Detection of a Prethrombotic State in Patients with Hepatocellular Carcinoma, Using a Clot Waveform Analysis.

Background: Although hepatocellular carcinoma (HCC) is frequently associated with thrombosis, it is also associated with liver cirrhosis (LC) which causes hemostatic abnormalities. Therefore, hemostatic abnormalities in patients with HCC were examined using a clot waveform analysis (CWA). Methods: Hemostatic abnormalities in 88 samples from HCC patients, 48 samples from LC patients and 153 samples from patients with chronic liver diseases (CH) were examined using a CWA-activated partial thromboplastin time (APTT) and small amount of tissue factor induced FIX activation (sTF/FIXa) assay. Results: There were no significant differences in the peak time on CWA-APTT among HCC, LC, and CH, and the peak heights of CWA-APTT were significantly higher in HCC and CH than in HVs and LC. The peak heights of the CWA-sTF/FIXa were significantly higher in HCC than in LC. The peak times of the CWA-APTT were significantly longer in stages B, C, and D than in stage A or cases of response. In the receiver operating characteristic (ROC) curve, the fibrin formation height (FFH) of the CWA-APTT and CWA-sTF/FIXa showed the highest diagnostic ability for HCC and LC, respectively. Thrombosis was observed in 13 HCC patients, and arterial thrombosis and portal vein thrombosis were frequently associated with HCC without LC and HCC with LC, respectively. In ROC, the peak time×peak height of the first derivative on the CWA-sTF/FIXa showed the highest diagnostic ability for thrombosis. Conclusion: The CWA-APTT and CWA-sTF/FIXa can increase the evaluability of HCC including the association with LC and thrombotic complications.

Association of D-dimer level with thrombotic events, bleeding, and mortality in Japanese patients with solid tumors: a Cancer-VTE Registry subanalysis.

BACKGROUND: The D-dimer test is a simple test frequently used in routine clinical screening for venous thromboembolism (VTE). The Cancer-VTE Registry was a large-scale, multicenter, prospective, observational study in Japanese patients with cancer. This study aimed to clarify the relationship between D-dimer level at cancer diagnosis (baseline) and the incidence of events during cancer treatment (1-year follow-up period). METHODS: This was a post hoc sub-analysis of patients from the Cancer-VTE Registry whose D-dimer levels were measured at baseline. The incidence of events during the 1-year follow-up period was evaluated stratified by baseline D-dimer level. Adjusted hazard ratios for D-dimer level and events during the follow-up period were evaluated. RESULTS: Among the total enrolled patients, baseline D-dimer level was measured in 9020 patients. The mean ± standard deviation baseline D-dimer level was 1.57 ± 3.94 µg/mL. During the follow-up period, the incidence of VTE, cerebral infarction/transient ischemic attack (TIA)/systemic embolic events (SEE), bleeding, and all-cause death increased with increasing baseline D-dimer level. The incidence of all-cause death increased with increasing D-dimer level regardless of cancer stage. The adjusted hazard ratio of all-cause death was 1.03 (95% confidence interval: 1.02-1.03) per 1.0-µg/mL increase in baseline D-dimer level. CONCLUSIONS: Increases in D-dimer levels were associated with a higher risk of thrombotic events, such as VTE and cerebral infarction/TIA/SEE, during cancer treatment. Furthermore, higher D-dimer levels at cancer diagnosis were associated with a higher mortality rate, regardless of cancer stage.

Super Formula for Soluble C-Type Lectin-Like Receptor 2 × D-Dimer in Patients With Acute Cerebral Infarction.

Acute cerebral infarction (ACI) includes atherosclerotic and cardiogenic ACI and involves a thrombotic state, requiring antithrombotic treatment. However, the thrombotic state in ACI cannot be evaluated using routine hemostatic examinations. Plasma soluble C-type lectin-like receptor 2 (sCLEC-2) and D-dimer levels were measured in patients with ACI. Plasma sCLEC-2 and D-dimer levels were significantly higher in patients with ACI than in those without it. The sCLEC-2 × D-dimer formula was significantly higher in patients with ACI than in those without it. A receiver operating characteristic curve showed a high sensitivity, area under the curve, and odds for diagnosing ACI in the sCLEC-2 × D-dimer formula. Although the sCLEC-2 and D-dimer levels were useful for the differential diagnosis between cardiogenic and atherosclerotic ACI, the sCLEC-2 × D-dimer formula was not useful. sCLEC2 and D-dimer levels are useful for the diagnosis of ACI and the sCLEC2 × D-dimer formula can enhance the diagnostic ability of ACI, and sCLEC2 and D-dimer levels may be useful for differentiating between atherosclerotic and cardioembolic ACI.

A systematic review and meta-analysis of recombinant human soluble thrombomodulin for the treatment of DIC associated with hematological malignancies.

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) is commonly used in Japan to treat disseminated intravascular coagulation (DIC), but its efficacy compared with other anticoagulants is unclear. We conducted a systematic review and meta-analysis to investigate this issue in DIC patients with hematological malignancies. METHODS: We searched PubMed, Cochrane, and Scopus for prospective and retrospective studies evaluating the efficacy and safety of rhTM in DIC patients with hematological malignancies between April 2008 and April 2023. We performed a systematic review and meta-analysis evaluating recovery from DIC, hemorrhagic adverse events (AEs), and overall survival (OS). RESULTS: We analyzed one prospective (64 patients) and seven retrospective studies (209 patients). Use of rhTM was associated with a higher rate of recovery from DIC (OR: 2.25 [1.09-4.63] and 1.98 [1.12-3.50] in prospective and retrospective studies, respectively; same order below) and fewer hemorrhagic AEs (OR: 0.83 [0.30-2.30] and 0.21 [0.08-0.57]). rhTM did not improve OS (OR: 1.06 [0.42-2.66] and 1.72 [0.87-3.39]), although the incidence of hemorrhagic death was lower in the rhTM group (0 of 94 patients). CONCLUSION: Use of rhTM in patients with hematological malignancy-associated DIC is strongly expected to be effective and safe.

The antithrombin activity recovery after substitution therapy is associated with improved 28-day mortality in patients with sepsis-associated disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a common and critical complication in sepsis. Antithrombin activity, which is considered a biomarker for disease severity, was measured in septic DIC treated with antithrombin concentrates in this study. METHODS: We conducted a retrospective analysis of post-marketing survey data that included 1,800 patients with sepsis-associated DIC and antithrombin activity of 70% or less who were treated with antithrombin concentrates. The changes in sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were sequentially assessed. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of antithrombin activity to assess 28-day survival. Furthermore, the relationship between post-treatment antithrombin activity and survival was examined by Logistic regression analysis. RESULTS: Sex, baseline SOFA score, baseline antithrombin activities, and the presence of pneumonia and soft tissue infection were significantly associated with 28-day mortality. The area under the curve for mortality was 0.639 for post-treatment antithrombin activity, and higher than those of baseline- and delta antithrombin activities. Logistic regression analysis revealed that higher post-treatment antithrombin activity was associated with better 28-day survival. When post-treatment antithrombin activity was more than 80%, the estimated survival was 88.2%. Whereas, the survival was 74.4% when the antithrombin activity was 80% or less (P < 0.0001). However, the relationship between post-treatment antithrombin activity and 28-day survival was considerably different between patients who recovered from DIC by Day 6 compared to those who did not. Similarly, the estimated 28-day survival, based on antithrombin activity, varied among patients with high and low SOFA scores, and the calculation needs to be adjusted based on the severity of the condition. CONCLUSIONS: Post-treatment antithrombin activity measurement was helpful in estimating the 28-day survival in patients with sepsis-associated DIC. However, patient outcomes vary considerably depending on factors that include baseline SOFA score, age, and baseline antithrombin activity. These variables play a substantial role in determining patient prognosis and should be considered when evaluating and interpreting the results.

The Evaluation of Clot Waveform Analyses for Assessing Hypercoagulability in Patients Treated with Factor VIII Concentrate.

BACKGROUND: Regular prophylactic therapy has become an increasingly common treatment for severe hemophilia. Therefore, hypercoagulability-a potential risk factor of thrombosis-is a cause for concern in hemophilic patients treated with a high dose of FVIII concentrate. In clot waveform analysis (CWA)-thrombin time (TT), a small amount of thrombin activates clotting factor VIII (FVIII) instead of fibrinogen, resulting in FVIII measurements using CWA-TT with a small amount of thrombin. METHODS: The coagulation ability of patients treated with FVIII concentrate or emicizumab was evaluated using activated partial thromboplastin time (APTT), TT and a small amount of tissue factor-induced FIX activation assay (sTF/FIXa) using CWA. RESULTS: The FVIII activity based on CWA-TT was significantly greater than that based on the CWA-APTT or chromogenic assay. FVIII or FVIII-like activities based on the three assays in plasma without emicizumab were closely correlated; those in plasma with emicizumab based on CWA-TT and chromogenic assays were also closely correlated. CWA-APTT and CWA-TT showed different patterns in patients treated with FVIII concentrates compared to those treated with emicizumab. In particular, CWA-TT in patients treated with FVIII concentrate showed markedly higher peaks in platelet-rich plasma than in platelet-poor plasma. CWA-APTT showed lower coagulability in hemophilic patients treated with FVIII concentrate than in healthy volunteers, whereas CWA-sTF/FIXa did not. In contrast, CWA-TT showed hypercoagulability in hemophilic patients treated with FVIII concentrate. CONCLUSIONS: CWA-TT can be used to evaluate the thrombin bursts that cause hypercoagulability in patients treated with emicizumab. Although routine APTT evaluations demonstrated low coagulation ability in patients treated with FVIII concentrate, CWA-TT showed hypercoagulability in these patients, suggesting that the evaluation of coagulation ability may be useful when using multiple assays.

Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) in Japan 2023.

Thrombotic thrombocytopenic purpura (TTP) can rapidly become a life-threatening condition, and the importance of its appropriate diagnosis and treatment cannot be overstated. Until recently, TTP has mainly been diagnosed by clinical findings such as thrombocytopenia and hemolytic anemia. In addition to these clinical findings, however, reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) below 10% has become internationally accepted as a diagnostic criterion for TTP. TTP is classified as immune-mediated TTP (iTTP) if the patient is positive for anti-ADAMTS13 autoantibodies, and as congenital TTP (cTTP) if ADAMTS13 gene abnormalities are detected. Fresh frozen plasma (FFP) transfusion is performed in patients with cTTP to supplement ADAMTS13. Plasma exchange therapy using FFP is conducted in patients with iTTP to supplement ADAMTS13 and to remove both anti-ADAMTS13 autoantibodies and unusually large von Willebrand factor (VWF) multimers. To suppress autoantibody production, corticosteroid therapy is administered in conjunction with plasma exchange. The monoclonal anti-CD-20 antibody rituximab is effective in patients with iTTP. In addition, caplacizumab, an anti-VWF A1 domain nanobody, has a novel mechanism of action, involving direct inhibition of platelet glycoprotein Ib-VWF binding. The recommended first-line treatments of iTTP in Japan are plasma exchange and corticosteroids, as well as caplacizumab.

Soluble C-type lectin-like receptor 2 in stroke (CLECSTRO) study: protocol of a multicentre, prospective cohort of a novel platelet activation marker in acute ischaemic stroke and transient ischaemic attack.

INTRODUCTION: Soluble C-type lectin-like receptor 2 (sCLEC-2) is a new biomarker for platelet activation, which can be easily measured by usual blood collection. We conducted the CLECSTRO, a prospective, observational cohort study, to evaluate the clinical implications of sCLEC-2 in patients with acute ischaemic stroke (AIS) and transient ischaemic attack (TIA). METHODS AND ANALYSIS: The participants are patients with AIS/TIA and control patients required for differentiation from AIS/TIA. The target population is 600, including the patients and controls, who would be recruited from eight stroke centres across Japan. The inclusion criteria are AIS within 24 hours of onset and a modified Rankin Scale (mRS) score of 0-2, TIA within 7 days of onset, and contemporary patients required for differentiation from AIS/TIA. Plasma sCLEC-2 will be measured by high-sensitive chemiluminescent enzyme immunoassay using residual blood samples from routine laboratory examinations at the first visit in all patients and 7 days later or at discharge in patients with AIS/TIA. The outcomes include plasma levels of sCLEC-2 in patients with AIS/TIA and controls, sCLEC-2/D-dimer ratio in non-cardioembolic and cardioembolic AIS/TIA, correlation of sCLEC-2 with recurrence or worsening of stroke, severity of stroke, infarct size, ABCD2 score in TIA and outcome (mRS) at 7 days and 3 months. ETHICS AND DISSEMINATION: This study was approved by the Ethical Committee of the University of Yamanashi as the central ethical committee in agreement with the ethical committees of all collaborative stroke centres. Informed consent will be obtained by an opt-out form from the patients at each stroke centre according to the Ethical Guidelines for Medical and Biological Research Involving Human Subjects by the Japanese Ministry of Health, Labour and Welfare. TRIAL REGISTRATION NUMBERS: NCT05579405, UMIN000048954.

Super Formula for Diagnosing Disseminated Intravascular Coagulation Using Soluble C-Type Lectin-like Receptor 2.

The scoring systems for disseminated intravascular coagulation (DIC) criteria require several adequate cutoff values, vary, and are complicated. Accordingly, a simpler and quicker diagnostic method for DIC is needed. Under such circumstances, soluble C-type lectin-like receptor 2 (sCLEC-2) received attention as a biomarker for platelet activation. MATERIALS AND METHODS: The diagnostic usefulness of sCLEC-2 and several formulas, including sCLEC-2xD-dimer, sCLEC-2/platelet count (sCLEC-2/PLT), and sCLEC-2/PLT × D-dimer (sCLEC-2xD-dimer/PLT), were evaluated among 38 patients with DIC, 39 patients with pre-DIC and 222 patients without DIC or pre-DIC (non-DIC). RESULTS: Although the plasma level of sCLEC-2 alone was not a strong biomarker for the diagnosis of DIC or pre-DIC, the sCLEC-2xD-dimer/PLT values in patients with DIC were significantly higher than those in patients without DIC, and in a receiver operating characteristic (ROC) analysis for the diagnosis of DIC, sCLEC-2xD-dimer/PLT showed the highest AUC, sensitivity, and odds ratio. This formula is useful for the diagnosis of both pre-DIC and DIC. sCLEC-2xD-dimer/PLT values were significantly higher in non-survivors than in survivors. CONCLUSION: The sCLEC-2xD-dimer/PLT formula is simple, easy, and highly useful for the diagnosis of DIC and pre-DIC without the use of a scoring system.

Clot Waveform Analysis for Hemostatic Abnormalities.

Clot waveform analysis (CWA) observes changes in transparency in a plasma sample based on clotting tests such as activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). Evidence indicates that not only an abnormal waveform but also peak times and heights in derivative curves of CWA are useful for the evaluation of hemostatic abnormalities. Modified CWA, including the PT with APTT reagent, dilute PT (small amount of tissue factor [TF]-induced clotting factor IX [FIX] activation; sTF/FIXa), and dilute TT, has been proposed to evaluate physiological or pathological hemostasis. We review routine and modified CWA and their clinical applications. In CWA-sTF/FIXa, elevated peak heights indicate hypercoagulability in patients with cancer or thrombosis, whereas prolonged peak times indicate hypocoagulability in several conditions, including clotting factor deficiency and thrombocytopenia. CWA-dilute TT reflects the thrombin burst, whereas clot-fibrinolysis waveform analysis reflects both hemostasis and fibrinolysis. The relevance and usefulness of CWA-APTT and modified CWA should be further investigated in various diseases.

Biomarkers of Hypercoagulability in COVID-19.

This issue focuses on the pathophysiology of coronavirus disease 2019 (COVID-19) [...].

Thrombotic Mechanism Involving Platelet Activation, Hypercoagulability and Hypofibrinolysis in Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) has spread, with thrombotic complications being increasingly frequently reported. Although thrombosis is frequently complicated in septic patients, there are some differences in the thrombosis noted with COVID-19 and that noted with bacterial infections. The incidence (6-26%) of thrombosis varied among reports in patients with COVID-19; the incidences of venous thromboembolism and acute arterial thrombosis were 4.8-21.0% and 0.7-3.7%, respectively. Although disseminated intravascular coagulation (DIC) is frequently associated with bacterial infections, a few cases of DIC have been reported in association with COVID-19. Fibrin-related markers, such as D-dimer levels, are extremely high in bacterial infections, whereas soluble C-type lectin-like receptor 2 (sCLEC-2) levels are high in COVID-19, suggesting that hypercoagulable and hyperfibrinolytic states are predominant in bacterial infections, whereas hypercoagulable and hypofibrinolytic states with platelet activation are predominant in COVID-19. Marked platelet activation, hypercoagulability and hypofibrinolytic states may cause thrombosis in patients with COVID-19.

Plasma Soluble Fibrin Is Useful for the Diagnosis of Thrombotic Diseases.

BACKGROUND: Soluble fibrin (SF) is a form of fibrinogen that is activated by thrombin and is considered to be useful for the diagnosis of the prethrombotic state or thrombosis. METHODS: Plasma levels of fibrin-related markers (FRMs), such as SF, D-dimer, fibrinogen, and fibrin degradation prioduct (FDP) levels in critically ill patients, were examined for the diagnosis of disseminated intravascular coagulation (DIC), venous thromboembolism (VTE), peripheral arterial thromboembolism (PATE), acute myocardial infarction (AMI), and acute cerebral infarction (ACI). RESULTS: FRMs showed the usefulness in diagnosing DIC and VTE and the cutoff values of D-dimer, FDP, and SF for DIC were 7.2-7.8 µg/mL, 10.0 µg/mL, and 9.5 µg/mL, respectively. The cutoff values of D-dimer and FDP for VTE were similar to the 97.5th percentile values of healthy volunteers, while the cutoff value of SF was 6.9 µg/mL. In AMI and ACI, the cutoff values of D-dimer and FDP were lower than the 97.5 percentile values of healthy volunteers. A receiver operating characteristic analysis for all thrombosis cases showed that an adequate cutoff value in only SF among FRMs was higher than the confidence interval of healthy volunteers. Only SF had high sensitivity for thrombosis, as the FDP/SF ratio was markedly low for ACI, AMI and VTE. CONCLUSIONS: FRMs, especially D-dimer and FDP, were useful for diagnosing thrombosis with hyperfibrinolysis (e.g., DIC). As SF showed high sensitivity for predominantly thrombotic diseases, including arterial thrombosis, such as ACI and AMI, a high SF value suggests the possibility of an association with thrombosis. Finally, SF is the most useful marker for raising suspicion of an association with thrombosis, especially arterial thrombosis.

Application of a scoring system in Japanese patients diagnosed with atypical hemolytic uremic syndrome to assess the relationship between the score and clinical responses to eculizumab.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is caused by complement dysregulation and is generally diagnosed by exclusion from other disorders of thrombotic microangiopathy (TMA). Eculizumab, a terminal complement inhibitor, has been approved for aHUS treatment since 2013 in Japan. Recently, a scoring system was published to support diagnosis of aHUS. Herein we modified this scoring system to apply it to patients diagnosed with aHUS and treated with eculizumab, and assessed the association between the score and clinical responses to eculizumab. METHODS: One hundred eighty-eight Japanese patients who were clinically diagnosed with aHUS, treated with eculizumab, and enrolled in post-marketing surveillance (PMS) were included in this analysis. Some of parameters in the original scoring system were replaced with clinically similar parameters collected in the PMS to modify the system, hereafter referred to as the TMA/aHUS score, which ranges from -15 to 20 points. Treatment responses within 90 days after eculizumab initiation were also assessed, and the relationship between treatment response and TMA/aHUS scores calculated at TMA onset was explored. RESULTS: The median (range) TMA/aHUS score was 10 (3-16). Receiver operating characteristic curve analysis showed that the cutoff value of TMA/aHUS score to predict treatment response to eculizumab was estimated as 10, and negative predictive value indicated that ≥ 5 points was appropriate to consider assessing the treatment response to eculizumab; 185 (98%) patients had ≥ 5 points and 3 (2%) had < 5 points. Among the patients with ≥ 5 points, 96.1% showed partial response and 31.1% showed complete response. One of the three patients with < 5 points met partial response criteria. No significant difference in the TMA/aHUS scores was observed between survivors and non-survivors, suggesting that the score was not appropriate to predict the outcome (i.e., survival/death) in patients treated with eculizumab. CONCLUSION: Almost all patients clinically diagnosed with aHUS scored ≥ 5 points and responded to eculizumab. The TMA/aHUS score system could become a supporting tool for the clinical diagnosis of aHUS and probability of response to treatment with a C5 inhibitor. TRIAL REGISTRATION: This study was conducted as per good PMS practice guidelines for drugs (MHLW Ministerial Ordinance No. 171 of 2004).

The Detection of Hypercoagulability in Patients with Acute Cerebral Infarction Using a Clot Waveform Analysis.

A few studies concerning hypercoagulable states have sufficiently been reported in patients with acute cerebral infarction (ACI), as ACI is generally considered to be caused by platelet activation. Clot waveform analyses (CWA) for activated partial thromboplastin time (APTT) and small amount of tissue factor FIX activation assay (sTF/FIXa) were examined in 108 patients with ACI, 61 patients without ACI, and 20 healthy volunteers. CWA-APTT and CWA-sTF/FIXa showed that the peak heights were significantly higher in ACI patients without anticoagulant therapy than in healthy volunteers. Absorbance exceeding 78.1 mm on the 1st DPH in the CWA-sTF/FIXa showed the highest odds ratio for ACI. The peak heights were significantly lower in the CWA-sTF/FIXa of ACI patients receiving argatroban therapy than in those of ACI patients without anticoagulant therapy. CWA can suggest a hypercoagulable state in ACI patients and may be useful for monitoring the need for anticoagulant therapy.

Cranial ultrasonography in diagnosis of infantile cerebral cavernous malformation.

The case of an infantile cerebral cavernous malformation detected by transfontanelle cranial ultrasonography. Infantile cerebral cavernous malformations tend to cause more major bleeding compared to those in older groups, so early detection and treatment are crucial. Cranial ultrasonography can contribute to the early diagnosis of infantile cerebral cavernous malformations.

Clinical Significance of Plasma Tenascin-C Levels in Recipients With Prolonged Jaundice After Living Donor Liver Transplantation.

BACKGROUND: Focusing on tenascin-C (TNC), whose expression is enhanced during the tissue remodeling process, the present study aimed to clarify whether plasma TNC levels after living donor liver transplantation (LDLT) could be a predictor of irreversible liver damage in the recipients with prolonged jaundice (PJ). METHODS: Among 123 adult recipients who underwent LDLT between March 2002 and December 2016, the subjects were 79 recipients in whom we could measure plasma TNC levels preoperatively (pre-) and on postoperative days 1 to 14 (POD1 to POD14). Prolonged jaundice was defined as serum total bilirubin level >10 mg/dL on POD14, and 79 recipients were divided into 2 groups: 56 in the non-PJ (NJ) group and 23 in the PJ group. RESULTS: The PJ group had significantly increased pre-TNC; smaller grafts; decreased platelet counts POD14; increased TB-POD1, -POD7, and -POD14; increased prothrombin time-international normalized ratio on POD7 and POD14; and higher 90-day mortality than the NJ group. As for the risk factors for 90-day mortality, multivariate analysis identified TNC-POD14 as a single significant independent prognostic factor (P = .015). The best cut-off value of TNC-POD14 for 90-day survival was determined to be 193.7 ng/mL. In the PJ group, the patients with low TNC-POD14 (<193.7 ng/mL) had satisfactory survival, with 100.0 % at 90 days, while the patients with high TNC-POD14 (≥193.7 ng/mL) had significantly poor survival, with 38.5 % at 90 days (P = .004). CONCLUSIONS: In PJ after LDLT, plasma TNC-POD14 is very useful for diagnosing postoperative irreversible liver damage early.

Sepsis-Associated DIC with Decreased Levels of Antithrombin and Fibrinogen is the Target for Combination Therapy with Thrombomodulin Alfa and Antithrombin.

Background Disseminated intravascular coagulation (DIC) is not a homogeneous condition, but rather includes heterogeneous conditions, and its pathophysiology and outcome vary considerably depending on the background. Although anticoagulant therapy is expected to be of benefit in the treatment of DIC, previous studies have suggested that the benefits are limited only to a specific subtype. Objects The purpose of this study was to identify the group that would benefit from combination therapy using thrombomodulin/antithrombin. Methods The data from 2,839 patients registered in the postmarketing surveillance of thrombomodulin were evaluated. The patients were divided into four groups depending on antithrombin and fibrinogen levels, and the additive effects of antithrombin on thrombomodulin were examined in the groups. Results The DIC score, Sequential Organ Failure Assessment score, and mortality were significantly higher in the DIC group with low-antithrombin/low-fibrinogen than in the DIC groups without either low antithrombin or low fibrinogen. The survival curve was significantly higher in DIC patients with combination therapy than in patients treated with thrombomodulin monotherapy, but this effect was seen only in patients with infection-based DIC. Conclusion DIC patients with low-antithrombin/low-fibrinogen risk poor outcomes, but they can be the target of combination therapy with antithrombin and thrombomodulin as long as the DIC is due to infection.

Platelet Activation and Thrombosis in COVID-19.

Although thrombosis frequently occurs in infectious diseases, the coagulopathy associated with COVID-19 has unique characteristics. Compared with bacterial sepsis, COVID-19-associated coagulopathy presents with minimal changes in platelet counts, normal prothrombin times, and increased D-dimer and fibrinogen levels. These differences can be explained by the distinct pathophysiology of the thromboinflammatory responses. In sepsis-induced coagulopathy, leukocytes are primarily responsible for the coagulopathy by expressing tissue factor, releasing neutrophil extracellular traps, multiple procoagulant substances, and systemic endothelial injury that is often associated with vasoplegia and shock. In COVID-19-associated coagulopathy, platelet activation is a major driver of inflammation/thrombogenesis and von Willebrand factor and platelet factor 4 are deeply involved in the pathogenesis. Although the initial responses are localized to the lung, they can spread systemically if the disease is severe. Since the platelets play major roles, arterial thrombosis is not uncommon in COVID-19. Despite platelet activation, platelet count is usually normal at presentation, but sensitive biomarkers including von Willebrand factor activity, soluble P-selectin, and soluble C-type lectin-like receptor-2 are elevated, and they increase as the disease progresses. Although the role of antiplatelet therapy is still unproven, current studies are ongoing to determine its potential effects.