Prediction of survival in patients suspected of ... - Wiley Online Library

ORIGINAL ARTICLE

Prediction of survival in patients suspected of disseminated intravascular coagulation E. Hjorleifsson1, M. I. Sigurdsson2,3, B. R. Gudmundsdottir4, G. H. Sigurdsson1,2 and P. T. Onundarson1,4 1

University of Iceland School of Health Sciences, Landspitali National University Hospital, Reykjavik, Iceland Department of Anaesthesiology and Intensive Care Medicine, Landspitali National University Hospital, Reykjavik, Iceland 3 Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA, USA 4 Central Laboratory, Division of Laboratory Hematology and Coagulation Disorders, Landspitali National University Hospital, Reykjavik, Iceland 2

Correspondence G. H. Sigurdsson, Department of Anaesthesiology and Intensive Care Medicine, Landspitali National University Hospital, Reykjavik, Iceland E-mail: [email protected] Conflicts of interest The authors declare that they have no conflict of interest. Funding This work was supported by a grant A-2014030 from the Landspitali National University Hospital Science Fund. Submitted 10 March 2015; accepted 15 March 2015; submission 19 January 2015. Citation Hjorleifsson E, Sigurdsson MI, Gudmundsdottir BR, Sigurdsson GH, Onundarson PT. Prediction of survival in patients suspected of disseminated intravascular coagulation. Acta Anaesthesiologica Scandinavica 2015 doi: 10.1111/aas.12537

Background: Although antithrombin (AT), protein C (PC), and antiplasmin (AP) are consumed during disseminated intravascular coagulation (DIC), their association with mortality in patients initially suspected of acute DIC is unknown. We examined how these proteins associate with mortality in consecutive patients initially suspected of DIC, fulfilling or not fulfilling overt DIC criteria. Methods: All consecutive patients clinically suspected of acute DIC during 5 years at a tertiary referral hospital were scored according to overt International Society of Thrombosis and Haemostasis (ISTH) DIC criteria. The influence of ISTH DIC score and measurements of AT, PC, and AP measured in all on mortality was assessed. Results: During 1825 occurrences in 1814 patients, 91 fulfilled ISTH criteria for overt DIC (score ≥ 5). Both 28-day and 1-year mortality increased progressively as AT and in particular PC decreased. AT and PC correlated inversely with ISTH score (AT: R2 = 0.14, P < 0.001, PC: R2 = 0.21, P < 0.001). AP decreased when ISTH score of > 3 was reached. The 28-day mortality was 3%, 11%, 16%, 23%, 35%, and 52% and 1-year mortality 5%, 18%, 24%, 36%, 54%, and 63%, respectively for patients with an ISTH score of 0, 1, 2, 3, 4, and ≥5 (P < 0.001 for all). Conclusions: Lowered AT and in particular PC activity was predictive of mortality risk upfront in critically ill patients suspected of acute DIC. Mortality in patients suspected of acute DIC increased progressively across the spectrum of the overt ISTH score and not only in those fulfilling overt DIC criteria.

Editorial comment: what this article tells us

In patients clinically suspected of disseminated intravascular coagulation, only 5% fulfilled the International Society of Thrombosis and Haemostasis criteria, but patients that do not fulfill these criteria should not be dismissed as that may lead to failure to identify many acutely ill patients at substantial risk of death. Measurement of antithrombin and in particular protein C is a simple and useful method of assessing mortality risk in severely ill patients suspected of acute disseminated intravascular coagulation.

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ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

SURVIVAL PREDICTION IN DIC

Acute or overt disseminated intravascular coagulation (DIC) is a severe consumptive coagulopathy complicating sepsis, acute leukemia, obstetric complications, surgery, trauma, and other serious conditions. It is caused by uncontrolled formation of intravascular thrombi with consequent consumption and depletion of coagulation factors and platelets as well as hyperfibrinolysis. The result is tissue ischemia, organ failure, and serious bleeding.1–3 However, consumptive coagulopathy demonstrates a spectrum of severity where only the most severe cases fulfill diagnostic criteria for overt DIC (overt ISTH criteria).2,4 Biochemical markers of acute DIC include decreased fibrinogen, elevated D-dimer, soluble fibrin monomer, thrombin–antithrombin (TAT) complexes, plasmin–antiplasmin (PAP) complexes, and soluble thrombomodulin.5–7 Antithrombin and protein C are known to decrease in patients with DIC and associate with worse prognosis8–10 and both have been applied in criteria for non-overt DIC.4,11 Finally, by direct measurement, alpha-2-antiplasmin (antiplasmin) has also been shown to be lower in patients with DIC12, but to our knowledge it has not been studied as prognostic marker. At our institution, we routinely measure antithrombin, protein C, and antiplasmin as a part of a diagnostic screening panel for DIC together with standard DIC screening tests, i.e., platelet count, activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, and D-dimer. As diagnosis of early consumptive coagulopathy could speed the diagnosis and treatment of underlying conditions, we aimed to study how these markers of coagulation associated with mortality in patients clinically suspected of DIC.4,13

Methods Overview The study was a retrospective cohort study reviewing the hospital charts of all consecutive patients clinically suspected of DIC during a 5year period at the Landspitali National University Hospital in Reykjavik, Iceland, the only tertiary care hospital in Iceland. The protocol was approved by the National Bioethics

Committee, Tryggvagata 17, 101 Reykjavik, No VSNb2011050025/03.15 and the Data Protection Agency of Iceland, Raudararstig 10, 105 Reykjavik No 20110506639ÞS who waived individual consent. Patient population It was estimated that a sample size of 1600 with suspected DIC would answer our questions, which corresponded to approximately 4.5 years sampling. However, we decided to collect samples from a 5-year period corresponding to approximately 1800 patients to have some margin. During the 5-year study period, antiplasmin was only measured as a part of the diagnostic DIC panel done in all patients clinically suspected of DIC. By reviewing all antiplasmin measurements from the laboratory information system, we could identify all patients, 18 years and older with clinically suspected DIC during the period. Subsequently, we extracted the entire DIC screening panel results (platelet count, D-Dimer, PT, fibrinogen, antiplasmin, antithrombin, and protein C) utilizing an inhouse customized software. All panels were scored according to the ISTH overt DIC criteria.4 Mortality was analyzed based on the whole study group. Patients with an ISTH score of 5 or more at any time were assigned to the overt DIC group, whereas those who never had a score of ≥ 5 were assigned to the non-DIC group. From the non-DIC group, patients were matched in a 1 : 1 manner according to gender, age, and the closest diagnosis date to form a matched non-DIC subgroup in order to compare co-morbidity in patients with and without overt DIC. Medical records of patients in the DIC group and the matched non-DIC subgroup were examined for date of hospital and intensive care unit (ICU) admission and discharge, date of death, associated underlying conditions and signs of end artery necrosis or limb amputation. The ICU record was used to assess the Acute Physiology and Chronic Health Evaluation II (APACHE II) score on ICU admission.14 In patients not admitted to the ICU, an APACHE II score was calculated based on hospital admission data, using a score of 0 for missing components of the score. Acute kidney injury (AKI) was

Acta Anaesthesiologica Scandinavica 59 (2015) 870–880 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

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estimated using baseline and worst creatinine during admission by RIFLE creatinine criteria.15 When baseline creatinine was not available, it was calculated according to the Modified diet in Renal Disease equation for glomerular filtration rate.16 The presence of acute respiratory distress syndrome or acute lung injury was assessed based on the 1994 consensus criteria using lowest PO2/FiO2 ratio and radiologic patchy pulmonary infiltrates without evidence of left ventricular failure.17 Information on mortality and date of death was acquired from Statistics Iceland (www.statice.is). DIC panel and ISTH scoring The DIC screening panel was measured on an emergency basis and included a complete blood count (CBC), PT, APTT, fibrinogen, D-dimer, antithrombin, protein C, and antiplasmin. CBCs were done using Abbott Cell-Dyn 3200 automated hematology analyzer (Abbott, Chicago, IL, USA) and later the Sysmex XE-5000 instrument (Sysmex, Kobe, Japan). All coagulation assays were done on a STA-R analyzer (Diagnostica Stago, Asni eres, France) with reagents from Stago except for APTT (TriniCLOTTM aPTT HS; Trinity Biotech, Bray, Ireland). APTT and PT were measured using standard clotting methods, fibrinogen using the Clauss method, and D-dimer immunoturbidimetrically with samples diluted 1 : 5 once the D-dimer reached > 4 mg/l and further diluted 1 : 20 if > 20 mg/l. Antithrombin, protein C, and antiplasmin activity was determined by chromogenic assays. Measurements from 115 healthy adults previously analyzed by the hospital laboratory served to calculate the 2 standard deviation (SD) (95% distribution, 2.5th percentile cut-off) laboratory reference values and the 3 SD (99% distribution, 0.5th percentile cut-off) reference values. The overt ISTH criteria include an assessment of fibrin degradation products (FDP), but do not specify which FDP assay to use or their cut-off values. In our study, in a manner similar to others,10,18 we used D-dimer for the criteria defining 0.5–5 mg/l (the upper reference value at our laboratory and up to 10 times the upper reference value) as moderate FDP elevation and over 5.0 mg/l as a strong FDP elevation.

Data handling and statistical analysis The whole study group was used to assess ISTH score and mortality. The DIC group and the matched non-DIC group were compared with assess co-morbidity, including APACHE II score, in patients with or without overt DIC. All statistical analysis was performed with the R software version 3.0.1 using the pROC, gplot, epitools, survival, rJava, xlsxjar, and xlsxpackages (R Foundation for Statistical Computing, Vienna, Austria). In the DIC group, day 0 was determined as the first measurement when a patient first scored 5 or higher according to overt ISTH criteria. In the non-DIC group and the matched non-DIC subgroup, the first measurement of each patient’s highest score was defined as day 0. All laboratory panels were timed according to day 0. The first measurement of each day was used for constructing time series. Continuous data were compared using the non-parametric Kruskal–Wallis test or Wilcoxon rank sum test. Categorical data were compared using the Fisher’s exact test. Correlation analyses were done using Spearman rank correlation, as well as analysis of coefficient of determination (R2). Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of antithrombin, protein C, and antiplasmin for DIC according to the overt ISTH criteria, both on day 0 and the first measurement of each patient. The area under the curve (AUC) for each ROC curve was calculated to estimate diagnostic accuracy of each test and the values of antithrombin, protein C, and antiplasmin, where the highest combination of sensitivity and specificity was determined to be the optimal cut-off value. Survival curves were compared using the Kaplan–Meier method and 28day and 1-year survival were compared using chi-square test. Survival was estimated based on presence or absence of DIC or according to initial ISTH score. Survival was also estimated by antithrombin, protein C, and antiplasmin quartile distribution or by using the 95th percentile distribution of the normal reference population (lower 2.5th percentile as cut-off) or the 99th percentile distribution (lower 0.5th percentile as cut-off) or ROC analysis to define cut-off values. In general, a P-value of < 0.05 was considered Acta Anaesthesiologica Scandinavica 59 (2015) 870–880

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Table 1 Patient characteristics. Comparison of patients in the DIC group and the age- and sex-matched non-DIC subgroup.

DIC, n (%)

Matched non-DIC subgroup, n (%)

All 91 90 Associated conditions Trauma 3 (3) 4 (4) Burn 0 (0) 0 (0) Obstetric 4 (4) 8 (9) Malignancy 20 (22) 11 (12) Major surgery 24 (26) 31 (34) Major bleeding 24 (26) 2 (2) SIRS 45 (50) 33 (37) Infection* 44 (48) 33 (37) Meningitis 2 (2) 0 (0.0) Septicemia 32 (35) 11 (12) Pneumonia 25 (28) 13 (14) Urinary tract 9 (10) 8 (9) infection Other 3 (3) 9 (10) infection Pancreatitis 4 (4) 3 (3) Liver failure 14 (15) 0 (0.0) Toxic/ 2 (2) 1 (1) immunological Major vascular 9 (10) 2 (2) events ICU admission 86 (94) 73 (81) Any 31 (34) 5 (6) hemofiltration Continuous 31 (34) 2 (2) Intermittent 10 (11) 5 (6) 73 (81) 49 (52) Mechanical ventilation Oscillator 5 (6) 0 (0.0) ECMO 6 (7) 0 (0.0) Days in hospital 30.9 (19, 1–239) 23.55 (12, 1–155) Days in ICU 12.2 (6, 0–108) 4.1 (2, 0–34) 7.9 (0, 0–322) 2.9 (0, 0–92) Days on hemofiltration Days on 9 (3.5, 0–81) 2.1 (1, 0–26) mechanical ventilation Acute kidney injury (AKI) classification No AKI 17 (19%) 51 (57%) Risk 9 (10%) 12 (13%) Injury 20 (22%) 9 (10%) Failure 38 (42%) 6 (7%) Long term 4 (4%) 3 (3%) End stage 1 (1%) 1 (1%)

statistically significant. Where appropriate, however, we accounted for multiple testing by Bonferroni’s approach, considering a P-value of 0.05/ n, where n is number of tests performed, statistically significant.

P-value

Results 0.72 – 0.25 0.11 0.25 < 0.001 0.10 0.13 0.5 < 0.001 0.04 1 0.08 0.72 < 0.001 1 0.06 < 0.01 < 0.001 < 0.001 0.28 < 0.001 0.06 0.03 0.20 < 0.001 < 0.001 < 0.001

< 0.001

Data are shown as the number of patients (percentage) or mean (median, range). *Percentages may reach above 100% due to multiple diagnoses being present in the same patient.

Patient population A total of 5994 DIC panels were identified from 1814 patients that were clinically suspected of DIC on 1825 occasions, including 10 patients who were suspected of DIC during two separate hospital admissions and one patient during three admissions. Of the 1814 patients, 92 (5%) fulfilled criteria for overt DIC, but one with no identifiable underlying disorder was excluded from analysis. The remaining 1733 incidents did not fulfill the overt DIC criteria. From that non-DIC group, 91 patients were matched based on age, gender, and date of illness to form a matched nonDIC subgroup, but due to incomplete records from a single patient, 90 patients could be analyzed. Thirty-two of the whole group of patients were lost to mortality follow-up, including two from the DIC group and four from the non-DIC subgroup. Of these 32 patients, 26 had emigrated, 4 were foreign citizens with unknown whereabouts, and the whereabouts of additional 2 patients were unknown. Therefore, data on 1781 patients were available for mortality analysis. The mean age in the DIC group, non-DIC group, and the matched non-DIC subgroup was 62, 61, and 62 years, respectively and 59%, 55%, and 60% were males, respectively. The gender distribution was not statistically different between the reference value population (47% male) and the DIC and non-DIC groups. However, the mean age of the reference value population was 42 years, statistically lower than both the DIC and the non-DIC groups (P < 0.001). The ISTH score and APACHE II score correlated positively (R2 = 0.25, P < 0.001) (Fig. S1). Compared with the matched non-DIC subgroup, the DIC group more frequently had sepsis, pneumonia, major bleeding, liver failure, AKI, and were more likely to need ICU admission and mechanical ventilation (Table 1).


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As shown in Fig. 1A, the 28-day (1-year) mortality of patients fulfilling DIC criteria was 52% (63%) compared with 16% (25%) in the whole non-DIC group (P < 0.001). Survival in the matched non-DIC subgroup did not differ from the whole non-DIC group, i.e., 28-day (1-year) mortality 13% (22%) vs. 16% (25%), P = 0.54. Mortality increased progressively as the maximum ISTH score rose across its spectrum. Thus, the 28-day mortality was 3%, 11%, 16%, 23%, 35%, and 52% and the 1-year mortality was 5%, 18%, 24%, 36%, 54%, and 63%, respectively for patients with an ISTH score of 0, 1, 2, 3, 4, and ≥ 5 (P < 0.001 for both observations, Fig. 1, panel B). Likewise, when survival was assessed based on the initial ISTH score, a similar stratification was seen (P < 0.001). The progressively increasing mortality with increasing ISTH score was as evident in non-septic patients suspected of DIC as in septic patients (data not shown).

As evident from Fig. 2, antithrombin and protein C were reduced to below the 0.5th percentile for 2 days prior to diagnosis of DIC (DIC group), whereas in the non-DIC group, both tests remained above the 0.5th percentile. Antiplasmin also for the most part remained above the 2.5th percentile and levels below the 0.5th percentile were only observed in the DIC group where most patients had antiplasmin under the 0.5th percentile at the time of DIC diagnosis. When antithrombin or protein C were compared with the ISTH score at the time of sampling, an inverse relationship was observed for both (AT: R2 = 0.14, P < 0.001, PC: R2 = 0.21, P < 0.001; Fig. 3, panel A and B). On the other hand, with antiplasmin, although the overall trend was statistically significant (R2 = 0.02, P < 0.001), it was only visible with an ISTH score of ≥ 4 (Fig. 3, panel C). B

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Fig. 1. Survival of patients according to ISTH score. There were 1825 instances of suspected DIC in 1814 patients. Panel A shows the survival of patients fulfilling criteria for DIC (DIC group, ISTH score ≥5) versus the survival of patients not fulfilling criteria (non-DIC group; ISTH score 1-4) and matched non-DIC subgroup. The one-year mortality of patients in the DIC group was 63% compared to 25% in the non-DIC group (P > 0.001). No statistical difference was found in the survival of the non-DIC group and the matched non-DIC subgroup. Panel B shows the one-year survival of all patients suspected of DIC in relation to their highest ISTH score. As evident, the higher the ISTH score, the higher is the mortality (P < 0.001). The number of analyzable patients at risk with each ISTH score is shown adjacent to the relevant curve. Acta Anaesthesiologica Scandinavica 59 (2015) 870–880

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Fig. 2. Serial measurements of antithrombin, antiplasmin, and protein C in patients suspected of DIC. The patients are split into those who fulfill criteria for overt DIC and those who never fulfill the criteria. The data are shown as means with 95% confidence intervals. For reference, the 2.5th–97.5th reference interval is shown in dark shading as well as the extended 0.5th–99.5th reference interval in lighter shading. The DIC group day 0 is defined as the day when overt ISTH criteria were fulfilled (≥ 5). Day 0 in the group that never fulfilled the DIC criteria is defined as the day with the highest ISTH score. Number of patients observed on each day is shown above the abscissa.

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Fig. 3. Antithrombin, protein C and antiplasmin in relation to simultaneous ISTH score calculation in samples from patients suspected of DIC. Data are shown as boxplots with median, 25/75% quartiles (boxes) and 10/90% range. For reference, the 2.5th to 97.5th reference interval is shown in dark shading as well as the extended 0.5th -99.5th reference interval in lighter shading. The number of measured samples with each ISTH score is shown above the x-axis.

The optimal cut-off values for antithrombin, protein C, and antiplasmin for the diagnosis of overt DIC were chosen based on the highest combination of sensitivity and specificity. In this manner, protein C was found to have the highest diagnostic accuracy based on AUC analysis, followed by antithrombin (Table 2). An antithrombin or protein C level above the cut-off value (58% and 44% of mean reference value, respectively) essentially ruled out overt

DIC, i.e., the negative predictive value (NPV) was 99% on day 0 for both markers. However, when DIC was first suspected the NPV was 86% and 89%, respectively. Antithrombin, protein C, and antiplasmin in relation to mortality Reduced initial (Fig. 4) and day 0 (data not shown) antithrombin and protein C levels were


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Table 2 Diagnostic capability of antithrombin, protein C, and antiplasmin. Capability of first or day 0 antithrombin, protein C, and antiplasmin to discriminate between overt DIC and non-DIC based on ISTH classification was estimated by area under the curve (AUC) of their ROC curves (data not shown). Optimal cut-off values for antithrombin (AT), protein C (PC), and antiplasmin (AP) for the diagnosis of overt disseminated intravascular coagulation (DIC) were chosen based on the highest combination of sensitivity and specificity.

AT First Day 0 AP First Day 0 PC First Day 0

Cut-off (percentile)*

AUC

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

44 58

0.69 0.84

41 82

89 75

31 15

86 99

85 52

0.59 0.70

77 56

39 84

24 16

88 97

43 44

0.75 0.88

57 78

84 86

36 15

89 99

*Percentile in relation to normal plasma (100%). AUC, area under the curve; PPV, positive predictive rate; NPV, negative predictive rate; First, first measurement for each patient up to 10 days prior to diagnosis; Day 0, day of diagnosis according to the International Society of Thrombosis and Hemostasis (ISTH) criteria for DIC.

both associated with significantly increased 28day and 1-year mortality (Table 3). This was particularly evident in patients with protein C activity in the lowest two quartiles. For both antithrombin and protein C, the diagnostic cutoff value identified by ROC analysis (43% activity) was considerably lower than the 0.5th percentile of the distribution in a healthy cohort (Table 3). However, the initial protein C activity predicted mortality better as the 28-day mortality risk increase was threefold between those in the lowest (30%) and highest (9%) protein C activity quartiles (Table 3) compared with twofold (26% and 13%) in the lowest and highest antithrombin quartiles. Although the initial antiplasmin did not appear to reflect 28-day mortality, patients with antiplasmin below 2.5th percentile and in particular those below the 0.5th percentile in the initial sample had lower 1-year mortality than those with higher antiplasmin (P = 0.03, n.s. by Bonferroni correction). This is also evident in Fig. 4 which demonstrates that patients with the highest initial antiplasmin suspected of DIC have the worst long-term outcome.

Table 3 Mortality of patients suspected of DIC in relation to their initial protein C, antithrombin, and antiplasmin activity measurements. Patients are grouped according to percentile, i.e., lowest to highest activity quartiles with absolute activity range shown in parenthesis, in relation to being below or above the 2.5th or 0.5th lower percentiles of the normal reference population, respectively, or below or above the ideal cut-off value identified by ROC analysis. We considered a P-value of 0.05/8 = 0.006 statistically significant to account for multiple testing. Percentile* (% activity range)† Protein C 0–25 (4–52) 25–50 (53–71) 50–75 (72–90) 75–100 (91–246) > 2.5 (≥ 71) < 2.5 (< 70) > 0.5 (≥ 55) < 0.5 (< 54) > ROC (≥ 44) < ROC (< 43) Antithrombin 0–25 (4–56) 25–50 (57–70) 50–75 (71–86) 75–100 (87–155) > 2.5 (≥ 71) < 2.5 (< 70) > 0.5 (≥ 62) < 0.5 (< 61) > ROC (≥ 44) < ROC (< 43) Antiplasmin 0–25 (3–55) 25–50 (56–74) 50–75 (75–91) 75–100 (92–200) > 2.5 (≥ 76) < 2.5 (< 75) > 0.5 (≥ 66) < 0.5 (< 65) > ROC (≥ 82) < ROC (< 81)

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*Quartiles or cut-offs in relation to normal population percentile activity. †Quartiles or cut-offs shown as plasma equivalent activity.

Discussion The current study of 1825 consecutive incidents of suspected DIC shows that antithrombin, antiplasmin, and in particular protein C can be used Acta Anaesthesiologica Scandinavica 59 (2015) 870–880

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Fig. 4. Survival of patients suspected of DIC in relation to their initial measured activity of antithrombin, protein C, and antiplasmin split into activity quartiles, from the lowest to the highest. The P-values shown refer the 1-year mortality base on the initial activity of antithrombin, protein C, and antiplasmin. We considered a P-value of 0.05/8 = 0.006 statistically significant to account for multiple testing.

to assess mortality risk upfront in patients suspected of acute DIC, and not only in those fulfilling the stringent overt DIC ISTH criteria (Figs 2 and 3). Secondly, contrary to prior results,10 we found that a clinically meaningful stratification of prognosis can be achieved across the entire ISTH score in patients suspected of DIC and not only in those categorically classified as acute DIC based on the ISTH score. It has been previously shown in septic patients with DIC8 and in patients with overt DIC19,20 that lowered antithrombin and protein C, respectively, associate with increased mortality. To our knowledge, however, in the much larger group of acutely ill patients initially suspected of DIC that never actually develop DIC, it has not been previously shown that lowered antithrombin and especially lowered protein C allows identification of many more patients who are at a high risk of death and would not be identified using the overt DIC criteria alone. Although these patients as evident from the non-DIC subgroup had less upfront morbidity than the overt DIC group in our study, their mortality rate was still high. Also, as they are in much greater numbers they contribute considerably more to mortality in acutely ill patients than do overt DIC patients. The seemingly paradoxical finding of better long-term prognosis in DIC patients with antiplasmin below the 0.5th percentile of the normal population, a reflection of removal of PAP complexes, deserves further comment. As

opposed to PAP complexes that have been shown to be elevated in DIC,21 the antiplasmin measurement is easily measured on an emergency basis together with other DIC panel tests. Although speculative, improved long-term survival may reflect a beneficial effect of plasmin generation favoring lysis of microthrombi with consequent less tissue ischemia and end-organ failure in those surviving the acute phase. Supporting this explanation, DIC patients without multiple organ failure (MOF) had more fibrinolytic activity measured by d-dimer, tissue plasminogen activator, plasminogen activator inhibitor 1, and PAP.22 Relatively preserved antiplasmin activity in DIC has also been linked to preserved fibrinogen, which in turn is linked to increase in MOF and mortality.23 In patients suspected of DIC with initial overt ISTH scores < 5, progression to overt DIC has been reported in 5–25%.21,24,25 To our knowledge, a progressive mortality increase across all ISTH scores irrespective of underlying cause has not been previously demonstrated although supported by a study using the Japanese Association of Acute Medicine criteria.26 Also, a single study has previously demonstrated increased mortality across the ISTH score range in septic patients27 and a second study has demonstrated increased mortality in septic patients with an ISTH score of 3–4 using modified overt ISTH criteria.18 In the initial overt ISTH score study, 217 consecutive ICU patients suspected of DIC were tested, 74 of whom fulfilled criteria for


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overt DIC. The authors found that mortality actually decreased with a rising overt ISTH score from 1 to 3 but increased once a score of ≥ 4 was reached and it was concluded that the overt ISTH score had sufficient accuracy to rule in or out the diagnosis of DIC.10 However, our results illustrate that only 5% of all patients clinically suspected of DIC do ever fulfill criteria for acute DIC but that many more have a milder form of coagulopathy that still associates with high mortality. Therefore, an emphasis on the categorical diagnosis of acute DIC based on a fixed ISTH score of ≥ 5 potentially leaves many patients with non-overt forms of life-threatening DIC undiagnosed. (Fig. 1). Taken together, we contend that the main value of the overt ISTH score is that it has prognostic implications in all severely ill patients that have an ISTH score of 1 or higher. Medical laboratories typically report the 95th percentile normal distribution as normal reference values but this inevitably leads to a number of false-positive diagnoses as exemplified by mild von Willebrand disease.28 In our study, cut-off values based either on ROC analysis or the 0.5th percentile for protein C, 55% and 43% activity respectively, reflected clinical outcome better than a cut-off based on the 2.5th percentile (70% activity). The same was true for antithrombin. As the 0.5th percentile cut-off was close to the ROC analysis cut-off value, we feel that it would be helpful for clinicians if 0.5th percentile cut-offs were provided for antithrombin and protein C rather than the classical 2.5th percentile. The strength of our study is its hospital wide enrollment as opposed to intensive care patients only in prior studies. However, our study has a number of limitations, including its retrospective design that might have lead to missing or inconsistent data. As we used antiplasmin, a part of the DIC diagnostic panel in general use, to identify patients suspected of DIC, it is unlikely that many patients were missed. Indeed, using antiplasmin to identify patients with suspected DIC led to the inclusion of a high number of patients with low ISTH scores allowing comparison of groups with coagulopathy of varying severity. Secondly, we used the APACHE II score to indicate morbidity in patients not admitted to the ICU. Retrospectively scoring patients with 0 for

missing components in non-ICU patients underestimates the APACHE II score, and the score is not designed for non-ICU populations. Thirdly, as our study was retrospective, we can only indirectly correlate our findings with studies that used different biochemical markers.7,21 Conclusions We conclude that the upfront measurement of antithrombin and in particular protein C is a simple and useful method of assessing mortality risk in severely ill patients suspected of acute DIC. The finding of lowered antithrombin or protein C in an acutely ill patient should initiate a rigorous search for a treatable life-threatening condition irrespective of the ISTH score. ISTH DIC scores in the 1–4 range are associated with progressively increasing mortality and should not be dismissed as that may lead to failure to identify many acutely ill patients at substantial risk of death. It remains to be investigated how a lowered protein C would modify various DIC criteria if appropriately low cut-offs were applied. References 1. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586–92. 2. Levi M, van der Poll T. Disseminated intravascular coagulation: a review for the internist. Intern Emerg Med 2013; 8: 23–32. 3. Bick RL, Arun B, Frenkel EP. Disseminated intravascular coagulation. clinical and pathophysiological mechanisms and manifestations. Haemostasis 1999; 29: 111–34. 4. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society on T, Haemostasis. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86: 1327–30. 5. Wada H, Sakuragawa N, Mori Y, Takagi M, Nakasaki T, Shimura M, Hiyoyama K, Nisikawa M, Gabazza EC, Deguchi K, Kazama M, Shiku H. Hemostatic molecular markers before the onset of disseminated intravascular coagulation. Am J Hematol 1999; 60: 273–8. 6. Okamoto K, Wada H, Hatada T, Uchiyama T, Kawasugi K, Mayumi T, Gando S, Kushimoto S, Seki Y, Madoiwa S, Asakura H, Koga S, Iba T, Acta Anaesthesiologica Scandinavica 59 (2015) 870–880

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Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Fig. S1. APACHE II score in relation to ISTH criteria for DIC in the DIC group and the matched non-DIC subgroup.

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