Low incidence of venous thrombosis but high incidence of arterial thrombotic complications among critically ill COVID-19 patients in Singapore.

BACKGROUND: Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. METHOD AND RESULTS: This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). CONCLUSIONS: Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

Assessing the Impact of a Pulmonary Embolism Response Team and Treatment Protocol on Patients Presenting With Acute Pulmonary Embolism.

BACKGROUND: Pulmonary embolism (PE) care has traditionally been fragmented. The newly introduced Pulmonary Embolism Response Team (PERT) model provides streamlined care based on expedient, multi-disciplinary decision-making. This study aimed to quantify the impact of PERT, as part of a hospital-wide PE treatment protocol, on clinical outcomes. METHODS: Consecutive adult patients with acute PE diagnosed via computed tomography pulmonary angiogram (CTPA) were included. The PERT and treatment protocol were introduced in January 2015. Patient characteristics, therapies, quality measures of CTPA reporting, and clinical outcomes of PE patients treated for 2 years before and after implementation of these changes were evaluated. Primary endpoints were median length of stay in intensive care (ICU) and survival to discharge. RESULTS: A total of 321 consecutive PE patients were enrolled, of which 154 (treated in 2013-2014) and 167 (2015-2016) patients formed the historical control and study groups, respectively. Implementation of the algorithm was associated with less variance in anticoagulation and improved reporting of right heart strain parameters on CTPA. The ICU stay was reduced from a median of 5 to 2 days (p < 0.01). Eligible massive PE patients receiving reperfusion increased from 30% to 92% (p = 0.01), with mean delay from diagnosis to reperfusion decreasing from 763 to 181 minutes (p < 0.01). Bleeding complications were not increased, but overall survival to discharge remained unchanged. CONCLUSIONS: Introducing a PERT and treatment protocol reduced ICU stay, enhanced quality measures, and improved access of massive PE patients to reperfusion therapies, without increasing bleeding complications or health care costs.

Iron status and risk factors of iron deficiency among pregnant women in Singapore: a cross-sectional study.

BACKGROUND: Iron deficiency is the most prevalent nutrient deficiency and the most common cause of anaemia worldwide. Because of the increased iron requirements during pregnancy, iron deficiency can lead to maternal anaemia and reduced newborn iron stores. We examined the proportion and risk factors of iron deficiency among pregnant women in a developed Asian country. METHODS: Within a prospective cohort in Singapore, 985 Asian women were assessed for iron status at 26-28 weeks' gestation, with plasma ferritin and soluble transferrin receptor (sTfR) measurements. Iron status was determined according to plasma ferritin concentrations at ≥30 µg/L (iron sufficiency), 15 to < 30 µg/L (modest iron depletion) and < 15 µg/L (severe iron depletion). Multivariable ordinal logistic regression was used to analyze risk factors for modest and severe iron depletion. RESULTS: The median (25-75th percentile) plasma ferritin concentration was 24.2 (19.9-30.6) µg/L. Overall, 660 (67.0%) and 67 (6.8%) women had modest and severe iron depletion, respectively. Higher plasma sTfR was observed in women with severe iron depletion than among those with iron sufficiency (median 17.6 versus 15.5 nmol/L; p < 0.001). Age < 25 years (odds ratio 2.36; 95% confidence interval 1.15-4.84), Malay (2.05; 1.30-3.24) and Indian (1.98; 1.14-3.44) ethnicities (versus Chinese), university qualification (1.64; 1.13-2.38), multiparity (1.73; 1.23-2.44) and lack of iron-containing supplementation (3.37; 1.25-8.53) were associated with increased odds of modest and severe iron depletion. CONCLUSIONS: Nearly three-quarters of Singaporean women were iron deficient in the early third trimester of pregnancy. These results suggest universal screening and supplementation of at-risk pregnancies may be evaluated as a preventive strategy. TRIAL REGISTRATION: NCT01174875 . Registered 1 July 2010 (retrospectively registered).

Direct costs associated with febrile neutropenia in inpatients with hematological diseases in Singapore.

PURPOSE: This prospective cohort study aims to investigate the direct hospitalization costs incurred during febrile neutropenia (FN) in inpatients with underlying hematological conditions and also to elucidate the factors associated with a high cost of managing febrile neutropenia. METHODS: Patients with underlying hematological conditions and documented FN were recruited between October 2008 and February 2011. FN-related costs included all costs incurred from the first day of FN until the last day of antibiotics prescribed. Relevant clinical factors were analyzed using generalized estimating equation models to elucidate the factors that were associated with higher costs of FN. RESULTS: A total of 175 patients were recruited with 303 documented episodes of FN. In non-transplant patients, 75.6 % of the FN episodes occurred. The median and mean cost incurred for each FN episode was USD9,060 (interquartile range = USD5,047-16,631) and USD15,298 (standard deviation ± USD17,459), respectively, accounting for approximately 38 % of the median total hospitalization cost and 37 % of the mean total hospitalization cost. The ward charges (44.1 %) constituted the largest component of the cost, followed by the laboratory charges (27.3 %) and medications (18.7 %), of which antimicrobials constituted 9.6 % of the cost of FN. The factors associated with higher costs of FN include cytomegalovirus reactivation (p < 0.001), longer duration of antibiotics (p < 0.001), lower absolute neutrophil count nadir (p < 0.001), allogeneic stem cell transplantation (p < 0.01), and diagnosis of invasive fungal infection (p < 0.05). CONCLUSION: The economic cost of management of FN in hematology inpatients is considerable and in addition to the overall risk of mortality for this condition. Strategies to reduce FN or ameliorate its costs are essential for this group of patients.

Hypertensive Emergency with Thrombotic Microangiopathy or TTP? A Case Series and Literature Review.

Thrombotic microangiopathy (TMA) is associated with both hypertensive emergency and primary thrombocytopenia purpura (TTP). However, their clinical management is vastly different, with the latter necessitating urgent plasma exchange (PEX). We report two cases of hypertension-associated TMA (HTN-TMA) and a literature review of the clinical management of malignant hypertension. We suggest that in patients presenting with hypertensive emergency associated with TMA, a clinical diagnosis of HTN-TMA should be made, with emergent treatment to lower blood pressure started immediately. Although TTP is a differential diagnosis for TMA, PEX should not be started concurrently in the absence of other supporting evidence for TTP.

Targeting the DNA damage response in hematological malignancies.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Reducing Chemotherapy Waiting Times in the Ambulatory Setting of a Tertiary Cancer Centre Using a Design Thinking Approach.

INTRODUCTION: Chemotherapy is complex. We hypothesized that a design thinking approach could redesign preparatory processes and reduce wait times. METHODS: A multidisciplinary process mapping exercise was undertaken to understand the current processes, followed by proposing and testing solutions. Proposals were selected based on desirability and feasibility. These focused on starting the morning treatments on time and scheduling pre-made regimens in these slots. The primary outcome measure was the time from the appointment to starting treatment. Treatments in the post-intervention study group were compared against a historical control group. RESULTS: The median time to start morning treatment decreased by 46%, from 83 min (with an interquartile range 50-127) in the control group to 45 min (with an interquartile range of 24-81 min) in the study group (p < 0.001). This translated into an overall improvement for the day, with the median time to start treatment decreasing from 77 min (with an interquartile range of 40-120 min) to 47 min (with an interquartile range of 20-79 min) (p < 0.001). Pre-makes increased by 258%, from 908 (28.5%) to 2340 (71.7%) regimens (p < 0.001). The number of patients starting treatment within an hour of their appointment increased from 1688 (32.8%) to 3355 (62.3%, p < 0.001). CONCLUSION: We have shown that a data-driven, design thinking approach can improve waiting times. This can be adapted to improve other processes in an empathetic, sustainable manner.

Factors Affecting Patient and Caregiver Preferences for Treatment of Myeloma and Indolent Lymphoma.

PURPOSE: Treatment options for myeloma and indolent lymphoma are increasing exponentially, with distinct efficacy, side effects, and cost. We aim to determine the factors influencing patient and caregiver treatment preferences. METHODS: Patients and caregivers of patients with myeloma and indolent lymphoma were recruited from two cancer centers in Singapore. Preferences were elicited using a discrete choice experiment. Attributes and levels were selected based on a previous qualitative study. The relative preference for levels within each attribute (part worth utility values) and the extent to which an attribute would influence decision making (relative importance) were calculated. Patient and caregiver participation in the treatment plan selection process were assessed using the Control Preference Scale. RESULTS: One hundred ninety-nine patients and 169 caregivers were recruited. Patients placed the highest importance on out-of-pocket costs (relative importance = 35%), followed by efficacy (25%), persistent side effects (19%), administration route (8%), treatment duration (7%), and short-term side effects (5%). Caregivers ranked efficacy (27%) as the most important attribute, over out-of-pocket costs (24%). Most patients preferred a collaborative role in the shared decision-making process, while similar proportions of caregivers favored active and collaborative roles. CONCLUSION: Our study demonstrates that both patients and caregivers consider cost seriously when making treatment decisions. Furthermore, as patient and caregiver preferences may differ, there are implications for treatment selection and counseling, especially in cultures where caregivers have more prominent roles in treatment planning.

Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis.

Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted.

Venous thromboembolism in an Asian COVID-19 cohort across 3 infection waves-a retrospective observational study.

Background: A high incidence of venous thromboembolism (VTE) in COVID-19 has led to international recommendations for thromboprophylaxis. With limited data on Asian patients with COVID-19, the role of thromboprophylaxis remains unclear. Objectives: To investigate the in-hospital incidence of VTE in an Asian COVID-19 cohort, describe the VTE trend through successive COVID-19 waves (wild-type, delta, and omicron), and characterize the risk factors for VTE. Methods: We performed a retrospective observational cohort study of hospitalized COVID-19 adults from January 2020 to February 2022. Objectively confirmed VTE were reviewed to obtain VTE incidence and trend. Subset analysis of critical (intensive care), moderate (oxygen supplementation), and mild cases hospitalized ≥5 days was performed to investigate risk factors and in-hospital hazards of VTE. Results: Sixteen VTE events occurred among 3574 patients. Overall, VTE incidence was 0.45%, or 0.21% in mild, 3.60% in moderate, and 5.38% in critical infection. The maximum cumulative risk of VTE was 1.14% at 14 days for mild, 8.13% at 21 days for moderate, and 11.55% at 35 days for critical infection. Thromboprophylaxis use in mild, moderate, and critical cases was 5.7%, 28.8%, and 81.7%, respectively. In multivariable analysis, the severity of infection remained the strongest independent predictor of VTE. Compared with mild infection, the relative risk was 8.26 (95% CI, 2.26-30.16) for critical infection and 6.29 (95% CI, 1.54-25.67) for moderate infection. Conclusion: Overall, VTE incidence in Asian patients with COVID-19 is <1% across successive waves. Patients with moderate and critical infections are at greater risk for VTE and should be considered for routine thromboprophylaxis.

Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma.

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. SIGNIFICANCE: Using single-cell-resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027.

Case report: cytomegalovirus-induced thrombosis in an immunocompetent patient.

Thrombotic manifestations of cytomegalovirus infection in immunocompetent individuals are rare. However, it has been postulated that cytomegalovirus infection can be both directly cytopathic and capable of inducing antiphospholipid antibodies due to shared "molecular mimicry" between cytomegalovirus virus antigens and antiphospholipid antibodies. The case of a previously well 30-year-old woman with primary cytomegalovirus infection complicated by splenic infarction and massive pulmonary embolus is described. The patient is unusual given the development of thromboses affecting both the arterial and venous circulation, associated with both transient anticardiolipin antibodies and persistently positive anti-ß(2) glycoprotein I antibodies. The temporal relationship between the primary infection and thrombosis was suggestive of a pathogenic role for cytomegalovirus.

Treatment outcomes of T and natural-killer/T-cell lymphoma with ifosfamide, carboplatin and etoposide chemotherapy.

BACKGROUND: Contemporary data of peripheral T-cell lymphoma (PTCL) and natural-killer/T-cell lymphoma (NKTL) patients treated with ifosfamide, carboplatin and etoposide (ICE) are limited. AIMS: We performed a retrospective analysis to estimate outcomes of ICE-treated PTCL and NKTL patients at three tertiary cancer centres in Singapore. METHODS AND RESULTS: Patients were identified through lymphoma databases from National Cancer Centre Singapore (NCCS), National University Hospital, Singapore (NUHS), and Singapore General Hospital (SGH). Responses and survival outcomes were determined from electronic medical records. A total of 75 patients with a median age of 50 were included. ICE was used as first-line treatment in 14 patients (19%) and as subsequent lines of treatment in 61 patients (81%). The overall response rates (ORR) for all patients was 63% (40% complete response [CR]). The ORR and CR in the first line were 86% and 64% respectively. At a median follow-up duration of 71.0 months, the median progression-free (PFS) and overall survival (OS) for all patients were 4.4 months (95%CI, 2.7-6.0) and 16 months (95%CI, 8.3-45.4) respectively. CONCLUSION: In summary, ICE showed high ORR but poor PFS in relapsed/refractory PTCL and NKTL. ORR of ICE in the first line setting appears better than real-world CHOP data and warrants further study.

An ex vivo platform to guide drug combination treatment in relapsed/refractory lymphoma.

Although combination therapy is the standard of care for relapsed/refractory non-Hodgkin's lymphoma (RR-NHL), combination treatment chosen for an individual patient is empirical, and response rates remain poor in individuals with chemotherapy-resistant disease. Here, we evaluate an experimental-analytic method, quadratic phenotypic optimization platform (QPOP), for prediction of patient-specific drug combination efficacy from a limited quantity of biopsied tumor samples. In this prospective study, we enrolled 71 patients with RR-NHL (39 B cell NHL and 32 NK/T cell NHL) with a median of two prior lines of treatment, at two academic hospitals in Singapore from November 2017 to August 2021. Fresh biopsies underwent ex vivo testing using a panel of 12 drugs with known efficacy against NHL to identify effective single and combination treatments. Individualized QPOP reports were generated for 67 of 75 patient samples, with a median turnaround time of 6 days from sample collection to report generation. Doublet drug combinations containing copanlisib or romidepsin were most effective against B cell NHL and NK/T cell NHL samples, respectively. Off-label QPOP-guided therapy offered at physician discretion in the absence of standard options (n = 17) resulted in five complete responses. Among patients with more than two prior lines of therapy, the rates of progressive disease were lower with QPOP-guided treatments than with conventional chemotherapy. Overall, this study shows that the identification of patient-specific drug combinations through ex vivo analysis was achievable for RR-NHL in a clinically applicable time frame. These data provide the basis for a prospective clinical trial evaluating ex vivo-guided combination therapy in RR-NHL.

Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.

Central nervous system (CNS) prophylaxis in antiCD20-CHOP treated DLBCL at intermediate to high risk for CNS relapse: A systematic review and meta-analysis.

CNS prophylaxis is commonly used in Diffuse Large B-Cell Lymphoma (DLBCL) patients with risk features for CNS relapse. This systematic review and meta-analysis compares CNS relapse rates with and without CNS prophylaxis, for patients at intermediate to high CNS relapse risk. Studies reporting CNS relapse risk category and CNS outcomes with and without CNS prophylaxis for antiCD20-CHOP treated DLBCL patients were included. 10 studies with 3770 patients at intermediate to high CNS relapse risk were analyzed. No significant difference in the pooled Absolute Risk Difference (ARD 0.01, 95 % CI -0.01 to 0.02, P = 0.61) or Risk (RR 1.22, 95 % CI 0.81-1.83, P = 0.34) was noted in patients with and without CNS prophylaxis. There were also no differences within pre-specified subgroups of IV Methotrexate or IT chemotherapy. However, the quality of evidence supporting these observations was low. A meta-analysis of individual patient data will help evaluate the benefit of CNS prophylaxis strategies.

Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma.

BACKGROUND: The potential therapeutic efficacy of daratumumab in natural killer T-cell lymphoma (NKTL) was highlighted when its off-label usage produced sustained remission in a patient with highly refractory disease. This is corroborated recently by a phase II clinical trial which established that daratumumab monotherapy is well tolerated and displayed encouraging response in relapsed/refractory NKTL patients. However, little is known regarding the molecular factors central to the induction and regulation of the daratumumab-mediated antitumor response in NKTL. METHODS: CD38 expression was studied via immunohistochemistry, multiplex immunofluorescence and correlated with clinical characteristics of the patient. The therapeutic efficacy of daratumumab was studied in vitro via CellTiter-Glo (CTG) assay, complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and in vivo, via a patient-derived xenograft mouse model of NKTL, both as a single agent and in combination with L-asparaginase. Signaling mechanisms were characterized via pharmacologic treatment, RNA silencing, flow cytometry and corroborated with public transcriptomic data of NKTL. RESULTS: Epstein-Barr virus-positive NKTL patients significantly express CD38 with half exhibiting high expression. Daratumumab effectively triggers Fc-mediated ADCC and CDC in a CD38-dependent manner. Importantly, daratumumab monotherapy and combination therapy with L-asparaginase significantly suppresses tumor progression in vivo. Ablation of complement inhibitory proteins (CIP) demonstrate that CD55 and CD59, not CD46, are critical for the induction of CDC. Notably, CD55 and CD59 expression were significantly elevated in the late stages of NKTL. Increasing the CD38:CIP ratio through sequential CIP knockdown, followed by CD38 upregulation via All-Trans Retinoic Acid treatment, potently augments complement-mediated lysis in cells previously resistant to daratumumab. The CD38:CIP ratio consistently demonstrates a statistically superior correlation to antitumor efficacy of daratumumab than CD38 or CIP expression alone. CONCLUSION: This study characterizes CD38 as an effective target for a subset of NKTL patients and the utilization of the CD38:CIP ratio as a more robust identifier for patient stratification and personalisation of treatment. Furthermore, elucidation of factors which sensitize the complement-mediated response provides an alternative approach toward optimizing therapeutic efficacy of daratumumab where CDC remains a known limiting factor. Altogether, these results propose a strategic rationale for further evaluation of single or combined daratumumab treatment in the clinic for NKTL.

Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors.

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.