Comparison of bleeding and thrombotic outcomes in veno-venous extracorporeal membrane oxygenation: Heparin versus bivalirudin.

OBJECTIVES: We aimed to evaluate thrombotic and hemorrhagic complications with heparin versus bivalirudin use in veno-venous extracorporeal membrane oxygenation (V-V ECMO). METHODS: We performed a retrospective cohort study of adult patients placed on V-V ECMO with intravenous anticoagulation with either heparin or bivalirudin. Time to thrombotic event and major bleed were analyzed in addition to related outcomes. RESULTS: We identified 95 patients placed on V-V ECMO: 61 receiving heparin, 34 bivalirudin. The bivalirudin group had a higher rate of severe COVID-19, higher BMI, and longer ECMO duration. Despite this, bivalirudin was associated with reduced risk of thrombotic event (HR 0.14, 95% CI 0.06-0.32, p < .001) and increased average lifespan of the circuit membrane lung (16 vs. 10 days, p = 0.004). While there was no difference in major bleeding, the bivalirudin group required fewer transfusions of packed red blood cells and platelets per 100 ECMO days (means of 13 vs. 39, p = 0.004; 5 vs. 19, p = .014, respectively). Lastly, the bivalirudin group had improved survival to ECMO decannulation in univariate analysis (median OS 53 vs. 26 days, p = .015). CONCLUSIONS: In this real-world analysis of bivalirudin versus heparin, bivalirudin is a viable option for V-V ECMO and associated with lower risk of thrombotic complications and fewer transfusion requirements.

Predictors of thrombosis during VV ECMO: an analysis of 9809 patients from the ELSO registry.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving therapy for critically ill patients, but it carries an increased risk of thrombosis due to blood interacting with non-physiological surfaces. While the relationship between clinical variables and thrombosis remains unclear, our study aimed to identify which factors are most predictive of thrombosis. The Extracorporeal Life Support Organization Registry was queried to obtain a cohort of VV-ECMO patients aged 18 years and older from 2015 to 2019. Patients who were over 80-years-old, at the extremes of weight, who received less than 24 h of ECMO, multiple rounds of ECMO, or had missing data were excluded. Multivariate logistic regression modeling was used to assess predictors of thrombosis and mortality. A total of 9809 patients were included in the analysis, with a mean age of 47.1 ± 15.1 years and an average ECMO run time of 305 ± 353 h. Thrombosis occurred in 19.9% of the cohort, with circuit thrombosis (8.6%) and membrane lung failure (6.1%) being the most common. Multivariate analysis showed that ECMO runs over 14 days (OR: 2.62, P < 0.001) and pregnancy-related complications (OR: 1.79, P = 0.004) were associated with an increased risk of thrombosis. Risk factors for circuit thrombosis included incremental unit increases in the pump flow rate at 24 h (OR: 1.07 [1.00-1.14], P = 0.044) and specific cannulation sites. Increased body weight (OR: 1.02 [1.00-1.04], P = 0.026) and increased duration on ECMO (OR: 3.82 [3.12-4.71], P < 0.001) were predictive of membrane lung failure. Additionally, patients with thrombosis were at increased likelihood of in-hospital mortality (OR: 1.52, P < 0.001). This study identified multiple thrombotic risk factors in VV-ECMO, suggesting that future studies investigating the impact of pregnancy associated complications and ECMO flow rate on hemostasis would be illuminating.

Psychological toxicity in classical hematology.

Although considered "benign," mild blood count abnormalities, genetic factors imparting inconsequential thrombotic risk, and low-risk premalignant blood disorders can have significant psychological and financial impact on our patients. Several studies have demonstrated that patients with noncancerous conditions have increased levels of anxiety with distress similar to those with malignancy. Additionally, referral to a classical hematologist can be a daunting process for many patients due to uncertainties surrounding the reason for referral or misconstrued beliefs in a cancer diagnosis ascribed to the pairing of oncology and hematology in medical practice. If not properly triaged, incidental laboratory abnormalities can trigger extensive and costly evaluation. These challenges are compounded by a lack of consensus guidance and generalizability of modern reference ranges that do not adequately account for common influencing factors. Although often benign, incidental hematologic findings can lead to emotional suffering and careful consideration of the potential psychological and financial duress imparted to an individual must be considered. In this article, we will review the current literature describing the psychological effect of some commonly known hematologic conditions, identify benign causes for variations in hematologic laboratory values, and provide recommendations to reduce psychological toxicity as it pertains to hematologic testing.

Estrogen-based hormonal therapy and the risk of thrombosis in COVID-19 patients.

OBJECTIVE: Estrogen-containing contraceptives and hormone replacement therapy are used commonly, however, the risks of venous and arterial thrombosis imparted by such medications during COVID-19 infection or other similar viral infections remain undescribed. METHODS: To assess the risk of venous and arterial thrombosis in patients receiving oral estrogen-containing therapy (ECT) with COVID-19 as compared to those receiving non-estrogen-based hormonal therapy, we conducted a multicenter cohort study of 991 patients with confirmed COVID-19 infection, 466 receiving estrogen-containing hormonal therapy, and 525 receiving progestin-only or topical therapy. RESULTS: The use of estrogen-containing therapy was found to significantly increase the risk of venous thromboembolism (VTE) following COVID-19 diagnosis after controlling for age (HR 5.46 [95% CI 1.12-26.7, p = .036]). This risk was highest in patients over age 50, with 8.6% of patients receiving estrogen-containing therapy diagnosed with VTE compared to 0.9% of those receiving non-estrogen-based therapies (p = .026). The risk of arterial thrombosis was not significantly associated with oral estrogen use. CONCLUSIONS: These results suggest that estrogen-containing therapy is associated with a significantly increased risk of VTE in COVID-19 patients, especially in older individuals. These findings may guide provider counseling and management of patients with COVID-19 on estrogen-containing therapy.

Real-World Evaluation of Disease Progression After CDK 4/6 Inhibitor Therapy in Patients With Hormone Receptor-Positive Metastatic Breast Cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKi) have changed the landscape for treatment of patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER-) metastatic breast cancer (MBC). However, next-line treatment strategies after CDKi progression are not yet optimized. We report here the impact of clinical and genomic factors on post-CDKi outcomes in a single institution cohort of HR+/HER2- patients with MBC. METHODS: We retrospectively reviewed the medical records of patients with HR+/HER2- MBC that received a CDKi between April 1, 2014 and December 1, 2019 at our institution. Data were summarized using descriptive statistics, the Kaplan-Meier method, and regression models. RESULTS: We identified 140 patients with HR+/HER2- MBC that received a CDKi. Eighty percent of patients discontinued treatment due to disease progression, with a median progression-free survival (PFS) of 6.0 months (95% CI, 5.0-7.1), whereas those that discontinued CDKi for other reasons had a PFS of 11.3 months (95% CI, 4.6-19.4) (hazard ratio (HR) 2.53, 95% CI, 1.50-4.26 [P = .001]). The 6-month cumulative incidence of post-CDKi progression or death was 51% for the 112 patients who progressed on CDKi. Patients harboring PTEN mutations pre-CDKi treatment had poorer clinical outcomes compared to those with wild-type PTEN. CONCLUSION: This study highlights post-CDKi outcomes and the need for further molecular characterization and novel therapies to improve treatments for patients with HR+/HER2- MBC.

Desmopressin as a hemostatic and blood sparing agent in bleeding disorders.

Intranasal, subcutaneous, or intravenous desmopressin can be utilized to release von Willebrand Factor and Factor VIII into circulation, enhance platelet adhesion and shorten bleeding time. Due to these properties, desmopressin can be effective in controlling bleeding in mild hemophilia A, certain subtypes of von Willebrand disease and in acute bleeding from uremia, end stage renal disease, and liver disease. Its use, however, can be complicated by hyponatremia and rarely arterial thrombotic events. While desmopressin has also been used as a prophylactic blood sparing agent in orthopedic, renal, and hepatic procedures, clinical studies have shown limited benefit in these settings. The purpose of this article is to review the evidence for desmopressin in primary hematologic disorders, discuss its mechanism of action and evaluate its utility as a hemostatic and blood sparing product in various bleeding conditions.

The diagnosis and management of suspected lymphoma in general practice.

With rapid advancements in diagnosis and treatment of malignancies, the gap between generalists and subspecialists continues to widen, particularly in cancers like lymphoma where the spectrum of disease varies from indolent to rapidly progressive. Prior to establishing with a hematologist/oncologist, patients must be accurately and comprehensively diagnosed and managed for lymphoma in the generalist setting. In the following manuscript, we review the common clinical presentations in which should raise concern for lymphoma. We summarize the literature regarding the role of laboratory studies including complete blood count and peripheral blood flow cytometry, the recommendations for lymph node sampling, the role and selection of imaging modalities, and ideal patient monitoring for high-risk clinical syndromes that may be encountered in lymphoma.

Hormonal therapies and venous thrombosis: Considerations for prevention and management.

Background: Venous thromboses are well-established complications of hormonal therapy. Thrombosis risk is seen with both hormonal contraceptive agents and with hormone replacement therapy for menopause and gender transition. Over the past several decades, large epidemiological studies have helped better define these risks. Objectives: To review and discuss the differences in thrombosis risk of the many of hormonal preparations available as well as their interaction with patient-specific factors. Methods: We conducted a narrative review of the available literature regarding venous thrombosis and hormonal therapies including for contraception, menopausal symptoms, and gender transition. Results: Thrombosis risk with estrogen-containing compounds increases with increasing systemic dose of estrogen. While progesterone-only-containing products are not associated with thrombosis, when paired with estrogen in combined oral contraceptives, the formulation of progesterone does impact the risk. These components, along with patient-specific factors, may influence the choice of hormonal preparation. For patients who develop thrombosis on hormonal treatment, anticoagulation is protective against future thrombosis. Duration of anticoagulation is dependent on ongoing and future hormone therapy choice. Finally, the optimal management of hormone therapy for individuals diagnosed with prothrombotic illnesses such as COVID-19 remains unclear. Conclusions: When contemplating hormonal contraception or hormone replacement therapy, clinicians must consider a variety of factors including hormone type, dose, route, personal and family history of thrombosis, and other prothrombotic risk factors to make informed, personalized decisions regarding the risk of venous thrombosis.

Thrombotic events in patients using cyclin dependent kinase 4/6 inhibitors, analysis of existing ambulatory risk assessment models and the potential influences of tumor specific risk factors.

Cyclin dependent kinase 4 of 6 inhibitors (CDKi) are key therapeutics in the treatment of advanced breast cancer and have recently been approved in small cell lung cancer for the prevention of myelosuppression. Thrombotic events have emerged as a significant treatment related adverse event in up to 5% of patients in clinical trials and has been reported at higher rates, up to 10%, in real world analysis. The prothrombotic mechanisms of CDKis, however, remain unknown. Cancer specific risk assessment models exist to identify who may be at highest risk of thrombosis and who could potentially benefit from prophylactic anticoagulation. However, these models may not be accurate in patients taking CDKis and may not fully capture recently identified thrombotic risk factors such as tumor specific somatic mutations. In the following manuscript, we summarize the literature on thrombotic events with CDKis in clinical trials and real-world settings, review the existing thrombosis risk assessment models for ambulatory cancer patients, and discuss the literature on tumor mutations and role in cancer associated thrombosis.

Assessing the risk of thromboembolism in cancer patients receiving immunotherapy.

Malignancy has long been implicated with hypercoagulability, leading to an increased rate of both venous and arterial thromboembolic events (VTE and ATE). Immunotherapy has established itself as a cornerstone of modern cancer therapy by promoting antitumor immune responses, though there have been some suggestions that immune-related adverse events could include increased rates of VTE and ATE. In this review, we examine the available evidence regarding the use of immune checkpoint inhibitors (ICIs) and thrombosis. First, we describe the potential mechanisms by which ICIs might lead to thrombophilia given the overlap between the immune system, coagulation cascade, and platelet adhesion and activation. In addition, while there are some preclinical data evaluating immunotherapy-associated ATEs in animal models, there is a paucity of evidence exploring potential mechanism of VTEs in ICIs. Second, we review the incidence of ATE and VTE in patients receiving ICIs in the published literature. Finally, we discuss current limitations in understanding, areas of conflicting evidence, and approaches to further investigation.

Phase I trials and therapeutic intent in the age of precision oncology: What is a patient's chance of response?

The advancement of therapeutic strategies in oncology such as precision oncology has generated significant interest in better estimating the response of modern phase I cancer clinical trials. These estimates have varied widely. In this commentary, we provide an umbrella review of phase I response rates and discuss methodological reasons for variation in prior estimates which include limited use of unpublished data, the inclusion of expansion cohorts that artificially raise response rates of cumulative response rates, varying enrolment of haematologic malignancies, and increased next in class drugs.