critically ill patients’ risk of bleeding and thrombosis. An intriguing perspective is that one could use TEM as a tool for assessing the need for transfusions and/or more efficient antithrombotic prophylaxis patient-wise. Instead of being an all-encompassing method for predicting outcome of large heterogeneous patient groups, TEM should be studied is better-restricted sub-groups, in which its advantages could be better achievable.

Neither traditional coagulation assays nor TEM/TEG respond sufficiently to the question of whether platelets function normally. For example, impaired platelet function measured by impedance aggregometry is associated with poor prognosis in severe sepsis.³¹² Platelet function in disseminated intravascular coagulation requires further research, as only a few studies have addressed this question.¹¹⁰

This study provided new data on MMP-8 and TIMP-1 levels in severe sepsis-associated DIC. Whether these changes are dependent on only disease severity or inflammatory factors or whether they have a real role in coagulation remain to be investigated in larger studies. Especially TIMP-1 is interesting. It seems to have an independent role in inflammatory states, however it is unknown whether these changes are compensatory or detrimental per se. Unpublished findings on the power of TIMP-1 in the diagnosis of DIC demand further studies. Also, due to uncertainty of comparability of plasma and serum-based studies, these findings concerning a role of TIMP-1 in DIC must be confirmed and validated with plasma samples in other patient populations and geographical areas.

Pathophysiology of the development of organ dysfunction and failure in severe sepsis is at least as challenging as the multiple cellular interactions in severe sepsis, in general. This study provided new information on circulating nuclear proteins and their association with thrombocytopenia and organ dysfunction, with special reference to AKI defined by new KDIGO criteria. Release of nuclear proteins has been suggested as a major contributor of organ dysfunction and failure in sepsis, although these findings are mainly based on experimental data. In humans, data on local effects of nuclear proteins on development of organ dysfunction are lacking.

Targeting both histones and HMGB1 with inhibitors in animal studies has proved very effective in preventing organ dysfunction.^313-317 These findings provide interesting future perspectives in developing new strategies in treatment of severe sepsis in humans. Especially being ‘late-mediators’ widens the time frame for treatment from the earliest moments of the disease to the later phases.

Critically ill patients form a heterogeneous group with several disease entities, different backgrounds and prior health states. Unique features of different subgroups of ICU patients prone to coagulation disturbances warrant further investigations.

One very interesting subgroup with high frequency of coagulation abnormalities, often quite profuse need for blood products, severely disturbed permeability, and organ dysfunction, is patients with severe burn injuries. In these patients, interactions between coagulation and organ dysfunction are particularly poorly known.

coagulation disorder are needed. The diagnostic repertoire of DIC can be significantly extended, as several recently studied markers have been properly validated.