Journal of Thrombosis and Thrombolysis

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Online ISSN: 1573-742X
Print ISSN: 0929-5305
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Search strategy for scoping review
Selection of articles for review
Models of care for managing direct oral anticoagulant (DOAC) therapy are evolving. Little is known of what services are provided by anticoagulation managements services (AMS) for DOACs, or what necessitates comprehensive DOAC management and what differentiates it from usual care. The purpose of this scoping review was to describe services, management, or monitoring of DOACs distinct from prescriber-managed or usual care of DOACs. This scoping review reported followed the 2018 Preferred Reporting Items for Systematic Review and Meta-Analyses extension for scoping reviews (PRISMA-ScR). We searched PubMed, CINAHL, and EMBASE from inception to November 2020 to identify articles of interest. No language restriction was applied. Articles were included if they provided a description of DOAC management services, and described longitudinal anticoagulation follow-up that occurred in ambulatory care, community, or outpatient-related settings. Data was extracted from a total of 23 articles. The specific types of DOAC management interventions provided varied across the included studies. Nearly all studies described some form of DOAC therapy appropriateness assessment. Other common interventions included assessments of DOAC therapy compliance, adverse event triage and management, assessment of DOAC dosing appropriateness, periprocedural management of DOAC therapy, educational interventions, and renal function monitoring. A variety of DOAC management interventions were identified, but additional studies are needed to help health systems decide whether specific interventions performed by dedicated services are preferred over the usual care provided by clinicians prescribing DOAC therapy.
Flowchart of pregnant patients with antiphopholipid syndrome
Women with antiphospholipid syndrome (APS) have an increased risk of adverse pregnancy outcomes. To define clinical, serologic, and treatment factors that can predict outcomes in pregnant women with APS. Retrospective cohort study of pregnant women with APS evaluated at a university medical center between January 2006 and August 2021. Demographics, personal and family history of thrombosis, autoimmune disease, antithrombotic use, pregnancy outcomes, maternal and fetal complications were collected. We compared pregnancy outcomes in the presence or absence of lupus anticoagulant (LA), systemic lupus erythematosus (SLE), prior thrombosis or pregnancy losses, and antithrombotic use. There were 169 pregnancies in 50 women; 79 (46.7%) occurred after maternal diagnosis of APS. The most common antithrombotic regimen was aspirin and low molecular weight heparin (LMWH) in 26.6% of pregnancies; 55.0% of all pregnancies and 68.4% of pregnancies post-APS diagnosis resulted in a live birth. In age-adjusted analyses, aspirin plus LMWH regardless of dosage was associated with significantly higher odds of live birth compared with no antithrombotic use (OR = 7.5, p < 0.001) and compared with aspirin alone (OR = 13.2, p = 0.026). SLE increased the risk for preterm birth and preeclampsia. A positive LA did not impact the outcomes evaluated and anticardiolipin IgM decreased the risk of pre-eclampsia. The presence of SLE is a significant risk factor for adverse outcomes in pregnant women with APS. Treatment with LMWH and aspirin was superior to aspirin alone. The creation of a global registry may be useful in improving the management of these patients.
The association of Parkinson’s Disease (PD) with atrial fibrillation (AF) is not well established and previous studies’ results were heterogeneous. This review aimed to evaluate if patients with PD are at increased risk of having AF. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, were searched from inception May 2021. Two reviewers independently selected observational studies with data allowing to estimate the risk of atrial fibrillation in PD patients compared with no-PD controls. Pooled estimates Odds Ratio (OR) and 95% confidence intervals (CIs) were derived through meta-analysis. Heterogeneity was assessed using I2 test. The risk of bias of individual studies was evaluated using the ROBINS-I tool. The study protocol was registered at PROSPERO: CRD42020216572. Seven studies were included: five case-control studies and two cohort studies. Three of the studies included were a population-based study. No significant difference was detected between PD and controls regarding atrial fibrillation (OR 1.10, 95% CI 0.81 to 1.49). Early PD present a significant higher risk of AF (OR 1.55, 95% CI 1.00 to 2.40, I2 98%). The overall risk of bias was serious, with only two studies being considered as having moderate risk. The best evidence available do not support that there is an increased risk of AF in PD patients. Further studies are needed to better conclude if there is a relation between AF and PD.
Several purinergic receptors have been identified on platelets which are involved in hemostatic and thrombotic processes. The aim of the present study was to investigate the effects of uridine and its nucleotides on platelet aggregation and hemostasis in platelet-rich plasma (PRP) and whole blood. The effects of uridine, UMP, UDP, and UTP at different final concentrations (1 to 1000 µM) on platelet aggregation were studied using an aggregometer. In PRP samples, platelet aggregation was induced by ADP, collagen and epinephrine 3 min after addition of uridine, UMP, UDP, UTP and saline (as a control). All thromboelastogram experiments were performed at 1000 µM final concentrations of uridine and its nucleotides in whole blood. UDP and UTP were also tested in thromboelastogram with PRP. Our results showed that UDP, and especially UTP, inhibited ADP- and collagen-induced aggregation in a concentration-dependent manner. In whole blood thromboelastogram experiments, UDP stimulated clot formation while UTP suppressed clot formation. When thromboelastogram experiments were repeated with PRP, UTP’s inhibitory effect on platelets was confirmed, while UDP’s stimulated clot forming effect disappeared. Collectively, our data showed that UTP inhibited platelet aggregation in a concentration-dependent manner and suppressed clot formation. On the other hand, UDP exhibited distinct effects on whole blood or PRP in thromboelastogram. These data suggest that the difference on effects of UTP and UDP might have arisen from the different receptors that they stimulate and warrant further investigation with regard to their in vivo actions on platelet aggregation and hemostasis.
12-month cumulative incidence of recurrent VTE, major bleeding or CRNMB. Cumulative incidence and 95% confidence intervals (indicated by shaded areas) of recurrent VTE, major bleeding or CRNMB during 12-month follow-up, stratified for type of anticoagulation one week after index. The dashed red line represents LMWH and the solid blue line indicates DOAC. Death was considered a competing risk. CRNMB, clinically relevant non-major bleeding; DOAC, direct oral anticoagulant; LMWH, low molecular weight heparin; VTE, venous thromboembolism
12-month cumulative incidence of major bleeding and CRNMB. Cumulative incidence and 95% confidence intervals (indicated by shaded areas) of major bleeding (panel A) or CRNMB (panel B) during 12-month follow-up, stratified for type of anticoagulation one week after index. The dashed red line represents LMWH and the solid blue line indicates DOAC. Death was considered a competing risk. CRNMB, clinically relevant non-major bleeding; DOAC, direct oral anticoagulant; LMWH, low molecular weight heparin
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.
Study patient flow diagram. CE contrast-enhanced echocardiography, COVID-19 coronavirus disease 2019
Patient examples of CE images. Patient A had the thrombus resolution at 6 weeks and 12 weeks, compared to LV thrombus (red arrows) at baseline. Patient B had the thrombus reduced at 6 weeks and 12 weeks, compared to LV thrombus (red arrows) at baseline. Patient C had the thrombus unchanged at 6 weeks and 12 weeks, compared to LV thrombus (red arrows) at baseline. LV left ventricular, CE contrast-enhanced echocardiography
Levels of biomarkers (y-axis) across time points (x-axis) between the thrombus resolved group (orange) and the thrombus unresolved group (green). *The level of D-dimer at 6 weeks shows a significant difference in the two groups. Error bars indicate standard error. In the measurements of anti-Xa (A) and FM (B), the timepoint of “1” refers to the blank baseline level, “2” refers to the level testing on the fourth day of rivaroxaban treatment, “3” refers to the level testing at 6 weeks, “4” refers to the level testing at 12 weeks, “_0” refers to the time before medication, and “_1” refers to 2–4 h after medication. (C) and (D) show the trend of D-dimer levels and FDP levels at baseline, 6 weeks, and 12 weeks. FM Fibrin monomer, FDP fibrin degradation products
Evidence on the treatment for left ventricular (LV) thrombus is limited and mainly derives from retrospective studies. The aim of R-DISSOLVE was to explore the effectiveness and safety of rivaroxaban in patients with LV thrombus. R-DISSOLVE was a prospective, interventional, single-arm study, conducted from Oct 2020 to June 2022 at Fuwai Hospital, China. Patients with a history of LV thrombus < 3 months and with systemic anticoagulation therapy < 1 month were included. The thrombus was quantitatively confirmed by contrast-enhanced echocardiography (CE) at baseline and follow-up visits. Eligible patients were assigned to rivaroxaban (20 mg once daily or 15 mg if creatinine clearance was between 30 and 49 mL/min) and its concentration was determined by detecting anti-Xa activity. The primary efficacy outcome was the rate of LV thrombus resolution at 12 weeks. The main safety outcome was the composite of ISTH major and clinically relevant non-major bleeding. A total of 64 patients with complete CE results were analyzed for efficacy outcomes. The mean LV ejection fraction was 25.4 ± 9.0%. The dose-response curve of rivaroxaban was satisfactory based on the peak and trough plasma levels and all concentrations were in the recommended treatment range according to NOAC guidelines. The incidence rate of thrombus resolution at 6 weeks was 66.1% (41/62, 95% CI 53.0–77.7%), and of thrombus resolution or reduction was 95.2% (59/62, 95% CI 86.5–99.0%). At 12 weeks, the thrombus resolution rate was 78.1% (50/64, 95% CI 66.0–87.5%) while the rate of thrombus resolution or reduction was 95.3% (61/64, 95% CI 86.9–99.0%). The main safety outcome occurred in 4 of 75 patients (5.3%) (2 ISTH major bleeding and 2 clinically relevant non-major bleeding). In patients with LV thrombus, we reported a high thrombus resolution rate with acceptable safety by rivaroxaban, which could be a potential option for further LV thrombus treatment. Trial registration This study was registered at as NCT 04970381.
Kaplan–Meier survival curves for MACCE according to P2Y12 dependent HPR (cut-off 208 PRU). A 1-year follow-up. B 3-months follow-up
High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario. Graphical abstract The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with
Ultrasound image of occlusive thrombus in the subclavian artery
Angiogram performed in the right subclavian artery demonstrates abrupt discontinuation of contrast just distal to the origin of the subscapular artery, with radiopaque wire extending into distal vessel
Follow-up angiography after 36 local tPA infusion demonstrates resolution of thrombus, with normal appearance of artery to level of radial-ulnar bifurcation
Non-catheter related arterial thromboembolism in the neonatal population is rare and carries a significant risk of organ damage or limb loss. Thrombolysis, whether systemic or catheter- directed, is reserved either for limb or life-threatening thrombosis due to risk of bleeding especially in premature neonates. In this case, an infant male born at 34 weeks and 4 days gestational age presented with limb-threatening clot in the distal right subclavian artery and proximal right axillary artery with no known cause. After discussion of risks and benefits of various treatment options, he received thrombolysis treatment with low dose recombinant TPA via an umbilical artery catheter. There was complete resolution of the thrombus with this treatment and the patient had no significant bleeding while receiving treatment. Further investigation is needed to identify the patient population that will benefit from catheter-directed thrombolytic therapy and how to best monitor these patients.
IVUS findings between layered and non-layered plaques
(A) shows the total atheroma volume (TAV) between patients with layered and non-layered plaques. Patients with layered plaques had significantly greater TAV than those with non-layered plaques. (B) shows the percent atheroma volume (PAV) between patients with layered and non-layered plaques. Patients with layered plaques had significantly greater PAV than those with non-layered plaques. (C) shows the plaque burden (PB) between patients with layered and non-layered plaques. Patients with layered plaques had significantly greater PB than those with non-layered plaques
IVUS findings between multi-layered, single-layered, and non-layered plaques
(A) shows the total atheroma volume (TAV) between patients in 3 groups. Patients with multi-layered plaques had significantly greater TAV than those with non-layered plaques. There was no significant difference between patients with multi-layered and single-layered plaques, and single-layered and non-layered plaques. (B) shows the percent atheroma volume (PAV) between patients in 3 groups. Patients with multi-layered plaques had the largest PAV of the three groups. There was no significant difference between patients with single-layered and non-layered plaques. (C) shows the plaque burden (PB) between patients in 3 groups. Patients with multi-layered plaques had significantly greater PB than those with non-layered plaques. There was no significant difference between patients with multi-layered and single-layered plaques, and single-layered and non-layered plaques
Background Layered plaque is a signature of previous subclinical plaque destabilization and healing. Following plaque disruption, thrombus becomes organized, resulting in creation of a new layer, which might contribute to rapid step-wise progression of the plaque. However, the relationship between layered plaque and plaque volume has not been fully elucidated. Methods Patients who presented with acute coronary syndromes (ACS) and underwent pre-intervention optical coherence tomography (OCT) and intravascular ultrasound (IVUS) imaging of the culprit lesion were included. Layered plaque was identified by OCT, and plaque volume around the culprit lesion was measured by IVUS. Results Among 150 patients (52 with layered plaque; 98 non-layered plaque), total atheroma volume (183.3 mm³[114.2 mm³ to 275.0 mm³] vs. 119.3 mm³[68.9 mm³ to 185.5 mm³], p = 0.004), percent atheroma volume (PAV) (60.1%[54.7–60.1%] vs. 53.7%[46.8–60.6%], p = 0.001), and plaque burden (86.5%[81.7–85.7%] vs. 82.6%[77.9–85.4%], p = 0.001) were significantly greater in patients with layered plaques than in those with non-layered plaques. When layered plaques were divided into multi-layered or single-layered plaques, PAV was significantly greater in patients with multi-layered plaques than in those with single-layered plaques (62.1%[56.8–67.8%] vs. 57.5%[48.9–60.1%], p = 0.017). Layered plaques, compared to those with non-layered pattern, had larger lipid index (1958.0[420.9 to 2502.9] vs. 597.2[169.1 to 1624.7], p = 0.014). Conclusion Layered plaques, compared to non-layered plaques, had significantly greater plaque volume and lipid index. These results indicate that plaque disruption and the subsequent healing process significantly contribute to plaque progression at the culprit lesion in patients with ACS. Clinical Trial Registration, NCT01110538, NCT03479723, UMIN000041692.
Flowchart of the study population
The areas under the receiver operating characteristic curve of postoperative d-dimer levels and INTEM LI60 for the prediction of venous thromboembolism are shown
Surgical resection of malignant bone tumors is associated with a high risk of venous thromboembolism (VTE). The purpose of this study was to evaluate the association between rotational thromboelastometry (ROTEM) parameters and VTE following oncologic resections, and to evaluate their prognostic capacity for this complication. A prospective observational study was conducted including 113 patients who underwent surgical resection of malignant bone tumors. ROTEM analysis and conventional coagulation studies were performed preoperatively and on the 2nd postoperative day, while patients were followed for the development of VTE. Logistic regression was used to assess the association between ROTEM parameters and occurrence of VTE. The area under the receiver operating characteristic curve (AUC), sensitivity and specificity were calculated as measures of discrimination and predictive accuracy. Fourteen patients (12.4%) developed symptomatic VTE. Development of VTE was associated with shortened INTEM CFT (Odds Ratio [OR] 0.90, 95% Confidence Interval [CI] 0.84 − 0.96, p = 0.004), higher INTEM A10 (OR 1.21, 95% CI 1.07 − 1.36, p = 0.002), higher INTEM MCF (OR 1.22, 95% CI 1.08 − 1.37, p = 0.001) and higher INTEM LI60 (OR 2.10, 95% CI 1.38 − 3.21, p = 0.001). An INTEM LI60 value indicative of fibrinolysis shutdown (≥ 98%) had the best predictive accuracy for VTE (AUC = 0.887, 95% CI 0.824 − 0.951, sensitivity = 100%, specificity = 67.0%), higher than that of D-dimer levels (p = 0.028). ROTEM parameters were promising predictors of symptomatic VTE. Fibrinolysis shutdown as reflected by ROTEM LI60 and high D-dimer levels can aid the identification of high-risk patients. Future studies should evaluate whether the addition of ROTEM findings to an expanded risk-assessing model can improve the predictive capacity and provide better guidance in thromboprophylaxis. Graphical abstract
Introduction: Postpartum hemorrhage (PPH) was the second leading cause of maternal death, accounting for approximately 14% of all pregnancy-related deaths between 2017 and 2019 in the United States. Several large multi-center studies have demonstrated decreased PPH rates with the use of tranexamic acid (TXA). Little data exists regarding the prevalence of TXA use in obstetric patients. Methods: We identified over 1.2 million US pregnancies between January 1, 2015 and June 30, 2021, with and without PPH by International Statistical Classification of Disease and Related Health Problems, Tenth Revision codes using Cerner Real-World Database™. TXA use and patient characteristics were abstracted from the electronic medical record. Results: During delivery, TXA was used approximately 1% of the time (12,394 / 1,262,574). Pregnant patients who did and did not receive TXA during delivery had similar demographic characteristics. Pregnant patients who underwent cesarean delivery (4,356 / 12,394), had a term delivery (10,199 / 12,394), and had comorbid conditions were more likely to receive TXA during hospitalization for delivery. The majority of TXA was use was concentrated in Arizona, Colorado, Idaho, New Mexico, Nevada, Utah, and Wyoming. During the study period the use of TXA increased in both patients with PPH and those without. Conclusion: The data illustrate a rapid increase in the use of TXA after 2017 while the total number of pregnancies remained relatively constant. The observed increase in TXA use may reflect changing practicing patterns as the support for use of TXA in the setting of PPH prophylaxis increases.
Use of direct oral anticoagulants (DOACs) in patients with cancer on active chemotherapy is challenging due to changes in renal or hepatic function, thrombocytopenia, chemotherapy-induced nausea and vomiting (CINV), and drug-drug interactions (DDIs) attributed to disease or treatment. The purpose of this retrospective cohort analysis was to characterize DOAC management through various interventions and evaluate the efficacy and safety of DOAC use in this patient population. A total of 58 patients with 97 unique index periods in which a patient was concomitantly on a DOAC and chemotherapy were identified. Several instances were observed in which an intervention should be made based on manufacturer guidance or clinical judgment. Of 37 instances attributed to changes in renal function, the following interventions were employed: dose adjustments (10/37), holding DOAC therapy until renal function improved (held 3/37, restarted 4/37), changing to an alternative anticoagulant (5/37), DOAC discontinuation (2/37), or no change (13/37). One change was made in response to decreased hepatic function (1/15). DOACs were held in the setting of platelet counts below 50 K/mm3 (8/20) and restarted when platelets improved above this threshold (5/20). In patients with CINV, DOAC therapy was continued (26/32) with few changes made. To manage DOAC-chemotherapy DDIs, changes in DOAC agents (4/6) and dose reductions in chemotherapy agents (2/6) were made. Thrombotic and bleeding events did not strongly correlate with renal or hepatic impairment, thrombocytopenia, CINV, or DDIs. Further guidance regarding the use of these agents in this patient population is warranted to address management strategies, efficacy, and safety.Graphical abstractUse of direct oral anticoagulants (DOACs) in patients with cancer on active chemotherapy is challenging due to changes in renal or hepatic function, thrombocytopenia, chemotherapy-induced nausea and vomiting (CINV), and drug-drug interactions (DDIs) attributed to disease or treatment. The purpose of this retrospective cohort analysis was to characterize DOAC management and evaluate the efficacy and safety of DOAC use in this patient population. A total of 58 patients with 97 unique index periods in which a patient was concomitantly on a DOAC and chemotherapy were identified. Several instances were observed in which an intervention should be made based on manufacturer guidance or clinical judgment. Interventions employed are summarized graphically. Thrombotic and bleeding events did not strongly correlate with renal or hepatic impairment, thrombocytopenia, CINV, or DDIs. CINV chemotherapy-induced nausea and vomiting, DDIs drug-drug interactions, DOAC direct oral anticoagulant, OAC oral anticoagulant
Enrollment. PE pulmonary embolism, CTA Computed tomography angiography, CT computed tomography, NLP natural language processing, CTEPH chronic thromboembolic pulmonary hypertension, ICD-10 international classification of diseases, 10th revision
Geographic/income distribution of acute pe referral and non-referral cohorts
Chronic thromboembolic pulmonary hypertension (CTEPH) is a treatable complication of acute pulmonary embolism (PE). Identification of factors that impact referral to a comprehensive CTEPH center may improve disease awareness and patient outcomes. We conducted a study of patients with acute PE. Cases were identified through a natural language processing algorithm. ICD coding was used to assess clinical documentation for dyspnea or CTEPH placed at least 90 days after their acute PE diagnosis. We analyzed characteristics of patients who were referred vs. not referred, as well as referral patterns for “at risk” patients. 2454 patients with acute PE were identified, of which 4.9% (120/2454) were referred for CTEPH evaluation. Patients who were not referred were older (61 vs. 54 years, p < 0.001), had higher rates of cancer (28% vs. 10%, p < 0.001), and lived further from the referral center (9.1 miles vs. 6.7 miles, p = 0.03). Of 175 patients identified as “at risk,” 12% (21/175) were referred. In the ‘at risk’ cohort, distance from referral center among referred and not referred was significant (5.7 miles vs. 8.8 miles, p = 0.04). There were low rates of referral to CTEPH center in post-PE patients, and in patients with symptoms who may be at higher risk of CTEPH. Age, co-morbid conditions, distance from comprehensive center, and presence of a primary care provider contribute to differences in referral to a comprehensive CTEPH center. Clinician education about CTEPH is important to ensure optimal care to patients with or at risk for chronic complications of acute PE.
Preferred Reporting Items for new systematic reviews, which included searches of databases, registers and other sources
a–d Evidence network plot of eligible comparisons for network meta-analysis. *LMWH represents a combination of LMWH alone or LMWH plus IPC. UFH represents a combination of UFH alone or UFH plus IPC. Size of the circle represents the sample size, and thickness of the line represents the volume of the studies. UFH unfractionated heparin; IPC intermittent pneumatic compression; LMWH low-molecular-weight heparin; DOACs Direct oral anticoagulants; PE pulmonary embolism; DVT deep venous thrombosis.
The efficacy (a VTE, b Proximal DVT or PE) and safety (c all occurrence of bleeding, d major bleeding, e minor bleeding, f all-cause mortality) according to the network meta-analysis using Log odds ratios and corresponding 95% credential intervals (Crls). *LMWH represents a combination of LMWH alone or LMWH plus IPC. UFH represents a combination of UFH alone or UFH plus IPC. P values in italics are significant. UFH unfractionated heparin; IPC intermittent pneumatic compression; LMWH low-molecular-weight heparin; LMWH_IPC LMWH plus IPC; UFH_IPC UFH plus IPC; DOACs Direct oral anticoagulants; PE pulmonary embolism; DVT deep venous thrombosis
a Ranking positions of 6 interventions and placebo in VTE. From rank 1—worst to rank 7—best. b Ranking positions of 4 interventions and placebo in Proximal DVT or PE. From rank 1—worst to rank 5—best. c Ranking positions of 3 interventions and placebo in all occurrences of bleeding. From rank 1—worst to rank 4—best. d Ranking positions of 3 interventions and placebo in major bleeding. From rank 1—worst to rank 4—best. e Ranking positions of 3 interventions and placebo in minor bleeding. From rank 1—worst to rank 4—best. f Ranking positions of 6 interventions and placebo in all-cause mortality. From rank 1—worst to rank 7—best. UFH unfractionated heparin; IPC intermittent pneumatic compression; LMWH low-molecular-weight heparin; LMWH_IPC LMWH plus IPC; UFH_IPC UFH plus IPC; DOACs Direct oral anticoagulants.
Comparison between direct and indirect evidence: a VTE, b all occurrence of bleeding, c major bleeding, d minor bleeding, e all-cause mortality. UFH unfractionated heparin; IPC intermittent pneumatic compression; LMWH low-molecular-weight heparin
Neurosurgeons often face this dilemma. Brain neoplasm patients undergoing neurosurgery are at a high risk of venous thrombosis. However, antithrombotic drugs may induce bleeding complications. Therefore, we compared the efficacy and safety of prophylaxis for venous thromboembolism (VTE) in brain neoplasm patients undergoing neurosurgery. We searched Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), and Embase from inception to January 2022 for randomized controlled trials (RCTs) comparing the prophylactic measures efficacy and safety for VTE in brain neoplasm patients undergoing neurosurgery. The main efficacy outcome was symptomatic or asymptomatic VTE. The safety outcomes included major bleeding, minor bleeding, all occurrences of bleeding, and all-cause mortality. We used (Log) odds ratio (OR) of various chemoprophylaxis regimens to judge the safety and effectiveness of VTE. Additionally, all types of intervention were ranked by the Surface Under the Cumulative Ranking (SUCRA) value. We included 10 RCTs with 1128 brain neoplasm patients undergoing neurosurgery. For symptomatic or asymptomatic VTE and proximal DVT or PE, DOACs, compared with placebo, can significantly reduce the events. DOACs were superior to all other interventions in the rank plot of these events. For major bleeding reduction, unfractionated heparin (SUCRA value = 0.21) demonstrated better safety efficacy than others. For minor bleeding reduction, DOACs had a significantly higher risk of minor bleeding compared with placebo [Log OR 16.76, 95% CrI (1.53, 61.13)], LMWH [Log OR 15.68, 95% CrI (0.26, 60.10)] and UFH [Log OR 15.93, 95% CrI (0.22, 60.16)] respectively. Except for placebo (SUCRA values of 0.13), UFH (SUCRA values of 0.37) depicted better safety efficacy than others. For all-cause mortality, we found UFH always had significantly lower all-cause mortality compared with low-molecular-weight heparin (LMWH) [Log OR = 14.17, 95% CrI (0.05, 48.35)]. UFH plus intermittent pneumatic compression (IPC) (SUCRA value of 0.12) displayed the best safety for all-cause mortality. In our study, DOACs were more effective as prophylaxis for VTE in brain neoplasm patients undergoing neurosurgery. Regarding the safety of prophylaxis for VTE, UFH of chemoprophylaxis consistently demonstrated better safety efficacy, involving either major bleeding, minor bleeding, bleeding, or all-cause mortality.
The use of acetylsalicylic acid (ASA) is problematic in subjects with histories of hypersensitivity reactions (HRs) to it or with cross-reactive types of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We sought to evaluate the efficacy of low-dose ASA challenge (LDAC) and desensitization to allow ASA therapy at an antiplatelet dose in patients with atherosclerotic cardiovascular disease (ASCVD) or multiple related risk factors and histories of HRs to ASA or ≥ 2 chemically unrelated NSAIDs. We studied prospectively all patients with such histories and ≥ 3 risk factors for ASCVD (group I), chronic coronary syndrome (CCS, group II), and acute coronary syndrome (ACS) with indication for ASA desensitization (group III). Patients from groups I and II underwent LDACs (cumulative dose of 110 mg), while those from group III were desensitized (cumulative dose of 100.1 mg). We evaluated 103 patients: 62 from group I, 24 from group II, and 17 from group III. Eighty-two of the 86 patients from the first two groups underwent LDACs and 2 reacted. Subsequently, 22 (27.5%) of the 80 patients with negative LDACs were administered dual antiplatelet therapy with ASA after successful percutaneous coronary interventions, thus sparing desensitizations. The remaining 4 patients with CCS and all 17 patients from group III were successfully desensitized. In this pragmatic study, LDAC proved to be a safe and reliable diagnostic tool for identifying patients with histories of HRs to ASA or ≥ 2 different NSAIDs who can tolerate ASA at antiplatelet doses. Routine LDAC is advisable in all patients at high risk for ASCVD or with CCS who report HRs to ASA or ≥ 2 NSAIDs. ASA desensitization remains a safe and effective option in patients with ACS. Graphical Abstract Study flow-chart.ASCVD atherosclerotic cardiovascular disease; CCS chronic coronary syndrome; ACS acute coronary syndrome; ASA acetylsalicylic acid; DAPT dual antiplatelet therapy; PCI percutaneous coronary intervention; NSAIDs nonsteroidal anti-inflammatory drugs; NERD NSAID-exacerbated respiratory disease; NECD NSAID-exacerbated cutaneous disease; NIUAA NSAID-induced urticaria-angioedema or anaphylaxis; SNIUAA single NSAID-induced urticaria-angioedema or anaphylaxis; SNIDHR single NSAID-induced delayed hypersensitivity reaction.
Odds of recurrent VTE on warfarin versus DOAC by BMI, adjusted for age, race, ethnicity and insurance. VTE venous thromboembolism, DOAC direct oral anticoagulant, BMI body mass index
Odds of major bleeding on warfarin versus DOAC by BMI.VTE venous thromboembolism, DOAC direct oral anticoagulant, BMI body mass index
Time to recurrent VTE by medication group, with death as competing risk. DOAC direct oral anticoagulant, rvte recurrent venous thromboembolism
The effectiveness and safety of direct oral anticoagulants (DOAC) compared with warfarin remains uncertain in obese patients. We assessed the comparative effectiveness and safety of DOACs with warfarin for the treatment of VTE among obese patients. This multi-center retrospective cohort study included adults with a BMI ≥ 35 kg/m² or weight ≥ 120 kg prescribed either DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) or warfarin for a VTE diagnosis. The primary outcome was the 12-month rate of recurrent VTE. The secondary outcome was the 12-month rate of major bleeding. Among 5626 patients, 67% were prescribed warfarin and 33% were prescribed a DOAC. The 12-month VTE recurrence rate was 3.6% (67/1823) for patients treated with DOAC compared with 3.8% (143/3664) for patients treated with warfarin [odds ratio for recurrent VTE on warfarin versus DOAC (OR) (95% CI).07 (0.80, 1.45)]. The 12-month major bleeding rate was 0.5% (10/1868) for patients on DOAC versus 2.4% (89/3758) on warfarin [OR 4.25 (2.19, 8.22)]. Similar proportions of recurrent VTE occurred across BMI thresholds on DOAC and warfarin: for BMI ≥ 35 kg/m² (N = 5412), 3.6% versus 3.8%, respectively [OR 1.08 (0.80, 1.46)]; for BMI ≥ 40 kg/m² (N = 2321), 4.4% versus 3.5%, respectively [OR 0.80 (0.51, 1.26)]; and for BMI ≥ 50 kg/m² (N = 560), 3.1% versus 3.7%, respectively [OR 1.18 (0.39, 3.56)]. Similar proportions of recurrent VTE occurred in patients with obesity treated for VTE with DOACs and warfarin. DOACs were associated with lower major bleeding compared to warfarin in patients with obesity and VTE.
The coagulation cascade and associated functional assays [1, 33, 43]
The coagulation cascade and the associated molecular biomarkers
Rivaroxaban is a direct, oral factor Xa inhibitor that is used for the prevention and treatment of various thromboembolic disorders. Several preclinical and clinical studies have utilized specific molecules as biomarkers to investigate the potential role of rivaroxaban beyond its anticoagulant activity and across a range of biological processes. The aim of this review is to summarize the existing evidence regarding the use of blood-based biomarkers to characterize the effects of rivaroxaban on coagulation and other pathways, including platelet activation, inflammation and endothelial effects. After a literature search using PubMed, almost 100 preclinical and clinical studies were identified that investigated the effects of rivaroxaban using molecular biomarkers. In agreement with the preclinical data, clinical studies reported a trend for reduction in the blood concentrations of D-dimers, thrombin–antithrombin complex and prothrombin fragment 1 + 2 following treatment with rivaroxaban in both healthy individuals and those with various chronic conditions. Preclinical and also some clinical studies have also reported a potential impact of rivaroxaban on the concentrations of platelet activation biomarkers (von Willebrand factor, P-selectin and thrombomodulin), endothelial activation biomarkers (matrix metalloproteinase-9, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and inflammation biomarkers (interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1). Based on the results of biomarker studies, molecular biomarkers can be used in addition to traditional coagulation assays to increase the understanding of the anticoagulation effects of rivaroxaban. Moreover, there is preliminary evidence to suggest that rivaroxaban may have an impact on the biological pathways of platelet activation, endothelial activation and inflammation; however, owing to paucity of clinical data to investigate the trends reported in preclinical studies, further investigation is required to clarify these observations.
Background Hyponatremia is associated with negative prognosis in several conditions like Congestive heart failure and acute MI (Myocardial Infarction), but its impact on the outcomes in patients with pulmonary embolism (PE) is not well studied. We aimed to study the association of hyponatremia in patients hospitalized with PE. Methods A retrospective cohort study was designed using data obtained from the 2016 to 2019 combined National Inpatient Sample (NIS) database. Adult patients admitted with PE were identified and stratified based on the presence of hyponatremia. Primary outcomes assessed were, mortality, length of stay (LOS), and Total Hospitalization Charges (THC). Secondary outcomes included a diagnosis of Acute Kidney Injury (AKI), Acute Respiratory Failure (ARF), sepsis, Acute Cerebrovascular accident (CVA), arrhythmias and acute MI. Multivariate linear and logistic regressions were used to adjust for confounders. Results There was a total of 750,655 adult hospitalizations for PE and among them 41,595 (5.5%) had a secondary diagnosis of hyponatremia. Hyponatremia was associated with an increased odds of mortality, 6.31% vs 2.91% (AOR:1.77, p = 0.000, 95% CI: 1.61—1.92), increased LOS, 6.79 days vs 4.20 days (adjusted difference of 2.20 days, p = 0.000, 95% CI: 2.04—2.37), as well as an increase in THC, 75,458.95 USD vs 46,708.27 USD (adjusted difference of 24,341.37 USD, p < 0.001, 95% CI: 21,484.58—27,198.16). Similarly, the presence of hyponatremia was associated with increased odds of several secondary outcomes measured. Conclusion Hyponatremia is associated with an increased odds of death and attendant increase in LOS and THC. The odds of several secondary adverse clinical outcomes were also increased.
Background: Reversal of dabigatran anticoagulation activity using idarucizumab is indicated for individuals suffering from life-threatening or non-controlled bleeding and those in need of urgent operation or invasive intervention. Through idarucizumab application patients with acute ischemic stroke (AIS) may regain eligibility for intravenous thrombolysis (IVT) and patients with intracranial hemorrhage (ICH) may show less hematoma growth, thereby improving functional outcome in both groups. However, evidence is limited, and international guidelines contain heterogenous recommendations substantiating the need for the review of evidence and standard operating procedures (SOPs). Materials and methods: For our review, we searched PubMed for all published articles using idarucizumab and ischemic stroke/hemorrhagic stroke as keywords. Illustrating two clinical cases, we discuss the current literature and national guidelines. Results: Our search retrieved 47 articles of which 8 case studies or series made public after 2020/2021, 28 reviews, 1 leading opinion article, 1 editorial and 10 guidelines. Summarizing the available evidence, idarucizumab application in stroke patients taking dabigatran results in decreased mortality rate and improved functional outcomes. Based on two clinical cases from our departments, we provide SOPs on how to deal with eligible patients in a time-efficient way, thereby reducing door-to-needle times in AIS and preventing early deterioration in ICH patients. Conclusion: Reversal of dabigatran with idarucizumab in stroke patients appears easy to manage, safe and beneficial. The SOPs aim to reassure stroke physicians to include dabigatran reversal into their daily clinical routine when dealing with patients presenting with ischemic or hemorrhagic stroke under dabigatran therapy.
Safety and efficacy of direct oral anticoagulants (DOAC) in low weight patients with atrial fibrillation (AF) is unclear due to few low body weight patients enrolled in clinical trials. To assess bleeding and thrombotic event rates for patients with AF that are prescribed apixaban and have a low versus normal body weight. We analyzed patients with AF prescribed apixaban from 2017 to 2020 with at least 12 months of follow-up. Patients were divided into low [< 60 kg (kg)] and normal (60–100 kg) weight cohorts. Bleeding and thrombotic event rates were compared. Poisson regression and Cox proportional hazard models were used to estimate adjusted adverse event rates. A total of 545 patients met inclusion criteria. In the unadjusted analysis, there was an increase in non-major bleeding events requiring an Emergency Department visit more often in the low versus normal weight cohort (10.8 versus 7.4 per 100 patient-years, p = 0.15). Thrombotic event rates also occurred more often in the lower versus normal weight cohort (2.4 versus 0.9 per 100 patient-years, p = 0.09). However, adjusted analysis found no statistically significant difference in bleeding or thrombotic events between low and normal weight cohorts. The adjusted hazard ratio for bleeding was similar between the two weight cohorts. The use of apixaban in low body weight patients was not associated with higher rates of bleeding or thrombotic events, compared to those with normal body weight, after adjusting for potential confounding covariates. Larger studies may offer further insight into the overall safety and efficacy of DOAC therapy in these patients.
Flow diagram of patient selection
VTE = venous thromboembolism
Venous thromboembolism events by Caprini score
VTE = venous thromboembolism
Pattern of transitions between prophylactic anticoagulant medications in inpatient and discharge settings
#1 = first chemoprophylaxis medication used, #2 = second chemoprophylaxis medication used, #3 = third chemoprophylaxis medication used
This study analyzes pancreatectomy cases performed between 2016 and 2021 to determine the impact of using Caprini guideline indicated VTE prophylaxis on VTE and bleeding complications. This is a retrospective study of cases performed in a single academic health care system, in which Caprini score and VTE prevention measures were determined retroactively and prevention practices binarized as appropriate or not appropriate. Univariate and multivariate analyses were performed of 1,299 pancreatectomy case. Most patients were stratified as high risk for postoperative VTE. Receiving appropriate VTE prophylaxis during admission was associated with a 3-fold reduction in VTE complications (0.82% vs. 2.64%, p=0.01) without increasing bleeding complications. All VTE complications occurring with 30-day (1.2%) and 90-day (2.7%) from hospital discharged occurred in those not receiving appropriate prophylaxis, and discharged bleeding complications were also not associated with receivng appropriate discharged VTE prophylaxis. The findings our the study are significant as it highlights the ongoing need for standardization in VTE risk assessment and prevention measures to increase compliance to risk adjusted VTE prevention practice guidelines, thus reducing preventable VTE complications and potentially associated morbidity and mortality.
Consort diagram with data represented by forest plot of the multivariate regression model for in-hospital complications and the results of the propensity score matched sample
High-risk pulmonary embolism (PE) patients can be managed with systemic lysis, catheter-based therapies, or surgical embolectomy. Despite the advent of newer therapies, patients with high-risk PE remain with a 50–60% short-term mortality risk. In such patients, extracorporeal membrane oxygenation (ECMO) is increasingly utilized for hemodynamic support. To evaluate the outcomes of the use of ECMO in patients with high-risk PE. Using the National Inpatient Sample (NIS) database, we identified patients with high-risk PE using ICD 10 codes and compared in-hospital outcomes of patients with and without ECMO support. We identified 38,035 patients with high-risk PE, of whom 820 had undergone ECMO placement. Most patients who underwent ECMO were male (54%), white (65%), and with a mean age of 53.7 years. ECMO use was not associated with a meaningful difference in patient mortality when comparing treatment groups (OR, 1.32 ± 0.39; 0.74–2.35; p = 0.35). Rather, ECMO use was associated with a higher frequency of inpatient complications. ECMO use was not associated with a significant difference in patient mortality in patients with high-risk PE.
Thrombosis-free survival in 149 essential thrombocythemia (ET) patients according to the three prediction models. (A) Without the models; (B) The conventional model; (C) The IPSET-thrombosis model; (D) The revised IPSET-thrombosis model
The percentage of thrombotic events in each risk group of the three prediction models
The calibration plot of three prediction models at median time of thrombosis-free survival (12.5 years) in the conventional, IPSET-thrombosis, and revised IPSET-thrombosis models
Background: Thrombosis is a major complication of essential thrombocythemia (ET). There are three well-known prediction models for thrombotic risk in ET patients. However, only few external validation studies for the performance of these models in Asian populations have been conducted. Thus, we aimed to evaluate the performance of these models for predicting the risk of thrombosis in Thai patients with ET. Methods: We retrospectively evaluated the clinical characteristics and thrombotic risk of 149 Thai ET patients in a university hospital in Southern Thailand between 2002 and 2019. Thrombotic risk variables were evaluated using Cox proportional hazard regression. The Brier score, calibration plot, and Harrel concordance index (C-index) were used to evaluate the performance of the three models. Results: With a median follow-up of 5.2 years, there were a total of 28 thrombotic events in 26 patients. Age > 60 years was a significant prognostic factor for thrombosis in the multivariate Cox regression analysis. The Brier scores were 0.251, 0.273, and 0.276 in the conventional, IPSET-thrombosis, and revised IPSET-thrombosis models, respectively. The conventional model had optimal calibration and good discrimination (C-index, 0.67; 95%CI:0.55-0.79). The IPSET thrombosis (C-index 0.33; 95%CI:0.20-0.49) and revised IPSET thrombosis (C-index 0.31; 95%CI:0.18-0.44) models showed poor discrimination. Conclusion: The conventional model, which is based on age and history of thrombosis, is the best model to predict thrombotic risk in Thai ET patients. Further studies with a larger number of patients with thrombotic events are needed to validate the IPSET-thrombosis and revised IPSET-thrombosis models.
Graphical flowchart of the prospective, observational registry
Vaccination against COVID-19 reduces infection-related mortality. Unfortunately, reports of vaccine-induced immune thrombotic thrombocytopenia (VITT) in individuals administered adenovirus-vector-based vaccines (ChAdOx1 nCoV-19 and Ad26.COV2.S) have spurred side effect concerns. To address vaccine hesitancy related to this, it is essential to determine the incidence of VITT (defined by a 50% decrease in platelet count and positive anti-PF4 immunoassay within 4–28 days after vaccination) among patients administered two doses of an mRNA-based COVID-19 vaccination. We identified a retrospective cohort of 223,345 patients in the Cleveland Clinic Enterprise administered a COVID-19 vaccine at any location in Northeast Ohio and Florida from 12/4/2020 to 6/6/2021. 97.3% of these patients received an mRNA-based vaccination. Patients with: (1) a serial complete blood count both before and after vaccination and (2) a decrease in platelet count of ≥ 50% were selected for chart review. The primary outcome was the incidence of thrombotic events, including venous thromboembolism (VTE) and arterial thrombosis, 4–28 days post vaccination. Of 74 cohort patients with acute thrombosis, 72 (97.3%) demonstrated clear etiologies, such as active malignancy. Of two patients with unprovoked thrombosis, only one had findings concerning for VITT, with a strongly positive anti-PF4 antibody assay. In this large, multi-state, retrospective cohort, of 223,345 patients (97.2% of whom received the mRNA-based mRNA-1273 or BNT162b2 vaccines), we detected a single case that was concerning for VITT in a patient who received an mRNA vaccine. The overwhelming majority of patients with a thrombotic event 4–28 days following vaccination demonstrated clear etiologies.
PRISMA flowchart. * Articles excluded because not provided data on VTE event; ** Articles excluded because not provided Hazard ratio for VTE events
Forest plots investigating the pooled incidence of acute pulmonary embolism after 8.5 months from COVID-19 infection
Forest plots investigating the pooled incidence of deep vein thrombosis after 8.5 months from COVID-19 infection
Forest plots investigating the long-term risk of incident acute pulmonary embolism after 8.5 months from COVID-19 infection
Forest plots investigating the long-term risk of incident deep vein thrombosis after 8.5 months from COVID-19 infection
Data regarding the occurrence of venous thromboembolic events (VTE), including acute pulmonary embolism (PE) and deep vein thrombosis (DVT) in recovered COVID-19 patients are scant. We performed a systematic review and meta-analysis to assess the risk of acute PE and DVT in COVID-19 recovered subject. Following the PRIMSA guidelines, we searched Medline and Scopus to locate all articles published up to September 1st, 2022, reporting the risk of acute PE and/or DVT in patients recovered from COVID-19 infection compared to non-infected patients who developed VTE over the same follow-up period. PE and DVT risk were evaluated using the Mantel–Haenszel random effects models with Hazard ratio (HR) as the effect measure with 95% confidence interval (CI) while heterogeneity was assessed using Higgins I2 statistic. Overall, 29.078.950 patients (mean age 50.2 years, 63.9% males), of which 2.060.496 had COVID-19 infection, were included. Over a mean follow-up of 8.5 months, the cumulative incidence of PE and DVT in COVID-19 recovered patients were 1.2% (95% CI:0.9–1.4, I2: 99.8%) and 2.3% (95% CI:1.7-3.0, I2: 99.7%), respectively. Recovered COVID-19 patients presented a higher risk of incident PE (HR: 3.16, 95% CI: 2.63–3.79, I2 = 90.1%) and DVT (HR: 2.55, 95% CI: 2.09–3.11, I2: 92.6%) compared to non-infected patients from the general population over the same follow-up period. Meta-regression showed a higher risk of PE and DVT with age and with female gender, and lower risk with longer follow-up. Recovered COVID-19 patients have a higher risk of VTE events, which increase with aging and among females.
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia associated with disseminated microvascular platelet-rich thrombus. Before the introduction of plasma therapy, acute TTP was almost universally fatal, which improved survival from < 10 to 80-90%. However, patients who survived an acute attack were at high risk for recurrence and long-term morbidity. It was reported that daratumumab can eradicate persistent ADAMTS13-inhibiting autoantibodies and restore ADAMTS13 activity in two patients with relapsed immune-mediated TTP without associated adverse drug reactions. Here we report a case series of patients with initial diagnosed acquired TTP treated with combination regimens containing daratumumab. All the patients achieved clinical response after the initial treatment. Three patients achieved clinical remission, one patient relapsed and one patient suffered an exacerbation during follow-up. The two patients were retreated with glucocorticoids, plasma exchange combined with daratumumab, and clinical remission was achieved again. Combination of daratumumab in the treatment of initial diagnosed acquired thrombotic thrombocytopenic purpura can rapidly restore ADAMST13 activity and turn negative for ADAMST13 inhibitors, resulting in long-term remission in patients.
Comparison of TG parameters of newly diagnosed multiple myeloma subjects (with and without prophylactic low molecular weight heparin) and the control group. Data represent mean and standard deviation. P values less than 0.05 were considered statistically significant
The issue of how to identify newly diagnosed multiple myeloma (NDMM) patients requiring thromboprophylaxis remains unsolved. Several changes in thrombin generation (TG)-derived parameters have been described in multiple myeloma (MM) patients recently. Assessment of prothrombotic risk with a fully automated TG analyzer could reduce interlaboratory variability. Our objective was to determine whether ST-Genesia® could reveal a hypercoagulable state in NDMM compared to healthy controls. We conducted a multicenter observational study of NDMM requiring initial treatment to compare TG parameters obtained with ST-Genesia® analyzer and ST-ThromboScreen® reagent with a control group. Clinical data were obtained from medical records and blood samples were collected before initial anti-myeloma therapy. A thrombophilia panel was performed in all patients. Compared to age- and sex-matched controls (n = 83), NDMM patients (n = 83) had significantly higher peak height, higher velocity index, shorter time-to-peak and lower percentage of endogenous thrombin potential (ETP) inhibition after adding thrombomodulin (TM) (ETP%inh). NDMM on prophylactic low molecular weight heparin (LMWH) showed reduced both peak height and velocity index compared to NDMM who had not yet started VTE prophylaxis, similar to that of controls. Moreover, partial correction of ETP%inh was observed in MM patients on LMWH. The presence of a thrombophilia did not modify the TG phenotype. Untreated NDMM patients showed an enhanced TG, regardless of their thrombophilia status. They generate a higher peak of thrombin, take less time to produce it, and exhibit resistance to TM inhibition. Our findings suggest that standard prophylactic dose of LMWH may reduce TG at levels of healthy controls.
The study flowchart. CAT cancer-associated thrombosis; HIT heparin-induced thrombocytopenia; PCDT pharmacomechanical catheter-directed thrombolysis
The progression of VAS score and limb circumference difference at pre-treatment and post-treatment. The differences of VAS score and limb circumference difference in the two groups at pre-treatment were comparable (p > .05). a The VAS score was statistically significant at post-treatment. b Limb circumference difference at 15 cm above the knee (p < .01) and 10 cm below the knee (p < .05) were statistically significant at post-treatment. PCDT pharmacomechanical catheter-directed thrombolysis; VAS visual analog scale
A 63-year-old male patient with CAT underwent PCDT and adjunctive CDT. a–c Venography from the catheter indicated that the trunk lumen from right popliteal vein to right superficial femoral vein was filled with massive filling-defects. The multiple occlusions of the right common femoral vein and iliac vein were shown. d rt-PA was intra-clot injected under the power pulse model of AngioJet device. e The efficient segment of AngioJet catheter (small black arrow) and the aspiration procedure were shown. f–h After adjunctive CDT using rt-PA infusion for continuous 24 h, venography via the dorsal vein revealed completely patent blood flow. CAT cancer-associated thrombosis; PCDT pharmacomechanical catheter-directed thrombolysis; CDT Catheter-directed thrombolysis
The therapeutic regimen option for the cancer-associated thrombosis (CAT) patients is still a major clinical challenge. The present study aimed to investigate the safety and efficacy of pharmacomechanical catheter-directed thrombolysis (PCDT) with AngioJet treatment compared with the conventional anticoagulation alone therapy in the patients with CAT. We retrospectively reviewed the patients who underwent PCDT and/or anticoagulation for the treatment of CAT between August 1, 2016 and March 1, 2022. Each patient was divided into the PCDT group or the anticoagulation alone group. The baseline demographics, comorbidities, clinical characteristics, treatment details, course data were reviewed. A total of 51 eligible patients were included, of whom 21 were in PCDT group (mean age, 60.1 ± 13.0 years; 52.4% male) and 30 in anticoagulation alone group (mean age, 66.6 ± 11.1 years; 50.0% male). No significant differences regarding age, sex, onset time, limb characteristics, cancer conditions or risk factors were detected (p > .05). After PCDT, grade III lysis was achieved in 8 and grade II lysis in 11 patients. Clinical success was achieved in 90.5% (19/21) patients. The symptoms of leg pain and swelling were significantly improved in both groups. Except for transient macroscopic hemoglobinuria occurring in PCDT group, none of all patients suffered from procedure-related and major complications. Minor complications such as bleeding events occurred in 23.8% (5/21) of patients in PCDT group compared with 10.0% (3/30) in anticoagulation alone group (p > .05). At the 6-month follow-up, iliofemoral patency was found an absolute risk reduction of 37.9% (70.0 vs. 32.1%) (95% CI: 1.183–4.008%; P = 0.010). The incidence of mild PTS was 5.0% (1/20) in PCDT group compared with 10.7% (3/28) in anticoagulation alone group (p > .05). The PCDT is a safe and effective modality in managing patients with CAT, leading to improved clinical outcomes with a low complication. The PCDT was more effective than anticoagulation alone in massive symptom relief and venous patency.
Flowchart of patient selection
Kaplan Meier survival curves for primary outcome of all-cause mortality between patients receiving enoxaparin (red) or heparin (blue). A Significant difference in increased survival with the enoxaparin group before matching, [HR 0.53, CI 0.35–0.78, P = 0.001] B There was no significant difference after matching, [HR 0.66, CI 0.38–1.15, p = 0.140]
Prevalence of DVT between patients receiving enoxaparin (red) compared to heparin (blue). A There was significant difference in prevalence of DVT before matching [HR 0.54, CI 0.35–0.86, p = 0.009] and B There was no significant difference after matching [HR 0.95, CI 0.50–1.86, p = 0.87]
Prevalence of PE between patients receiving enoxaparin (red) compared to heparin (blue). A There was no significant difference in PE before matching [HR 1.16, CI 0.68–1.97, p = 0.58] and B after matching [HR 1.16, CI 0.54–2.52, p = 0.70]
Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are often administered to prevent venous thromboembolism (VTE) in critically ill patients. However, the preferred prophylactic agent (UFH or LMWH) is not known. We compared the all-cause mortality rate in patients receiving UFH to LMWH for VTE prophylaxis. We conducted a retrospective propensity score adjusted analysis of patients admitted to neuro-critical, surgical, or medical intensive care units. Patients were included if they were screened with venous duplex ultrasonography or computed tomography angiography for detection of VTE. The primary outcome was all-cause mortality. Secondary outcomes included the prevalence of VTE, deep vein thrombosis (DVT), pulmonary embolism (PE), and hospital length of stay (LOS). Initially 2228 patients in the cohort were included for analysis, 1836 (82%) patients received UFH, and 392 (18%) patients received enoxaparin. After propensity score matching, a well-balanced cohort of 618 patients remained in the study (309 patients receiving UFH; 309 patients receiving enoxaparin). The use of UFH for VTE prophylaxis in ICU patients was associated with similar rates of all-cause mortality compared with enoxaparin [RR 0.73; 95% CI 0.43–1.24, p = 0.310]. There were no differences in the prevalence of DVT, prevalence of PE or hospital LOS between the two groups, DVT [RR 0.93; 95% CI 0.56–1.53, p = 0.889], PE [RR 1.50; 95% CI 0.78–2.90, p = 0.296] and LOS [9 ± 9 days vs 9 ± 8; p = 0.857]. A trend toward mortality benefit was observed in NICU [RR 0.37; 95% CI 0.13–1.07, p = 0.062] and surgical patients [RR 0.43; 95% CI 0.17–1.02, p = 0.075] favoring the enoxaparin group. The use of UFH for VTE prophylaxis in ICU patients was associated with similar rates of VTE, all-cause mortality and LOS compared to enoxaparin. In subgroup analysis, neuro-critical and surgical patients who received UFH had a higher rate of mortality than those who received enoxaparin.
Flow chart of cohort formation. Patients in the registry were 414,699. Then, 311,512 patients were excluded due to not being warfarin or DOAC naïve. Following, 42,212 patients were excluded due to not being treated with warfarin or reduced dose DOAC, 20,408 patients were excluded due to indication mechanical heart valve (MHV) and lastly 3 patients younger than 18 years were excluded, forming a study cohort of 40,564 patients
Hazard ratios with confidence intervals in comparisons after full match weighted Cox regression for all DOAC as a group as well as individually, compared with matched warfarin controls
Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are dose-reduced in elderly and patients with impaired renal function. Only reduced dose dabigatran is concluded as having similar stroke risk reduction and lower risk of major bleeding than warfarin in the pivotal studies. In clinical practice, reduced dose is prescribed more often than expected making this an important issue. The objective of this study was to compare effectiveness and safety between reduced dose DOACs and high TTR warfarin treatment (TTR ≥ 70%) in NVAF. A Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 40,564 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) (11,083 patients) or warfarin treatment (29,481 patients) after exclusion of 374,135 patients due to not being warfarin or DOAC naïve, not being prescribed reduced dose, having previous mechanical heart valve (MHV), or being under 18 years old. The median durations of follow up were 365, 419, 432 and 473 days for apixaban, dabigatran, rivaroxaban and warfarin, respectively. Warfarin TTR identified from Auricula was 70.0%. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores. DOACs are associated with lower risk of major bleeding (HR with 95% CI) 0.85 (0.78-0.93), intracranial bleeding HR 0.64 (0.51-0.80), hemorrhagic stroke HR 0.68 (0.50-0.92), gastrointestinal bleeding HR 0.81 (0.69-0.96) and all-cause stroke HR 0.87 (0.76-0.99), than warfarin. Apixaban and dabigatran are associated with lower risk of major bleeding, HR 0.70 (0.63-0.78) and HR 0.80 (0.69-0.94), and rivaroxaban is associated with lower risk of ischemic stroke, HR 0.73 (0.59-0.96), with higher major bleeding risk, HR 1.31 (1.15-1.48), compared to warfarin. Apixaban is associated with higher all-cause mortality compared to warfarin, HR 1.12 (1.03-1.21). DOACs are associated with lower risk of major bleeding and all-cause stroke, than high quality warfarin treatment, with exception of rivaroxaban that carried higher risk of major bleeding and lower risk of stroke or systemic embolism. In this large observational registry-based NVAF cohort, DOACs are preferred treatment in patients with indication for DOAC dose reduction, even in a high TTR setting.
Patient selection flowchart
Thrombin generation outcomes compared at T0 and T1
Thrombin generation outcomes compared at T0 and T1
EPCs count and function compared at T0 and T1
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. Graphical abstract
Three key assumptions of the present Mendelian randomization study. A. SNPs are strongly associated with physical activity; B. SNPs are independent of confounders; C. SNPs must only be associated with the risk of venous thromboembolism via physical activity. SNP single nucleotide polymorphism
Associations of genetically predicted physical activity with venous thromboembolism. CI confidence interval; OR odd ratio; SNP single nucleotide polymorphism
Scatter plot (A), forest plot (B), leave-one-out sensitivity analysis (C), and funnel plot (D) of the association of physical activity with venous thromboembolism
Previous studies have shown conflicting results about the impact of moderate to vigorous physical activity on the risk of venous thromboembolism (VTE). Using Mendelian randomization, we assessed whether moderate to vigorous physical activity causally affects VTE from genetic level. Genetic instruments associated with moderate to vigorous physical activity at the genome-wide significance level (P < 5×10− 8) were selected from the UK Biobank. Summary-level data for VTE were obtained from the FinnGen consortium. Univariable and multivariable Mendelian randomization analyses were conducted. Genetically predicted moderate to vigorous physical activity had no effect on VTE [odds ratio (OR) = 1.08; 95% confidence interval (CI) 0.66–1.78; P = 0.75] under a multiplicative random-effects inverse-variance weighted model. MR-Egger (OR = 0.20; 95% CI 0.01–4.70; P = 0.33), weighted median (OR = 1.08; 95% CI 0.52–2.25; P = 0.84), simple mode (OR = 2.53; 95% CI 0.59–10.92; P = 0.23), weighted mode (OR = 2.21; 95% CI 0.50–9.74; P = 0.31), and multivariable Mendelian randomization (OR = 0.74; 95% CI 0.46–1.19; P = 0.22) also yielded no significant association. The overall estimate was not influenced by individual single nucleotide polymorphism. No evidence of heterogeneity or horizontal pleiotropy was observed. Therefore, moderate to vigorous physical activity had no causal association with VTE in the general population.
Prevalence of PPH (%) among platelet count (× 10³/µL) groups in pregnant women with anemia at time of delivery (P < 0.001)
Both thrombocytopenia (platelet count < 150 × 103/µL) and anemia have been associated with postpartum hemorrhage (PPH). However, the impact of thrombocytopenia on PPH risk among women with mild and severe anemia is unknown. We sought to evaluate the association between thrombocytopenia and anemia in increasing risk of PPH. We performed a secondary analysis of a retrospective cohort of pregnant women from 19 hospitals across the United States from 2016 to 2021. Women who had a term singleton pregnancy and hematocrit (Hct) ≤ 33% at delivery were included in the study. The primary outcome was PPH (defined as blood loss ≥ 1000 mL or blood transfusion). We also analyzed the effect of severe anemia (Hct < 28%) on the association between PPH and thrombocytopenia. Chi-squared tests and Fisher’s exact tests were used for categorical variables and an independent t-test was used for continuous variables. There were 20,808 women who met our inclusion criteria, of which 1793 (8.6%) had platelet count < 150 × 103/µL. The prevalence of PPH was 6.4%. Compared with women with normal platelet count, those with thrombocytopenia had 1.3-fold higher odds of PPH [6.8% vs. 4.5%, adjusted OR 1.3 (1.1–1.7)]. Platelet count ≥ 150 × 103/µL was associated with decreased odds of PPH among patients with hct between 28 and 33% and hct < 28%. In conclusion, anemic women with term singleton pregnancies who delivered with thrombocytopenia had a higher frequency of PPH. Normal platelet count at delivery was protective against PPH in the setting of anemia regardless of severity.
Vasopressor Requirements. A Number of patients that received norepinephrine, epinephrine, phenylephrine, or vasopressin at any time point from 12 h pre-intervention until 48 h post-intervention. B Box and whisker plot describing the total norepinephrine equivalents (NEE) received by each group of patients at each time interval from 12 h pre-intervention until 48 h post-intervention. P-value > 0.05 for comparisons of total NEE at each time interval
Treatment of acute pulmonary embolism (PE) varies based upon risk stratification and ranges from outpatient oral anticoagulation to emergency surgical embolectomy. Patients with high-risk PE can be considered for systemic thrombolytic (ST) based upon guideline recommendations, but intermediate-risk PE does not currently have strong evidence to guide primary reperfusion strategies via thrombolytic administration. Ultrasound-assisted catheter-directed thrombolysis (USAT) is an alternative reperfusion option to ST but is not currently recommended as first line in any key guidelines due to limited available evidence. This retrospective, multicenter, observational study compares 210 patients treated with USAT (n = 105) or ST (n = 105) for acute high- or intermediate-risk PE in three hospitals. Baseline characteristics were significant in that severity of illness was higher in those that received ST, which limited comparisons of outcomes. The primary outcome of major bleeding in patients receiving USAT was 15.2% and 22.9% in those that received ST. Efficacy of reperfusion strategy was observed to be 86.7% of patients in USAT group and 65.7% in ST group. Reperfusion strategies had no difference in in-hospital death, intensive care length of stay, or hospital length of stay. Predefined subgroup analysis found that high-risk PE had higher mortality (14.7%) than intermediate-risk PE (0%) regardless of reperfusion strategy. Upon multivariate analysis, high-risk PE was the only independent risk factor for major bleeding while USAT therapy and intermediate-risk PE were independent predictors of efficacy. Due to the difference in baseline severity of illness, direct comparisons in primary outcomes to each group was not performed. We have described real world usage of both USAT and ST and which patients were likely to receive each therapy at these institutions.
Cerebral microbleeds (CMBs) are commonly detected in the brains of patients with acute ischemic stroke (AIS). With the development of neuroimaging, clinicians are paying more attention to the presence of CMBs. CMBs were found to significantly increase the risk of intracranial hemorrhagic transformation and hemorrhage in patients with AIS, especially in patients with concurrent atrial fibrillation (AF). Additionally, the presence of CMBs is thought to be a symbol of a high risk of recurrent ischemic stroke (IS). A few researchers have found that the presence of CMBs has no significant effect on the prognosis of patients with AIS. Therefore, the current views on the role of CMBs in the prognoses of patients with IS are controversial. The use of anticoagulants and other drugs has also become a dilemma due to the special influence of CMBs on the prognosis of these patients. Due to the large number of patients with AF and CMBs, many studies have been conducted on the effects of CMBs on these patients and subsequent pharmacological treatments. However, at present, there are no relevant guidelines to guide the secondary preventive treatment of patients with stroke, CMBs, and AF. In this paper, we summarized the role of CMBs in AIS combined with AF and relevant preventive measures against the recurrence of stroke and the occurrence of intracerebral hemorrhage to help clarify the specifics of drug therapies for this group of patients.
Patient selection for primary outcome analysis
The purpose of this study was to evaluate and compare clinical outcomes in patients who experienced intracranial hemorrhage (ICH) while taking apixaban or rivaroxaban and were reversed with four-factor prothrombin complex concentrates (4F-PCC) or andexanet alfa (AA). This retrospective cohort included adult patients that received 4F-PCC or AA for the initial management of an apixaban- or rivaroxaban-associated ICH. A primary outcome of excellent or good hemostatic efficacy at 12 h post-reversal was assessed. Secondary outcomes evaluated were change in hematoma volume size at 12 h, functional status at discharge, need for surgical intervention or additional hemostatic agents post-reversal, new thrombotic event within 28 days, 28-day all-cause mortality, discharge disposition, and hospital and intensive care unit lengths of stay. A total of 70 patients were included (4F-PCC, n = 47; AA, n = 23). For the primary outcome analysis, 21 patients were included in the 4F-PCC group and 12 in the AA group. The rate of effective hemostasis was similar between the 4F-PCC and AA groups (66.7% vs 75%, p = 0.62). There were no statistically significant differences between the groups for secondary outcomes, including 28-day mortality (40.4% vs 39.1%, p = 0.92) and thrombotic complications within 28 days of reversal (17.0% vs 21.7%, p = 0.63). In patients who experienced an ICH while taking apixaban or rivaroxaban, 4F-PCC and AA were found to have similar rates of excellent or good hemostatic efficacy.
Receiver operating characteristic curve of the ADA vs. IMPROVE score in predicting arterial and venous thrombosis
Receiver operating characteristic curve of the ADA vs. IMPROVE score in predicting arterial thrombosis
Receiver operating characteristic curve of the ADA vs. IMPROVE score in predicting venous thrombosis
The ADA (Age–D-dimer–Albumin) score was developed to identify hospitalized patients at an increased risk for thrombosis in the coronavirus infectious disease-19 (COVID-19) setting. The study aimed to validate the ADA score for predicting thrombosis in a non-COVID-19 medically ill population from the APEX trial. The APEX trial was a multinational, randomized trial that evaluated the efficacy and safety of betrixaban vs. enoxaparin among acutely ill hospitalized patients at risk for venous thromboembolism. The study endpoints included the composite of arterial or venous thrombosis and its components. Metrics of model calibration and discrimination were computed for assessing the performance of the ADA score as compared to the IMPROVE score, a well-validated VTE risk assessment model. Among 7,119 medical inpatients, 209 (2.9%) had a thrombosis event up to 77 days of follow-up. The ADA score demonstrated good calibration for both arterial and venous thrombosis, whereas the IMPROVE score had adequate calibration for venous thrombosis (p > 0.05 from the Hosmer-Lemeshow test). For discriminating arterial and venous thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.620 [95% CI: 0.582 to 0.657] vs. 0.590 [95% CI: 0.556 to 0.624]; ∆ c statistic = 0.030 [95% CI: −0.022 to 0.081]; p = 0.255). Similarly, for discriminating arterial thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.582 [95% CI: 0.534 to 0.629] vs. 0.609 [95% CI: 0.564 to 0.653]; ∆ c statistic = −0.027 [95% CI: −0.091 to 0.036]; p = 0.397). For discriminating venous thrombosis, the ADA score was modestly superior to the IMPROVE score (c statistic = 0.664 [95% CI: 0.607 to 0.722] vs. 0.573 [95% CI: 0.521 to 0.624]; ∆ c statistic = 0.091 [95% CI: 0.011 to 0.172]; p = 0.026). The ADA score had a higher sensitivity (0.579 [95% CI: 0.512 to 0.646]; vs. 0.440 [95% CI: 0.373 to 0.507]) but lower specificity (0.625 [95% CI: 0.614 to 0.637] vs. 0.747 [95% CI: 0.737 to 0.758]) than the IMPROVE score for predicting thrombosis. Among acutely ill hospitalized medical patients enrolled in the APEX trial, the ADA score demonstrated good calibration but suboptimal discrimination for predicting thrombosis. The findings support the use of either the ADA or IMPROVE score for thrombosis risk assessment. The applicability of the ADA score to non-COVID-19 populations warrants further research.Clinical Trial Registration: Unique identifier: NCT01583218.
Response Operator Curve analysis featuring viral load (Ct) and thrombosis events
COVID-19 patients may develop thrombotic complications, and data regarding an association between nasopharyngeal viral load and thrombosis is scarce. The aim of our study was to evaluate whether SARS-CoV-2 nasopharyngeal viral load upon admission is a useful prognostic marker for the development of thromboembolic events in patients hospitalized for SARS-CoV-2 infection. We performed a retrospective study of all hospitalized patients with a positive PCR test for SARS-CoV2 who had deep vein thrombosis (DVT), pulmonary embolization (PE), or arterial thrombosis diagnosed during their clinical course in a single academic center. The study population was divided according to the cycle threshold (Ct) value upon admission in patients with high viral load (Ct < 25), intermediate/medium viral load (Ct 25–30), and low viral load (Ct > 30). A regression model for propensity was performed matching in a 1:3 ratio those patients who had a thrombotic complication to those who did not. Among 2,000 hospitalized COVID-19 patients, 41 (2.0%) developed thrombotic complications. Of these, 21 (51.2%) were diagnosed with PE, eight (19.5%) were diagnosed with DVT, and 12 (29.2%) were diagnosed with arterial thrombosis. Thrombotic complications occurred as frequently among the nasopharyngeal viral load or severity stratification groups with no statistically significant differences. Univariate logistic regression revealed increased odds for thrombosis only in mechanically ventilated patients OR 3.10 [1.37, 7.03] (p = 0.007). Admission SARS-CoV-2 nasopharyngeal viral loads, as determined by Ct values, were not independently associated with thromboembolic complications among hospitalized patients with COVID-19.
NSCLC specimen stained with PD-L1 antibody A exhibiting TPS < 1% (20 × magnification), B exhibiting TPS 1–49% (40 × magnification), C exhibiting TPS ≥ 50% (40 × magnification). NSCLC Non-small cell lung cancer, PD-L1 Programmed cell death ligand 1, TPS Tumour proportion score
The flowchart of the study population. PD-L1 Programmed cell death ligand 1, VTE Venous thromboembolism (DVT, PE and concurrent PE and DVT), DVT Deep venous thrombosis, PE Pulmonary embolism
The cumulative incidence curves of VTEs for A all study population, B the PD-L1 positive and PD-L1 negative groups, C the low – positive PD-L1 and the high – positive PD-L1 groups. CI Confidence interval, CumIn Cumulative incidence, PD-L1 Programmed cell death ligand 1, VTE Venous thromboembolism
The cumulative incidence curves of PEs for A all study population, B the PD-L1 positive and PD-L1 negative groups, C the low – positive PD-L1 and the high – positive PD-L1 groups. CI Confidence interval, CumIn Cumulative incidence, PD-L1 Programmed cell death ligand 1, PE Pulmonary embolism
The risk of venous thromboembolism (VTE) is increased in non-small cell lung cancer (NSCLC), and defining at-risk patients is important. Thus, we aimed to assess the association between programmed cell death ligand 1 (PD-L1) expression and VTE [pulmonary embolism (PE), deep venous thrombosis (DVT)] in NSCLC. In this retrospective, observational multicentre study, 369 patients with NSCLC who had PD-L1 immunohistochemistry based on biopsies taken between January 2017 and December 2019, were divided as PD-L1-positive (n = 181) and -negative (n = 188) groups, and low-positive (n = 99) and high-positive (n = 82) PD-L1 groups. Among all population, 12.5% of them developed a VTE during a median follow-up of 474 days. The rates of DVT, PE, and PE + DVT were 5.7%, 6% and 0.8%, respectively. VTE (15.5% vs. 9.5%) and DVT (3.8% vs. 7.4%) were similar between two groups, while PE was significantly higher in PD‑L1-positive group than those in PD-L1-negative group (11.1% vs 1%, p < 0.001). There were no significant differences between low- and high-positive groups in terms of VTE (14.1% vs. 17%), PE (12.1% vs. 9.8%), and DVT (2% vs. 6.1%). In the multivariate analysis, multiple metastases (Hazard ratio [HR] 4.02; 95% confidence interval [Cl] 1.18–13.63; p = 0.07) and PD-L1 positivity was associated with an increased PE risk (HR 8.39; 95% Cl 2.07–34.07; p = 0.003). In conclusion, PD-L1 positivity may be of important role in predicting the increased risk of PE in patients with NSCLC and thereby may be used to define patients likely to benefit from thromboprophylaxis.
Patient dispositions
Kaplan–Meier plot of composite outcome
The few studies that compared direct oral anticoagulants (DOAC) vs. warfarin in the setting of advanced renal insufficiency have focused on patients with atrial fibrillation. The purpose of this observational, matched, cohort study of patients was to assess the effectiveness and safety of DOAC vs. warfarin for the treatment of venous thromboembolism (VTE) among patients with a creatinine clearance (CrCl) < 30 mL/min. This observational, cohort study included patients with VTE and CrCl < 30 mL/min who were newly initiated on a DOAC or warfarin between January 1, 2016 and December 31, 2020. DOAC patients were matched up to 1:2 to warfarin patients. Primary outcome was a composite of recurrent VTE, clinically-relevant bleeding, ischemic stroke, and all-cause mortality. Adjusted conditional, multivariate Cox proportional hazards modeling was used to assess outcomes. 626 DOAC patients were matched to 1071 warfarin patients. DOAC patients had a higher mean age, higher mean baseline CrCl, and were less likely to have been receiving dialysis. There was no statistically significant difference in the composite outcome between groups (adjusted hazard ratio [aHR] 1.13, 95% confidence interval [CI] 0.87–1.47) or in the individual components of the composite (all HR 95% CI crossed 1.00). Identification of statistically non-significant rates of bleeding and thromboembolic outcomes suggest that the use of DOAC or warfarin is reasonable in patients with VTE and CrCl < 30 mL/min.
Individual factor IX and factor VIII activity for HB and HA patients respectively at different perioperative timepoints. Factor IX activity levels were those before additional boluses, where applicable. HA patients overall had higher factor activity levels longitudinally throughout the perioperative period, compared to HB. POD post-operative day, HA hemophilia A, HB hemophilia B
Boxplot of factor VIII and IX activity at various perioperative timepoints shown as delta from pre-bolus levels to account for baseline factor activity. Factor IX activity levels were those before additional boluses, where applicable. The median initial post-bolus recovery (post-bolus—pre-bolus factor activity) was higher for factor VIII than factor IX, and this pattern was also seen longitudinally for the other timepoints. POD post-operative day, HA hemophilia A, HB hemophilia B
Continuous factor VIII (FVIII) or factor IX (FIX) infusions are commonly used for patients with hemophilia A (HA) or B (HB) undergoing surgery to secure perioperative hemostasis. To describe differences between the initial recovery and subsequent FIX and FVIII levels, and describe clinical outcomes among HB and HA patients receiving perioperative continuous infusion (CI) of recombinant FVIII and FIX concentrates. Retrospective chart review was conducted on 8 consecutive patients with HB and 7 consecutive patients with HA who underwent major surgery between 2014 and 2018 and received continuous infusions of standard half-life factor concentrate. Median initial bolus dose per kilogram was higher for HB compared to HA patients [90.8 (IQR 78.0–98.7) vs. 52.1 (IQR 48.6–55.6) IU/kg], while initial CI dose-rates were similar [4.3 (IQR 3.8–4.6) vs. 4.2 (IQR 3.8–4.4) IU/kg/h]. Median post-bolus recovery was higher for FVIII compared to FIX [1.70 (IQR 1.23–1.75) vs. 0.88 (IQR 0.75–1.00) IU/mL]. Median factor levels also were higher for FVIII on post-operative days 1 to 3. HB patients had greater mean intraoperative estimated blood loss [285.7 (range 0–1000) vs. 142.8 (range 0–400) mL] and longer median length of hospital stay [9 (IQR 8–12) vs. 5 (IQR 4–6.5) days]. Our initial evidence suggests greater in vivo yield of rFVIII compared to rFIX in the perioperative setting. We identified poorer clinical outcomes in this small cohort of perioperative HB patients indicating that they may benefit from a higher CI rate for adequate surgical hemostatic coverage. Graphical abstract
Catheter-directed interventions have slowly been gaining ground in the treatment of pulmonary embolism (PE), especially in patients with increased risk of bleeding. The goal of this study is to summarize the evidence for the efficacy and safety of percutaneous thrombectomy (PT) in patients with contraindications to systemic and local thrombolysis. We performed a systematic review and meta-analysis using MEDLINE, Cochrane, Scopus and the Web of Science databases for studies from inception to March 2022. We included patients with intermediate- and high-risk PE with contraindications to thrombolysis; patients who received systematic or local thrombolysis were excluded. Primary endpoint was in-hospital and 30-day mortality, with secondary outcomes based on hemodynamic and radiographic changes. Major bleeding events were assessed as a safety endpoint. Seventeen studies enrolled 455 patients, with a mean age of 58.6 years and encompassing 50.4% females. In-hospital and 30-day mortality rates were 4% (95% CI 3–6%) and 5% (95% CI 3–9%) for all-comers, respectively. We found a post-procedural reduction in systolic and mean pulmonary arterial pressures by 15.4 mmHg (95% CI 7–23.7) and 10.3 mmHg (95% CI 3.1–17.5) respectively. The RV/LV ratio and Miller Index were reduced by 0.42 (95% CI 0.38–46) and 7.8 (95% CI 5.2–10.5). Major bleeding events occurred in 4% (95% CI 3–6%). This is the first meta-analysis to report pooled outcomes on PT in intermediate- and high-risk PE patients without the use of systemic or local thrombolytics. The overall mortality rate is comparable to other contemporary treatments, and is an important modality particularly in those with contraindications for adjunctive thrombolytic therapy. Further studies are needed to understand the interplay of anticoagulation with PT and catheter-directed thrombolysis.
Results from systematic PubMed literature review using search terms: “COVID and aortic valve”, “COVID and mitral valve”, “COVID and tricuspid valve”, and “COVID and pulmonic valve”
Collection of Images Presented with Selected Imaging Modalities. Top to Bottom: bioprosthetic aortic valve, mechanical aortic valve, mechanical mitral valve, bioprosthetic mitral valve. Left to Right Row 1 Alexander et al., TEE and CT images demonstrating leaflet thickening; Manghat et al., CT and MRI images visualizing paravalvular thrombus (arrows). Left to Right Row 2 Al Helali et al., Fluoroscopy and CT images demonstrating thrombus, pannus formation and restricted leaflet mobility. Left to Right Row 3 Jeckelman et al., TEE image demonstrating isoechoic mass; Cardona Buitrago et al., TEE image demonstrating hyperechogenic image; Aruğaslan et al., TEE image demonstrating restricted leaflet mobility and thrombus. Left to Right Row 4 Llopis Gisbert et al., TEE image demonstrating thrombus; Vinnakota et al., CT image demonstrating thrombus. TEE (Transesophageal Echocardiogram); CT (Computed Tomography); MRI (Magnetic Resonance Imaging) [5–12]
Since the beginning of the SARS-CoV-2 (COVID-19) pandemic, correlation of venous thromboembolism (VTE) and COVID-19 infection has been well established. Increased inflammatory response in the setting of COVID-19 infection is associated with VTE and hypercoagulability. Venous and arterial thrombotic events in COVID-19 infection have been well documented; however, few cases have been reported involving cardiac valve prostheses. In this review, we present a total of eight cases involving COVID-19-related prosthetic valve thrombosis (PVT), as identified in a systematic review. These eight cases describe valve position (mitral versus aortic) and prosthesis type (bioprosthetic versus mechanical), and all cases demonstrate incidents of PVT associated with simultaneous or recent COVID-19 infection. None of these eight cases display obvious non-adherence to anticoagulation; five of the cases occurred greater than three years after the most recent valve replacement. Our review offers insights into PVT in COVID-19 infected patients including an indication for increased monitoring in the peri-infectious period. We explore valve thrombosis as a mechanism for prosthetic valve failure. We describe potential differences in antithrombotic strategies that may offer added antithrombotic protection during COVID-19 infection. With the growing population of valve replacement patients and recurring COVID-19 infection surges, it is imperative to explore relationships between COVID-19 and PVT.
Obesity is a known risk factor for venous thromboembolism (VTE) and poses a unique set of challenges in anticoagulation management. We report a 10-year experience of VTE management in morbidly obese patients. We conducted a retrospective analysis of VTE presentations to Northern Health, Victoria, Australia, from January 2011 to December 2020, with median follow-up of 44 months. Morbidly obese patients (defined as weighing > 120 kg) were compared to those ≤ 120 kg. Patients with active malignancy were excluded. 194 VTE cases with weight > 120 kg were compared to 2168 cases weighing ≤ 120 kg. Patients > 120 kg were more likely to present with unprovoked VTE (59.3% vs. 45.2%, p < 0.001) and major VTE (74.7% vs. 67.4%, p = 0.028). Overall, patients > 120 kg were more likely to develop VTE recurrence after anticoagulation cessation (7.80 vs. 3.92 per 100-patient-years, HR 1.97, 95%CI 1.29–3.00), while there were no significant differences in major bleeding or 30-day all-cause mortality. There were no significant differences in outcomes in patients > 120 kg treated with warfarin compared to direct oral anticoagulants (DOAC), or when comparing those treated with an uncapped (1 mg/kg BD) vs. capped (< 1 mg/kg) enoxaparin dosing regimen. Morbid obesity is associated with increased clot burden at presentation and VTE recurrence following anticoagulation cessation, without significant differences in bleeding compared to those ≤ 120 kg. There were no significant differences in morbidly obese patients’ outcomes when treated with warfarin or DOAC, or when treated with an uncapped or capped enoxaparin dosing strategy. Larger randomised controlled trials evaluating the safety of DOACs and different enoxaparin dosing strategies in patients > 120 kg are warranted.
Patient selection and treatment classification. Query terms used included calf deep vein thrombosis (DVT) and various types of intracranial hemorrhages including epidural, subdural, subarachnoid, and intracerebral hemorrhages and ruptured aneurysm. Patients with concurrent proximal DVT or pulmonary embolism and those with incomplete medical records were excluded from the analysis. Those who met the study criteria were divided into 3 groups based on treatment strategy: inferior vena cava (IVC) filter placement, anticoagulation, or imaging surveillance
In this study, we sought to investigate the effectiveness of inferior vena cava (IVC) filter placement in reducing the incidence of venous thromboembolism (VTE) in patients diagnosed with isolated calf deep vein thrombosis (DVT) after an intracranial hemorrhage or intracranial operation. A retrospective chart review (January 2000–December 2019) was performed to identify patients diagnosed with calf DVT after intracranial hemorrhage or intracranial operation. A total of 100 patients met the study criteria and were divided into groups based on treatment: IVC filter placement (n = 22), prophylactic anticoagulation (n = 42), or imaging surveillance (n = 36). Treatment-related complications were identified, and differences between groups in the primary endpoint (VTE occurrence after DVT diagnosis) were assessed using logistic regression. VTE occurred in 15 patients after calf DVT diagnosis. The rate of VTE was higher in the IVC filter group (9/22; 41%) than in the anticoagulation (2/42; 5%; p = 0.002) and surveillance (4/36; 11%; p = 0.013) groups. These treatment effects remained significant after adjustments were made for baseline characteristics (IVC filter vs anticoagulation, p = 0.009; IVC filter vs surveillance, p = 0.019). There was a single occurrence of pulmonary embolism in the surveillance group (3%). A single case of IVC filter thrombus was identified; no anticoagulation-related complications were reported. The findings of this study do not support IVC filter placement as a primary and solitary treatment for isolated calf DVT occurring after intracranial hemorrhage or intracranial operation.
The association between thromboembolic events (TE) and COVID-19 infection is not completely understood at the population level in the United States. We examined their association using a large US healthcare database. We analyzed data from the Premier Healthcare Database Special COVID-19 Release and conducted a case–control study. The study population consisted of men and non-pregnant women aged ≥ 18 years with (cases) or without (controls) an inpatient ICD-10-CM diagnosis of TE between 3/1/2020 and 6/30/2021. Using multivariable logistic regression, we assessed the association between TE occurrence and COVID-19 diagnosis, adjusting for demographic factors and comorbidities. Among 227,343 cases, 15.2% had a concurrent or prior COVID-19 diagnosis within 30 days of their index TE. Multivariable regression analysis showed a statistically significant association between a COVID-19 diagnosis and TE among cases when compared to controls (adjusted odds ratio [aOR] 1.75, 95% CI 1.72–1.78). The association was more substantial if a COVID-19 diagnosis occurred 1–30 days prior to index hospitalization (aOR 3.00, 95% CI 2.88–3.13) compared to the same encounter as the index hospitalization. Our findings suggest an increased risk of TE among persons within 30 days of being diagnosed COVID-19, highlighting the need for careful consideration of the thrombotic risk among COVID-19 patients, particularly during the first month following diagnosis.
Top-cited authors
Frederick A Spencer
  • McMaster University
John A Heit
  • Mayo Foundation for Medical Education and Research
Adam Cuker
  • University of Pennsylvania
Jack Ansell
  • Lenox Hill Hospital
Massimo Franchini
  • Azienda Ospedaliera Carlo Poma Mantova