Novel Monitoring and Dose Adjustment of Argatroban, a Direct Thrombin Inhibitor, to Maintain Therapeutic Anticoagulation in a Patient With Antiphospholipid Antibody Syndrome, Heparin-Induced Thrombocytopenia, and COVID-19 Pneumonia.

In patients who require systemic anticoagulation, a reliable monitoring method is required to ensure anticoagulation is maintained within the correct therapeutic window and patients are treated appropriately. When titrating direct thrombin inhibitors (DTIs), dilute thrombin time (dTT) measurements have been demonstrated to be more reliable and accurate than activated partial thromboplastin time (aPTT) measurements and thus often the preferred DTI assessment. However, a clinical need arises when both dTT measurements are not readily available and aPTT measurements are unreliable. CASE SUMMARY: A 57-year-old woman with a history of antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, and multiple prior deep venous thromboses and pulmonary emboli was admitted with COVID-19 pneumonia and intubated due to hypoxic respiratory failure. Argatroban was initiated in place of her home medication warfarin. However, the patient had a prolonged aPTT value at baseline and overnight dTT assay measurements were limited at our institution. A multidisciplinary team of hematology and pharmacy clinicians created a modified patient-specific aPTT target range and argatroban dosing was titrated accordingly. Subsequent aPTT values in the modified target range corresponded to therapeutic dTT values, indicating therapeutic anticoagulation was successfully achieved and maintained. Patient blood samples were additionally evaluated retrospectively using an investigational novel point-of-care test that detected and quantified the argatroban anticoagulant effect. CONCLUSIONS: Therapeutic anticoagulation with a DTI in a patient with unreliable aPTT measurements can be achieved with use of a modified patient-specific aPTT target range. Early validation of an investigational rapid testing alternative for DTI monitoring is promising.

Anticoagulation practice patterns in COVID-19: A global survey.

Background: Best practice for prevention, diagnosis, and management of venous thromboembolism (VTE) in patients with coronavirus disease 2019 (COVID-19) is unknown due to limited published data in this population. Objectives: We aimed to assess current global practice and experience in management of COVID-19-associated coagulopathy to identify information to guide prospective and randomized studies. Methods: Physicians were queried about their current approach to prophylaxis, diagnosis, and treatment of VTE in patients with COVID-19 using an online survey tool distributed through multiple international organizations between April 10 and 14, 2020. Results: Five hundred fifteen physicians from 41 countries responded. The majority of respondents (78%) recommended prophylactic anticoagulation for all hospitalized patients with COVID-19, with most recommending use of low-molecular-weight heparin or unfractionated heparin. Significant practice variation was found regarding the need for dose escalation of anticoagulation outside the setting of confirmed or suspected VTE. Respondents reported the use of bedside testing when unable to perform standard diagnostic imaging for diagnosis of VTE. Two hundred ninety-one respondents reported observing thrombotic complications in their patients, with 64% noting that the complication was pulmonary embolism. Of the 44% of respondents who estimated incidence of thrombosis in patients with COVID-19 in their hospital, estimates ranged widely from 1% to 50%. One hundred seventy-four respondents noted bleeding complications (34% minor bleeding, 14% clinically relevant nonmajor bleeding, and 12% major bleeding). Conclusion: Well-designed epidemiologic studies are urgently needed to understand the incidence and risk factors of VTE and bleeding complications in patients with COVID-19. Randomized clinical trials addressing use of anticoagulation are also needed.

COVID-19 and venous thromboembolism: A narrative review.

COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) is associated with coagulopathy through numerous mechanisms. The reported incidence of venous thromboembolism (VTE) in hospitalized patients with COVID-19 has varied widely, and several meta-analyses have been performed to assess the overall prevalence of VTE. The novelty of this coronavirus strain along with its unique mechanisms for microvascular and macrovascular thrombosis has led to uncertainty as to how to diagnose, prevent, and treat thrombosis in patients affected by this virus. This review discusses the epidemiology and pathophysiology of thrombosis in the setting of SARS-CoV-2 infection along with an updated review on the preventative and treatment strategies for VTE associated with SARS-CoV-2 infection.

Pulmonary embolism response teams: Changing the paradigm in the care for acute pulmonary embolism.

Pulmonary embolism response teams (PERTs) have emerged as a multidisciplinary, multispecialty team of experts in the care of highly complex symptomatic acute pulmonary embolism (PE), with a centralized unique activation process, providing rapid multimodality assessment and risk stratification, formulating the best individualized diagnostic and therapeutic approach, streamlining the care in challenging clinical case scenarios (e.g., intermediate-high risk and high-risk PE), and facilitating the implementation of the recommended therapeutic strategies on time. PERTs are currently changing how complex acute PE cases are approached. The structure, organization, and function of a given PERT may vary from hospital to hospital, depending on local expertise, specific resources, and infrastructure for a given academic hospital center. Current emerging data demonstrate the value of PERTs in improving time to PE diagnosis; shorter time to initiation of anticoagulation reducing hospital length of stay; increasing use of advanced therapies without an increase in bleeding; and in some reports, decreasing mortality. Importantly, PERTs are positively impacting outcomes by changing the paradigm of care for acute PE through global adoption by the health-care community.

Geriatric risk factors for serious COVID-19 outcomes among older adults with cancer: a cohort study from the COVID-19 and Cancer Consortium.

BACKGROUND: Older age is associated with poorer outcomes of SARS-CoV-2 infection, although the heterogeneity of ageing results in some older adults being at greater risk than others. The objective of this study was to quantify the association of a novel geriatric risk index, comprising age, modified Charlson comorbidity index, and Eastern Cooperative Oncology Group performance status, with COVID-19 severity and 30-day mortality among older adults with cancer. METHODS: In this cohort study, we enrolled patients aged 60 years and older with a current or previous cancer diagnosis (excluding those with non-invasive cancers and premalignant or non-malignant conditions) and a current or previous laboratory-confirmed COVID-19 diagnosis who reported to the COVID-19 and Cancer Consortium (CCC19) multinational, multicentre, registry between March 17, 2020, and June 6, 2021. Patients were also excluded for unknown age, missing data resulting in unknown geriatric risk measure, inadequate data quality, or incomplete follow-up resulting in unknown COVID-19 severity. The exposure of interest was the CCC19 geriatric risk index. The primary outcome was COVID-19 severity and the secondary outcome was 30-day all-cause mortality; both were assessed in the full dataset. Adjusted odds ratios (ORs) and 95% CIs were estimated from ordinal and binary logistic regression models. FINDINGS: 5671 patients with cancer and COVID-19 were included in the analysis. Median follow-up time was 56 days (IQR 22-120), and median age was 72 years (IQR 66-79). The CCC19 geriatric risk index identified 2365 (41·7%) patients as standard risk, 2217 (39·1%) patients as intermediate risk, and 1089 (19·2%) as high risk. 36 (0·6%) patients were excluded due to non-calculable geriatric risk index. Compared with standard-risk patients, high-risk patients had significantly higher COVID-19 severity (adjusted OR 7·24; 95% CI 6·20-8·45). 920 (16·2%) of 5671 patients died within 30 days of a COVID-19 diagnosis, including 161 (6·8%) of 2365 standard-risk patients, 409 (18·5%) of 2217 intermediate-risk patients, and 350 (32·1%) of 1089 high-risk patients. High-risk patients had higher adjusted odds of 30-day mortality (adjusted OR 10·7; 95% CI 8·54-13·5) than standard-risk patients. INTERPRETATION: The CCC19 geriatric risk index was strongly associated with COVID-19 severity and 30-day mortality. Our CCC19 geriatric risk index, based on readily available clinical factors, might provide clinicians with an easy-to-use risk stratification method to identify older adults most at risk for severe COVID-19 as well as mortality. FUNDING: US National Institutes of Health National Cancer Institute Cancer Center.

The CoVID-TE risk assessment model for venous thromboembolism in hospitalized patients with cancer and COVID-19.

BACKGROUND: Hospitalized patients with COVID-19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well-known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID-19 is lacking. OBJECTIVES: To assess the incidence of and risk factors for thrombosis in hospitalized patients with cancer and COVID-19. METHODS: Among patients with cancer in the COVID-19 and Cancer Consortium registry (CCC19) cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID-19-associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap. RESULTS: From March 17, 2020 to November 30, 2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti-cancer therapy. A simplified RAM for VTE was derived and named CoVID-TE (Cancer subtype high to very-high risk by original Khorana score +1, VTE history +2, ICU admission +2, D-dimer elevation +1, recent systemic anti-cancer Therapy +1, and non-Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low-risk, 0-2 points, n = 1423 vs. high-risk, 3+ points, n = 1034) where VTE occurred in 4.1% low-risk and 11.3% high-risk patients (c statistic 0.67, 95% confidence interval 0.63-0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission. CONCLUSIONS: Hospitalized patients with cancer and COVID-19 have elevated thrombotic risks. The CoVID-TE RAM for VTE prediction may help real-time data-driven decisions in this vulnerable population.

Temporal Trends in Inpatient Oncology Census Before and During the COVID-19 Pandemic and Rates of Nosocomial COVID-19 Among Patients with Cancer at a Large Academic Center.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted health care systems. However, to date, the trend of hospitalizations in the oncology patient population has not been studied, and the frequency of nosocomial spread to patients with cancer is not well understood. The objectives of this study were to evaluate the impact of COVID-19 on inpatient oncology census and determine the nosocomial rate of COVID-19 in patients with cancer admitted at a large academic center. MATERIALS AND METHODS: Medical records of patients with cancer diagnosed with COVID-19 and admitted were reviewed to evaluate the temporal trends in inpatient oncology census during pre-COVID-19 (January 2019 to February 2020), COVID-19 (March to May 2020), and post-COVID-19 surge (June to August 2020) in the region. In addition, nosocomial infection rates of SARS-CoV-2 were reviewed. RESULTS: Overall, the daily inpatient census was steady in 2019 (median, 103; range, 92-118) and until February 2020 (median, 112; range, 102-114). However, there was a major decline from March to May 2020 (median, 68; range, 57-104), with 45.4% lower admissions during April 2020. As the COVID-19 surge eased, the daily inpatient census over time returned to the pre-COVID-19 baseline (median, 103; range, 99-111). One patient (1/231, 0.004%) tested positive for SARS-CoV-2 13 days after hospitalization, and it is unclear if it was nosocomial or community spread. CONCLUSION: In this study, inpatient oncology admissions decreased substantially during the COVID-19 surge but over time returned to the pre-COVID-19 baseline. With aggressive infection control measures, the rates of nosocomial transmission were exceedingly low and should provide reassurance to those seeking medical care, including inpatient admissions when medically necessary. IMPLICATIONS FOR PRACTICE: The COVID-19 pandemic has had a major impact on the health care system, and cancer patients are a vulnerable population. This study observes a significant decline in the daily inpatient oncology census from March to May 2020 compared with the same time frame in the previous year and examines the potential reasons for this decline. In addition, nosocomial rates of COVID-19 were investigated, and rates were found to be very low. These findings suggest that aggressive infection control measures can mitigate the nosocomial infection risk among cancer patients and the inpatient setting is a safe environment, providing reassurance.

Case of right ventricular and aortic thrombi in a patient with severe COVID-19.

Emerging evidence suggests that novel COVID-19 is associated with increased prothrombotic state and risk of thromboembolic complications, particularly in severe disease. COVID-19 is known to predispose to both venous and arterial thrombotic disease. We describe a case of a 61-year-old woman with history of type II diabetes, hypertension and hyperlipidaemia who presented with dry cough and acute abdominal pain. She was found to have a significantly elevated D-dimer, prompting imaging that showed thrombi in her right ventricle and aorta. She had rapid clinical deterioration and eventually required tissue plasminogen activator with subsequent durable clinical improvement. This case highlights a rare co-occurrence of venous and arterial thrombi in a patient with severe COVID-19. Further studies are needed to clarify the molecular mechanism of COVID-19 coagulopathy, the utility of D-dimer to predict and stratify risk of thrombosis in COVID-19, and the use of fibrinolytic therapy in patients with COVID-19.

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19.

BACKGROUND: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. DESIGN: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. SETTING: 67 hospitals in the United States. PARTICIPANTS: Adults with COVID-19 admitted to a participating ICU. MEASUREMENTS: Time to death, censored at hospital discharge, or date of last follow-up. RESULTS: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). LIMITATION: Observational design. CONCLUSION: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. PRIMARY FUNDING SOURCE: None.

Diagnosis and Treatment of Pulmonary Embolism During the Coronavirus Disease 2019 Pandemic: A Position Paper From the National PERT Consortium.

The coexistence of coronavirus disease 2019 (COVID-19) and pulmonary embolism (PE), two life-threatening illnesses, in the same patient presents a unique challenge. Guidelines have delineated how best to diagnose and manage patients with PE. However, the unique aspects of COVID-19 confound both the diagnosis and treatment of PE, and therefore require modification of established algorithms. Important considerations include adjustment of diagnostic modalities, incorporation of the prothrombotic contribution of COVID-19, management of two critical cardiorespiratory illnesses in the same patient, and protecting patients and health-care workers while providing optimal care. The benefits of a team-based approach for decision-making and coordination of care, such as that offered by pulmonary embolism response teams (PERTs), have become more evident in this crisis. The importance of careful follow-up care also is underscored for patients with these two diseases with long-term effects. This position paper from the PERT Consortium specifically addresses issues related to the diagnosis and management of PE in patients with COVID-19.

Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations.

Critically ill patients with COVID-19 are at increased risk for thrombotic complications which has led to an intense debate surrounding their anticoagulation management. In the absence of data from randomized controlled clinical trials, a number of consensus guidelines and recommendations have been published to facilitate clinical decision-making on this issue. However, substantive differences exist between these guidelines which can be difficult for clinicians. This review briefly summarizes the major societal guidelines and compares their similarities and differences. A common theme in all of the recommendations is to take an individualized approach to patient management and a call for prospective randomized clinical trials to address important anticoagulation issues in this population.

A low dose heparinized saline protocol is associated with improved duration of arterial line patency in critically ill COVID-19 patients.

PURPOSE: Critically ill patients with Coronavirus Disease 2019 (COVID-19) have high rates of line thrombosis. Our objective was to examine the safety and efficacy of a low dose heparinized saline (LDHS) arterial line (a-line) patency protocol in this population. MATERIALS AND METHODS: In this observational cohort study, patients ≥18 years with COVID-19 admitted to an ICU at one institution from March 20-May 25, 2020 were divided into two cohorts. Pre-LDHS patients had an episode of a-line thrombosis between March 20-April 19. Post-LDHS patients had an episode of a-line thrombosis between April 20-May 25 and received an LDHS solution (10 units/h) through their a-line pressure bag. RESULTS: Forty-one patients (pre-LDHS) and 30 patients (post-LDHS) were identified. Baseline characteristics were similar between groups, including age (61 versus 54 years; p = 0.24), median Sequential Organ Failure Assessment score (6 versus 7; p = 0.67) and systemic anticoagulation (47% versus 32%; p = 0.32). Median duration of a-line patency was significantly longer in post-LDHS versus pre-LDHS patients (8.5 versus 2.9 days; p < 0.001). The incidence of bleeding complications was similar between cohorts (13% vs. 10%; p = 0.71). CONCLUSIONS: A LDHS protocol was associated with a clinically significant improvement in a-line patency duration in COVID-19 patients, without increased bleeding risk.

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection.

Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels. Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited. This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation. Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications. Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death. The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death. Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without. DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations. Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.