Hipertensión pulmonar y leiomiomas uterinos, ¿existe relación causal? Serie de casos y revisión fisiopatológica / Pulmonary Hypertension and Uterine Leiomyomas, Is there a Causal Relationship? Case Series and Pathophysiological Review

Introducción: Los leiomiomas uterinos son un tipo de neoplasia benigna de frecuente aparición en mujeres de edad reproductiva, relacionados con enfermedad tromboem- bólica venosa. Este vínculo surge del efecto producido por la compresión de fibromas que genera estasis venosa en la región pelviana. Sin embargo, este pareciera no ser el único factor que lo relaciona con el desarrollo posterior de hipertensión pulmonar, sino que su presencia es gatillo de una serie de fenómenos que influyen sobre la vasculatu - ra pulmonar y también a nivel sistémico. Método: Revisión de una serie de casos (seis) atendidos en nuestra unidad, seguido de una revisión sobre la relación entre leiomio- mas y distintas formas de hipertensión pulmonar con una revisión desde la fisiopatología. Resultado y conclusiones: Encontramos sustento bibliográfico en los múltiples caminos fisiopatológicos que relacionan los mediadores vasculares comunes, que parecieran ser el punto clave en la relación entre estas dos patologías.

Introduction: Uterine leiomyomas are a type of benign neoplasm that frequently appears in women of reproductive age, related to venous thromboembolic disease. This link arises from the effect produced by the compression of fibroids, which generates venous stasis in the pelvic region. However, this seems not to be the only factor that re- lates it to the subsequent development of pulmonary hypertension, but rather its presence is a trigger for a series of phenomena that influence the pulmonary vasculature and also at a systemic level. Method: Review of a series of cases (six) cared for in our unit, followed by a review on the relationship between leiomyomas and different forms of pulmonary hypertension with a review from the pathophysiology. Result and conclusions: We found bibliographic support in the multiple pathophysiological paths that relate the common vascular mediators, which appear to be the key point in the relationship between these two pathologies.

Tromboprofilaxis entrauma / Thromboprophylaxis in Trauma Santiago Castañeda Palacio1

Introducción: Las lesiones traumáticas son una de las principales causas de morbilidad y mortalidad en todo el mundo. Los pacientes que sufren traumatismos tienen riesgo de estados de hipercoagulación y aumentan el riesgo de sufrir enfermedad tromboembólica venosa. La tromboprofilaxis hace referencia a cualquier intervención usada para prevenir el desarrollo del tromboembolismo venoso como son la trombosis venosa profunda y el tromboembolismo pulmonar. Objetivo: Realizar una revisión sobre los principales mecanismos de tromboprofilaxis y sus principales esquemas en relación con el trauma ortopédico. Métodos: Se realizó una búsqueda de artículos de investigaciones originales en las bases de datos MEDLINE, EMBASE, Lilacs y Science Direct. Se seleccionaron palabras claves y términos del MeSH relacionados con anticoagulantes, tromboembolismo venoso, y embolismo pulmonar entre otros. La mayoría de bibliografía utilizada tuvo un rango de publicación no mayor a 5 años. Conclusiones: Los pacientes que sufren traumas tienen riesgo de sufrir estados de hipercoagulación y aumentan el riesgo de una enfermedad tromboembólica venosa. Con el fin de prevenirla se utilizan en la tromboprofilaxis distintos medicamentos, como heparinas de bajo peso molecular, y dispositivos de compresión(AU)

Introduction: Traumatic injuries are one of the leading causes of morbidity and mortality worldwide. Up to six million people die due to this cause. Trauma patients are at risk for hypercoagulable states and are at increased risk for venous thromboembolic disease. Thromboprophylaxis refers to any intervention used to prevent the development of venous thromboembolism such as deep vein thrombosis and pulmonary thromboembolism. Objective: To carry out a practical review of the main mechanisms of thromboprophylaxis and its main schemes in relation to orthopedic trauma. Methods: A search for original research articles was conducted in MEDLINE, EMBASE, Lilacs, and Science Direct databases. The keywords and MeSH terms related to anticoagulants, venous thromboembolism, and pulmonary embolism were selected among others. Most of the bibliography used had a publication range of no more than 5 years. Conclusions: Patients who suffer trauma are at risk of hypercoagulable states and these increase the risk of venous thromboembolic disease. In order to prevent it, different drugs are used in thromboprophylaxis, such as low molecular weight heparins, among others, as well as other compression devices(AU)

Comparative efficacy and safety of oral anticoagulants for the treatment of venous thromboembolism in the patients with different renal functions: a systematic review, pairwise and network meta-analysis.

OBJECTIVES: To compare the efficacy and safety of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and different renal functions. DESIGN: Systematic review containing pairwise and Bayesian network meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: MEDLINE, EMBASE and Cochrane Library. ELIGIBILITY CRITERIA: RCTs reporting the efficacy and safety outcomes of DOACs in different creatinine clearance (CrCl) subgroups. DATA EXTRACTION AND SYNTHESIS: Data extraction and quality assessment were undertaken by two independent reviewers. Data were pooled using the DerSimonian-Laird method in pairwise meta-analysis. Network meta-analysis within a Bayesian framework was conducted. RESULTS: Data from 10 RCTs were included. In the treatment of acute VTE, DOACs did not significantly reduce recurrent VTE or VTE-related death (OR, 0.96; 95% CI, 0.82 to 1.11) but significantly reduced bleeding events (0.76, 0.68 to 0.90) compared with warfarin. In the extended treatment of VTE, DOACs produced significant benefits in recurrent VTE or VTE-related death (0.23, 0.16 to 0.29), but significantly increased bleeding events (1.86, 1.04 to 3.33) compared with placebo/aspirin. There were no significant differences in efficacy and safety of DOACs among the three CrCl stratified subgroups in acute and extended treatment of VTE (p for subgroup heterogeneity >0.1). Bayesian network meta-analysis suggested that apixaban 2.5 mg and 5 mg two times per day were associated with a lower risk of bleeding than dabigatran, rivaroxaban, warfarin and aspirin in the subgroup with CrCl >80 mL/min. CONCLUSIONS: For the treatment of acute VTE, DOACs are similar to warfarin in reducing recurrent VTE and VTE-related death but are significantly superior to warfarin in reducing the risk of bleeding. For the efficacy and safety of DOACs across different CrCl stratifications (30-50, 50-80 and more than 80 mL/min), no significant difference was found. In light of minimal evidence, apixaban might be associated with a lower risk of bleeding in patients with VTE and CrCl >80 mL/min. PROSPERO REGISTRATION NUMBER: CRD42018090896.

Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation.

Whether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10-8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

Reduced Activity of Protein S in Plasma: A Risk Factor for Venous Thromboembolism in the Japanese Population.

The quantitative assay of protein S can help in rapidly identifying carriers of abnormal protein S molecules through a simple procedure (by determining the total protein S mass, total protein S activity, and protein S-specific activity in blood), without genetic testing. To clarify the relationship between venous thromboembolism (VTE) and protein S-specific activity, and its role in the diagnosis of thrombosis in Japanese persons, the protein S-specific activity was measured and compared between patients with thrombosis and healthy individuals. The protein S-specific activity of each participant was calculated from the ratio of total protein S activity to total protein S antigen level. Plasma samples were collected from 133 healthy individuals, 57 patients with venous thrombosis, 118 patients with arterial thrombosis, and 185 non-thrombotic patients. The protein S-specific activity of one-third of the patients with VTE was below the line of Y = 0.85X (-2 S.D.). Most protein S activities in the plasma of non-thrombotic patients were near the Y = X line, as observed in healthy individuals. In conclusion, it was clearly shown that monitoring protein S activity and protein S-specific activity in blood is useful for predicting the onset and preventing venous thrombosis in at least the Japanese population.

Combined Effect of MTHFR C677T and PAI-1 4G/5G Polymorphisms on the Risk of Venous Thromboembolism in Chinese Lung Cancer Patients.

Venous thromboembolism (VTE) is a common and potentially fatal complication in cancer patients. Although several genetic risk factors related to thrombophilia have been identified, their contributions for the occurrence of VTE in cancer patients have conflicting results. The aim of this study was to evaluated the gene polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor-1 (PAI-1) 4G/5G in lung cancer patients, with and without VTE, and the combined effect on the risk of VTE. 92 lung cancer patients diagnosed with VTE (VTE group) and 122 lung cancer patients without VTE (non-VTE group) were enrolled in the study. The gene polymorphisms were analyzed by the method of polymerase chain reaction-restriction fragment length polymorphism. Gene mutation of factor V Leiden was not detected both in non-VTE group and VTE group. The frequency of MTHFR C677T homozygous mutation in VTE group was 25.00%, higher than that in the non-VTE group without statistical difference. It was found that the PAI-1 4G4G genotype is associated with a higher risk of VTE (OR: 2.62, 95%CI: 1.19-5.75). Interestingly, the interaction between MTHFR C677T and PAI-1 4G/5G polymorphisms showed that the coexistence of the 2 homozygous mutation could further increase the risk of VTE. In conclusion, PAI-1 4G/5G polymorphism may be an increased risk factor for VTE among lung cancer patients in Chinese population. The homozygous MTHFR C677T mutation may be not a risk factor for VTE but increases the risk, accompanied with PAI-1 4G5G genotype.

Validation of the 2019 European Society of Cardiology Risk Stratification Algorithm for Pulmonary Embolism in Normotensive Elderly Patients.

BACKGROUND: The 2019 European Society of Cardiology (ESC) guidelines recommend evaluation for right ventricular dysfunction in all normotensive patients with acute pulmonary embolism (PE). We compared the predictive performance of the 2019 and 2014 ESC risk stratification algorithms and the Pulmonary Embolism Severity Index (PESI). METHODS: We performed a posthoc analysis of normotensive patients aged ≥ 65 years with acute PE from a prospective cohort. The primary outcome was overall mortality; secondary outcomes were PE-related mortality and adverse outcomes (PE-related death, cardiopulmonary resuscitation, intubation, catecholamine use, recurrent venous thromboembolism) at 30 days. We assessed outcomes in intermediate-high, intermediate-low, and low-risk groups according to the 2019 and 2014 ESC algorithms and the PESI. Discriminative power was compared using the area under the receiver operating characteristic curve (AUC). RESULTS: Among 419 patients, 14 (3.3%) died (7 from PE) and 16 (3.8%) had adverse outcomes within 30 days. The 2019 ESC algorithm classified more patients as intermediate-high risk (45%) than the 2014 ESC algorithm (24%) or the PESI (37%), and only 19% as low risk (32% with 2014 ESC or the PESI). Discriminatory power for overall mortality was lower with the 2019 ESC algorithm (AUC: 63.6%), compared with the 2014 ESC algorithm (AUC: 71.5%) or the PESI (AUC: 75.2%), although the difference did not reach statistical significance (p = 0.063). Discrimination for PE-related mortality and adverse outcomes was similar. CONCLUSION: While categorizing more patients in higher risk groups, the 2019 ESC algorithm for PE did not improve prediction of short-term outcomes compared with the 2014 ESC algorithm or the PESI.

Outpatient treatment of emergency department patients diagnosed with venous thromboembolism.

Venous thromboembolism (VTE) includes the diagnosis of either deep venous thrombosis (DVT) and/or pulmonary embolism (PE). This review discusses an evidence-based approach to the outpatient treatment of VTE in the emergency care setting. Main findings: The majority of patients diagnosed with VTE in the acute care setting are at low risk for an adverse event. Outpatient treatment for patients deemed low-risk by validated clinical decision tools leads to safe, efficacious, patient-centered, and cost-effective care. From a patient perspective, outpatient treatment of VTE can been simplified by the use of direct oral anticoagulant (DOACs) medications, and is supported by clinical trial evidence, and clinical practice guidelines from international societies. Outpatient treatment of patients with DVT has been more widely accepted as a best practice, while adoption of outpatient treatment of low-risk patients with acute PE has lagged. Many acute care clinicians remain wary of discharging patients with PE, concerned about drug access, adherence, and follow-up. Patients with VTE should be risk stratified identically as emerging evidence has demonstrated efficacy and safety in the interdependence of acute care protocols for the outpatient treatment of low-risk DVT and PE. Clinicians who practice in the acute care setting should be comfortable with risk stratification, anticoagulation, and discharge of low-risk VTE.

Prophylaxis and treatment of COVID-19 related venous thromboembolism.

COVID-19 pneumonia has been associated with high rates of thrombo-embolic complications, mostly venous thromboembolism (VTE), which is thought to be a combination of conventional VTE and in situ immunothrombosis in the pulmonary vascular tree. The incidence of thrombotic complications is dependent on setting (intensive care unit (ICU) versus general ward) and the threshold for performing diagnostic tests (screening versus diagnostic algorithms triggered by symptoms). Since these thrombotic complications are associated with in-hospital mortality, all current guidelines and consensus papers propose pharmacological thromboprophylaxis in all hospitalized patients with COVID-19. Several trials are ongoing to study the optimal intensity of anticoagulation for this purpose. As for the management of thrombotic complications, treatment regimens from non-COVID-19 guidelines can be adapted, with choice of anticoagulant drug class dependent on the situation. Parenteral anticoagulation is preferred for patients on ICUs or with impending clinical deterioration, while oral treatment can be started in stable patients. This review describes current knowledge on incidence and pathophysiology of COVID-19 associated VTE and provides an overview of guideline recommendations on thromboprophylaxis and treatment of established VTE in COVID-19 patients.

Reduced calf muscle pump function is a risk factor for venous thromboembolism: a population-based cohort study.

The calf muscle pump is a major determinate of venous return in the legs but has not been studied as a risk factor for venous thromboembolism (VTE). A population-based cohort study of Olmsted County, Minnesota residents was performed using calf pump function (CPF) measurements from venous plethysmography studies from 1998 to 2015. Patients with a history of VTE were excluded. Nursing validated VTE outcomes from the Rochester Epidemiology Project were identified after the index study date, and patients with reduced CPF (rCPF) were compared with patients with normal CPF. A total of 1532 patients with recorded CPF (28% air and 72% strain gauge plethysmography) were included; 591 (38.5%) had normal CPF, 353 (23.0%) had unilateral rCPF, and 588 (38.3%) had bilateral rCPF. Any VTE occurred in 87 patients (5.7%) after a median follow-up of 11.7 years (range, 0-22.0 years). Comparing patients with bilateral reduced to bilateral normal CPF, the unadjusted hazard ratio (HR) for incident VTE was 2.0 (95% confidence interval [CI], 1.2-3.4) and after adjusting for age, BMI, and Charlson Comorbidity Index, the HR was 1.68 (95% CI, 0.98-2.89). The adjusted HR for ipsilateral deep vein thrombosis was evaluated in 3064 legs comparing legs with reduced to normal CPF and was 1.71 (95% CI, 1.03-2.84). Mortality was significantly higher in both the bilateral (P < .001) and unilateral (P < .001) rCPF groups compared with normal CPF. Our results demonstrate that CPF is a risk factor for VTE in an otherwise low-risk ambulatory population and might be a useful component in risk stratification models.

Patient- and Health-Care-Provider-Reported Outcomes to Consider in Research on Pregnancy-Associated Venous Thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) in pregnancy can have numerous adverse impacts on patients and health care systems. Ongoing research aimed at improving maternal and fetal/neonatal outcomes is hampered by the lack of patient perspective in determining which outcomes are considered important to assess the effectiveness of interventions. OBJECTIVES: The objective of this study was to elicit outcomes from those who experienced or were at risk for pregnancy-associated VTE (health service users, HSUs) and health care providers (HCPs) involved in their care. METHODS: Canadian HSUs and HCPs were recruited using convenience and purposive sampling, respectively. Individual, semistructured interviews aimed specifically at eliciting pregnancy-related outcomes were conducted until data saturation was attained. Interviews were audio-recorded and transcribed verbatim. Written transcripts were de-identified and interpretatively analyzed in duplicate to obtain outcomes related to participant experiences. Outcomes were grouped based on a taxonomy developed for medical research and compared between and across interviews with patients and HCPs, and with those obtained through a systematic review of the published literature. RESULTS AND CONCLUSION: We interviewed 10 HSUs and eight HCPs and elicited 52 outcomes, 21 of which have not been reported in the literature. Although the majority of elicited outcomes were in the clinical/physiological core outcome area, both HSUs and HCPs highlighted the importance of outcomes related to functioning/life impact and general wellbeing of mother and baby. These outcomes representing the perspectives of HSUs and HCPs should be considered while conducting trials on pregnancy-associated VTE.

Screening for Cancer in Patients with Acute Venous Thromboembolic Disease.

Active cancer causes approximately 25% of all acute events of venous thromboembolism (VTE). While most of the cancer diagnoses are known or clinically apparent at the time of VTE, care providers and patients may be worried about the 3 to 8% risk of occult cancer occurring in the year after VTE. Several studies have compared limited to extensive cancer screening after acute VTE, especially with the addition of abdominal computed tomography (CT) or whole-body PET-CT, with the hope to shorten the time to cancer diagnosis and lead to less advanced cancer stages. These studies have not shown improved clinical outcomes with an extensive screening, and have led to current recommendations of limited screening for cancer in patients with acute VTE, including unprovoked cases. Several risk assessment models have been developed to identify patients at greatest risk of occult cancer, however, with low discriminative performances and no current clinical usefulness. Some clinical situations may empirically deserve a more thorough cancer screening, such as unprovoked upper extremity deep vein thrombosis (DVT), bilateral leg DVT, descending leg DVT, or recurrent VTE during anticoagulation.

Solid Tumor Complicated With Venous Thromboembolism: A 10-Year Retrospective Cross-Sectional Study.

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) occurs more frequently in cancer patients than in the general population. A retrospective cross-sectional study was carried out in patients with solid tumor complicated with VTE admitted to the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 1st, 2008 and December 31th, 2017. The incidence of VTE in hospitalized cancer patients was 1.8%, twice the incidence of VTE in hospitalized non-cancer patients. The annual incidence of cancer-associated VTE in our center varied between 1.6% in 2015 and 0.4% in 2009 with an overall average incidence of 1.3% over the research decade. BMI values of 549(67.7%) cancer patients were within the normal range, but none of patients had BMI greater than 35 kg/m2. 747(92.1%) cancer patients had ECOG PS score ≤ 2 and 481(59.3%) had distant metastasis. Patients with pancreatic, bladder, ovarian and endometrial cancer had the highest incidence of VTE. Upper extremity DVT (47.2%) was more common in cancer patients and might be closely associated with CVC (74.9%), while lower extremities DVT (36.1%) intended to PE development (15.0%). The annual incidence rates showed a fluctuating and upward trend over the research decade. VTE occurrence was closely related to tumor stage, tumor site, catheterization and anti-neoplasm therapy in cancer patients.

Complement activation and coagulopathy - an ominous duo in COVID19.

INTRODUCTION: COVID-19 has similarities to the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, as severe patients and non-survivors have frequently shown abnormal coagulation profiles. Immune-mediated pathology is a key player in this disease; hence, the role of the complement system needs assessment. The complement system and the coagulation cascade share an intricate network, where multiple mediators maintain a balance between both pathways. Coagulopathy in COVID-19, showing mixed features of complement-mediated and consumption coagulopathy, creates a dilemma in diagnosis and management. AREAS COVERED: Pathophysiology of coagulopathy in COVID-19 patients, with a particular focus on D-dimer and its role in predicting the severity of COVID-19 has been discussed. A comprehensive search of the medical literature on PubMed was done till May 30th, 2020 with the keywords 'COVID-19', 'SARS-CoV-2', 'Coronavirus', 'Coagulopathy', and 'D-dimer'. Twenty-two studies were taken for weighted pooled analysis of D-dimer. EXPERT OPINION: A tailored anticoagulant regimen, including intensification of standard prophylactic regimens with low-molecular-weight heparin is advisable for COVID-19 patients. Atypical manifestations and varying D-dimer levels seen in different populations bring forth the futility of uniform recommendations for anticoagulant therapy. Further, direct thrombin inhibitors and platelet inhibitors in a patient-specific manner should also be considered.

Pharmacologic Thromboprophylaxis Other Than Aspirin Is Associated With Increased Risk for Procedural Intervention for Arthrofibrosis After Anterior Cruciate Ligament Reconstruction.

PURPOSE: To compare rates of procedural intervention for arthrofibrosis following anterior cruciate ligament reconstruction (ACLR) among patients who were not prescribed any pharmacologic thromboprophylaxis compared with patients who were prescribed aspirin and to patients who were prescribed other agents. METHODS: A search of a national insurance claims database was performed to identify all patients who underwent ACLR from 2007 to 2017 who were active within the database at a minimum of 6 months before and 18 months after their surgery. The primary outcome studied was a subsequent procedure for arthrofibrosis, manipulation under anesthesia, and lysis of adhesions (MUA/LOA). Patients who filled a prescription for aspirin, low-molecular weight heparin, direct factor Xa inhibitors, fondaparinux, and warfarin within 2 days after their surgery were included and those who filled a prescription within 3 months before surgery were excluded. Thromboprophylaxis status was defined as no thromboprophylaxis, aspirin, and any agent other than aspirin. Logistic regression analysis was performed to determine the association between prophylaxis status and MUA/LOA. RESULTS: Of the 14,081 patients in our final surgical population, 191 patients had MUA/LOA and 13,890 patients did not. In total, 499 patients were prescribed pharmacologic prophylaxis. Rates of MUA/LOA across groups were 1.3% in the group with no thromboprophylaxis, 1.9% in the group prescribed aspirin, and 4.3% in the group prescribed any agent other than aspirin. Only the group prescribed an agent other than aspirin was significantly associated with subsequent procedure for arthrofibrosis (odds ratio 2.6, 95% confidence interval 1.3-4.8, P = .004). CONCLUSIONS: Patients who were prescribed a pharmacologic agent other than aspirin had a 2.6 times greater likelihood of requiring a procedural intervention for arthrofibrosis following ACLR compared with patients who were not prescribed a thromboprophylaxis agent LEVEL OF EVIDENCE: III, Retrospective Cohort Study.

Compared to randomized studies, observational studies may overestimate the effectiveness of DOACs: a metaepidemiological approach.

BACKGROUND AND OBJECTIVES: Randomized controlled trials (RCTs) are criticized for including patients who are overselected. Health authorities consequently encourage "real-world" postmarketing cohort studies. Our objective was to determine the differences between RCTs and observational studies as regards their populations and efficacy/safety results. METHODS: A systematic review was conducted to identify RCTs and observational studies including patients with venous thromboembolism receiving direct oral anticoagulants or conventional treatment. Ratios of hazard ratio (RHR) comparing epidemiological studies (prospective and retrospective cohort studies and studies using living databases) with RCTs were computed. RESULTS: Six RCTs (27,121 patients) and twenty observational studies (248,971 patients) were identified and analyzed. Prospective cohort studies seemed to recruit patients who were no less selected than those of RCTs whereas other types of observational studies may reflect the population treated in real life. Among observational studies, prospective cohort studies yielded the most favorable estimates of treatment effect compared with RCTs. These studies were associated with a nonsignificant 33% increase in efficacy estimate (RHR 0.67, [95% CI, 0.39-1.18]) but no effect on safety estimate. Studies using living databases were associated with nonsignificant trends toward a greater effect on efficacy (RHR 0.82, [0.66-1.01]) and a smaller effect on safety (RHR 1.33, [0.96-1.84]). DISCUSSION: Overall, in this clinical setting, an exaggeration of the treatment efficacy estimate was seen with observational studies compared with RCTs. CONCLUSIONS: As the presence of residual confounding cannot be excluded, these results should be interpreted cautiously.

COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management.

Coronavirus-2019 (COVID-19) predisposes patients to arterial and venous thrombosis commonly complicating the clinical course of hospitalized patients and attributed to the inflammatory state, endothelial dysfunction, platelet activation and blood stasis. This viral coagulopathy may occur despite thromboprophylaxis and raises mortality; the risk appears highest among critically ill inpatients monitored in the intensive care unit. The prevalence of venous thromboembolism in COVID-19 patients has been reported to reach ∼10-35%, while autopsies raise it to nearly 60%. The most common thrombotic complication is pulmonary embolism, which though may occur in the absence of a recognizable deep venous thrombosis and may be due to pulmonary arterial thrombosis rather than embolism, resulting in thrombotic occlusion of small- to mid-sized pulmonary arteries and subsequent infarction of lung parenchyma. This micro-thrombotic pattern seems more specific for COVID-19 and is associated with an intense immuno-inflammatory reaction that results in diffuse occlusive thrombotic micro-angiopathy with alveolar damage and vascular angiogenesis. Furthermore, thrombosis has also been observed in various arterial sites, including coronary, cerebral and peripheral arteries. Biomarkers related to coagulation, platelet activation and inflammation have been suggested as useful diagnostic and prognostic tools for COVID-19-associated coagulopathy; among them, D-dimer remains a key biomarker employed in clinical practice. Various medical societies have issued guidelines or consensus statements regarding thromboprophylaxis and treatment of these thrombotic complications specifically adapted to COVID-19 patients. All these issues are detailed in this review, data from meta-analyses and current guidelines are tabulated, while the relevant mechanisms of this virus-associated coagulopathy are pictorially illustrated.

Clinical characteristics and outcomes of patients with venous thromboembolism according to diagnosis on weekends versus on weekdays.

There are uncertainties on the influence of the days of diagnosis in a week (weekends versus weekdays) on clinical outcomes in patients with acute venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT). The COMMAND VTE registry is a multicenter cohort study enrolling 3027 consecutive patients with acute symptomatic VTE. The current study population consisted of 337 patients diagnosed on weekends and 2690 patients diagnosed on weekdays. We compared the clinical characteristics, management strategies and 30-day outcomes between the 2 groups. The patients diagnosed on weekends more often presented with PE (72% vs. 55%, P < 0.001), and with more severe hemodynamic condition for PE patients. The patients diagnosed on weekends more often received initial parenteral anticoagulation therapy and thrombolysis than those diagnosed on weekdays. The cumulative 30-day incidence of all-cause death was not significantly different between the two groups among PE patients (diagnosis on weekends: 6.2% vs. diagnosis on weekdays: 6.5%, P = 0.87), as well as among DVT patients (0.0% vs. 1.5%, P = 0.24). The most frequent cause of deaths was fatal PE in both groups among PE patients. The risks for recurrent VTE and major bleeding at 30-day were not significantly different between the 2 groups among PE patients, nor among DVT only patients. In conclusion, the VTE patients diagnosed on weekends presented more often with PE, and with more severe condition for PE patients. Nevertheless, the risk for 30-day mortality was not significantly different between patients diagnosed on weekends and on weekdays.

Cerebral venous sinus thrombosis associated with spontaneous heparin-induced thrombocytopenia syndrome after total knee arthroplasty.

Spontaneous heparin-induced thrombocytopenia (HIT) syndrome, characterized by clinical and serologic features of HIT despite the absence of proximate heparin exposure, can be triggered by total knee arthroplasty (TKA). A 56-year-old female receiving aspirin thromboprophylaxis post-TKA presented with aphasia and thrombocytopenia on post-operative day 11. Imaging studies revealed cerebral venous sinus thrombosis (CVST) and intravenous bivalirudin was initiated. Her serum tested strong-positive for IgG anti-PF4/polyanion complexes and serotonin-release assay in the presence and absence of heparin; strong-positive IgG-specific chemiluminescent immunoassay; and moderate-positive latex immunoturbidimetric assay. Two 65 g doses of IVIG were administered. With the improvement of her platelet count, she was transitioned from bivalirudin to warfarin. At one-year follow-up, she remained free of recurrent thrombosis and neurologically stable with a normal platelet count. Previous reports of post-TKA spontaneous HIT syndrome include venous/arterial thrombosis and adrenal hemorrhage, and this report of CVST expands the clinical spectrum of this rare complication of orthopedic surgery.

Venous thrombosis epidemiology, pathophysiology, and anticoagulant therapies and trials in severe acute respiratory syndrome coronavirus 2 infection.

OBJECTIVE: Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus confers a risk of significant coagulopathy, with the resulting development of venous thromboembolism (VTE), potentially contributing to the morbidity and mortality. The purpose of the present review was to evaluate the potential mechanisms that contribute to this increased risk of coagulopathy and the role of anticoagulants in treatment. METHODS: A literature review of coronavirus disease 2019 (COVID-19) and/or SARS-CoV-2 and cell-mediated inflammation, clinical coagulation abnormalities, hypercoagulability, pulmonary intravascular coagulopathy, and anticoagulation was performed. The National Clinical Trials database was queried for ongoing studies of anticoagulation and/or antithrombotic treatment or the incidence or prevalence of thrombotic events in patients with SARS-CoV-2 infection. RESULTS: The reported rate of VTE among critically ill patients infected with SARS-CoV-2 has been 21% to 69%. The phenomenon of breakthrough VTE, or the acute development of VTE despite adequate chemoprophylaxis or treatment dose anticoagulation, has been shown to occur with severe infection. The pathophysiology of overt hypercoagulability and the development of VTE is likely multifactorial, with evidence supporting the role of significant cell-mediated responses, including neutrophils and monocytes/macrophages, endothelialitis, cytokine release syndrome, and dysregulation of fibrinolysis. Collectively, this inflammatory process contributes to the severe pulmonary pathology experienced by patients with COVID-19. As the infection worsens, extreme D-dimer elevations, significant thrombocytopenia, decreasing fibrinogen, and prolongation of prothrombin time and partial thromboplastin time occur, often associated with deep vein thrombosis, in situ pulmonary thrombi, and/or pulmonary embolism. A new phenomenon, termed pulmonary intravascular coagulopathy, has been associated with morbidity in patients with severe infection. Heparin, both unfractionated heparin and low-molecular-weight heparin, have emerged as agents that can address the viral infection, inflammation, and thrombosis in this syndrome. CONCLUSIONS: The overwhelming inflammatory response in patients with SARS-CoV-2 infection can lead to a hypercoagulable state, microthrombosis, large vessel thrombosis, and, ultimately, death. Early VTE prophylaxis should be provided to all admitted patients. Therapeutic anticoagulation therapy might be beneficial for critically ill patients and is the focus of 39 ongoing trials. Close monitoring for thrombotic complications is imperative, and, if confirmed, early transition from prophylactic to therapeutic anticoagulation should be instituted. The interplay between inflammation and thrombosis has been shown to be a hallmark of the SARS-CoV-2 viral infection.