Anticoagulation in cancer patients with atrial fibrillation and grade 3-4 thrombocytopenia.

INTRODUCTION: Atrial fibrillation or flutter (AF) is prevalent in cancer patients. Many of these patients have an indication for anticoagulation (AC) but are also at risk for developing chemotherapy-induced thrombocytopenia. There are scarce data regarding management of AC and risk of bleeding and thrombosis in cancer patients with AF and thrombocytopenia. AIM: To assess anticoagulation management and incidence of bleeding and arterial thromboembolism (ATE) in cancer patients with AF and grade 3-4 thrombocytopenia (platelets <50 × 109/L). METHODS: A retrospective cohort study included adults with active cancer, grade 3-4 thrombocytopenia and AF with CHA2DS2-VASc score ≥ 1. Patients were stratified according to AC discontinuation (No-AC) or continuation (Continue-AC) when platelets dropped below 50 × 109/L and followed for 30 days. The study outcomes were ATE (ischemic stroke, transient ischemic attack or systemic emboli) and major bleeding. Cox proportional hazards model was used to calculate hazard ratios (HR) with death as a competing risk (Fine and Gray model). RESULTS: The cohort included 131 patients; 90 in the No-AC group and 41 in the Continue-AC group. Patient characteristics were balanced between the groups. The 30-day cumulative incidence of ATE was 2 % [95 % CI 0.4 %-7 %] in the No-AC group and 2 % [0.2 %-11 %] in the Continue-AC group (HR 0.92 [95 % CI 0.09-9.88]). The 30-day cumulative incidence of major bleeding was 7.8 % [95 % CI 3.40 %-14.52 %] and 2.44 % [95 % CI 0.18 %-11.22 %] in the No-AC and Continue-AC groups, respectively (HR 3.29 [95 % CI 0.42-26.04]). CONCLUSIONS: The high rate of bleeding and low rate of ATE in thrombocytopenic cancer patients with AF suggests that holding AC during time-limited periods may be a reasonable approach.

The procoagulant potential before and after surgery for endometriosis and its association with disease severity.

OBJECTIVES: Previous studies have suggested that endometriosis is associated with increased hypercoagulable state. We aimed to determine the procoagulant potential among women with endometriosis before and after surgery. METHODS: A prospective longitudinal study performed during 2020-2021 at a university hospital. Women undergoing laparoscopic surgery for endometriosis served as the study group. Blood samples were taken preoperatively and 3 months after surgery. The degree of hypercoagulability was assessed by thrombin generation, a global marker of the activation of the coagulation system, expressed as the endogenous thrombin potential (ETP). Healthy volunteers, without any medical condition or medications use, matched for age and weight of the study group, served as a control group. RESULTS: Thirty women with histologically-proven endometriosis and thirty healthy control subjects were enrolled in this study. Median preoperative ETP was significantly higher in women with moderate-to-severe endometriosis (3313 [interquartile range, IQR 3067-3632] nM) as compared to those with minimal-to-mild disease (2368 [IQR 1850-2621] nM) and the control group (2451 [2096-2617] nM) ( P  < 0.001 for both comparisons). Following surgery, the ETP significantly decreased in those with moderate-to-severe endometriosis (postoperative: 2368 vs. preoperative: 3313 nM, P  < 0.001) and was comparable to the ETP in the control group ( P  = 0.35). In multivariate analysis, moderate-to-severe endometriosis was the only independent predictor of the preoperative ETP level ( P  < 0.001), with a direct positive correlation between disease revised American Society for Reproductive Medicine severity score and the preoperative ETP level ( rs  = 0.67; P  < 0.0001). CONCLUSION: Moderate-to-severe endometriosis is associated with enhanced hypercoagulable state, which decreases significantly after surgery. Disease severity was independently associated with the degree of hypercoagulability.

Arterial Thromboembolism in Patients With AF and CHA2DS2-VASc Score 0-2 With and Without Cancer.

Background: It is unclear whether newly diagnosed cancer adds to the risk of arterial thromboembolism (ATE) in patients with atrial fibrillation/flutter (AF). This is especially relevant for AF patients with low to intermediate CHA2DS2-VASc scores in whom the risk-benefit ratios between ATE and bleeding are delicately balanced. Objectives: The objectives were to evaluate the ATE risk in AF patients with a CHA2DS2-VASc score of 0 to 2 with and without cancer. Methods: A population-based retrospective cohort study was performed. Patients with a CHA2DS2-VASc score of 0 to 2 not receiving anticoagulation at cancer diagnosis (or the matched index date) were included. Patients with embolic ATE or cancer before study index were excluded. AF patients were categorized into AF and cancer and AF and no cancer cohorts. Cohorts were matched for multinomial distribution of age, sex, index year, AF duration, CHA2DS2-VASc score, and low/high/undefined ATE risk cancer. Patients were followed from study index until the primary outcome or death. The primary outcome was acute ATE (ischemic stroke, transient ischemic attack, or systemic ATE) at 12 months using International Classification of Diseases-Ninth Revision codes from hospitalization. The Fine-Gray competing risk model was used to estimate the HR for ATE with death as a competing risk. Results: The 12-month cumulative incidence of ATE was 2.13% (95% CI: 1.47-2.99) in 1,411 AF patients with cancer and 0.8% (95% CI: 0.56-1.10) in 4,233 AF patients without cancer (HR: 2.70; 95% CI: 1.65-4.41). The risk was highest in men with CHA2DS2-VASc = 1 and women with CHA2DS2-VASc = 2 (HR: 6.07; 95% CI: 2.45-15.01). Conclusions: In AF patients with CHA2DS2-VASc scores of 0 to 2, newly diagnosed cancer is associated with an increased incidence of stroke, transient ischemic attack, or systemic ATE compared with matched controls without cancer.

Arterial and Venous Thromboembolism in ALK-Rearrangement-Positive Non-small Cell Lung Cancer: A Population-Based Cohort Study.

INTRODUCTION: There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK)-positive NSCLC and thromboembolic events. METHODS: A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK-positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. RESULTS: The study included 4762 patients, of which 155 (3.2%) were ALK-positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK-positive patients had a higher VTE risk compared to ALK-negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK-negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). CONCLUSIONS: In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK-rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK-positive NSCLC.

Direct oral anticoagulants in patients with venous thromboembolism and hematological malignancies.

Data are needed on direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) in hematological malignancies (HM). Retrospective studies to date lacked a control group and did not focus on patients with VTE. Out aim was to assess the incidence of VTE recurrence and bleeding in HM patients treated with low molecular weight heparin (LMWH) or DOACs for acute VTE. This is a retrospective cohort study including patients with active HM and newly-diagnosed VTE, indexed on the first day of anticoagulation and followed for 12 months. The outcome was a composite of recurrent VTE, major bleeding or clinically relevant non-major bleeding. Cumulative incidence [95% confidence interval (CI)] was calculated for each anticoagulation group (LMWH, DOAC) and hazard ratios (HR) were calculated using cox-proportional hazards model, with death as a competing risk. 143 HM patients treated with LMWH (96) or DOACs (47) for acute VTE were included. The most common HM types were lymphoma in 83 (58%) and plasma cell dyscrasia in 32 (22.3%). The 12-month cumulative incidence of the composite outcome was 24.2% (95% CI 15.9-33.5%; n = 22) in the LMWH group and 18.5% (8.5-31.5%; n = 8) in the DOAC group (HR 1.51 [0.695-3.297]). Two recurrent VTE occurred (both in the DOAC group while off-treatment). Nine (9.4%) LMWH-treated patients had major bleeding compared to 1 (2.1%) DOAC-treated patient (HR 4.85 [0.64-36.56]). This study generates the hypothesis that DOACs may be a safe and effective alternative to LMWH for VTE in patients with HM types represented in the study.

Thrombogenicity and endothelial progenitor cells function during Acute myocardial infarction - comparison of Prasugrel versus Ticagrelor.

BACKGROUND: Thrombin generation (TG), platelet function and circulating endothelial progenitor cells (EPCs) have an important role in the pathophysiology of coronary artery disease (CAD). To date, the effect of novel P2Y12 inhibitors on these aspects has mostly been studied in the sub-acute phase following myocardial infarction. OBJECTIVES: Comparing the effects of prasugrel and ticagrelor on TG and EPCs in the acute phase of ST-segment elevation myocardial infarction (STEMI). METHODS: STEMI patients were randomized to either ticagrelor or prasugrel treatment. TG, platelet reactivity and EPCs were evaluated prior to P2Y12 inhibitor loading dose (T0), and one day following (T1). RESULTS: Between December 2018 - July 2021, 83 consecutive STEMI patients were randomized to ticagrelor (N = 42) or prasugrel (N = 41) treatment. No differences were observed at T0 for all measurements. P2Y12 reactivity units (PRU) at T1 did not differ as well (prasugrel 13.2 [5.5-20.8] vs. ticagrelor 15.8 [4.0-26.3], p = 0.40). At T1, prasugrel was a significantly more potent TG inhibitor, with longer lag time to TG initiation (7.7 ± 7.5 vs. 3.9 ± 2.1 min, p < 0.01), longer time to peak (14.1 ± 12.6 vs. 8.3 ± 9.7 min, p = 0.03) and a lower endogenous thrombin potential (AUC 2186.1 ± 1123.1 vs. 3362.5 ± 2108.5 nM, p < 0.01). Furthermore, EPCs measured by percentage of cells expressing CD34 (2.6 ± 4.1 vs. 1.1 ± 1.1, p = 0.01) and CD133 (2.3 ± 1.8 vs. 1.4 ± 1.5, p = 0.01) and number of colony forming units (CFU, 2.1 ± 1.5 vs. 1.1 ± 1.0, p < 0.01) were significantly higher in the prasugrel group. CONCLUSION: Among STEMI patients, prasugrel as compared to ticagrelor was associated with more potent TG inhibition and improved EPCs count and function.

Cancer-associated non-bacterial thrombotic endocarditis.

This paper reviews the current evidence on the pathogenesis, clinical manifestations, diagnosis and management of cancer-associated non-bacterial thrombotic endocarditis (NBTE). NBTE is an underdiagnosed condition characterized by sterile valvular vegetations composed of platelets and fibrin which are susceptible to systemic embolization. Cancer is a leading cause of NBTE and should be excluded in NBTE cases without a clear etiology. Malignancies most frequently associated with NBTE are mucin-releasing adenocarcinomas of the lung, ovary, biliary system, pancreas, breast and stomach. NBTE carries a high risk of arterial thromboembolism, while cardiac valvular dysfunction is much less frequent. NBTE appears to be an important underdiagnosed cause of cancer-associated embolic stroke of undetermined source. Characteristics associated with cancer-associated NBTE include elevated D-dimer, visceral infarcts, cerebral infarcts in multiple vascular territories, transcranial doppler microembolic signals, disseminated cancer and adenocarcinoma histology. Transesophageal echocardiography is the diagnostic test of choice, and all suspected cases should be evaluated for the presence of elevated D-dimers and disseminated intravascular coagulation. Long-term anticoagulation with low molecular weight heparin should be strongly considered, and surgical intervention is usually not needed. Underlying cancer must be diagnosed swiftly (if previously undiagnosed) and anti-cancer treatment should be initiated as soon as possible. The paucity of data regarding all aspects of NBTE, and the severe clinical consequences of untreated NBTE, are an urgent call for future research.

Cancer-associated venous thromboembolism in Israel: Incidence, risk factors, treatment, and health care utilization in a population based cohort study.

Background: Recent international guidelines recommend thromboprophylaxis in patients with cancer at intermediate-high venous thromboembolism (VTE) risk. Objectives: We aimed to assess the current incidence, risk factors and management of cancer-associated VTE and associated health care resource utilization in a 2.5-million-member state-mandated health service in Israel. Methods: Patients aged ≥18 years with newly diagnosed cancer, initiating systemic anticancer treatment from 2010 through 2018 were identified from the Israel National Cancer Registry. The index date was fixed as the first day of systemic anticancer treatment. The cumulative VTE incidence from the first day of systemic anticancer treatment and the respective hazard ratios for VTE risk factors were calculated at 12 months of follow-up. Health care resource utilization (primary care physician, emergency room, and hospital visits) during the study period was compared between patients with and without VTE. Results: A total of 15 388 patients were included, and 338 had VTE with a 12-month cumulative incidence of 2.2% (95% confidence interval, 1.96%-2.43%). In a multivariable model, older age, higher comorbidity index, intermediate-high-risk Khorana score, certain malignancy types, and chemotherapy were significantly associated with an increased VTE risk in the year after initiating anticancer treatment. Compared with matched controls, the VTE subcohort were more likely to be hospitalized (81.4% vs 35.2%), have longer hospital stays (20.1 days vs 13.1 days), have an emergency room visit (41.5% vs 19.3%), and have a larger number of primary care physician visits (17.6 vs 12.5). Conclusion: Several risk factors, including the Khorana score, were associated with VTE incidence. VTE was associated with long-term use of anticoagulation. Health care utilization was higher in patients with VTE.

Exacerbation of immune thrombocytopenia following initial and booster vaccination with Pfizer-BioNTech COVID-19 vaccine.

As the immune thrombocytopenia exacerbation rate after booster COVID-19 vaccines is unknown, we explore the rates after first, second and booster Pfizer-BioNTech COVID-19 vaccines. A retrospective study of adult ITP patients, receiving 1-3 vaccines was performed. The primary outcome was clinical ITP exacerbation defined as platelet count decrease requiring initiation/escalation of ITP treatment and/or new medical attention due to bleeding, within 3 months. Secondary outcome was any clinically relevant platelet decrease during the 3 months post-vaccination. The study included 93 ITP patients receiving 1 (n = 2), 2 (n = 22) or 3 (n = 69) vaccines. ITP exacerbation occurred in 2/93 (2.2%) patients following initial vaccination and in 3/69 (4.3%) following booster dose. Clinically relevant platelet decreases after initial doses occurred in 8/72 (11.1%) patients and in 8/39 (20.5%) after the booster. Clinical ITP exacerbation after booster doses did not follow clinical exacerbation after initial doses. Half of patients with clinically relevant platelet decreases after booster dose also had clinically relevant decreases following initial vaccination. We concluded that clinical ITP exacerbation is infrequent following Pfizer-BioNTech COVID-19 vaccine. Clinical exacerbation after booster doses was not preceded by clinical exacerbation after initial doses. Clinically relevant platelet decreases after booster doses occur frequently in patients with clinically relevant decreases after initial doses.

Implementation of a Novel Protocol for Preventing Venous Thromboembolism in Otolaryngology Patients.

OBJECTIVE: Venous thromboembolism (VTE) is a preventable cause of postoperative morbidity and mortality. The Caprini risk assessment model (CRAM) is a validated tool for estimating the risk for postoperative VTE. Previous studies demonstrated a low risk of VTE among otorhinolaryngology-head and neck surgery (ORL-HNS). Hence, our objective was to modify the CRAM-based protocol to be applicable for otolaryngology patients and assess protocol efficacy and safety. STUDY DESIGN: Observational pilot study conducted on ORL-HNS patients undergoing surgery. SETTING: University-affiliated tertiary care center. METHODS: We constructed a modified protocol based on the CRAM and previous reports in the ORL-HNS literature using a reduced postoperative anticoagulation regimen. Primary end point was symptomatic VTE up to 3 months after surgery. Main secondary outcome was postoperative bleeding. RESULTS: A total of 508 patients were enrolled. Of them, 48% underwent head and neck surgery, 18% direct laryngoscopy and transoral robotic surgery, 15% endoscopic sinus surgery, and 11% otology surgery. Adherence to the protocol was 79%. Mean follow-up time was 115 days (range, 30-448 days). Only 1 patient developed deep vein thrombosis, and none developed pulmonary embolism. Two patients had major bleeding not related to the use of anticoagulation. CONCLUSIONS: Our novel CRAM-based protocol appears to be efficacious and safe for VTE prevention in otolaryngology. A larger-scale study is required to validate these findings. LEVEL OF EVIDENCE: Level 2b.

Previously undiagnosed cancer in patients with arterial thrombotic events - A population-based cohort study.

BACKGROUND: Emerging data suggest increased arterial thrombosis risk in the months preceding a cancer diagnosis. OBJECTIVES: To assess whether patients without documented vascular risk factors or pre-existing cardiovascular disease have a higher relative risk of cancer 12 months after arterial thrombotic events (ATE), compared to unselected patients. PATIENTS/METHODS: A population-based cohort study of Clalit Health Services (CHS) database included CHS members ≥25 years without prior cancer or ATE (n = 2 804 584). An iterative matching process selected 10 potential controls chronologically for each consecutive exposed, age- and sex-matched (actual controls drawn 1:1 from a lot). Study exposure, ATE, was defined as ischemic stroke, transient ischemic attack, myocardial infarction or systemic arterial thromboembolism during hospitalization. The outcome was newly-diagnosed cancer within 12 months, based on Israeli national cancer registry. Cox proportional hazards multivariate regression calculated hazard ratio (HR) for outcomes, adjusted for cancer risk factors. Analysis also performed for three subgroups: age ≤50 years; no cardiovascular risk factors; no prior cardiovascular disease. RESULTS: The full ATE and matched control cohorts included 43 108 patients. The 12-month cumulative incidence of cancer (95% confidence interval) was 0.020 (0.019-0.022) in the ATE cohort and 0.012 (0.011-0.013) in controls, corresponding to an adjusted HR of 1.665 (1.489-1.862). The relative risk of cancer was high in all subgroups up to a HR of 3.754 (1.912-7.372) in patients without cardiovascular risk factors. CONCLUSION: There is an increased risk of previously undiagnosed cancer at 12 months after ATE, especially in patients without documented vascular risk factors or pre-existent cardiovascular disease.

Outcome of Elderly Patients with Venous Thromboembolism Treated with Direct Oral Anticoagulants-A Retrospective Cohort Study.

INTRODUCTION: Randomized controlled trials that compared direct oral anticoagulants (DOACs) to vitamin K antagonists (VKA) for the treatment of venous thromboembolism (VTE), demonstrated both efficacy and safety of DOACs. The aim of the current study was to compare DOACs to VKA for the treatment of VTE in the elderly, in a real-life setting. METHODS: A retrospective cohort study was performed in Rabin Medical Center encompassing a 7-year period. Hospitalized patients >65 years, with a diagnosis of VTE discharged with DOACs or VKA were included. The primary outcome was a composite of all-cause mortality, major bleeding, recurrent VTEs and hospitalizations throughout the follow-up period of one year. RESULTS: A total of 603 patients were included in the final analysis. The mean age was 79.6 ± 8.5 years. The primary composite outcome occurred in 74.6% and 56.7% of the patients in the VKA group and DOACs group, respectively, hazard ratio 0.59, 95% confidence interval 0.46 to 0.76, in favor of the DOACs group. In a matched cohort analysis, the results were the same as the original analysis. CONCLUSION: In the elderly population, treatment of VTE with DOACs was associated with a lower rate of the composite outcome. DOACs are safe and effective for elderly patients with VTE.

Characteristics and outcomes of patients on concurrent direct oral anticoagulants and targeted anticancer therapies-TacDOAC registry: Communication from the ISTH SSC Subcommittee on Hemostasis and Malignancy.

BACKGROUND: Cancer patients are increasingly prescribed direct oral anticoagulants (DOACs) and targeted anticancer therapies, but limited data are available on the outcomes during concurrent use. OBJECTIVES: We conducted an international registry through the Scientific and Standardization Committee of the ISTH to evaluate the characteristics, bleeding, and thrombotic outcomes in patients receiving concurrent DOACs and targeted anticancer therapies. PATIENTS/METHODS: Patients receiving concurrent DOACs for venous thromboembolism (VTE) or atrial fibrillation and selected targeted anticancer therapies were followed for 6 months after the start of concurrent use. Data including patient and cancer characteristics, major bleeding, non-major bleeding events, and venous or arterial thromboses were collected. RESULTS: Two hundred and two patients were included from six institutions in the United States and Israel. The most common malignancies were hematologic (N = 57, 28.2%), followed by breast (N = 50, 24.8%) and lung (N = 44, 21.8%). The most common anticancer therapies were epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors (N = 43, 21.3%), followed by Bruton's tyrosine kinase (BTK) inhibitors (N = 42, 20.8%) and palbociclib (N = 42, 20.8%). During follow-up, there were 9 major bleeding and 12 non-major bleeding events, corresponding to cumulative incidences of 4% (95% confidence interval [CI]: 2-8%) and 6% (95% CI: 3-10%), respectively. The cumulative incidence of major bleeding events was highest in BTK inhibitor users (10%). There were 3 VTE and 2 arterial thromboses, corresponding to cumulative incidences of 1.5% (95% CI: 0.4-4.0%) and 1.0% (95% CI: 0.2-3.3%), respectively. CONCLUSIONS: In this cohort receiving concurrent DOACs and targeted anticancer therapies, the incidence of bleeding is higher compared to thrombosis, particularly with BTK inhibitors. Future larger prospective studies are needed.

Challenges and Advances in Managing Thrombocytopenic Cancer Patients.

Cancer patients have varying incidence, depth and duration of thrombocytopenia. The mainstay of managing severe chemotherapy-induced thrombocytopenia (CIT) in cancer is the use of platelet transfusions. While prophylactic platelet transfusions reduce the bleeding rate, multiple unmet needs remain, such as high residual rates of bleeding, and anticancer treatment dose reductions/delays. Accordingly, the following promising results in other settings, antifibrinolytic drugs have been evaluated for prevention and treatment of bleeding in patients with hematological malignancies and solid tumors. In addition, Thrombopoeitin receptor agonists have been studied for two major implications in cancer: treatment of severe thrombocytopenia associated with myelodysplastic syndrome and acute myeloid leukemia; primary and secondary prevention of CIT in solid tumors in order to maintain dose density and intensity of anti-cancer treatment. Furthermore, thrombocytopenic cancer patients are often prescribed antithrombotic medication for indications arising prior or post cancer diagnosis. Balancing the bleeding and thrombotic risks in such patients represents a unique clinical challenge. This review focuses upon non-transfusion-based approaches to managing thrombocytopenia and the associated bleeding risk in cancer, and also addresses the management of antithrombotic therapy in thrombocytopenic cancer patients.

An Early Unexpected Immune Thrombotic Thrombocytopenic Purpura Relapse Associated with SARS-CoV-2 Infection: A Case Report and Literature Review.

SARS-CoV-2 has been reported as a possible triggering factor for the development of several autoimmune diseases and inflammatory dysregulation. Here, we present a case report of a woman with a history of systemic lupus erythematosus and antiphospholipid syndrome, presenting with concurrent COVID-19 infection and immune thrombotic thrombocytopenic purpura (TTP). The patient was treated with plasma exchange, steroids, and caplacizumab with initial good response to therapy. The course of both TTP and COVID-19 disease was mild. However, after ADAMTS-13 activity was normalized, the patient experienced an early unexpected TTP relapse manifested by intravascular hemolysis with stable platelet counts requiring further treatment. Only 3 cases of COVID-19 associated TTP were reported in the literature thus far. We summarize the literature and suggest that COVID-19 could act as a trigger for TTP, with good outcomes if recognized and treated early.

Venous thromboembolism incidence and risk assessment in lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: There are scarce data on venous thromboembolism (VTE) rates among non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICI). The Khorana Score (KS), used to guide thromboprophylaxis in cancer patients, was validated in patients receiving chemotherapy. OBJECTIVE: To assess VTE rates and KS performance among NSCLC patients treated with ICI or chemotherapy. METHODS: We performed a retrospective cohort study of NSCLC patients starting either ICI or platinum-based chemotherapy. The 6-month cumulative incidence of VTE in the ICI and chemotherapy cohorts and hazard ratios (HR) with 95% confidence intervals (CI) were calculated, using death as a competing risk. Subgroup analysis of low (0-1) and high (≥2) KS risk groups was performed. RESULTS: The study included 345 NSCLC patients receiving single agent ICI (n = 176) or chemotherapy (n = 169). The 6-month cumulative incidence of VTE was 7.1% in the chemotherapy cohort and 4.5% in the ICI cohort (HR for chemotherapy = 1.6, 95% CI 0.66-3.9). Among chemotherapy treated patients, the high-risk KS group had a trend toward a higher VTE incidence, compared with patients with a low-risk KS (HR 3.04, 95% CI 0.82-11.22). Among ICI-treated patients, the high-risk KS group had a trend toward a lower VTE incidence compared with the low-risk group (HR 0.17, 95% CI 0.02-1.36). CONCLUSIONS: VTE rates were higher among NSCLC patients treated with platinum-based chemotherapy than those treated with ICI alone, though the precision of the relative estimate is low. The KS did not identify high-risk ICI-treated patients, suggesting that an ICI-specific risk model is warranted.

Anticoagulation in patients with atrial fibrillation, thrombocytopenia and hematological malignancy.

Managing anticoagulation in hematological malignancy patients with atrial fibrillation and thrombocytopenia is a clinical challenge with limited data. We aimed to identify anticoagulation management strategies and evaluate bleeding and thrombosis rates associated with each approach. A retrospective cohort study in Israel and the Netherlands was conducted. Patients with hematological malignancy and atrial fibrillation were indexed when platelets were < 50 × 109/L and followed for 30 days. The cohort included 61 patients of whom 42 (69%) had anticoagulation held at index. On multivariate analysis, holding anticoagulation was associated with age < 65 years and atrial fibrillation diagnosed within 30 days prior index. Clinically relevant bleeding was diagnosed in 7 (16.7%) and 1 (5.3%) of patients who had anticoagulation held and continued respectively, while arterial thromboembolism occurred in 1 patient in each group (2.4% and 5.3%, respectively). All-cause mortality rate was high at 45%. Accordingly, the 30-day bleeding risk may outweigh the risk of arterial thromboembolism in hematological malignancy, platelets < 50 × 109/L and atrial fibrillation.

Thrombin Generation in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

BACKGROUND: The optimal antithrombotic treatment for patients with atrial fibrillation (AF) that undergo percutaneous coronary intervention (PCI) is controversial. Dual therapy (clopidogrel and a direct oral anticoagulant [DOAC]) is safer than triple therapy (warfarin, aspirin, and clopidogrel), while efficacy is unclear. We aimed to evaluate thrombin generation (TG) under dual and triple therapy. METHODS: A noninterventional prospective trial in patients with AF undergoing PCI. Patients received 4 weeks of triple therapy with aspirin, clopidogrel, and a DOAC followed by aspirin withdrawal. TG was measured in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) at 3 five to 21 points, day 1 after PCI (TIME 0), 4 weeks after PCI (TIME 1), and 2 weeks after aspirin withdrawal (TIME 2). RESULTS: Twenty-three patients (18 men, median age 78 years, 83% with acute coronary syndrome) were included. Endogenous thrombin potential (ETP) in PPP was high at TIME 0 compared with TIME 1 (ETP 3,178 ± 248 nM vs. 2,378 ± 222 nM, p = 0.005). These results remained consistent when measured in PRP. No significant difference in ETP was found before (TIME 1) and after aspirin withdrawal (TIME 2) although few patients had high ETP levels after stopping aspirin. CONCLUSIONS: TG potential is high immediately after PCI and decreases 4 weeks after PCI in patients receiving triple therapy. TG remains constant after aspirin withdrawal in most patients, suggesting that after 1 month the antithrombotic effect of dual therapy may be similar to triple therapy.

Apixaban Level and Its Influence on Immunosuppression and Graft Outcome in Kidney Transplant Recipients With Atrial Fibrillation.

BACKGROUND: Currently, there is limited information on the level of apixaban in kidney transplant (KT) patients with atrial fibrillation and the influence of apixaban therapy on the level of immunosuppression and graft function. METHODS: This was a cross-sectional prospective study of 19 KT patients treated with apixaban. The levels of apixaban were measured using a chromogenic assay calibrated for apixaban and compared with those predicted by the manufacturer. Mean immunosuppression trough levels before and after apixaban treatment initiation were calculated using 3 consecutive measurements. Apixaban levels were compared with a historical control group comprising of 20 nontransplant patients with atrial fibrillation who were treated with the standard 5-mg bid apixaban dosage. RESULTS: All KT patients should have been treated with the standard 5-mg bid apixaban dosage according to the clinical parameters; however, 7 were inappropriately treated with a reduced dosage (2.5-mg bid). There was no significant difference in apixaban level between KT patients treated with the 5-mg bid dosage and nontransplant patients. No KT patient administered the standard dose had out-of-range levels. Peak GM level was significantly lower in KT patients administered an inappropriately reduced dose (P = 0.05). Two patients had below-range peak levels. Apixaban treatment initiation had minimal influence on the level of immunosuppression. Furthermore, it had no adverse impact on graft function. CONCLUSIONS: Similar to nontransplant patients, KT patients administered the standard 5-mg bid dosage had apixaban levels that were well within the recommended manufacturers' expected ranges. In addition, this dosage had minimal influence on immunosuppression and no effect on graft function.

Pregnancy and non-pregnancy related immune thrombotic thrombocytopenic purpura in women of reproductive age.

Pregnancy is a precipitating factor for immune thrombotic thrombocytopenic purpura (iTTP). We compared the clinical course and outcomes of iTTP in women of reproductive age, between those with pregnancy- and non-pregnancy-related iTTP. A review of all reproductive-aged women diagnosed with iTTP during 2010-2019 in seven university hospitals in Israel. Of 42 cases of iTTP, 12 (28.6%) were pregnancy-related. At presentation, the laboratory profiles did not differ significantly between those with pregnancy- and non-pregnancy-related iTTP, including hemoglobin (median 8.4 vs 8.0 g/dL), platelet count (12.5 vs. 11.5 X 109/L); and levels of bilirubin (1.23 vs. 1.82 mg/dL), lactate dehydrogenase (1615 vs. 1701 U/L), creatinine (0.61 vs. 0.79 mg/dL) and anti-ADAMTS13 antibodies titer (75 vs. 82 U/mL). The proportions of women with renal, neurologic, or hepatic involvement were similar between the groups. Cardiac involvement was more common among those with pregnancy-related disease (25.0% vs. 3.3%, P = 0.06). The median number of courses of plasma-exchange therapy was 11 for both groups. All the women were treated with parenteral corticosteroids and the rate of adjunctive treatments did not differ between the groups (P = 0.30). Four women (one-third) with pregnancy-related disease had preeclampsia. Two women (16.7%) with pregnancy-related iTTP died during the acute episode (P = 0.07); no deaths were observed in the non-pregnancy-related group. Among reproductive-aged women with iTTP, most clinical and laboratory profiles were similar between those with pregnancy- and non-pregnancy-related disease. However, the higher rates of cardiac involvement and mortality among women with pregnancy-related iTTP highlight its challenging management.