Pharmacotherapy for Venous Thromboprophylaxis following Total Hip or Knee Arthroplasty: A Systematic Review and Network Meta-analysis.

The optimal pharmacological prophylaxis for venous thromboembolism (VTE) after hip or knee arthroplasty is uncertain. We conducted a systematic review and network meta-analysis to compare the efficacy and safety of various medications. We searched multiple databases for randomized clinical trials (RCTs) comparing medications (including factor Xa inhibitors, factor IIa inhibitor, warfarin, unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], aspirin, pentasaccharide) for VTE prophylaxis post-arthroplasty. Outcomes included any postoperative VTE identified with screening, major bleeding, and death. We used LMWH as the main comparator for analysis and performed trial sequential analysis (TSA) for each pairwise comparison. Certainty of evidence was assessed using GRADE (Grading of Recommendations, Assessments, Developments and Evaluations). We analyzed 70 RCTs (55,841 participants). Factor Xa inhibitors decreased postoperative VTE significantly compared with LMWH (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.44-0.68, high certainty). Pentasaccharides probably reduce VTE (OR: 0.61, 95% CI: 0.36-1.02, moderate certainty), while the factor IIa inhibitor dabigatran may reduce VTE (OR: 0.75, 95% CI: 0.40-1.42, low certainty). UFH probably increases VTE compared with LMWH (OR: 1.31, 95% CI: 0.91-1.89, moderate certainty), and other agents like warfarin, aspirin, placebo, and usual care without thromboprophylaxis increase VTE (high certainty). Factor Xa inhibitors may not significantly affect major bleeding compared with LMWH (OR: 1.06, 95% CI: 0.81-1.39, low certainty). No medications had a notable effect on mortality compared with LMWH (very low certainty). TSA suggests sufficient evidence for the benefit of factor Xa inhibitors over LMWH for VTE prevention. Compared with LMWH and aspirin, factor Xa inhibitors are associated with reduced VTE after hip or knee arthroplasty, without an increase in bleeding and likely no impact on mortality.

Hemorrhage, Disseminated Intravascular Coagulopathy, and Thrombosis Complications Among Critically Ill Patients with COVID-19: An International COVID-19 Critical Care Consortium Study.

OBJECTIVES: To determine the prevalence and outcomes associated with hemorrhage, disseminated intravascular coagulopathy, and thrombosis (HECTOR) complications in ICU patients with COVID-19. DESIGN: Prospective, observational study. SETTING: Two hundred twenty-nine ICUs across 32 countries. PATIENTS: Adult patients (≥ 16 yr) admitted to participating ICUs for severe COVID-19 from January 1, 2020, to December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: HECTOR complications occurred in 1,732 of 11,969 study eligible patients (14%). Acute thrombosis occurred in 1,249 patients (10%), including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial ischemia, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic strokes. Hemorrhagic complications were reported in 579 patients (4.8%), including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, 77 (13%) with pulmonary hemorrhage, and 68 (12%) with hemorrhage associated with extracorporeal membrane oxygenation (ECMO) cannula site. Disseminated intravascular coagulation occurred in 11 patients (0.09%). Univariate analysis showed that diabetes, cardiac and kidney diseases, and ECMO use were risk factors for HECTOR. Among survivors, ICU stay was longer (median days 19 vs 12; p < 0.001) for patients with versus without HECTOR, but the hazard of ICU mortality was similar (hazard ratio [HR] 1.01; 95% CI 0.92-1.12; p = 0.784) overall, although this hazard was identified when non-ECMO patients were considered (HR 1.13; 95% CI 1.02-1.25; p = 0.015). Hemorrhagic complications were associated with an increased hazard of ICU mortality compared to patients without HECTOR complications (HR 1.26; 95% CI 1.09-1.45; p = 0.002), whereas thrombosis complications were associated with reduced hazard (HR 0.88; 95% CI 0.79-0.99, p = 0.03). CONCLUSIONS: HECTOR events are frequent complications of severe COVID-19 in ICU patients. Patients receiving ECMO are at particular risk of hemorrhagic complications. Hemorrhagic, but not thrombotic complications, are associated with increased ICU mortality.

Clinical trials on the pharmacological treatment of long COVID: A systematic review.

The postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), also known as post-acute coronavirus disease 19 (COVID-19) or the long COVID syndrome (long COVID) is an emerging public health concern. A substantial proportion of individuals may remain symptomatic months after initial recovery. An updated review of published and ongoing trials focusing on managing long COVID will help identify gaps and address the unmet needs of patients suffering from this potentially debilitating syndrome. A comprehensive literature search was conducted on the international databases and clinical trial registries from inception to 31 July 2022. This review included 6 published trials and 54 trial registration records. There is significant heterogeneity in the characterization of long COVID and ascertainment of primary outcomes. Most of the trials are focused on individual symptoms of long COVID or isolated organ dysfunction, classified according to cardiovascular, respiratory and functional capacity, neurological and psychological, fatigue, and olfactory dysfunction. Most of the interventions are related to the mechanisms causing the individual symptoms. Although the six published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability. This review provides an update of the pharmacological agents that could be used to treat long COVID. Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.

The clinical application of venous ultrasound in diagnosis and follow-up of lower extremity deep vein thrombosis (DVT): a case-based discussion.

Current clinical practice guidelines lack explicit guidance on the indications and appropriate timing of venous ultrasound (US) in lower extremity deep vein thrombosis (DVT) follow-up. Moreover, abnormal findings reported on venous US in DVT follow-up or suspected recurrent DVT may be difficult for clinicians to interpret, which carries risk of harm from inappropriate use of anti- coagulation and increased healthcare resource utilization. Due to the above factors, over-use of ultrasound in diagnosis and follow-up of lower extremity DVT has been reported in western health systems. We have undertaken a case-based discussion and a scoping review of existing guidelines on the use of venousUS following prior diagnosis of DVT, to guide appropriate interpretation of commonly reported US abnormalities and provide our suggestions in the light of best available evidence on appropriate timing to perform follow-up US in management of lower extremity DVT.

Extracorporeal membrane oxygenation in patients with hematologic malignancies: a systematic review and meta-analysis.

Hematological malignancies (HM) have been, until recently, viewed as contraindications to extracorporeal membrane oxygenation (ECMO) due to bleeding and infectious complications. However, conflicting literature regarding whether ECMO should be used for patients with HM still exists. We conducted a random effects meta-analysis to investigate the outcomes of patients with HM on ECMO. We searched Medline, Embase, Scopus, and Cochrane through 10 October 2021. Risk of bias and certainty of evidence were assessed using the JBI checklists and GRADE approach respectively. Thirteen observational studies (422 patients with HM, 9778 controls without HM) were included. The pooled in-hospital mortality for patients with HM and those with hematopoietic stem cell transplants for HM indications needing ECMO were 79.1% (95%CI: 70.2-86.9%) and 87.7% (95%CI: 80.4-93.8%), respectively. Subgroup analyses found that mortality was higher in adults than children (85.1% vs 67.9%, pinteraction = 0.003), and in Asia compared to North America and Europe (93.8% vs 69.6%, pinteraction < 0.001). Pooled ECMO duration was 10.0 days (95%CI: 7.5-12.5); pooled ICU and hospital lengths of stay were 19.8 days (95%CI: 12.4-27.3) and 43.9 days (95%CI: 29.4-58.4) respectively. Age (regression coefficient [B]: 0.008, 95%CI: 0.003-0.014), proportion of males (B: 1.799, 95%CI: 0.079-3.519), and ECMO duration (B: - 0.022, 95%CI: - 0.043 to - 0.001) were significantly associated with higher mortality. In-hospital mortality of patients with HM who needed ECMO was 79.1%, with better outcomes in children, and in North America and Europe. ECMO should not be regarded as routine support therapy in these patients but can be carefully considered on a case-by-case basis.

Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients.

Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU µg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42-2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.

Thrombosis in VEXAS syndrome.

VEXAS syndrome, an autoinflammatory syndrome due to a Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) somatic mutation, has a high thrombotic burden. We report a case of a 69-year-old male that was diagnosed with VEXAS syndrome who developed venous thromboembolism (VTE). Review of literature of existing VEXAS syndrome cases showed a high thrombotic burden, with the reported incidence of VTE (36.4%) being markedly higher than arterial thrombosis (1.6%), with deep vein thrombosis being more common than pulmonary embolism. Somatic mutation in the UBA1 gene results in decreased ubiquitylation which is a key driver in the development of thrombosis in VEXAS syndrome, due to chronic inflammation and cytokine release from abnormal crosstalk between the intrinsic effector mechanism of innate immune cells, platelets and endothelium resulting in dysregulated haemostasis and endothelial dysfunction. Targeting endothelial dysfunction and reducing inflammatory milieu causing hypercoagulability with immunosuppressants and immunomodulatory agents, together with anticoagulation may be the strategy to prevent recurrent thrombotic events.

Global haemostatic tests demonstrate the absence of parameters of hypercoagulability in non-hypoxic mild COVID-19 patients: a prospective matched study.

Severe COVID-19 patients demonstrate hypercoagulability, necessitating thromboprophylaxis. However, less is known about the haemostatic profile in mild COVID-19 patients. We performed an age and gender-matched prospective study of 10 severe and 10 mild COVID-19 patients. Comprehensive coagulation profiling together with Thromboelastography and Clot Waveform Analysis were performed. FBC, PT, APTT, D-dimer, fibrinogen and CWA were repeated every 3 days for both groups and repeat TEG was performed for severe patients up till 15 days. On recruitment, severe patients had markers reflecting hypercoagulability including raised median D-dimer 1.0 µg/mL (IQR 0.6, 1.4) (p = 0.0004), fibrinogen 5.6 g/L (IQR 4.9, 6.6) (p = 0.002), Factor VIII 206% (IQR 171, 203) and vWF levels 265.5% (IQR 206, 321). Mild patients had normal values of PT, aPTT, fibrinogen and D-dimer, and slightly elevated median Factor VIII and von Willebrand factor (vWF) levels. Repeated 3-day assessments for both groups showed declining trends in D-dimer and Fibrinogen. CWA of severe COVID-19 group demonstrated hypercoagulability with an elevated median values of aPTT delta change 78.8% (IQR 69.8, 85.2) (p = 0.001), aPTT clot velocity (min1) 7.8%/s (IQR 6.7, 8.3) (p = 0.001), PT delta change 22.4% (IQR 19.4, 29.5) (p = 0.004), PT min1 7.1%/s (IQR 6.3, 9.0) (p = 0.02), PT clot acceleration (min 2) 3.6%/s2 (IQR 3.2, 4.5) (p = 0.02) and PT clot deceleration (max2) 2.9%/s2 (IQR 2.5, 3.5) (p = 0.02). TEG of severe patients reflected hypercoagulability with significant increases in the median values of CFF MA 34.6 mm (IQR 27.4,38.6) (p = 0.003), CRT Angle 78.9° (IQR 78.3, 80.0) (p = 0.0006), CRT A10 67.6 mm (IQR 65.8, 69.6) (p = 0.007) and CFF A10 32.0 mm (IQR 26.8, 34.0) (p = 0.003). Mild COVID-19 patients had absent hypercoagulability in both CWA and TEG. 2 severe patients developed thromboembolic events while none occurred in the mild COVID-19 group. Mild COVID-19 patients show absent parameters of hypercoagulability in global haemostatic tests while those with severe COVID-19 demonstrated parameters associated with hypercoagulability on the global haemostatic tests together with raised D-Dimer, fibrinogen, Factor VIII and vWF levels.

Low incidence of venous thrombosis but high incidence of arterial thrombotic complications among critically ill COVID-19 patients in Singapore.

BACKGROUND: Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. METHOD AND RESULTS: This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). CONCLUSIONS: Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

COVID-19 associated coagulopathy in critically ill patients: A hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis.

Patients with COVID-19 are known to be at risk of developing both venous, arterial and microvascular thrombosis, due to an excessive immuno-thrombogenic response to the SARS-CoV-2 infection. Overlapping syndromes of COVID-19 associated coagulopathy with consumptive coagulopathy and microangiopathy can be seen in critically ill patients as well. Blood was collected from 12 Intensive Care Unit (ICU) patients with severe COVID-19 who were on either mechanical ventilation or on high flow oxygen with a PaO2/FiO2 ratio of <300 mmHg. Laboratory tests were performed for parameters of haemostasis, clot waveform analysis and anti-phospholipid antibodies. CWA parameters were raised with elevated aPTT median Min1 (clot velocity) 9.3%/s (IQR 7.1-9.9%/s), elevated PT median Min1 10.3%/s (IQR 7.1-11.1%/s), elevated aPTT median Min2 (clot acceleration) 1.5%/s2 (IQR 1.0-1.6%/s2), elevated PT median Min2 5.2%/s2 (3.6-5.7%/s2), elevated aPTT median Max2 (clot deceleration) 1.3%/s2 (IQR 0.8-1.4%/s2) elevated PT median Max2 3.8%/s2 (IQR 2.6-4.2%/s2), increased aPTT median Delta change (decreased light transmission due to increased clot formation) 87.8% (IQR 70.2-91.8%) and PT median Delta change 33.0%. This together with raised median Factor VIII levels of 262.5%, hyperfibrinogenemia (median fibrinogen levels 7.5 g/L), increased median von Willebrand factor antigen levels 320% and elevated median D-dimer levels 1.7 µg/dl support the diagnosis of COVID-19 associated coagulopathy. A lupus anticoagulant was present in 50% of patients. Our laboratory findings further support the view that severe SARS-CoV-2 infection is associated with a state of hypercoagulability.