The efficacy and associated bleeding complications of recombinant antithrombin supplementation among intensive care unit patients

Accepted Manuscript The efficacy and associated bleeding complications of recombinant antithrombin supplementation among intensive care unit patients

Hiroyuki Koami, Yuichiro Sakamoto, Ryota Sakurai, Miho Ohta, Hisashi Imahase, Mayuko Yahata, Mitsuru Umeka, Toru Miike, Futoshi Nagashima, Takashi Iwamura, Kosuke Chris Yamada, Satoshi Inoue PII: DOI: Reference:

S0049-3848(17)30399-7 doi: 10.1016/j.thromres.2017.06.035 TR 6716

To appear in:

Thrombosis Research

Received date: Revised date: Accepted date:

2 May 2017 12 June 2017 27 June 2017

Please cite this article as: Hiroyuki Koami, Yuichiro Sakamoto, Ryota Sakurai, Miho Ohta, Hisashi Imahase, Mayuko Yahata, Mitsuru Umeka, Toru Miike, Futoshi Nagashima, Takashi Iwamura, Kosuke Chris Yamada, Satoshi Inoue , The efficacy and associated bleeding complications of recombinant antithrombin supplementation among intensive care unit patients, Thrombosis Research (2017), doi: 10.1016/j.thromres.2017.06.035

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Title: The efficacy and associated bleeding complications of recombinant antithrombin supplementation among intensive care unit patients.

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Author names and affiliations: Hiroyuki Koami a,*, Yuichiro Sakamoto a, Ryota Sakurai b, Miho Ohta b, Hisashi Imahase b, Mayuko Yahata b, Mitsuru Umeka b, Toru Miike b, Futoshi Nagashima c, Takashi Iwamura a, Kosuke Chris Yamada b, Satoshi Inoue c

of Emergency and Critical Care Medicine, Faculty of Medicine, Saga University, Saga,

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a Department

Japan

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Emergency Care Center, Saga University Hospital, Saga, Japan

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b Advanced

Division of Trauma Surgery and Surgical Critical Care, Faculty of Medicine, Saga University,

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Saga, Japan

Corresponding author:

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Hiroyuki Koami

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5-1-1, Nabeshima, Saga city, Saga, 849-8501, Japan. Tel.: +81-952343160

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Fax: +81-952341061

E-mail address: [email protected]

E-mail addresses. [email protected] (H. Koami) [email protected] (Y. Sakamoto) [email protected] (R. Sakurai) [email protected] (M. Ohta)

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[email protected] (H. Imahase) [email protected] (M. Yahata) [email protected] (M. Umeka) [email protected] (T. Miike)

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[email protected] (F. Nagashima) [email protected] (T. Iwamura) [email protected] (K. C. Yamada)

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[email protected] (S. Inoue)

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ABSTRACT Introduction: The aim of this study was to evaluate the efficacy and complications of recombinant antithrombin (rAT) supplementation for adult patients with disseminated intravascular coagulation (DIC) compared with conventional plasma derived AT (pAT) treatment in the intensive care unit.

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Materials and Methods: This study was performed in a single national university hospital in Japan. Adult patients from April 2015 to March 2016 with DIC were divided into two groups based on the type of AT agent used: the pAT group (n=24) and the rAT group (n=21). Patient demographics, medical history, diagnosis, blood tests, various clinical scores, AT activity, complications, and clinical outcome were collected and analyzed retrospectively.

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Results: Significantly higher SIRS and APACHEII scores were confirmed in the rAT group than the pAT group. The initial dose of AT was significantly higher in the rAT group than in the pAT group.

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ATIII values before and after initial supplementation and during their ten-day clinical course were statistically similar between two groups. During the same period, 10 bleeding adverse events were found and there was no significant difference between both groups. Significantly more cases of the

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rAT group were administered with recombinant thrombomodulin concomitantly than those of the

same in each group.

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pAT group. Despite significantly more severe patients in rAT group, the clinical outcomes were the

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Conclusions: Compared with pAT, the supplementation of rAT indicates clinical effectiveness

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without increasing the risk of bleeding complications in adult DIC patients with low AT activity.

KEY WORDS antithrombin

recombinant antithrombin intensive care unit disseminated intravascular coagulation bleeding complication

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MAIN DOCUMENT

1. Introduction Antithrombin (AT) is a serine protease inhibitor which forms complexes to inactivate thrombin and

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factors IIa, VIIa, IXa, Xa, XIa, and XIIa [1-3]. In addition, the anti-inflammatory properties of AT have been shown to play an important role in prevention of worsening systemic inflammation such as sepsis, post cardiopulmonary bypass, and reperfusion injury in organ transplantation [2]. The AT agent possesses not only an anticoagulation effect on thrombin and other coagulation factors, but also anti-inflammatory activity in sepsis [4].

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In Japan, antithrombin administration is officially approved for maintaining adequate levels of plasma ATIII in patients with hereditary or acquired AT deficiency, especially in disseminated

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intravascular coagulation (DIC) [5]. The recent Japanese expert consensus recommends AT supplementation for septic DIC patients with less than 70% of AT activity [5]. Indeed, a number of previous studies demonstrate the clinical advantages of replacement therapy by AT supplementation

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[5-12]. The Survival Sepsis Campaign guidelines have globally improved the quality of clinical management for sepsis over the past decade [13], but specific anticoagulation therapy including AT

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therapy has yet to be recommended worldwide [13, 14].

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The recombinant AT (rAT) agent has been officially approved for commercial use in Japan since July 2015, and it is expected to prevent plasma-product-related complications. At Saga University

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Hospital, the conventional type of AT (pAT) has been completely replaced with rAT since November 2015. The recommended volume of rAT is calculated based on body weight (36 IU/kg), which is equivalent to the volume of conventional therapy by pAT (1500IU/day or 30IU/kg) [15]. However, few studies about the efficacy and safety of rAT for DIC patients with low AT level have been performed. The aim of this study was to retrospectively evaluate the efficacy and bleeding complications of rAT supplementation compared with treatment by pAT among intensive care unit patients.

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2. Materials and Methods

2.1. Study design and patients

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This is a retrospective observational study performed in the two ICUs of a single national university hospital in Japan. The study was certified by the institutional review board of Saga University Hospital (20160705). Patients 18 years of age and older who received an AT agent during their ICU stay from April 2015 to March 2016 were included in the present study. During this period, pAT was replaced with rAT starting in November 2015 in this hospital. All cases were divided into two groups

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based on the type of AT agent: pAT group (n=24 cases) and rAT group (n=21 cases).

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2.2. Variables related to patient demographics, medical history, and diagnosis

Patient data including age, sex, and past medical histories such as malignancy, ischemic heart

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disease (IHD), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM) and liver cirrhosis (LC) were collected. Sepsis was defined as an infection induced condition with more than a

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two-point increase in the systemic inflammatory response syndrome (SIRS) score. Infection sources

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manifestations.

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were categorized according to the results of blood cultures in combination with clinical

2.3. Blood testing and various clinical scores

The following blood test results were analyzed were: white blood cell (WBC) count, platelet (PLT) count, C-reactive protein (CRP), prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen (FIB), fibrin degradation products (FDP), and D-dimer (DD). In addition to blood tests, we calculated various clinical scores to evaluate the patient’s severity

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as follows: SIRS score, sequential organ failure assessment score (SOFA) score, acute physiology and chronic health evaluation (APACHE) II score, and Japanese association for acute medicine (JAAM) disseminated intravascular coagulation (DIC) score. All variables described above were recorded before AT administration on the first day of treatment. DIC was defined when a patient’s

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DIC score was greater than 4 points.

2.4. AT administration and measurement of plasma AT value

Data on the treatment of AT included the initial dose, the initial dose of AT adjusted for BW, the

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timing of AT treatment before or after surgery, the route of administration, and the number of treatment days. The recommended injection dose of pAT used in Saga University Hospital was 1500

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international unit (IU) or 30 IU/kg, whereas that of rAT was 36 IU/kg. There is no institutional protocol on AT supplementation. Therefore, the indication of AT was determined by each physician in charge.

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Plasma ATIII levels were measured in all patients before initial AT administration (day 0). However, after the first injection of AT, the timing and the number of tests for the ATIII level was

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dependent on each individual physician. We retrospectively analyzed the ATIII data from day 0 to

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day 10, which was categorized as follows: “Day 0”, “Day 1-2”, “Day 3-5” and “Day 6-10”. Since the number and timing of blood sampling varied, the highest ATIII value was used for the analysis

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from each category.

2.5. Clinical outcomes related to AT administration

In this study, we specifically focused on the bleeding complications resulting from AT supplementation. We collected data on bleeding events and AT related bleeding from the medical charts. We also checked the combined anti-DIC medications when the first AT was initiated in the ICU. Clinical outcomes included DIC recovery on day 7, the length of the ICU stay, the 28-day

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survival, and sepsis related deaths.

2.6. Statistical analysis

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All continuous variables of each group are represented as median (interquartile range; IQR) and categorical variables as number (percentage). We used the Mann-Whitney U test and the Student’s ttest for continuous variables, and the Fisher’s exact test and Chi-square test for categorical variables. A P-value <0.05 was considered statistically significant. We used IBM SPSS Statistics version 22

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(IBM Corp., Armonk, NY, USA) for statistical analyses.

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3. Results

During the period of one year, all 45 adult patients administered with AT during their ICU stay were enrolled in this study. During the time period of this study, 24 patients received pAT therapy,

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whereas 21 patients received rAT.

3.1. Patient characteristics, medical history and information about infection

Patient characteristics are shown in Table 1. The AT therapy was administered to 45 patients

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admitted in 2 ICUs during the time period of April 2015 to March 2016. Both groups were statistically equal regarding age, sex, body weight, and past medical history. There was also no

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statistical difference in sepsis cases in the two groups (66.7% of the pAT group and 76.2% of the rAT group). Finally, there was no significant difference regarding the sources of infection and the

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percentage of positive blood cultures in each group.

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3.2. Blood tests and clinical scores

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We analyzed blood tests results and several clinical scores obtained from both AT groups (Table 2). Significantly higher WBC counts (rAT 13800/µL vs. pAT 8950/µL; P = 0.028) and higher DD levels

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(15.96 µg/mL vs. 8.14 µg/mL; P = 0.031) were confirmed in the rAT group compared with the pAT group. In addition, the rAT group had significantly higher SIRS scores (3 pts vs. 2 pts; P = 0.007) and APACHEII scores (29.1 pts vs. 23.2 pts; P = 0.020) than the pAT group. No other parameters investigated were statistically significant.

3.3. Variables on the AT administration

The initial dose of AT (1800 units vs. 1500 units; P < 0.001) and the initial dose adjusted for BW

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(33.9 units vs. 26.1 units; P < 0.001) were significantly higher in the rAT group compared to the pAT group, respectively (Table 3). There were significantly more patients who were injected with AT following surgery in the pAT than in the rAT group (pAT 58.3% vs. rAT 23.8%; P = 0.019). The types of IV administration were statistically similar in both groups. Interestingly, the total median

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days of AT therapy administration was only two days in both groups.

3.4. Transition of plasma ATIII values during AT treatment

The plasma ATIII values quickly increased in response to AT administration (Fig. 1 and Table 4).

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More than 160% increases of were found on “Days 1-2” and these values were sustained for three to five days (Fig. 1A). These levels then gradually declined for 10 days from the initiation of AT

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treatment (Fig. 1A). However, the ATIII values during “Days 6-10” were significantly higher than that of Day 0. In addition, the ATIII values and their transition for ten days were statistically similar

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between groups (Fig. 1B and Table 4).

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3.5. Bleeding complications and combined medications

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Bleeding events were observed in 10 patients (22%) during the first 10 days following the initial AT injection (Table 5). There was no statistical difference between the two groups. Within the bleeding

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complications, hemorrhage in the digestive tract was the most common occurrence, but there was no statistical difference between the groups. In addition, no AT therapy related hemorrhagic events were reported in either group. In respect to the combined medication with AT, significantly more cases in the rAT group were injected with rTM than those in the pAT group (rAT 81.0% vs. pAT 50.0%; P=0.030). All other medications for supplemental anti-DIC agents were used equally in each group.

3.6. Clinical outcomes in both groups

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The recovery from DIC was equally accomplished in both AT groups (Table 6). Although the median length of the ICU stay was shorter in the rAT group than the pAT group, no statistical difference was found (8 days vs. 14 days; P=0.175). Further, there was no difference among the two groups in terms

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of 28-day survival and sepsis related death. Next, we analyzed the relationship between the 28-day mortality and the estimated mortality based on the APACHEII score in both groups (Fig. 2). The estimated mortality of the rAT group was significantly higher than that of pAT group. However, the observed 28-day mortality rate remained

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the same in each group.

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4. Discussion

The present study indicated that more units of AT were administered in the rAT group than in the pAT group. In addition, a higher APACHEII score and an increased number of patients who received

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combined administration of rTM were found in the rAT group than the pAT group. However, clinical outcome and incidence rate of hemorrhagic complications were similar in both groups. To the best of our knowledge, this is the first report to show the efficacy and safety of rAT supplementation in DIC patients with low AT activity in the ICU.

In this study, the rAT group showed a higher score of systemic inflammation (SIRS score and hypercoagulation (DD), and more severe clinical conditions

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WBC), an increased state of

(APACHEII score) than the pAT group. However, the increasing ratio comparing ATIII levels before

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treatment and at “Days 1-2” was similar in both groups. A similar tendency was confirmed in the change of ATIII levels during the first 10 days following the initial AT administration. There were no statistical differences in regard to the ratio of DIC recovery on day 7, the length of ICU stay, the 28-

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day survival rate, and the sepsis related death within rAT and pAT groups. Although no significant difference was found in terms of clinical outcomes between the two groups, Fig. 2 suggests that rAT

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treatment might improve prognosis of DIC patients with low ATIII value more so than pAT.

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It is possible that the findings described above may be attributable to the differences in the dose of AT given in each group. The drug information for rAT states that 36 IU/kg of rAT has the same

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clinical efficacies and safety compared with 30 U/kg of pAT (pAT: rAT doses= 1:1.2). Although the median doses of both types of AT agents used in this study were less than the recommended doses, the dose of rAT (33.9 U/kg) was greater than the dose of pAT (26.1 U/kg). Interestingly, a prospective cohort study of 729 septic DIC patients with ATIII activity of 70% or less demonstrated that the survival rate of patients who received 3000 IU/day was higher than that of the patients who received 1500 IU/day (74.7% vs. 65.2%) [6]. In addition, high dose of AT (3000 IU/day) is recommended if the baseline of ATIII activity is below 40% in septic patients [7]. A case-control prospective trial in pre-eclamptic patients demonstrated that the high-dose AT group (3000 units per

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day for 5 days) showed significantly longer periods of pregnancy by 2.5 days compared with the control group (maintained at least 80% of AT activity) [16]. Structural differences between the two types of AT agents might affect their pharmacokinetic and pharmacodynamic effects. Another difference of these agents is their components and production

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process. Generally, plasma-derived AT concentrates are purified from human blood through a complicated process [3]. Whereas, recombinant AT is produced by several mammalian cells: baby hamster kidney cells, Chinese hamster ovary cells, a budding yeast strain, and transgenic goats (derived from their milk). Indeed, Yamada, et al. reported that it is difficult to produce a recombinant AT which is equally efficacious as a plasma derived AT [3]. Moreover, physiological activities of

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human AT, including heparin affinity, anti-thrombin activity, and anti-coagulant activities, depend on the structure of its oligosaccharide. Interestingly, drug information states that a phase III study

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demonstrated decreased 28-day survival in the rAT group compared with the pAT group (87.3% vs. 77.7%, respectively). Pharmacokinetics data showed longer periods of the half-life of rAT (81.82 +/50.07 h) than pAT (58.02 +/-18.52 h). We propose that these data may result from the different

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oligosaccharide structures of rAT and pAT.

In addition, no statistical difference regarding bleeding complications was seen between the two

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groups. There were no bleeding complications induced by AT in this study, although the pAT group

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included significantly more postoperative patients and the rAT group included more severe cases. In addition, the concomitant administration of rTM did not increase any bleeding events. Recent

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prospective studies have demonstrated that the risk of severe bleeding following AT administration is 2% or below in septic DIC patients with low AT activity [6, 17]. Another large-scale retrospective study reported that bleeding complications were significantly higher when septic DIC patients required transfusion after AT therapy than those who did not receive AT therapy (17.8% vs. 11.5%; P=0.007) [10]. However, there was no statistical difference with respect to fatal hemorrhagic events between both groups. Other than sepsis cases, supplementation of AT is considered to have an increased risk for a bleeding event. Conversely, recent studies demonstrated that no abnormal bleeding induced by AT therapy was found in patients with hereditary AT deficiency, pre-eclampsia

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and liver transplantation [16, 18, 19]. In recent years, multiple studies have shown that the incidence of bleeding complications was not associated with concomitant rTM administration in septic DIC patients with AT therapy [20-22]. Finally, this retrospective study also highlights the importance of the length of AT therapy for

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future DIC patients with depressed AT activity. AT therapy is typically continued for 3 to 5 consecutive days [9, 10, 17, 23]. However, more than 70% of patients in both groups were not treated for the recommended consecutive days in the present study (data not shown). Indeed, the median days of AT therapy for all patients was only two days. Notably, normal level of ATIII activity (70%) or more was maintained for approximately five days despite the relatively short duration of

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AT therapy. Therefore, longer administration period might be able to prolong sufficient AT activity, which might improve clinical outcome.

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The present study possesses some drawbacks. Firstly, this survey is performed in a single national university hospital utilizing a small sample-size. In addition, the patients’ characteristics of the two ICUs are not same. One is emergency ICU (EICU) which mainly included patients from emergency

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department. Some patients after emergency surgery are also admitted in the EICU. The other is surgical ICU and CCU. Both are not the “closed ICU”. Secondly, we also enrolled all adult patients

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with various pathologic backgrounds of nine different hospital departments. Therefore, a large

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discrepancy was observed in each group. Thirdly, there is no institutional protocol for the treatment of sepsis and DIC in our hospital. Thus, in every case, the individual intensivist determined the

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timing, volume, and administration method of AT, which resulted in patient-to-patient differences. Finally, we cannot ignore the possibilities of advantageous or disadvantageous properties of rTM, which is administrated to the 64% of all patient. However, it is statistically impossible to evaluate the efficacy of rTM with or without AT agent in present heterogenous populations. Large-scale prospective study analyzing the use of rAT supplementation will provide novel therapeutic options for DIC populations in the future.

5. Conclusions

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Compared with pAT, the supplementation of rAT indicates clinical effectiveness and also does not increase the risk of bleeding complication in adult DIC patients with low ATIII activity.

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Conflicts of interest statement

The authors have no conflict of interest.

Authors’ contributions

Koami H, Sakamoto Y, Miike T and Inoue S contributed to the concept and design of the

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study. Sakurai R, Ohta M and Yahata M were assigned to acquisition of data. Koami H and Yamada CK performed statistical analyses. Imahase H, Umeka M, Nagashima F and Iwamura T interpreted

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the data. Drafting the article was done by Koami H and Sakamoto Y. Yamada CK, Imahase H, Miike T, Nagashima F, and Inoue S revised the article for important intellectual content. All authors

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approved the final manuscript.

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Acknowledgments

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I would like to acknowledge Dr. Janet Markman for her continuing support in English editing.

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[20] N. Yasuda, K. Goto, Y. Ohchi, T. Abe, H. Koga, T. Kitano, The efficacy and safety of antithrombin and recombinant human thrombomodulin combination therapy in patients with severe sepsis and disseminated intravascular coagulation, Journal of critical care 36 (2016) 29-34. [21] J.L. Vincent, M.K. Ramesh, D. Ernest, S.P. LaRosa, J. Pachl, N. Aikawa, E. Hoste, H. Levy, J. Hirman, M. Levi, M. Daga, D.J. Kutsogiannis, M. Crowther, G.R. Bernard, J. Devriendt, J.V. Puigserver, D.U. Blanzaco, C.T. Esmon, J.E. Parrillo, L. Guzzi, S.J. Henderson, C. Pothirat, P. Mehta, J. Fareed, D. Talwar, K. Tsuruta, K.J. Gorelick, Y. Osawa, I. Kaul, A randomized, doubleblind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human

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soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation, Critical care medicine 41(9) (2013) 2069-79. [22] T. Iba, S. Gando, D. Saitoh, T. Ikeda, H. Anan, S. Oda, N. Kitamura, S. Mori, J. Kotani, Y. Kuroda, Efficacy and Bleeding Risk of Antithrombin Supplementation in Patients With Septic Intravascular

Coagulation:

A

Third

Survey,

Clinical

and

applied

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Disseminated

thrombosis/hemostasis: official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis (2016).

[23] A. Sawamura, S. Gando, M. Hayakawa, H. Hoshino, N. Kubota, M. Sugano, Effects of antithrombin III in patients with disseminated intravascular coagulation diagnosed by newly

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developed diagnostic criteria for critical illness, Clinical and applied thrombosis/hemostasis: official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 15(5) (2009)

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561-6.

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Figure legends

Fig. 1: Plasma antithrombin values of all patients (A) and that of each type of antithrombin agent (B).

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More than 160% increases of ATIII values (closed squares) were found on “Days 1-2” and these values were sustained for three to five days. These levels then gradually declined for 10 days from the initiation of AT treatment. However, the ATIII value during “Days 6-10” was significantly higher than that of Day 0. The ATIII values of pAT (open circles) and rAT (closed circles), and their transition over ten days were statistically similar between groups.

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*p-value < 0.05, **p-value < 0.01.

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Fig. 2: Estimated mortalities based on APACHEII and 28-day mortalities in both groups. The estimated mortality of the rAT group was significantly higher than that of the pAT group. Although patients in the rAT group were significantly more severe with worse expected survival rate

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than those in the pAT group, there was no statistical difference in respect to the observed 28-day mortality rate between each group.

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**p-value < 0.05.

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Table 1 Patient characteristics in each group. IHD: ischemic heart disease, COPD: pulmonary disease, pAT chronic group obstructive rAT group P-value DM: diabetes mellitus, LC: liver cirrhosis. (n = 24) (n = 21) *Median [IQR], **Mean ± SD, p-value < 0.05. Age, year old,* 75 [58-82] 75 [63-83] 0.793 15

(62.5)

Body Weight, kg,**

60.6 ± 11.6 7

(29.2)

IHD, n (%)

2

(8.3)

COPD, n (%)

1

(4.2)

DM, n (%)

6

(25.0)

LC, n (%)

3

Sepsis, n (%)

0.771

60.3 ± 12.5

0.936

9

(42.9)

0.338

3

14.3

0.435

0

(0.0)

0.533

9

(42.9)

0.205

(12.5)

6

(28.6)

0.166

16

(66.7)

16

(76.2)

0.482

digestive, n (%)

5/16

(31.3)

7/16

(43.8)

respiratory, n (%)

3/16

(18.8)

3/16

(18.8)

0/16

(0.0)

1/16

(6.3)

0/16

(0.0)

2/16

(12.5)

7/16

(43.8)

2/16

(12.5)

1/16

(6.3)

1/16

(6.3)

8/15

(53.3)

9/12

(75.0)

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Infection sources

biliary, n (%) others, n (%)

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unknown, n (%)

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urinary, n (%)

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Positive blood culture, n (%)

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Malignancy, n (%)

(66.7)

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Past medical history

14

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Male, n (%)

0.296

0.226

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Table 2 Blood tests and clinical scores on the first day of AT therapy. pAT group (n = 24) 8950 4

[8025-11575]

Platelet, 10 /µL,*

7.8

[5.1-11.1]

Alb, g/dL,*

2.4

[1.9-2.8]

CRP, mg/dL,**

[1.27-1.74]

APTT, second,*

51.6

[42.8-89.2]

Fibrinogen, mg/dL,**

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371.0 ± 204.6

0.028

8.0

[4.0-14.8]

0.829

2.4

[2.1-2.8] (n = 20)

0.868

17.5 ± 11.0

[1.33-2.04] (n = 20)

0.389

53.2

[47.0-92.2]

0.585

420.0 ± 222.4 (n = 20)

0.451

FDP, µg/mL,*

23.7

[16.2-36.7] (n = 23)

38.1

DD, µg/mL,*

8.14

[6.17-17.25] (n = 16)

15.96

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0.099

1.53

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1.44

[8650-21750]

13800

12.5 ± 8.6 (n = 23)

PT-INR,*

Pvalue

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WBC, /µL,*

rAT group (n = 21)

[18.6-104.0]

0.159

[8.72-54.38] (n = 17)

0.031

2

[1-3]

3

[2-3]

0.007

SOFA, pts,*

12

[9-14]

11

[9-14]

0.973

PT

SIRS, pts,*

APACHEII, pts,**

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23.2 ± 9.4

JAAM DIC score, pts,*

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JAAM DIC, n (%)

5

18

[3-6] (75.0)

29.1 ± 6.6 6 16

0.020

[4-8]

0.298

(76.2)

0.926

WBC: white blood cell, Alb: albumin, CRP: C-reactive protein, PT-INR: international normalized ratio of prothrombin time, APTT: activated partial thromboplastin time, FDP: fibrinogen and fibrin degradation products, DD: D-dimer, SIRS: systemic inflammatory response syndrome, SOFA: sequential organ failure assessment, APACHEII: acute physiology and chronic health evaluation, JAAM: Japanese association for acute medicine, DIC: disseminated intravascular coagulation. *Median [IQR], **Mean ± SD, p-value < 0.05.

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Table 3 Variables for AT administration in the intensive care unit. pAT group (n = 24)

rAT group (n = 21)

Pvalue

1500

[1500-1500]

1800

[1800-2400]

<0.001

Initial dose of AT adjusted for BW, unit/ kg,*

26.1

[22.6-28.8]

33.9

[31.2-37.1]

<0.001

2

(9.5)

0.565

5

(23.8)

0.019

19

(90.5)

Timing of the AT therapy

after operation, n (%)

3

(12.5)

14

(58.3)

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Type of DIV

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before operation, n (%)

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Initial dose, unit,*

intermittent, n (%)

20 4

Total days of therapy, day,*

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continuous, n (%)

2

(83.3) (16.7)

2

(9.5)

[1-3]

2

[1-4]

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DIV: intravenous drip. *Median [IQR], **Mean ± SD, p-value < 0.05.

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0.400

0.461

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Table 4 Plasma ATIII values during AT treatment

Day 1-2, %,**

rAT group (n = 21)

Pvalue

42.7 ± 14.0

48.4 ± 10.9

0.139

82.8 ± 17.6 (n = 20)

0.426

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before administration, %,**

pAT group (n = 24)

78.3 ± 18.1 (n = 22)

increasing ratio between “before” and “Day 1-2”, %,*

166

[146-205] (n = 22)

161

[132-186] (n = 20)

0.302

74.2 ± 15.6 (n = 20)

78.4 ± 15.1 (n = 15)

0.430

Day 6-10, %,**

63.8 ± 24.5 (n = 12)

62.7 ± 16.0 (n = 10)

0.901

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Day 3-5, %,**

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*Median [IQR], **Mean ± SD, p-value < 0.05.

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Table 5 Bleeding complications and combined medications during the first 10 days following the initiation of AT administration. pAT group (n = 24) (25.0)

Digestive tract, n (%)

4/6

(66.7)

2/4

(50.0)

Soft tissue, n (%)

0/6

(0.0)

1/4

(25.0)

Wound, n (%)

2/6

(33.3)

0/4

(0.0)

Urinary tract, n (%)

0/6

(0.0)

1/4

(25.0)

Bleeding due to AT therapy, n (%)

heparin, n (%)

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rTM, n (%)

PT

GM, n (%)

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NM, n (%)

(19.0)

0.217

5

(20.8)

4

(19.0)

0.590

12

(50.0)

17

(81.0)

0.030

1

(4.2)

1

(4.8)

0.721

14

(58.3)

14

(66.7)

0.565

(0.0)

(0.0)

-

rTM: recombinant thrombomodulin, GM: gabexate mesylate, NM: nafamostat mesilate. P-value < 0.05.

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0.454

0

0

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Combined medications

4

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P-value

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Bleeding during AT therapy, n (%)

rAT group (n = 21)

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Table 6 Clinical outcomes. pAT group (n = 24) (58.3)

Length of ICU stay, days,*

14

[7-22]

8

[4-16]

0.175

28-day survival, n (%)

16

(66.7)

13

(61.9)

0.739

7/16

(43.8)

6/16

(37.5)

0.719

Sepsis related death, n (%)

6/9

(66.7)

P-value

7/12

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DIC recovery on day 7, n (%)

rAT group (n = 21)

0.528

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DIC: disseminated intravascular coagulation, ICU: intensive care unit. *Median [IQR], p-value < 0.05.

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Highlights 1. Efficacy of rAT agent in adult DIC patients with low AT value was evaluated. 2. Despite more severe in rAT group, the clinical outcomes were equal within groups.

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3. Administration of rAT didn’t increase the risk of bleeding complication.