Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation

doi:10.1016/j.thromres.2013.03.008

Thrombosis Research

Volume 131, Issue 5, May 2013, Pages 436-443

https://doi.org/10.1016/j.thromres.2013.03.008 Get rights and content

Abstract

Introduction

We assessed the safety and effectiveness of recombinant soluble thrombomodulin (thrombomodulin alfa, TM-α) in the treatment of disseminated intravascular coagulation (DIC) in a post-marketing surveillance.

Methods

The cases of 3548 patients with DIC caused by infection (n = 2516, Infection-DIC) or hematological malignancy (n = 1032, Hemat-DIC) were analyzed and compared to the results of a phase III (P-III) study.

Results

The DIC scores were significantly decreased in the Infection-DIC and Hemat-DIC groups with TM-α treatment (both P < 0.001). The incidences of critical bleeding adverse drug reactions (ADRs) in the Infection-DIC and Hemat-DIC groups were 2.6% and 2.4%, and the survival rates were 64.1% and 70.7%, respectively. Patients with DIC were subcategorized into three groups (Infection-DIC-1 or Hemat-DIC-1, P-III criteria-matched patients; Infection-DIC-2 or Hemat-DIC-2, P-III criteria-non-matched patients treated solely with TM-α; and Infection-DIC-3 or Hemat-DIC-3, P-III criteria-non-matched patients treated with TM-α and other concomitant anticoagulants). Subcategory analysis revealed that the incidences of critical bleeding ADRs of Hemat-DIC-2 and Hemat-DIC-3 were significantly higher and their survival rates were significantly lower than those of Hemat-DIC-1. By multivariate analysis in Hemat-DIC, younger age (odds ratio: 2.629, P = 0.0033) and pre-existing bleeding (odds ratio: 2.044, P = 0.019) were found to affect bleeding ADRs and the severity of underlying disease was the most important factor for survival rate (odds ratio: 0.288, P < 0.001).

Conclusions

This surveillance provided real-world data for the safety and effectiveness of TM-α in the treatment of Infection-DIC and Hemat-DIC in general practice settings.

Introduction

Disseminated intravascular coagulation (DIC) is pathological microthrombus formation followed by thrombolysis in the systemic circulation, leading to the consumption of coagulation factors and platelets [1], [2], [3], [4]. Microthrombus formation causes organ ischemia, often leading to organ failure. The consumption of platelets and coagulation factors results in thrombocytopenia and a deficiency of coagulation factors, creating a bleeding tendency. In addition, neutrophil proteases and fibrinolysis inhibitors modulate the pathological condition of DIC [5], [6], [7]. Disseminated intravascular coagulation is frequently associated with a variety of diseases, such as severe infection, hematological malignancies, and advanced tumors. In addition to these diseases, many pathological conditions provoke DIC [1], [2], [3], [4]. The mortality rate in patients having DIC was higher than those without DIC and DIC treatment reduces the mortality of patients with DIC [8], [9], [10]. In this regard, treatment of DIC together with therapy for the underlying diseases may be important to increase survival rates and improve the prognosis of patients with DIC.

Anticoagulant therapy to address systemic pathological thrombus formation is the principle of DIC treatment. In addition to unfractionated heparin (the mainstay of DIC treatment), low molecular weight heparin, heparinoid, synthetic protease inhibitors, and antithrombin concentrates have been developed and used for the treatment of DIC [4], [8], [9]. Two recombinant bioactive molecules, activated protein C (drotrecogin alfa) and soluble thrombomodulin (thrombomodulin alfa, TM-α), have been developed. The safety and effectiveness of a novel medicine as evidenced by a randomized clinical trial need to be confirmed by a post-marketing evaluation enrolling a large number and broad spectrum of patients in general practice settings [11], [12].

Thrombomodulin alfa was developed for the treatment of patients with DIC. Thrombomodulin alfa suppresses thrombus formation by inhibiting thrombin coagulation activity and by activating protein C in complex with thrombin [13], [14]. Thrombomodulin alfa was shown to be more effective than heparin for the treatment of infection-induced DIC (Infection-DIC) and hematological malignancy-associated DIC (Hemat-DIC) in a phase III trial (P-III) in Japan [15]. The TM-α P-III employed patient criteria that excluded patients who had renal failure, severe liver diseases, or a severe clinical condition. Therefore, the safety and efficacy of TM-α in such patients with DIC were not demonstrated by P-III. Since the approval of TM-α for DIC treatment by the Japanese Ministry of Health, Labour, and Welfare (JMHLW) in 2008, an all-case registered post-marketing surveillance (PMS) of TM-α has been conducted by the requirement of, and under the supervision of, the JMHLW. The aims of this surveillance are to assess the safety and effectiveness of TM-α and to identify risk factors affecting the safety and effectiveness of TM-α in general practice settings. Here we show the results of the surveillance of 3548 patients with DIC associated with infection or hematological malignancy treated with TM-α.

Section snippets

Study Design

This PMS was started in May 2008 with an all-case investigation method. All patients who received TM-α were consecutively registered upon initiation of treatment for DIC by documenting the patient demographics using a central registration system. All patients were prospectively monitored during the observation period (from the initiation of TM-α administration to Day 28 after the last administration). Thrombomodulin alfa was drip-infused for 30 min once daily in the same manner as in P-III [15].

Registry of the Patients with DIC Enrolled in this Surveillance and Their Demographics

The registration of patients treated with TM-α is shown schematically in Fig. 1. Of the 4342 patients reported to the surveillance center, 82 patients were excluded because of double entry or no case records reported. There were 198 patients who were treated with TM-α at least twice because of recurrence of DIC. There were 4062 patients treated with TM-α for the first time during the surveillance period. The two major underlying disease categories were Infection-DIC (n = 2516, 61.9%) and

Discussion

The safety and effectiveness of a novel medicine as evidenced by a randomized clinical trial need to be confirmed by a post-marketing evaluation enrolling a large number and broad spectrum of patients in general practice [11]. For example, the effectiveness of drotrecogin alfa for sepsis was not confirmed by the post-marketing PROWESS SHOCK trial [12] and many serious bleeding ADRs of dabigatran, including death from bleeding, occurred in elderly patients after marketing [22], [23]. Many

Acknowledgments

The authors thank all physicians who participated in this post-marketing surveillance. This work was partly supported by the Japanese Society on Thrombosis and Hemostasis.

Conflict of Interest Statement

Tatsuhiko Kuroda is an employee of Asahi Kasei Pharma Corporation. The other authors declare no competing financial interests.

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Miliary tuberculosis-associated hemophagocytic lymphohistiocytosis with a high level of soluble interleukin-2 receptor successfully treated with concomitant recombinant thrombomodulin: A case report
2023, Journal of Infection and Chemotherapy
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Recombinant thrombomodulin (rTM) is an anticoagulant clinically approved for DIC treatment in Japan [6]. Owing to its anticoagulant and anti-inflammatory properties, rTM has proved to be effective for infection-based DIC, with a low incidence of bleeding events [7]. Since the severity of HLH is dependent upon uncontrolled T lymphocyte activation and secretion of a large number of cytokines, such as IL-1, IL-6, and tumor necrosis factor-alpha, the anti-inflammatory effect of rTM may help curb HLH activity.
Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease characterized by a highly inflammatory state due to the abnormal activation of T lymphocytes and macrophages. Miliary tuberculosis (MTB) is a rare cause of HLH and its clinical appearances occasionally resembles that of intravascular lymphoma (IVL). A 76-year-old woman presented with persistent fever and fatigue. Abnormal laboratory findings showing thrombocytopenia (13,000/μL), hypofibrinogenemia (101 mg/dL), hyperferritinemia (2,312 ng/mL), and markedly elevated soluble interleukin-2 receptor (sIL-2R) level (32,200 U/mL), in addition, hemophagocytosis in the bone marrow (BM) smear, were suggestive of IVL-associated HLH. The pathology of the BM biopsy specimen showed granuloma with non-caseous necrosis, and culture tests using sputum, gastric fluid, urine, and peripheral and bone marrow blood revealed the presence of Mycobacterium tuberculosis, leading to the final diagnosis of MTB-associated HLH. Anti-TB medications and corticosteroids were administered, but thrombocytopenia, hypofibrinogenemia, and hyperferritinemia persisted. Concomitant use of recombinant thrombomodulin (rTM) enabled regression of clinical status. In this case, BM biopsy served as the diagnosis of MTB-associated HLH, although IVL-associated HLH is initially suspected by an extremely high level of sIL-2R. Furthermore, this case report informs that using rTM could improve the outcomes of MTB-associated HLH.
A case of thrombomodulin mutation causing defective thrombin binding with absence of protein C and TAFI activation
2020, Blood Advances
Thrombomodulin functions as an anticoagulant through thrombin binding and protein C activation. We herein report the first case of hereditary functional thrombomodulin deficiency presenting with recurrent subcutaneous hemorrhage and old cerebral infarction. The patient had a homozygous substitution of glycine by aspartate at amino acid residue 412 (Gly412Asp) in the thrombin-binding domain of the thrombomodulin gene (designated thrombomodulin-Nagasaki). In vitro assays using a recombinant thrombomodulin with the same mutation as the patient showed a total lack of thrombin binding and activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI). Marked clinical and laboratory improvement was obtained with recombinant human soluble thrombomodulin therapy.
Surveillance of the safety and efficacy of recombinant human soluble thrombomodulin in patients with obstetrical disseminated intravascular coagulation
2017, Thrombosis Research
Citation Excerpt :
Consequently, the hemorrhage could not be clearly attributed to TM-α itself. The incidences of ADRs related to hemorrhage in patients with DIC resulting from infection or hematologic malignancy in the post-marketing surveillance for TM-α were 5.4% and 4.6%, respectively [22], showing no apparent increase with obstetrical DIC. TAFIa, produced in response to TM-α, has an inhibitory effect on fibrinolysis.
Recombinant human soluble thrombomodulin (TM-α) has been shown to be useful in the treatment of disseminated intravascular coagulation (DIC) in a heparin-controlled study, and has been available for clinical use in Japan since 2008. However, use of TM-α for obstetrical DIC has not yet been established, so efficacy and safety were analyzed in 117 obstetrical DIC patients identified from post-marketing surveillance.
From June 2010 to March 2012, the cases of 117 patients with obstetrical DIC treated with TM-α were registered.
In the majority of cases, the underlying disease was DIC-type postpartum hemorrhage (n = 43) or placental abruption (n = 37). Mean (± standard deviation) obstetrical DIC score was 10.6 ± 4.9. Mean duration of TM-α administration was 2.2 ± 1.7 days. The most commonly used concomitant anticoagulants were antithrombin (n = 60) and gabexate mesilate (n = 37). Concomitantly used blood components products included red blood cell concentrate (n = 72), fresh frozen plasma (n = 70), and platelet concentrate (n = 31). Hemostatic test result profiles revealed significant improvement of fibrinogen/fibrin degradation products, D-dimer, fibrinogen, prothrombin time and activated partial thromboplastin time. Efficacies of TM-α as evaluated by “The efficacy evaluation criteria for DIC in obstetrics” at 24 h, 48 h and the day after last administration of TM-α were 72.3%, 82.4% and 90.2%, respectively. Total bleeding adverse drug reactions occurred in 6 patients (5.1%).
This surveillance confirmed the safety and efficacy of TM-α in clinical practice. These findings thus indicated that the efficacy of TM-α is comparable to that of previously investigated obstetrical DIC pharmacotherapies.
Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting
2017, Progress in Biophysics and Molecular Biology
Citation Excerpt :
One might also expect that anticoagulant therapies might show benefit, and there are some significant hints that this too might indeed be the case (Barber et al., 2004; Murthy et al., 2009; Ratner et al., 1972; Walsh, 1996; Walsh et al., 1978), to the extent that this would seem to be well worth exploring properly. The success of the anticoagulant thrombomodulin in sepsis/septic shock (Eguchi et al., 2014; Hayakawa et al., 2016; Levi, 2015; Levi and Van Der Poll, 2013b; Mimuro et al., 2013; Saito et al., 2007; Shirahata et al., 2014; Vincent et al., 2013; Yamakawa et al., 2015; Yoshimura et al., 2015) also implies an important role of coagulopathies there. Since the levels of fibrinogen themselves seem to correlate with a propensity for AD (see above), and indeed for hypertension (Bembde, 2012; Haenni and Lithell, 1996; Letcher et al., 1981; Shankar et al., 2006), lowering them to more appropriate levels (by means other than by converting them to amyloid forms of fibrin!)
The chief and largely terminal element of normal blood clotting is considered to involve the polymerisation of the mainly α-helical fibrinogen to fibrin, with a binding mechanism involving ‘knobs and holes’ but with otherwise little change in protein secondary structure. We recognise, however, that extremely unusual mutations or mechanical stressing can cause fibrinogen to adopt a conformation containing extensive β-sheets. Similarly, prions can change morphology from a largely α-helical to largely β-sheet conformation, and the latter catalyses both the transition and the self-organising polymerisation of the β-sheet structures. Many other proteins can also do this, where it is known as amyloidogenesis. When fibrin is formed in samples from patients harbouring different diseases it can have widely varying diameters and morphologies. We here develop the idea, and summarise the evidence, that in many cases the anomalous fibrin fibre formation seen in such diseases actually amounts to amyloidogenesis. In particular, fibrin can interact with the amyloid-β (Aβ) protein that is misfolded in Alzheimer's disease. Seeing these unusual fibrin morphologies as true amyloids explains a great deal about fibrin(ogen) biology that was previously opaque, and provides novel strategies for treating such coagulopathies. The literature on blood clotting can usefully both inform and be informed by that on prions and on the many other widely recognised (β-)amyloid proteins. A preprint has been lodged in bioRxiv (Kell and Pretorius, 2016).
Recombinant soluble thrombomodulin for postoperative disseminated intravascular coagulation
2015, Journal of Surgical Research
Citation Excerpt :
These patients were treated with or without rhTM from April 2010–July 2013. Patients who fulfilled the criteria of the Japanese Association for Acute Medicine (JAAM) DIC scoring system [17] (DIC score of ≥4) were included in the investigation, and those who did not fulfill these criteria (DIC score of ≤3) were excluded (Fig. 1). No predefined protocol regarding the definite indications for rhTM treatment was used in this retrospective study.
Thrombomodulin is a thrombin receptor on the endothelial cell surface that plays an important role in the regulation of intravascular coagulation. The purpose of this study was to evaluate the efficacy and safety of treatment with recombinant human soluble thrombomodulin (rhTM) for patients with septic-disseminated intravascular coagulation (DIC) associated with gastroenterological surgery.
From April 2011–September 2013, 201 patients with DIC associated with gastroenterological surgery were treated in 16 institutions in Kumamoto, Japan. The patients were diagnosed according to the Japanese Association for Acute Medicine DIC scoring system. The clinical course, mortality rate at 28 d, and adverse events were evaluated retrospectively.
Forty-five patients were excluded because they did not meet the Japanese Association for Acute Medicine DIC criteria or had an insufficient duration of drug administration. Thus, 156 patients were analyzed. Of these patients, 107 received rhTM at the discretion of the attending surgeon and 49 did not. The most common reason for surgery in both groups was peritonitis due to perforation of the colon. Within 7 d, the platelet count, prothrombin time–international normalized ratio, DIC score, neutrophil count, and C-reactive protein level significantly improved in the rhTM group compared with those in the control. Treatment with rhTM was significantly associated with reduced inhospital mortality at 28 d. The incidence of adverse events did not differ between the two groups.
Therapy with rhTM may be associated with reduced inhospital mortality in patients with septic DIC associated with gastroenterological surgery without increasing adverse events.
Recombinant human soluble thrombomodulin in severe sepsis: A systematic review and meta-analysis
2015, Journal of Thrombosis and Haemostasis
Although recombinant human soluble thrombomodulin (rhTM) is a widely used novel anticoagulant agent for disseminated intravascular coagulation (DIC) in Japan, its clinical efficacy in sepsis‐induced DIC has not been demonstrated convincingly.
To assess the benefits and harms of rhTM in sepsis‐induced DIC patients.
We conducted a systematic review and meta‐analysis of rhTM therapy for sepsis‐induced DIC for both randomized controlled trials (RCTs) and observational studies (retrospective case‐control studies and/or prospective cohort studies) separately. All‐cause mortality (28–30 days) as efficacy and serious bleeding complications as adverse effect were measured as primary outcomes. We assessed body of evidence quality at the outcome level by using the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach.
We analyzed 12 studies (838 patients/3 RCTs; 571 patients/9 observational studies). Pooled relative risk was 0.81 (95% CI, 0.62–1.06) in the RCTs, indicating non‐significant reduction in mortality, and 0.59 (95% CI, 0.45–0.77) in the observational studies. Meta‐regression analysis revealed a significant negative slope between effect size of rhTM therapy and baseline mortality rate in individual studies (P=0.012), suggesting that probability of a beneficial effect with rhTM therapy increases with increasing baseline risk. Risk of serious bleeding complications was not significantly different between rhTM and control groups. We judged the quality of evidence as moderate for mortality and serious bleeding.
The rhTM was associated with a trend in reduction of mortality at 28–30 days in sepsis‐induced DIC patients. Further large rigorous trials are needed to confirm or refute these findings before implications for practice are clear.

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Regular ArticleImpact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation

Abstract

Introduction

Methods

Results

Conclusions

Introduction

Section snippets

Study Design

Registry of the Patients with DIC Enrolled in this Surveillance and Their Demographics

Discussion

Acknowledgments

Blood

Thromb Res

J Thromb Haemost

Thromb Res

J Thromb Haemost

Lancet

J Thromb Haemost

Biologicals

Am J Geriatr Pharmacother

Leuk Res

Disseminated intravascular coagulation

N Engl J Med

Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation

Thromb Haemost

Disseminated intravascular coagulation: old disease, new hope

BMJ

Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology

Br J Haematol

Regular Article
Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation