Intensive Care Med (2017) 43:581–583DOI 10.1007/s00134-017-4725-0

EDITORIAL

What do sepsis-induced coagulation test result abnormalities mean to intensivists?Marcel Levi1* and Marcus J. Schultz2,3

© 2017 Springer-Verlag Berlin Heidelberg and ESICM

Sepsis is frequently associated with abnormal coagulation test results, with deviations ranging from delicate activa-tion of coagulation that can only be recognized by highly sensitive assays to stronger hemostatic activation like a fall in platelet count and elongations of global clotting assays and more outspoken manifestations of coagulation activation such as fulminant disseminated intravascular coagulation (DIC) [1].

The relevance of coagulopathy in sepsis is most clear in patients with overt DIC in whom severe hemorrhage, as a result of consumption and subsequent depletion of coagulation factors and platelets, may be the dominant presentation [2]. These patients may even develop overt thromboembolic complications or thrombo-hemorrhagic skin infarctions. However, a more common consequence of coagulation activation in sepsis is its contribution to multiple organ failure (MOF) as a result of microvascu-lar thrombosis. Postmortem findings in septic patients with DIC include the presence of microthrombi in small blood vessels and also thrombi in mid-size and larger arteries and veins [3]. Fibrin deposition in various organs is a characteristic finding in animal models of DIC, and experimental sepsis results in intra- and extravascular fibrin deposition in the kidneys, lungs, liver, brain, and other organs. Amelioration of the hemostatic defect by various interventions in these models reduces fibrin deposition, improves organ function and, in some cases, reduces mortality. Finally, DIC has shown to be an inde-pendent predictor of MOF and mortality [1]. Hence, the presence of coagulopathy or DIC, assessed by readily available routine laboratory tests or more comprehensive coagulometers, may be helpful to assess disease severity.

Observational studies have demonstrated the predictive value of changes in coagulation parameters for an adverse outcome in sepsis, which may be helpful to identify patients at increased risk for severe organ dysfunction and death and whom may benefit from more intensive treatment strate-gies. In a consecutive series of patients with severe sepsis the severity of coagulopathy was directly related to mortal-ity, and patients with DIC had 20% lower survival compared with those that had no DIC [4]. Other studies have con-firmed a 1.5-fold higher mortality in patients with sepsis and DIC compared with septic patients that have less severe coagulopathy. A large cohort study in more than 800 patients found that a diagnosis of DIC according to the international scoring system in addition to the Acute Physiology and Chronic Evaluation (APACHE) II score more precisely pre-dicted mortality than the APACHE II score alone [5].

Severe thrombocytopenia (less than 50  ×  109/L) in septic patients is an independent predictor of ICU mor-tality in multivariate analyses of large sepsis cohorts and increases the risk of death by 1.9- to 4.2-fold [6]. In par-ticular, thrombocytopenia that persists more than 4 days after ICU admission or a decrease of at least 50% in platelet count during ICU stay is associated with a four to sixfold increase in mortality. In fact, the platelet count appears to be a stronger predictor of ICU mortality than composite scoring systems, such as the APACHE II or Multiple Organ Dysfunction Score (MODS) [7].

A recent study indicates that an indicator as simple as D-dimer has similar predictive power for an adverse sepsis outcome. Mortality in patients with severe sepsis increased with increasing D-dimer levels and was 12.6-fold increased (crude OR, 95% CI 3–52; p =  0.001) in patients with a D-dimer level of 4 μg/mL or more [8].

In the last three decades the pathways involved in the coagulopathy of sepsis have for an important part been elucidated (Fig. 1) [1]. This insight has resulted in poten-tial targets to improve the outcome in sepsis. Activated

*Correspondence: marcel.levi@uclh.nhs.uk 1 Department of Medicine, University College London Hospitals, 250 Euston Road, London, UKFull author information is available at the end of the article

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protein C plays an important role in the pathogenesis of the coagulopathy and was extensively evaluated as an adjunctive treatment for sepsis in clinical studies. Although the drug had some effects on amelioration of coagulopathy and other downstream pathways, it was not effective for clinically relevant outcomes [3]. An alterna-tive target in the same pathway may be recombinant sol-uble thrombomodulin, which shows promising results. In the most recent phase IIb study in 750 patients with sepsis and disseminated intravascular coagulation 28-day mortality was 17.8% in the thrombomodulin group and 21.6% in the placebo group [9].

In addition, new findings have pointed toward platelet–vessel wall interaction as an interesting target in sepsis [10]. Platelet–vessel wall interaction is primarily medi-ated by von Willebrand factor (VWF). VWF is released as ultra-large multimers from endothelial cells, where-upon it is cleaved by ADAMTS13, also known as von Willebrand factor-cleaving protease. The prohemostatic properties of VWF are dependent on its multimeric size;

hence, ADAMTS13 activity is an important determinant in platelet–vessel wall interaction. Apart from classical ADAMTS13 deficiency in thrombotic thrombocyto-penic purpura, there are a growing number of conditions, including sepsis, in which ADAMTS13 levels have been found to be decreased resulting in reduced cleavage of VWF. Hence, restoration of VWF cleavage by pharmaco-logical modulation of ADAMTS13 levels is a potentially promising approach in sepsis.

Another example of a new target for adjunctive treat-ment in sepsis may be represented by microparticles. Microparticles are shed from endothelial and immune cells expressing coagulation proteins reflecting cellular injury during sepsis-induced disseminated intravascular coagulation and may shuttle these procoagulant factors from cell to cell. A recent study showed a strong correla-tion between presence of microparticles and sepsis [11].

Lastly, in an article recently published in Intensive Care Medicine, Davies et al. show that in various stages of sep-sis, clot microstructure (i.e., mechanical clot strength

Fig. 1 Schematic representation of the most important pathways in the coagulopathy of sepsis. PAR protease-activated receptors

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and elasticity) shows differential features [12]. In the early phase of sepsis there was a remarkable increase in clot strength and elasticity, indicating a prohemostatic environment and reduced fibrinolysis, whereas in more advanced stages clot strength decreased, potentially because of hyperfibrinolysis and loss of coagulation fac-tors. This approach to studying clot formation and deg-radation in sepsis is original and may explain why some studies demonstrate impairment of endogenous fibrinol-ysis as an important feature of the coagulopathy of sepsis, whereas others feel that hyperfibrinolysis is a crucial fea-ture of this condition [1]. It may well be that these differ-ent results are due to the fact that samples were collected in various stages of sepsis development. An obvious question is whether this new technique will be helpful in the diagnostic and therapeutic management of patients with sepsis and coagulation abnormalities. Although rou-tine coagulation tests are relatively blind for clot strength and elasticity, it cannot automatically be concluded that measuring these properties will improve the diagnostic accuracy or guide better adjunctive treatment strategies. In fact, alternative whole clot viscoelastic tests that are increasingly available have so far not been validated in prohemostatic settings such as sepsis and have not been shown to be helpful to improve clinical management [13, 14]. Hence, the real value of the present observations relies on a better understanding of factors leading to thrombotic microvascular obstruction in sepsis. Under-standing these differential properties of thrombi formed during the various stages of sepsis may potentially better target adjunctive treatments to the right patients.

In conclusion, monitoring and understanding coagu-lopathy in patients with sepsis may be helpful to get an impression of the severity of sepsis and may predict adverse outcome and select patients for more intensive treatment strategies. In addition, new insights into the coagulopathy of sepsis may contribute to the develop-ment of better adjunctive management strategies.

Author details1 Department of Medicine, University College London Hospitals, 250 Euston Road, London, UK. 2 Department of Intensive Care Medicine, Academic Medi-cal Center, University of Amsterdam, Amsterdam, The Netherlands. 3 Labora-tory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Received: 2 February 2017 Accepted: 11 February 2017Published online: 20 February 2017

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