[Congenital thrombotic thrombocytopenic purpura diagnosed in adulthood after repeated thrombocytopenia since neonatal period].

A 27-year-old woman was diagnosed with idiopathic thrombocytopenic purpura in the neonatal period, and was admitted to our hospital after presenting with impaired consciousness, purpura, nausea and vomiting, with a platelet count of 10×109/l. Congenital thrombotic thrombocytopenic purpura (cTTP) was suspected on the basis of recurrent thrombocytopenia and impaired consciousness, so tests for ADAMTS13 activity and inhibitor were performed. ADAMTS13 activity was severely decreased, ADAMTS13 inhibitor was negative, and platelet count increased after transfusion of fresh frozen plasma. These findings and the results of genetic testing done on all family members led to a diagnosis of cTTP. cTTP requires differential diagnosis even in adults. If a patient diagnosed with ITP in childhood has a history or findings that suggest cTTP during follow-up observation, it is necessary to actively consider ADAMTS13 testing.

ADAMTS-13: A Prognostic Biomarker for Portal Vein Thrombosis in Japanese Patients with Liver Cirrhosis.

Portal vein thrombosis (PVT), one of the most prevalent hepatic vascular conditions in patients with liver cirrhosis (LC), is associated with high mortality rates. An imbalance between a disintegrin-like metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS-13) enzyme and von Willebrand factor (VWF) is responsible for hypercoagulability, including spontaneous thrombus formation in blood vessels. Herein, we aimed to identify potential prognostic and diagnostic biomarkers in Japanese patients with LC and PVT. In total, 345 patients were divided into two groups: 40 patients who developed PVT (PVT group) and 305 who did not develop PVT (NPVT group). Among the 345 patients with LC, 81% (279/345) were deemed ineligible due to the presence of preventive comorbidities, active or recent malignancies, and organ dysfunction. The remaining 66 patients were divided into two groups: the PVT group (n = 33) and the NPVT group (n = 33). Plasma ADAMTS-13 activity (ADAMTS-13:AC) and the vWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. Contrast-enhanced, three-dimensional helical computed tomography (CT) was used to detect and characterize PVT. ADAMTS-13:AC was significantly lower in the PVT group than in the NPVT group. No significant differences in plasma vWF:Ag or liver stiffness were observed between the two groups. ADAMTS-13:AC of <18.8 was an independent risk factor for PVT on multivariate analyses (odds ratio: 1.67, 95% confidence interval: 1.21-3.00, p < 0.002). The receiver operating characteristic analysis of ADAMTS-13:AC revealed an area under the curve of 0.913 in PVT detection. Patients with PVT having ADAMTS-13:AC ≥18.8 (n = 17) had higher albumin levels and better prognoses than those with ADAMTS-13:AC <18.8 (n = 16). No significant correlations of ADAMTS-13:AC levels with either fibrin degradation product or D-dimer levels were observed. ADAMTS-13:AC levels could be potential diagnostic and prognostic biomarkers for PVT in Japanese patients with LC.

Persistent ADAMTS13 Inhibitor Delays Recovery of ADAMTS13 activity in Caplacizumab-Treated Japanese iTTP Patients.

For patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), caplacizumab, a nanobody against von Willebrand factor A1 domain, has become crucial. Delayed normalization of ADAMTS13 activity during caplacizumab therapy has been identified. In a retrospective analysis, we compared platelet count, ADAMTS13 activity, its inhibitor, and anti-ADAMTS13 IgG levels in acute iTTP cases treated with caplacizumab (N=14) or without it (N=16). The median time from initial therapeutic plasma exchange (TPE) to the first rituximab administration was 12 days in the caplacizumab group (N=11) and 10 days in the group without caplacizumab (N=13). We evaluated ADAMTS13-related parameters at onset and once a week until day 28 after the first TPE. The number of days until the platelet counts reached >= 150×109/L was significantly shorter in the caplacizumab group than in the non-caplacizumab group. The median ADAMTS13 activity levels on days 14, 21, and 28 were significantly lower in the caplacizumab group than in the non-caplacizumab group. The median titers of the ADAMTS13 inhibitor and anti-ADAMTS13 IgG on the same days were significantly higher in the caplacizumab group than in the non-caplacizumab group. Furthermore, the median number of days from the first TPE until finally achieving an ADAMTS13 activity >= 10% was significantly longer in the caplacizumab group than in the non-caplacizumab group (42 days vs. 23 days, p=0.014). We observed delayed ADAMTS13 activity recovery and continued inhibitor and anti-ADAMTS13 IgG detection in acute iTTP patients on caplacizumab, possibly due to the decreased number of TPEs and delayed frontline rituximab.

Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

VWF/ADAMTS13 Ratio as a Potential Predictive Biomarker for Acute Kidney Injury Onset in Cirrhosis.

AIM: We investigated the von Willebrand factor to ADAMTS13 ratio (von Willebrand factor [VWF]:Ag/ADAMTS13:AC) as a potential biomarker for the outcomes of acute kidney injury (AKI) in liver cirrhosis (LC). METHODS: This retrospective cross-sectional study included patients with LC who developed AKI (AKI group: n = 91) and patients with LC who did not develop AKI [non-AKI (NAKI) group, n = 91] as a control group. Plasma levels of the von Willebrand factor antigen (Ag) and ADAMTS13 activity (AC) were measured in patients with AKI or NAKI. Moreover, risk factors for onset of AKI, AKI-associated 90-day mortality, and poor AKI treatment response were identified. RESULTS: The AKI group had a significantly higher VWF:Ag/ADAMTS13:AC than the NAKI group. Values of VWF:Ag/ADAMTS13:AC ≥ 5.7 were identified as risk factors for AKI onset in patients with LC (odds ratio [OR] 2.56; 95% CI 1.26-4.99; p < 0.001). Among patients with AKI, values of VWF:Ag/ADAMTS13:AC ≥ 9.0 were identified as risk factors for 90-day mortality (OR 6.83; 95% CI 2.32-20.10; p < 0.001). Cumulative survival was significantly lower in those with high (≥ 9.0) than in those with low (< 9.0) VWF:Ag/ADAMTS13:AC. Furthermore, values of VWF:Ag/ADAMTS13:AC ≥ 7.4 were identified as risk factors for poor treatment response (OR 4.2; 95% CI 1.39-12.70; p < 0.001). The treatment response rates were significantly higher in those with low (< 7.4) VWF:Ag/ADAMTS13:AC than in those with high (≥ 7.4) VWF:Ag/ADAMTS13:AC. CONCLUSION: VWF:Ag/ADAMTS13:AC potentially predicts the onset, prognosis, and treatment response of AKI in patients with LC.

von Willebrand factor Ristocetin co-factor activity to von Willebrand factor antigen level ratio for diagnosis of acquired von Willebrand syndrome caused by aortic stenosis.

Background: Severe aortic stenosis (AS) causes acquired von Willebrand syndrome by the excessive shear stress-dependent cleavage of high molecular weight multimers of von Willebrand factor (VWF). While the current standard diagnostic method is so-called VWF multimer analysis that is western blotting under nonreducing conditions, it remains unclear whether a ratio of VWF Ristocetin co-factor activity (VWF:RCo) to VWF antigen levels (VWF:Ag) of <0.7, which can be measured with an automated coagulation analyzer in clinical laboratories and is used for the diagnosis of hereditary von Willebrand disease. Objectives: To evaluated whether the VWF:RCo/VWF:Ag is useful for the diagnosis of AS-induced acquired von Willebrand syndrome. Methods: VWF:RCo and VWF:Ag were evaluated with the VWF large multimer index as a reference, which represents the percentage of a patient's VWF high molecular weight multimer ratio to that of standard plasma in the VWF multimer analysis. Results: We analyzed 382 patients with AS having transaortic valve maximal pressure gradients of >30 mmHg, 27 patients with peripheral artery disease, and 46 control patients free of cardiovascular disease with osteoarthritis, diabetes, and so on. We assumed a large multimer index of <80% as loss of VWF large multimers since 59.0% of patients with severe AS had the indices of <80%, while no control patients or patients with peripheral artery disease, except for 2 patients, exhibited the indices of <80%. The VWF:RCo/VWF:Ag ratios, measured using an automated blood coagulation analyzer, were correlated with the indices (rs = 0.470, P < .001). When the ratio of <0.7 was used as a cut-off point, the sensitivity and specificity to VWF large multimer indices of <80% were 0.437 and 0.826, respectively. Conclusion: VWF:RCo/VWF:Ag ratios of <0.7 may indicate loss of VWF large multimers with high specificity, but low sensitivity. VWF:RCo/VWF:Ag ratios in patients with AS having a ratio of <0.7 may be useful for monitoring the loss of VWF large multimers during their clinical courses.

[Novel treatment strategies for acquired thrombotic thrombocytopenic purpura].

Thrombotic thrombocytopenic purpura (TTP) is a poor prognosis disease caused by platelet thrombi produced in the microvessels throughout the body. The thrombus is mainly composed of von Willebrand factor (VWF) and platelets. Acquired TTP is an autoimmune disease wherein autoantibodies against ADAMTS13, a VWF-cleaving enzyme, are produced and ADAMTS13 activity is markedly decreased. Plasma exchange using fresh-frozen plasma as a replacement fluid effective against acquired TTP was reported in 1991. Since then, plasma exchange and corticosteroids have been the standard of care in Japan. Caplacizumab, which is a monoclonal antibody against the VWF A1 domain, finally became available for use in 2022, and the number of cases is still increasing in Japan. A clinical trial of recombinant ADAMTS13 product is being conducted for congenital TTP, and an era is expected to come in the future when plasma exchange will no longer be necessary.

The Combination of the Lactate Dehydrogenase/Hemoglobin Ratio with the PLASMIC Score Facilitates Differentiation of TTP from Septic DIC Without Identification of Schistocytes.

In some cases, differentiating thrombotic thrombocytopenic purpura (TTP) from septic disseminated intravascular coagulation (DIC) without measuring ADAMTS13 activity is critical for urgent lifesaving plasma exchange. To investigate whether PLASMIC score without identifying the presence of schistocytes, D-dimer, fibrin/fibrinogen degradation products (FDP), FDP/D-dimer ratio, prothrombin time-international normalized ratio (PT-INR), lactate dehydrogenase (LD), hemoglobin (Hb), and LD/Hb ratio are useful in differentiating patients with TTP from those with septic DIC. Retrospective analysis was conducted on the medical records of the patients with septic DIC (32 patients) or TTP (16 patients). The PLASMIC score and other laboratory measurements all were helpful in differentiating TTP from septic DIC. When dichotomized between high risk (scores 6-7) and intermediate-low risk (scores 0-5), the PLASMIC score predicted TTP with a sensitivity of 75.0% and a specificity of 100%. However, 4 of 16 patients with TTP and 19 of 32 patients with septic DIC showed comparable PLASMIC scores of 4 or 5, making it difficult to distinguish between the two by PLASMIC score alone. Among the measurements examined, the LDH/Hb ratio was the most useful for differentiation. Receiver operating characteristic analysis of the LD/Hb ratio for predicting TTP revealed a cutoff of 53.7 (IU/10 g) (sensitivity 0.94, specificity 0.91). If the LD/Hb ratio was less than 53.7, it was unlikely that the patient had TTP. A combination of the LD/Hb ratio and the PLASMIC score may be useful for distinguishing between TTP and DIC and identifying patients who need rapid plasma exchange or caplacizumab administration.

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.

Two pregnant women with immune-mediated thrombotic thrombocytopenic purpura: A case report.

Thrombotic thrombocytopenic purpura (TTP) during pregnancy is life-threatening. We encountered two pregnant women with immune-mediated TTP (iTTP). A 40-year-old primigravida woman was referred at 19 gestational weeks (GWs) owing to iTTP. She received plasma exchange (PE) and steroid therapies and delivered a live infant at 27 GWs by cesarean delivery. A 29-year-old primigravida woman was referred owing to intrauterine fetal death and thrombocytopenia at 20 GWs. She was diagnosed with iTTP and received PE therapy. She required additional PE and steroid therapies owing to relapse. Before her second pregnancy, she received prednisolone and hydroxychloroquine according to the therapy for systemic lupus erythematosus (SLE). She had induced labor at 37 GWs owing to decrease plasma level of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) activity. Close monitoring of plasma ADAMTS13 activity level and treatments for underlying SLE may prevent iTTP relapse and lead to a good prognosis.

Pseudomonas aeruginosa hijacks the murine nitric oxide metabolic pathway to evade killing by neutrophils in the lung.

Neutrophils play a critical role in the eradication of Pseudomonas aeruginosa, a major pathogen causing lung infection. However, the mechanisms used by the pathogen to evade neutrophil-mediated killing remain poorly understood. Using a high-density transposon screen, we find that P. aeruginosa colonization in the lung is promoted by pathogen nitrite reductase nirD. nirD is required for ammonia production from nitrite, a metabolite derived from nitrogen oxide (NO) generated by inducible NO synthetase (iNOS) in phagocytes. P. aeruginosa deficient in nirD exhibit reduced survival in wild-type neutrophils but not in iNOS-deficient neutrophils. Mechanistically, nirD enhances P. aeruginosa survival in neutrophils by inhibiting the localization of the pathogen in late phagosomes. P. aeruginosa deficient in nirD show impaired lung colonization after infection in wild-type mice but not in mice with selective iNos deficiency in neutrophils. Thus, P. aeruginosa uses neutrophil iNOS-mediated NO production to limit neutrophil pathogen killing and to promote its colonization in the lung.

Study protocol for assessment of the coagulation potential of concomitantly used factor VIII concentrates in patients with haemophilia A with emicizumab prophylaxis (CAGUYAMA Study): a multicentre open-label non-randomised clinical trial.

INTRODUCTION: Emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (HA). The haemostatic efficacy of emicizumab in patients with HA is estimated as approximately 15% based on mimic activity of factor (F) VIII. Although it has been proven effective in preventing bleeding, its haemostatic effect during breakthrough bleeding or surgery is considered insufficient. Therefore, haemostatic management of emicizumab-treated patients with HA without inhibitors frequently requires FVIII replacement therapy. In haemostatic management of emicizumab-treated patients with HA, conventional FVIII dosage calculations are used in clinical practice without considering the coagulant effects of emicizumab. METHODS AND ANALYSIS: In the CAGUYAMA study, 100 patients with HA without inhibitors will be enrolled for a maximum duration of 1 year, and samples of 30 events following the concomitant use of FVIII concentrates (30±5 U/kg) with emicizumab will be collected. An 'event' is defined as obtaining blood samples at preadministration and postadministration of FVIII concentrates during a breakthrough bleeding or a surgical procedure. Global coagulation assays will be used to measure the coagulation potential of the obtained samples. Clot waveform analysis (CWA) is used to identify the primary end-point, that is, the degree of improvement in the maximum coagulation rate at preadministration and post-administration of fixed-dose FVIII concentrations. The parameter obtained from CWA, which is triggered by an optimally diluted mixture of prothrombin time reagent and activated partial thromboplastin time reagent, is reported to be an excellent marker for assessing the degree of improvement of the coagulation potential in emicizumab-treated plasmas. ETHICS AND DISSEMINATION: The CAGUYAMA study was approved by the Japan-Certified Review Board of Nara Medical University (Approval ID; nara0031). The study results will be communicated through publication in international scientific journals and presentations at (inter)national conferences. TRIAL REGISTRATION NUMBER: jRCTs051210137.

Clinical Manifestations, Current and Future Therapy, and Long-Term Outcomes in Congenital Thrombotic Thrombocytopenic Purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an extremely rare disease characterized by the severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), caused by ADAMTS13 mutations. While ADAMTS13 supplementation by fresh frozen plasma (FFP) infusion immediately corrects platelet consumption and resolves thrombotic symptoms in acute episodes, FFP treatment can lead to intolerant allergic reactions and frequent hospital visits. Up to 70% of patients depend on regular FFP infusions to normalize their platelet counts and avoid systemic symptoms, including headache, fatigue, and weakness. The remaining patients do not receive regular FFP infusions, mainly because their platelet counts are maintained within the normal range or because they are symptom-free without FFP infusions. However, the target peak and trough levels of ADAMTS13 to prevent long-term comorbidity with prophylactic FFP and the necessity of treating FFP-independent patients in terms of long-term clinical outcomes are yet to be determined. Our recent study suggests that the current volumes of FFP infusions are insufficient to prevent frequent thrombotic events and long-term ischemic organ damage. This review focuses on the current management of cTTP and its associated issues, followed by the importance of upcoming recombinant ADAMTS13 therapy.

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).

Usefulness of blood biomarkers for predicting venous thromboembolism in Japanese patients with cancer.

Prospective studies on risk factors for the occurrence of venous thromboembolism (VTE) in Asian patients with cancer are limited. Therefore, the present study assessed risk factors for VTE, including multiple blood biomarkers and risk scores consisting of several risk factors, in Japanese patients receiving anticancer drug therapy. In this single-center, prospective, observational study, 200 patients with six types of cancer were enrolled and followed for 1 year to observe the occurrence of symptomatic or asymptomatic VTE. The present study evaluated risk factors, Khorana and Vienna cancer and thrombosis study (CATS) scores at enrollment, and longitudinal data on various blood biomarkers. A Vienna CATS score of ≥3 was significantly associated with VTE occurrence (HR, 2.8; 95% CI, 0.9-8.7; P=0.045). In multivariable analysis, there was a significant association between VTE and the presence of pancreatic cancer (HR, 3.2; 95% CI, 1.1-8.8; P=0.028) and high soluble fibrin (HR, 3.7; 95% CI, 1.1-7.8; P=0.036). Covariate analysis using the propensity score also showed a significant association with hemoglobin dichotomized at <100 g/l (HR, 3.9; 95% CI, 1.1-14.0; P=0.034). Longitudinal data indicated that VTE was associated with soluble fibrin baseline values and an increase in D-dimer levels over time. The present results suggested that blood biomarkers are beneficial for predicting the risk of VTE in Japanese patients with cancer. The present study also provided novel evidence for the importance of measuring soluble fibrin in patients with cancer.

Distinguishing immune-mediated thrombotic thrombocytopenic purpura from septic disseminated intravascular coagulation using plasma levels of haptoglobin and factor XIII activity.

Background: Both immune-mediated thrombotic thrombocytopenic purpura (iTTP) and septic disseminated intravascular coagulation (DIC) are life-threatening disorders developed by platelet-consuming microvascular thrombi and necessitate immediate therapeutic interventions. Although severe deficiencies of plasma haptoglobin in iTTP and factor XIII (FXIII) activity in septic DIC have been reported, few studies have focused on the possibility of using these markers to distinguish between iTTP and septic DIC. Objectives: We investigated whether the plasma levels of haptoglobin and FXIII activity could be helpful for differential diagnosis. Methods: Thirty-five patients with iTTP and 30 with septic DIC were enrolled in the study. Patient characteristics, coagulation, and fibrinolytic markers were collected from the clinical data. Plasma haptoglobin and FXIII activities were measured using chromogenic Enzyme-Linked Immuno Sorbent Assay and an automated instrument, respectively. Results: The median plasma haptoglobin level was 0.39 mg/dL and 54.20 mg/dL in the iTTP and septic DIC groups, respectively. The median plasma FXIII activities were 91.3% and 36.3% in the iTTP and septic DIC groups, respectively. In the receiver operating characteristic curve analysis, the cutoff level of plasma haptoglobin was 2.868 mg/dL and the area under the curve was 0.832. The cutoff level for plasma FXIII activity and the area under the curve were 76.0% and 0.931, respectively. The thrombotic thrombocytopenic purpura (TTP)/DIC index was defined by FXIII activity (percentage) and haptoglobin (milligrams per decilitre). Laboratory TTP was defined as an index ≥60 and laboratory DIC <60. The sensitivity and specificity of the TTP/DIC index were 94.3% and 86.7%, respectively. Conclusion: The TTP/DIC index, composed of plasma levels of haptoglobin and FXIII activity, is useful in differentiating iTTP from septic DIC.

Frontiers in pathophysiology and management of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a fatal disease in which platelet-rich microthrombi cause end-organ ischemia and damage. TTP is caused by markedly reduced ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. Hereditary or congenital TTP (cTTP) is caused by ADAMTS13 gene mutations. In acquired or immune TTP (iTTP), ADAMTS13 activity is reduced by anti-ADAMTS13 autoantibodies. TTP is characterized by thrombocytopenia, hemolytic anemia, fever, renal dysfunction, and neuropsychiatric symptoms. Therapeutic plasma exchange (TPE) and immunosuppressive therapy are the mainstays of treatment. As untreated TTP has a high mortality rate, immediate initiation of TPE is recommended when TTP is suspected. Conventionally, corticosteroids have been used for immunosuppressive therapy. Current drug therapies include rituximab, an anti-CD20 antibody that is effective in newly diagnosed cases and refractory cases, as well as for relapse prevention, and caplacizumab, an anti- von Willebrand factor (VWF) nanobody that inhibits the binding of platelets to VWF and prevents microthrombi formation. Recombinant human ADAMTS13 is a promising treatment for cTTP. Although these therapeutic advances have improved the outcomes of TTP, early diagnosis and prompt initiation of appropriate therapy are necessary to achieve these outcomes.

The Ratio of von Willebrand Factor Antigen to ADAMTS13 Activity: Usefulness as a Prognostic Biomarker in Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) has a high risk of short-term mortality. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). Imbalance between ADAMTS13 and VWF is associated with portal hypertension, which induces ACLF development. A previous study reported that ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) are predictive biomarkers of ACLF development in patients with cirrhosis. This study investigated the changes in ADAMTS13:AC and VWF:Ag levels from before to after the development of ACLF to determine their usefulness as a prognostic biomarker in patients with ACLF. In total, 101 patients with cirrhosis were enrolled in this study. The level of ADAMTS13:AC and VWF:Ag was determined by an enzyme-linked immunosorbent assay. Cox proportional hazard regression analysis was conducted to determine independent prognostic factors for patients with liver cirrhosis in the post-ACLF group. ADAMTS13:AC levels gradually decreased in the order of non-ACLF group, pre-ACLF group, and finally post-ACLF group. VWF:Ag and the ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) levels gradually increased in the order of non-ACLF group, pre-ACLF group, followed by post-ACLF group. VWF:Ag/ADAMTS13:AC and CLIF-C ACLF scores were associated with prognosis in the post-ACLF group in multivariate analysis. The cumulative survival of the post-ACLF group was significantly lower for patients with high VWF:Ag/ADAMTS13:AC (>9) compared with those with low VWF:Ag/ADAMTS13:AC (≤9) (HR: 10.72, 95% confidence interval: 1.39-82.78, p < 0.05). The VWF:Ag/ADAMTS13:AC increased according to the progression of ACLF in patients with cirrhosis and predicted prognosis in patients with cirrhosis with ACLF.

COVID-19-associated myocardial injury: A case report.

Coronavirus disease 2019 (COVID-19) is often accompanied by pneumonia and can be fatal. We report a case of COVID-19-associated myocardial injury mimicking fulminant myocarditis. Endomyocardial biopsy revealed numerous von Willebrand factor-rich microthrombi with small myocardial necrotic areas, complement deposits in small vessels/microthrombi, and macrophage-predominant interstitial infiltration. These findings, distinct from those of typical lymphocytic myocarditis, show diffuse endothelial injury, complement activation, and activated macrophages as characteristic features of COVID-19-associated pathogenesis. Dysregulated serum cytokine profiles predicting severe/critical COVID-19-associated myocardial injury were also determined. This case emphasizes the occurrence of fatal cardiac manifestation with microthrombotic injury in the early stage of COVID-19.