Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank.

ABSTRACT: The factor V Leiden (FVL; rs6025) and prothrombin G20210A (PTGM; rs1799963) polymorphisms are 2 of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with previous studies showing marked disagreement regarding thrombosis risk conferred by the DH genotype. Using multidimensional data from the UK Biobank (UKB) and FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937 939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared with wild-type individuals (odds ratio [OR] = 5.24; 95% confidence interval [CI], 4.01-6.84; P = 4.8 × 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N = 445 144) found that effect size estimates for the DH genotype remained largely unchanged (OR = 4.53; 95% CI, 3.42-5.90; P < 1 × 10-16) after adjustment for commonly cited VTE risk factors, such as body mass index, blood type, and markers of inflammation. In contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic data sets to conduct, to our knowledge, the largest study to date on the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and may confer a similarly increased risk of VTE.

The dos, don'ts, and nuances of thrombophilia testing.

Considerable progress has been made in elucidating genetic and biologic risk factors for venous thromboembolism (VTE). Despite being able to identify heritable defects in a substantial proportion of patients with VTE, testing has not, in general, proven useful in management. Despite efforts to reduce inappropriate testing, it often falls to the hematologist to consult on patients having undergone thrombophilia testing. Through a series of cases, we discuss how D-dimer testing can be helpful in VTE recurrence risk stratification in younger women as well as how to approach patients with persistently elevated D-dimer levels in the absence of thrombosis. While elevated factor VIII coagulant activity levels are a significant risk factor for a first episode of VTE, its biologic basis is not fully understood, and studies have not shown it to be a useful predictor of recurrence. Abnormal results of genetic tests for methylene tetrahydrofolate reductase or plasminogen activator 1 promoter polymorphisms may be encountered, which carry little if any thrombotic risk and should never be ordered. We also discuss protein S deficiency, the most difficult of the hereditary thrombophilias to diagnose due to a wider "normal" range in the general population as compared with protein C, the presence of both free and bound forms in plasma, and the characteristics of the various assays in use. We also present a rare type of protein C deficiency that can be missed by functional assays using an amidolytic rather than a clotting end point.

Periprocedural management of type 2N von Willebrand disease with efanesoctocog alfa.

Type 2 Normandy von Willebrand disease (type 2N VWD) is a rare qualitative defect in von Willebrand factor (VWF) that results in impaired factor VIII (FVIII) binding and consequently reduced FVIII levels. Current perioperative strategies require VWF concentrates to attain durable hemostatic FVIII levels. This case highlights the successful perioperative management of a 78-year-old female with type 2N VWD and coronary artery disease utilizing efanesoctocog alfa, a novel long-acting recombinant FVIII product approved for hemophilia A. By decoupling the FVIII-VWF interaction, efanesoctocog alfa achieves prolonged FVIII circulation independent of VWF. A single administration targeting 90% FVIII levels yielded sustained FVIII elevation without achieving supraphysiologic VWF levels, thus mitigating potential cardiovascular risks. This is the first report of efanesoctocog alfa use in type 2N VWD. Further clinical studies are necessary to corroborate its efficacy and safety for this indication.

Four-factor prothrombin complex concentrate plus andexanet alfa for reversal of factor Xa inhibitor-associated bleeding: Case series.

PURPOSE: To manage factor Xa (FXa) inhibitor-associated bleeding, andexanet alfa or 4-factor prothrombin concentrate (4F-PCC) has been used to restore hemostasis. However, literature on the outcomes for patients who received both andexanet alfa and 4F-PCC is limited. SUMMARY: We report a case series of 5 patients who received andexanet alfa plus 4F-PCC for reversal of FXa inhibitor-associated bleeding. Patients were included in this case series if they received both andexanet alfa and 4F-PCC for reversal of FXa inhibitor-associated bleeding. They were followed to either discharge or death, and in-hospital complications related to concurrent use of andexanet alfa and 4F-PCC were documented. We report an incidence of thromboembolism of 40% (2 of 5 cases) and an in-hospital mortality rate of 60% (3 of 5 cases). Taking these cases together with those in the existing literature, we found a total of 23 reported cases of safety outcomes with andexanet alfa plus 4F-PCC. The overall incidence of thromboembolism was 35% (8 of 23 cases). CONCLUSION: This case series adds to the limited literature describing the outcomes for patients receiving andexanet alfa plus 4F-PCC. We encourage other institutions to report safety data on administering both agents.

Aspirin thromboprophylaxis in joint replacement surgery.

BACKGROUND: Aspirin is commonly used as the only pharmacologic agent for prevention of venous thromboembolism (VTE) after joint replacement surgery in the United States. Despite this, prospective studies investigating VTE events after aspirin-only thromboprophylaxis in joint replacement surgery are lacking in the real-world setting. OBJECTIVES: The aim of this study was to estimate the risk of VTE with aspirin-only pharmacologic prophylaxis following joint replacement surgery. METHODS: We carried out a prospective observational study of 350 low-risk patients (no prior history of VTE and low cardiovascular risk factors) who underwent total knee and total hip arthroplasty and received only aspirin for thromboprophylaxis postoperatively. RESULTS: The observed risk of symptomatic VTE was 1.7% (95% confidence interval, 0.9%-3.3%) over 3 months of follow up, with only one major bleeding event and no surgical hematomas. CONCLUSION: The risk of VTE with aspirin monotherapy for thromboprophylaxis in joint replacement surgery in this real-world cohort was higher than previously reported.

Thromboembolism in ALK+ and ROS1+ NSCLC patients: A systematic review and meta-analysis.

INTRODUCTION: Increased thromboembolism (TE) has been reported in ALK+ and ROS1+ non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Odds ratios (OR) and hazard ratios (HR) of TE were calculated from meta-analysis and time-to-event analysis respectively for either ALK+ or ROS1+ NSCLC patients. RESULTS: We identified eight studies (766 ALK+, 143 ROS1+, 2314 non-ALK+ and non-ROS1+ NSCLC patients) for the meta-analysis. For ALK+ NSCLC, the pooled OR was 2.00 (95% CI: 1.60-2.50) for total TE (TTE) by random-effects model, 2.10 (95% CI: 1.70-2.60) for venous thromboembolism (VTE), and 1.24 (95% CI: 0.80-1.91) for arterial thromboembolism (ATE). For ROS1+ NSCLC, the pooled OR was 3.08 (95% CI: 1.95-4.86) for TTE, and 3.15 (95% CI: 1.83-5.43) for VTE. Six studies (739 ALK+, 137 ROS1+, 561 EGFR+, 714 "wildtype" NSCLC patients) were included in the time-to-event analysis. The TTE incidence rate was 17.4 (95% CI: 15.3-19.5) per 100 pateint-years for ALK+ NSCLC, and 32.1 (95% CI: 24.6-39.6) per 100 patient-years for ROS1+ NSCLC with a 50 % cumulative incidence rate at year 3 of diagnosis. HR for TTE was 2.35 (95% CI: 1.90-2.92, p < 0.001) and 3.23 (95% CI: 2.40-4.34, p < 0.001) for ALK+ and ROS1+ NSCLC, respectively. Comparing ROS1+ NSCLC to ALK+ NSCLC, HR for TTE was 1.37 (95% CI: 1.05-1.79, p = 0.020). CONCLUSIONS: ALK+ and ROS1+ NSCLC patients had an increased risk of TE. ROS1+ NSCLC had further increased risk of TE over ALK+ NSCLC.

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.

Thrombolytic therapy in acute venous thromboembolism.

Although anticoagulation remains the mainstay of treatment of acute venous thromboembolism (VTE), the use of thrombolytic agents or thrombectomy is required to immediately restore blood flow to thrombosed vessels. Nevertheless, systemic thrombolysis has not clearly been shown to improve outcomes in patients with large clot burdens in the lung or legs as compared with anticoagulation alone; this is in part due to the occurrence of intracranial hemorrhage in a small percentage of patients to whom therapeutic doses of a thrombolytic drug are administered. Algorithms have been developed to identify patients at high risk for poor outcomes resulting from large clot burdens and at low risk for major bleeding in an effort to improve outcomes in those receiving thrombolytic therapy. In acute pulmonary embolism (PE), hemodynamic instability is the key determinant of short-term survival and should prompt consideration of immediate thrombolysis. In hemodynamically stable PE, systemic thrombolysis is not recommended and should be used as rescue therapy if clinical deterioration occurs. Evidence is accumulating regarding the efficacy of administering reduced doses of thrombolytic agents systemically or via catheters directly into thrombi in an effort to lower bleed rates. In acute deep venous thrombosis, catheter-directed thrombolysis with thrombectomy can be used in severe or limb-threatening thrombosis but has not been shown to prevent postthrombotic syndrome. Because the management of acute VTE can be complex, having a rapid-response team (ie, PE response team) composed of physicians from different specialties may aid in the management of severely affected patients.

Risk-assessment models for VTE and bleeding in hospitalized medical patients: an overview of systematic reviews.

Multiple risk-assessment models (RAMs) for venous thromboembolism (VTE) in hospitalized medical patients have been developed. To inform the 2018 American Society of Hematology (ASH) guidelines on VTE, we conducted an overview of systematic reviews to identify and summarize evidence related to RAMs for VTE and bleeding in medical inpatients. We searched Epistemonikos, the Cochrane Database, Medline, and Embase from 2005 through June 2017 and then updated the search in January 2020 to identify systematic reviews that included RAMs for VTE and bleeding in medical inpatients. We conducted study selection, data abstraction and quality assessment (using the Risk of Bias in Systematic Reviews [ROBIS] tool) independently and in duplicate. We described the characteristics of the reviews and their included studies, and compared the identified RAMs using narrative synthesis. Of 15 348 citations, we included 2 systematic reviews, of which 1 had low risk of bias. The reviews included 19 unique studies reporting on 15 RAMs. Seven of the RAMs were derived using individual patient data in which risk factors were included based on their predictive ability in a regression analysis. The other 8 RAMs were empirically developed using consensus approaches, risk factors identified from a literature review, and clinical expertise. The RAMs that have been externally validated include the Caprini, Geneva, IMPROVE, Kucher, and Padua RAMs. The Padua, Geneva, and Kucher RAMs have been evaluated in impact studies that reported an increase in appropriate VTE prophylaxis rates. Our findings informed the ASH guidelines. They also aim to guide health care practitioners in their decision-making processes regarding appropriate individual prophylactic management.

Postdischarge thrombosis and hemorrhage in patients with COVID-19.

Coronavirus disease 2019 (COVID-19) is associated with a prothrombotic state with a high incidence of thrombotic events during hospitalization; however, data examining rates of thrombosis after discharge are limited. We conducted a retrospective observational cohort study of discharged patients with confirmed COVID-19 not receiving anticoagulation. The cohort included 163 patients with median time from discharge to last recorded follow-up of 30 days (interquartile range [IQR], 17-46 days). The median duration of index hospitalization was 6 days (IQR, 3-12 days) and 26% required intensive care. The cumulative incidence of thrombosis (including arterial and venous events) at day 30 following discharge was 2.5% (95% confidence interval [CI], 0.8-7.6); the cumulative incidence of venous thromboembolism alone at day 30 postdischarge was 0.6% (95% CI, 0.1-4.6). The 30-day cumulative incidence of major hemorrhage was 0.7% (95% CI, 0.1-5.1) and of clinically relevant nonmajor bleeds was 2.9% (95% CI, 1.0-9.1). We conclude that the rates of thrombosis and hemorrhage appear to be similar following hospital discharge for COVID-19, emphasizing the need for randomized data to inform recommendations for universal postdischarge thromboprophylaxis.

Incidence of thrombosis and hemorrhage in hospitalized cancer patients with COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is a recognized prothrombotic state. Patients hospitalized with active cancer are predisposed to thrombosis but whether active cancer further amplifies thrombotic risk with COVID-19 is not known. OBJECTIVES: To evaluate cumulative incidences of thrombotic and hemorrhagic events in hospitalized COVID-19 patients with and without active cancer at 28 days. METHODS: A retrospective cohort analysis of consecutive adults hospitalized with COVID-19 was performed. Active cancer required cancer-directed therapy within previous 6 months. The cumulative incidences of thrombosis or hemorrhage were estimated considering death as a competing risk. RESULTS: Patients without cancer (n = 353) and active cancer (n = 45) were comparable in terms of age, sex, antibiotics administered, length of hospitalization, and critical care. The most common malignancies were lymphoid (17.8%), gastrointestinal (15.6%), lung (13.3%), and genitourinary (13.3%). At day 28, the cumulative incidence of thrombotic events was 18.2% (95% confidence interval [CI], 10.2%-27.9%) in the non-cancer cohort and 14.2% (95% CI, 4.7%-28.7%) in the cancer cohort. The cumulative incidence of major and fatal bleeding at day 28 was 20.8% (95% CI, 12.1%-31.0%) in the non-cancer group and 19.5% (95% CI, 5.5%-39.8%) in the cancer cohort. Three patients experienced fatal bleeds, all of whom were in the non-cancer cohort. Survival was significantly shorter in the group with active cancer (P = .038). CONCLUSIONS: We observed a similarly high incidence of thrombosis and bleeding among patients admitted with COVID-19 with or without active cancer.

Extrapulmonary manifestations of COVID-19.

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

Dose-adjusted enoxaparin thromboprophylaxis in hospitalized cancer patients: a randomized, double-blinded multicenter phase 2 trial.

Hospitalized patients with cancer are at an increased risk of developing venous thromboembolism (VTE). The recommendation for routine pharmacologic thromboprophylaxis in hospitalized patients with cancer to prevent VTE is based on extrapolation of results from noncancer cohorts. There are limited data to support the efficacy and safety of fixed-dose low-molecular-weight heparin (LMWH) regimens in high-risk hospitalized patients with cancer. We conducted a randomized, double-blinded, phase 2 trial in hospitalized patients with active cancer at high risk of developing VTE based on Padua risk score. Patients were randomly assigned to fixed-dose enoxaparin (40 mg daily) vs weight-adjusted enoxaparin (1 mg/kg daily) during hospitalization. The primary objectives were to evaluate the safety of dose-adjusted enoxaparin and evaluate the incidence of VTE with fixed-dose enoxaparin. Blinded clinical assessments were performed at day 14, and patients randomly assigned to fixed-dose enoxaparin subsequently underwent a bilateral lower extremity ultrasound. A total of 50 patients were enrolled and randomized. The median weight of patients enrolled in weight-adjusted enoxaparin arm was 76 kg (range, 60.9-124.5 kg). There were no major hemorrhages or symptomatic VTE in either arm. At time of completion of the blinded clinical assessment, there was only 1 incidentally identified pulmonary embolus that occurred in the weight-adjusted arm. In the group randomly assigned to fixed-dose enoxaparin who subsequently underwent surveillance ultrasound, the cumulative incidence of DVT was 22% (90% binomial confidence interval, 0%-51.3%). This phase 2 trial confirms a high incidence of asymptomatic VTE among high-risk hospitalized patients with cancer and that weight-adjusted LMWH thromboprophylaxis is feasible and well-tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02706249.

Changes in Care for Acute Pulmonary Embolism Through A Multidisciplinary Pulmonary Embolism Response Team.

BACKGROUND: Optimal management of acute pulmonary embolism requires expertise offered by multiple subspecialties. As such, pulmonary embolism response teams (PERTs) have increased in prevalence, but the institutional consequences of a PERT are unclear. METHODS: We compared all patients that presented to our institution with an acute pulmonary embolism in the 3 years prior to and 3 years after the formation of our PERT. The primary outcome was in-hospital pulmonary embolism-related mortality before and after the formation of the PERT. Sub-analyses were performed among patients with elevated-risk pulmonary embolism. RESULTS: Between August 2012 and August 2018, 2042 patients were hospitalized at our institution with acute pulmonary embolism, 884 (41.3%) pre-PERT implementation and 1158 (56.7%) post-PERT implementation, of which 165 (14.2%) were evaluated by the PERT. There was no difference in pulmonary embolism-related mortality between the two time periods (2.6% pre-PERT implementation vs 2.9% post-PERT implementation, P = .89). There was increased risk stratification assessment by measurement of cardiac biomarkers and echocardiograms post-PERT implementation. Overall utilization of advanced therapy was similar between groups (5.4% pre-PERT implementation vs 5.4% post-PERT implementation, P = 1.0), with decreased use of systemic thrombolysis (3.8% pre-PERT implementation vs 2.1% post-PERT implementation, P = 0.02) and increased catheter-directed therapy (1.3% pre-PERT implementation vs 3.3% post-PERT implementation, P = 0.05) post-PERT implementation. Inferior vena cava filter use decreased after PERT implementation (10.7% pre-PERT implementation vs 6.9% post-PERT implementation, P = 0.002). Findings were similar when analyzing elevated-risk patients. CONCLUSION: Pulmonary embolism response teams may increase risk stratification assessment and alter application of advanced therapies, but a mortality benefit was not identified.

Should You Treat This Acutely Ill Medical Inpatient With Venous Thromboembolism Chemoprophylaxis?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Venous thromboembolism (VTE), which includes both deep venous thrombosis and pulmonary embolism, is a common and potentially fatal condition. Medical inpatients are at high risk for VTE because of immobility as well as acute and chronic illness. Several randomized trials demonstrated that chemoprophylaxis, or low-dose anticoagulation, prevents VTE in selected medical inpatients. The 2018 American Society of Hematology clinical practice guideline on prophylaxis for hospitalized and nonhospitalized medical patients conditionally recommends chemoprophylaxis for non-critically ill medical inpatients, leaving much to the discretion of the treating physician. Here, 2 experts, a hematologist and a hospitalist, reflect on the care of a woman hospitalized with a rheumatologic disorder. They consider the risks and benefits of chemoprophylaxis, discuss VTE risk stratification, and recommend which patients should receive chemoprophylaxis and with which agents.

Managing thromboembolic risk in patients with hereditary and acquired thrombophilias.

While we are now able to diagnose inherited thrombophilias in a substantial number of patients with venous thromboembolism (VTE), the initial hope that their presence would inform recurrence risk and thus decisions on anticoagulation duration has largely been disappointing. Indeed, the presence or absence of transient provoking risk factors has proven to be the most important determinant of VTE recurrence risk. Thus, particular attention to transient acquired risk factors for VTE remains paramount, as they have generally been shown to carry more prognostic weight than inherited thrombophilias. The presence of other acquired risk factors may require additional management considerations, whether pertaining to anticoagulant choice, as in antiphospholipid antibody syndrome, or to addressing a new predisposing medical condition, as in malignancy. Antithrombin deficiency or the presence of ≥1 thrombophilic defect may be exceptions that can have a role in prognostication; however, as illustrated in this review through several case vignettes, interpretation and clinical application of the results of inherited thrombophilia testing is nuanced. We have chosen to focus on cases in which patients have been identified as having thrombophilic defects rather than the indications for undertaking testing in the first place or the extent of investigation. Management decisions in such cases ultimately hinge on individualized consideration of the benefits and risks of anticoagulation along with patient preference rather than on an algorithmic pathway based on thrombophilia status.