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Hypobrinogenemia is Associated With a High Degree of Risk in Infectious and Hematological Diseases: A Post-Hoc Analysis of Post-Marketing Surveillance of Patients With Disseminated Intravascular Coagulation Treated With Thrombomodulin Alfa

Introduction In patients with infectious diseases, disseminated intravascular coagulation (DIC) is often diagnosed without the brinogen value and the relationship between hypobrinogenemia and the outcomes of infectious DIC has remained unclear. Materials and Methods We analyzed 3204 patients who received with thrombomodulin alfa (TM-α) for with DIC and suspected DIC. Hypobrinogenemia was dened by a brinogen level of <1.5 g/L. Results Hypobrinogenemia was observed in 10.3% of patients with infectious diseases. The frequencies of both bleeding and organ failure symptoms, and the scores for organ failure or the DIC diagnostic criteria were signicantly high in infectious disease patients with hypobrinogenemia, suggesting that in patients with infectious diseases, hypobrinogenemia is associated with more progressive and severe DIC. Although the 28-day survival rate and the DIC resolution rate were both signicantly lower in infectious disease patients with DIC with hypobrinogenemia than in those without hypobrinogenemia, this difference was not observed in DIC patients with hematological diseases. Conclusion In infectious disease patients with DIC, hypobrinogenemia may reect from the increased consumption of brinogen due to an accelerated coagulating reaction, while that in hematological disease patients DIC may be caused by brinogenolysis due to hyperbrinolysis, and frequently results in bleeding and multiple-organ failure. monocytic myeloma stem cell chronic myelogenous


Introduction
Disseminated intravascular coagulation (DIC), which occurs in association with various underlying diseases, such as sepsis, hematological malignancy, solid tumors and aneurysm, is often associated with severe and life-threatening bleeding or organ failure with [1][2][3]. DIC is characterized by the systemic activation or consumption of components in the coagulation pathways, such as increased brin generation or thrombocytopenia, resulting in multiple-organ failure or bleeding tendency [4][5].
The diagnostic criteria for DIC have been established by the Japanese Ministry of Health and Welfare (JMHW) [6], the International Society of Thrombosis Haemostasis (ISTH) [4], the Japanese Association for Acute Medicine (JAAM) [7] and the Japanese Society of Thrombosis and Hemostasis (JSTH) [8]. These four sets of diagnostic criteria are all based on scoring systems using similar laboratory tests; however, the cutoff values for DIC scores and laboratory test results differ. The JSTH diagnostic criteria [8,9] classi ed the diseases underlying DIC into infectious, hematopoietic disorder and basic types.
The guidelines for the diagnosis and treatment of DIC have been published by the British Committee for Standards in Haematology (BCSH) [10], the JSTH [11], the Italian Society for Thrombosis and Haemostasis (SISET) [12] and the ISTH [13]. Most guidelines show that infectious-type DIC is frequently associated with organ failure, whereas hypo brinogenemia or bleeding tendency are less common. They have recommended the treatment of DIC via treatment of the underlying diseases, along with supportive therapy such as administration of platelet concentrates and fresh frozen plasma [10][11][12][13]. The administration of antithrombin (AT) and thrombomodulin alfa (TM-α) are also recommended in the JSTH guidelines [11,14]. A phase 3 study [15] and several retrospective studies [16][17][18], including post-marketing surveillance (PMS), have reported the e cacy and safety of TM-α for DIC patients with infectious and hematological diseases. A randomized controlled trial of AT, activated protein C and TM-α for severe sepsis failed to con rm any signi cant improvement in the outcomes of patients with severe sepsis [19][20][21].
The present study examined the frequency of hypo brinogenemia in infectious and hematological diseases with DIC and suspected DIC, and analyzed the characteristics of hypo brinogenemia in infectious disease patients with DIC.

Patients And Methods
The clinical characteristics and treatment outcomes of patients with DIC and suspected DIC that was treated with TM-α between May 2008 and April 2010 were retrospectively analyzed in a subgroup analysis of PMS data. The original PMS study was an open-label, multicenter, non-interventional, prospective, observational cohort study of patients with DIC who received TM-α [16]. The PMS for TM-α was conducted in accordance with the Japanese Society on Thrombosis and Hemostasis Post-Marketing Surveillance Committee for Recomodulin Injection and the guidelines for Good Postmarketing Study Practice, as required by the Japanese Ministry of Health, Labour, and Welfare (JMHLW). We used existing data without personally identi able information throughout our study. The original PMS study was therefore exempted from local institutional review and formal approval, as well as the requirement for informed consent. In the PMS for TM-α, all patients were diagnosed with DIC and suspected DIC by attending physicians based on JMHLW or JAAM diagnostic criteria.
The DIC resolution rate, 28-day survival rate, rates of adverse drug reaction and bleeding-related adverse drug reactions were investigated. The degree of coagulopathy was evaluated by calculating DIC scores according to the DIC diagnostic criteria of the JAAM [7] for infectious diseases and those of the JMHW [6] and ISTH [4] for hematological diseases. After treatment with TM-α, resolution of DIC was de ned as a score ≤3 using the diagnostic criteria of the JAAM, ≤2 using the diagnostic criteria of the JMHW for DIC in patients with hematological diseases, ≤5 using the diagnostic criteria of the JMHW for infectious diseases, and ≤4 using the diagnostic criteria of the ISTH for both diseases. The PMS for TM-α started before the establishment of the JSTH DIC diagnostic criteria. As a result, there were few records that included "change of platelet count" or a few data for SF and TAT; thus, the JSTH scores could not be calculated. Survival was calculated at 28 days from the beginning of TM-α treatment or at the end of observation.
In patients with infectious diseases, the severity of organ failure was assessed using the sequential organ failure assessment (SOFA) score [22]. The symptoms of organ failure were decided by the attending physician based on clinical signs indicating organ dysfunction due to DIC [6]. Laboratory tests such as the white blood cell (WBC) count and platelet count, and the measurement of hemoglobin, albumin, lactate dehydrogenase (LDH), total bilirubin (T-Bil), creatine and Creactive protein (CRP) levels, and hemostatic tests such as the prothrombin time (PT)-international ratio (INR), activated partial thromboplastin time (APTT), brinogen, brinogen, brin degradation products (FDP), D-dimer, AT, protein C, thrombin-AT complex (TAT) and plasmin-α2 plasmin inhibitor complex (PIC) were performed in each participating institute. Patients with brinogen < 1.5 g/L were considered to have hypo brinogenemia. The rates of adverse drug reaction and bleeding-related adverse drug reaction were evaluated from the start of TM-α treatment to day 28 after the end of TM-α treatment. The safety data were coded using preferred terms from the Japanese translation of the Medical Dictionary for Regulatory Activities (version 13.1)

Statistical analysis
In the descriptive analyses of baseline characteristics, numerical data were expressed as the median (Q1, Q3; interquartile range). The chi-square test and the Wilcoxon signed-rank test were performed as statistical analyses. P values of < 0.05 were considered to indicate statistical signi cance. Multiplicity adjustment was not considered. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) by EPS Corporation (Tokyo, Japan) according to the plan for the statistical analysis.

Results
Among cases in which the brinogen levels were measured, hypo brinogenemia ( brinogen < 1.5 g/L) was observed in 10.3% (215/2083) of the patients with infectious diseases, and 27.8% (312/1121) of the patients with hematological diseases (Table 1). In both diseases, the ratio of males was slightly lower among patients with hypo brinogenemia than among those without hypo brinogenemia. Before registration, the administration rate of AT concentrate administration was signi cantly lower in the infectious disease patients with hypo brinogenemia than in those without hypo brinogenemia. The rates of bleeding and organ failure symptoms were both signi cantly higher in infectious disease patients with hypo brinogenemia than in those without hypo brinogenemia. The median SOFA, JMHW, ISTH and JAAM scores were signi cantly higher in infectious disease patients with hypo brinogenemia (11, 9, 5 and 6, respectively) than in those without hypo brinogenemia (10, 6, 4 and 5, respectively; Table 2).
Regarding the hemostatic examinations, the PT-INR was signi cantly prolonged among patients with hypo brinogenemia, and the brinogen and AT levels were signi cantly lower among patients with hypo brinogenemia than among those without hypo brinogenemia ( Table 3). The FDP, D-dimer and TAT levels were signi cantly higher among patients with hypo brinogenemia than among those without hypo brinogenemia. The PIC levels in infectious disease patients with and without hypo brinogenemia did not differ to a statistically signi cant extent; however, the PIC levels in hematological disease patients with hypo brinogenemia were signi cantly higher than in those without hypo brinogenemia. The platelet counts in infectious disease patients were signi cantly lower among patients with hypo brinogenemia than among those without hypo brinogenemia (Supplementary Table 1). In both diseases, the albumin and LDH levels were signi cantly higher and the CRP levels were signi cantly lower in patients with hypo brinogenemia than in those without hypo brinogenemia.
In the treatment of DIC, the TM-α dose and the period of administration in patients with and without hypo brinogenemia did not differ to a statistically signi cant extent (Supplementary Table 2). AT concentrate, gabexate mesylate, nafamostat mesylate, unfractionated heparin, low molecular weight heparin, danaparoid sodium, platelet concentrates, fresh frozen plasma and red blood cells were also administered, as shown in Supplementary Table 2. Although the 28-day survival rate of infectious disease patients with hypo brinogenemia (50.0%) was signi cantly lower (p < 0.0001) than that of infectious disease patients without hypo brinogenemia (71.6%), the 28-day survival rate of hematological diseases patients with and without hypo brinogenemia did not differ to a statistically signi cant extent ( Table 4). The resolution rates according to the JMHW, ISTH and JAAM DIC diagnostic criteria were signi cantly lower (p = 0.0058, p < 0.0001 and p < 0.0001, respectively) in infectious disease patients with hypo brinogenemia than in those without hypo brinogenemia; this difference was not observed in the hematological disease patients with and without hypo brinogenemia. In both the infectious disease and hematological disease groups, the clinical course of bleeding symptoms did not differ between patients with and without hypo brinogenemia.

Discussion
As hypo brinogenemia is frequently related to the bleeding tendency in hematological diseases patient with DIC and organ failure is often associated with infectious disease patient with DIC, hypo brinogenemia is considered to be frequently associated with DIC in patients with hematological diseases but rarely with DIC in patients with infectious disease [5,14]. However, some septic cases have been reported to be associated with severe bleeding [23,24]. Our analysis of the PMS data revealed that hypo brinogenemia was present in 10.3% of infectious diseases with DIC and suspected DIC, suggesting that hypo brinogenemia is sometimes associated with infectious-type DIC. As the DIC scores were high, many patients in this study were considered to meet the de nition of severe DIC. Thus, the frequency of hypo brinogenemia in infectious disease DIC may generally be less than 10.3%. Both the frequency of bleeding and organ failure symptoms, and SOFA, JMHW, ISTH and JAAM scores were signi cantly higher in infectious-type DIC patients with hypo brinogenemia than in those without hypo brinogenemia, suggesting that the hypo brinogenemia in infectious-type DIC can be considered to indicate severe and advanced DIC, in which patients exhibit both bleeding and organ-failure symptoms.
The platelet count in infectious-type DIC patients with hypo brinogenemia was lower in comparison to those without hypo brinogenemia, suggesting that the more severer thrombocytopenia contributes to increased bleeding symptoms or is re ected by multiple thrombi and a subsequent poor prognosis.
The APTT, AT, FDP, D-dimer and TAT levels were signi cantly greater in patients with hypo brinogenemia than in those without. In patients with infectious-type DIC, no signi cant differences in PIC levels were seen between the subgroups with and without hypo brinogenemia; however, in hematological disease patients with DIC, the PIC levels were signi cantly higher in patients with hypo brinogenemia than in those without. These ndings indicate that the mechanisms of hypo brinogenemia may differ between infectious-type DIC and DIC in patients with hematological diseases, in whom DIC often causes hyper brinolysis due to hyper-plasminogen activation by leukemic cells [25,26]. Conversely, the relatively low levels of PIC did not show hyper brinolysis in patients with infectious-type DIC with hypo brinogenemia, and the increased FDP and D-dimer levels showed the progression of DIC, resulting in high SOFA scores in patients with this type of DIC.
Reduced AT levels may be caused by decreased production due to liver dysfunction, the consumption of AT, leakage into the third space due to increased permeability of vascular endothelial cells [27] or less administration of AT. Although a high DIC score indicates the existence of consumption coagulopathy in DIC patients with severe AT de ciency, decreased albumin and choline esterase levels and increased T-Bil and creatinine levels suggest that liver dysfunction, plasma leakage, or renal dysfunction might play some role in AT de ciency in patients with DIC. In comparison, the mechanisms underlying hypo brinogenemia in infectious-type DIC are suggested to involve a progressive hypercoagulable state that disseminates and causes the consumption of coagulation factors, such as brinogen.
Before registration, the frequency of AT administration was signi cantly lower in infectious disease patients with hypo brinogenemia than in those without, suggesting that single anticoagulation therapy tended to be selected in daily clinical practice. An another possibility is that infectious-type DIC may result in hypo brinogenemia with low AT levels in patients who are not treated with AT. The effect of recombinant thrombomodulin administration in sepsis-induced coagulopathy in the SCARLET study [21] was not statistically signi cant. However, a post hoc analysis revealed a 5.4% reduction in absolute mortality among patients who ful lled the entry criterion at baseline [28]. Although no signi cant differences in the TM-α dose or the period of administration were seen between these two states in both types of DIC, the 28-day survival rate and resolution rate according to JMHW, ISTH or JAAM diagnostic criteria in infectious-type DIC with hypo brinogenemia were signi cantly lower than in infectious-type DIC without hypo brinogenemia; this was only observed in infectious-type DIC. As the mechanism of hypo brinogenemia differs between infectious-type DIC and hematological-type DIC, hypo brinogenemia is considered to be associated with a high risk of infectious-type DIC, but not hematological-type DIC. That is, hypo brinogenemia may be correlated with the severity of infectious-type DIC, but in hematological-type DIC, it may be caused by hyper brinolysis, which is not associated with poor outcomes. Conversely, no signi cant differences in the 28-day survival rate or the resolution rate (according to the JMHW, ISTH or JAAM diagnostic criteria for DIC) were evident in hematological disease patients with DIC. DIC patients with increased brinogen levels were previously reported to show poor outcomes; however, that previous study included many patients with hematological diseases [29]. High brinogen levels might be associated with a hypo brinolytic state and elevated levels of plasminogen activator inhibitor 1 [30], which is a biomarker for a poor outcome or organ failure due to infection. PMS data for TM-α did not show details of bleeding or organ failure symptoms related to the mortality in infectious disease patients with hypo brinogenemia. Further studies to examine the relationships between severe bleeding or organ failure with hypo brinogenemia and poor outcome in infectious disease patients with DIC are needed.
In conclusion, infectious-type DIC is sometimes associated with hypo brinogenemia, which re ects the increased consumption of brinogen due to accelerated coagulation. Hypo brinogenemia in infectious type-DIC is therefore associated with poor outcomes, and the monitoring of brinogen levels appears important in the management of infectious-type DIC. Availability of data and materials: The data supporting the ndings of this study are available from Asahi Kasei Pharma Corporation; however, restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.