Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Validation of a Major and Clinically Relevant Nonmajor Bleeding Phenotyping Algorithm on Electronic Health Records.

PURPOSE: Bleeding is an important health outcome of interest in epidemiological studies. We aimed to develop and validate rule-based algorithms to identify (1) major bleeding and (2) all clinically relevant bleeding (CRB) (composite of major and all clinically relevant nonmajor bleeding) within real-world electronic healthcare data. METHODS: We took a random sample (n = 1630) of inpatient admissions to Singapore public healthcare institutions in 2019 and 2020, stratifying by hospital and year. We included patients of all age groups, sex, and ethnicities. Presence of major bleeding and CRB were ascertained by two annotators through chart review. A total of 630 and 1000 records were used for algorithm development and validation, respectively. We formulated two algorithms: sensitivity- and positive predictive value (PPV)-optimized algorithms. A combination of hemoglobin test patterns and diagnosis codes were used in the final algorithms. RESULTS: During validation, diagnosis codes alone yielded low sensitivities for major bleeding (0.16) and CRB (0.24), although specificities and PPV were high (>0.97). For major bleeding, the sensitivity-optimized algorithm had much higher sensitivity and negative predictive values (NPVs) (sensitivity = 0.94, NPV = 1.00), however false positive rates were also relatively high (specificity = 0.90, PPV = 0.34). PPV-optimized algorithm had improved specificity and PPV (specificity = 0.96, PPV = 0.52), with little reduction in sensitivity and NPV (sensitivity = 0.88, NPV = 0.99). For CRB events, our algorithms had lower sensitivities (0.50-0.56). CONCLUSIONS: The use of diagnosis codes alone misses many genuine major bleeding events. We have developed major bleeding algorithms with high sensitivities, which can ascertain events within populations of interest.

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.

Examining Barriers and Motivations to Speak up on Medical Errors in a Simulated Clinical Emergency: A Mixed-Methods Study.

Phenomenon: Effective communication between team members is essential during the resuscitation of critically-ill patients. Failure of junior doctors to speak up and challenge erroneous clinical decisions made by their senior doctors is a serious communication failure which can result in catastrophic outcomes and jeopardize patient safety. Crisis resource management (CRM) and conflict resolution tools have been increasingly employed in the healthcare setting to reduce communication failure among healthcare providers and improve patient safety during crisis situations. The aims of our study were to: 1) evaluate the factors affecting junior doctors' ability to speak up on medical errors, 2) examine the effectiveness of CRM and conflict resolution tools, and 3) formulate a communication framework directed at training junior doctors in appropriate intellectual questioning of authority. Approach: From January to April 2019, we recruited twenty-five second-year postgraduate junior doctors working in an Emergency Department in Singapore. We provided training in CRM and conflict resolution communication for participants in the intervention arm. Participants underwent a high-fidelity simulated resuscitation scenario which was standardized to include faculty misdirection in the form of erroneous instructions given by a role-played senior doctor. We observed if participants appropriately challenged the erroneous instructions. We subsequently interviewed participants on their response during the simulation to elicit their barriers and motivations toward challenging authority. Video recordings were analyzed by an independent panel of investigators. Findings: Participants employed various non-verbal and verbal approaches when challenging erroneous decisions. We uncovered multiple personal, interpersonal, and situation-based factors influencing the junior doctor's willingness to challenge erroneous decisions made by seniors. From their responses, we conceptualized a theoretical model designed as a "weighing scale" to demonstrate how junior doctor's eventual response is the outcome of a delicate interplay of multiple barriers and motivations. Our intervention did not significantly increase the participants' likelihood of challenging authority (69% in control arm vs 75% in intervention arm, p = 1.00). Insights: Our study provides insights into the mindset of junior doctors when faced with the dilemma of challenging authority on medical errors. Established CRM training may not be effective in addressing the challenges junior doctors face when communicating against the hierarchal gradient. We propose strategies to further develop and optimize CRM training to enhance its value for junior doctors. Drawing from our findings, we formulated a "SAFE" communication tool (State the safety concern, suggest Alternative course of action, Support with Facts, Engage via Enquiry) directed at helping junior doctors in appropriate intellectual questioning of authority.

Etiologies, mechanisms, and risk factors of ischemic stroke in a young Asian adult cohort.

OBJECTIVES: Risk factors and causes of acute ischemic stroke (AIS) are more diverse in young adults, and traditional stroke classifications may be inadequate. Precise characterisation of AIS is important for guiding management and prognostication. We describe stroke subtypes, risk factors and etiologies for AIS in a young Asian adult population. MATERIALS AND METHODS: Young AIS patients aged 18-50 years admitted to two comprehensive stroke centres from 2020-2022 were included. Stroke etiologies and risk factors were adjudicated using Trial of Org 10172 in Acute Stroke Treatment (TOAST) and International Pediatric Stroke Study (IPSS) risk factors. Potential embolic sources (PES) were identified in a subgroup with embolic stroke of undetermined source (ESUS). These were compared across sex, ethnicities and age groups (18-39 years versus 40-50 years). RESULTS: A total of 276 AIS patients were included, with mean age 43±5.7 years and 70.3% male. Median duration of follow-up was 5 months (IQR: 3-10). The most common TOAST subtypes were small-vessel disease (32.6%) and undetermined etiology (24.6%). IPSS risk factors were identified in 95% of all patients and 90% with undetermined etiology. IPSS risk factors included atherosclerosis (59.5%), cardiac disorders (18.7%), prothrombotic states (12.4%) and arteriopathy (7.7%). In this cohort, 20.3% had ESUS, of which 73.2% had at least one PES, which increased to 84.2% in those <40 years old. CONCLUSIONS: Young adults have diverse risk factors and causes of AIS. IPSS risk factors and ESUS-PES construct are comprehensive classification systems that may better reflect heterogeneous risk factors and etiologies in young stroke patients.

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.

Surgery for chronic arthropathy in people with haemophilia.

BACKGROUND: Chronic arthropathy is a potentially debilitating complication for people with haemophilia - a genetic, X-linked, recessive bleeding disorder, characterised by the absence or deficiency of a clotting factor protein. Staging classifications, such as the Arnold-Hilgartner classification for haemophilic arthropathy of the knee, radiologically reflect the extent of knee joint destruction with underlying chronic synovitis. Management of this highly morbid disease process involves intensive prophylactic measures, and chemical or radioisotope synovectomy in its early stages. However, failure of non-surgical therapy in people with progression of chronic arthropathy often prompts surgical management, including synovectomy, joint debridement, arthrodesis, and arthroplasty, depending on the type of joint and extent of the damage. To date, management of people with mild to moderate chronic arthropathy from haemophilia remains controversial; there is no agreed standard treatment. Thus, the benefits and disadvantages of non-surgical and surgical management of mild to moderate chronic arthropathy in people with haemophilia needs to be systematically reviewed.  OBJECTIVES: To assess the efficacy and safety of surgery for mild to moderate chronic arthropathy in people with haemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, and two trial registers to August 2022. We also handsearched relevant journals and conference abstract books. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs comparing surgery and non-surgical interventions, for any joint with chronic arthropathy, in people with haemophilia, who were at least 12 years old. DATA COLLECTION AND ANALYSIS: The review authors did not identify any trials to include in this review. MAIN RESULTS: The review authors did not identify any trials to include in this review. AUTHORS' CONCLUSIONS: The review authors did not identify any trials to include in this review. Due to a lack of research in this particular area, we plan to update the literature search every two years, and will update review if any new evidence is reported. There is a need for a well-designed RCT that assesses the safety and efficacy of surgical versus non-surgical interventions for chronic arthropathy in people with haemophilia.

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 and ischemic stroke: a systematic review and meta-summary of the literature.

Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection. Increasing reports suggest an association between COVID-19 and AIS, although the underlying mechanism remains uncertain. We performed a systematic review to characterize the clinical characteristics, neuroimaging findings, and outcomes of AIS in COVID-19 patients. A literature search was performed in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 29th May 2020. All studies reporting AIS occurrence in COVID-19 patients were included. A total of 39 studies comprising 135 patients were studied. The pooled incidence of AIS in COVID-19 patients from observational studies was 1.2% (54/4466) with a mean age of 63.4 ± 13.1 years. The mean duration of AIS from COVID-19 symptoms onset was 10 ± 8 days, and the mean NIHSS score was 19 ± 8. Laboratory investigations revealed an elevated mean D-dimer (9.2 ± 14.8 mg/L) and fibrinogen (5.8 ± 2.0 g/L). Antiphospholipid antibodies were detected in a significant number of cases. The majority of AIS neuroimaging patterns observed was large vessel thrombosis, embolism or stenosis (62.1%, 64/103), followed by multiple vascular territory (26.2%, 27/103). A high mortality rate was reported (38.0%, 49/129). We report the pooled incidence of AIS in COVID-19 patients to be 1.2%, with a high mortality rate. Elevated D-dimer, fibrinogen and the presence of antiphospholipid antibodies appear to be prominent in COVID-19 patients with concomitant AIS, but further mechanistic studies are required to elucidate their role in pathogenesis.

Chemoprophylaxis in addition to mechanical prophylaxis after total knee arthroplasty surgery does not reduce the incidence of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) of the lower limbs is an important complication post total knee arthroplasty (TKA). Current guidelines recommend routine chemical prophylaxis to all patients undergoing this procedure but this is rarely done in Asia as it is believed that Asians have a lower risk of VTE. However, recent evidence suggests otherwise. AIMS: We evaluated the incidence of DVT after TKA in a multi-ethnic Asian population with and without pharmacological prophylaxis, as well as the management and outcome of patients with post-operative DVTs. METHODS: We conducted a retrospective study of consecutive patients who underwent TKA in our hospital from 1st January 2004 to 30th December 2014. All patients were on mechanical thromboprophylaxis via calf pumps after TKA with a postoperative day 3 to 5 doppler ultrasound (DUS) of bilateral lower limbs. 2258 (80.7%) patients did not receive additional chemoprophylaxis, while 540 (19.3%) received chemoprophylaxis on top of mechanical thromboprophylaxis. All patients who received chemoprophylaxis were administered the drug until they were ambulating, with a median administration duration of 6 days. Patients were followed up for a period of 3 months for recurrence of DVTs and 24 months for postoperative outcome scores. RESULTS: Two thousand nine hundred seventy-eight patients had DUS of the lower limbs with 134 diagnosed with DVT giving an incidence of 4.5%. Six of these patients had concurrent PEs. There were 26 (19.4%) proximal DVTs and 108 (80.6%) distal DVTs. After 3 months of follow up, no additional VTE occurred. None of the DVTs or PEs progressed.All DVTs with accompanying PE were proximal. 102 out of 2200 patients (4.6%) without chemoprophylaxis developed DVT as compared to 32 out of 540 patients (5.9%) with chemoprophylaxis, which was not statistically significant (p = 0.13). 19 (0.8%) proximal and 83 (3.8%) distal DVT developed in the patient group without chemoprophylaxis while 4 (0.7%) proximal and 28 (5.2%) distal DVT developed in the patient group with (p = 0.62). Comparison of the incidence of PEs between the two groups, revealed a similar incidence with 5 out of 2200 patients (0.2%) without chemoprophylaxis developing PE as compared to 1 out of 540 patients (0.2%) with chemoprophylaxis (p = 0.87).In addition, patients with chemoprophylaxis showed an association with higher post-operative outcome scores such as post op 6 months SF36 (PCS), post op 12 months SF36 (PCS), post op 12 months SF36 (MCS), post op 24 months SF36 (MCS) and post op 24 months WOMAC. CONCLUSION: In one of the largest Asian studies specifically investigating the incidence of DVT after TKA, we found that the incidence is low at 4.5%. This is in contrast to recent studies that showed higher post-operative VTE rates similar to Western populations. In addition, patients who were administered chemoprophylaxis did not have a statistically significant difference in incidence of VTE although it did show a correlation with higher post-operative outcome scores which may indicate better function. This was seen in functional outcome scores such as post op 6 months SF36 (PCS), post op 12 months SF36 (PCS), post op 12 months SF36 (MCS), post op 24 months SF36 (MCS) and post op 24 months WOMAC.

The diagnosis and treatment of venous thromboembolism in asian patients.

Although the incidence of venous thromboembolism (VTE) in Asian populations is lower than in Western countries, the overall burden of VTE in Asia has been considerably underestimated. Factors that may explain the lower prevalence of VTE in Asian populations relative to Western populations include the limited availability of epidemiological data in Asia, ethnic differences in the genetic predisposition to VTE, underdiagnoses, low awareness toward thrombotic disease, and possibly less symptomatic VTE in Asian patients. The clinical assessment, diagnostic testing, and therapeutic considerations for VTE are, in general, the same in Asian populations as they are in Western populations. The management of VTE is based upon balancing the treatment benefits against the risk of bleeding. This is an especially important consideration for Asian populations because of increased risk of intracranial hemorrhage with vitamin K antagonists. Non-vitamin K antagonist oral anticoagulants have shown advantages over current treatment modalities with respect to bleeding outcomes in major phase 3 clinical trials, including in Asian populations. Although anticoagulant therapy has been shown to reduce the risk of postoperative VTE in Western populations, VTE prophylaxis is not administered routinely in Asian countries. Despite advances in the management of VTE, data in Asian populations on the incidence, prevalence, recurrence, risk factors, and management of bleeding complications are limited and there is need for increased awareness. To that end, this review summarizes the available data on the epidemiology, risk stratification, diagnosis, and treatment considerations in the management of VTE in Asia.

Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications.

Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. There are nearly 100 million new dengue cases yearly in more than 120 countries, with a five-fold increase in incidence over the past four decades. While many patients experience a mild illness, a subset suffer from severe disease, which can be fatal. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. While thrombocytopaenia and coagulopathy are major causes of bleeding in severe dengue, leucocyte abnormalities are emerging as important markers of prognosis. In this review, we provide our perspective on the clinical aspects and pathophysiology of haematologic manifestations in dengue. We also discuss the key gaps in our current practice and areas to be addressed by future research.

Consensus recommendations for optimising the diagnosis and treatment of paroxysmal nocturnal haemoglobinuria in Singapore.

Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematologic disease characterised by intravascular haemolysis, thrombophilia and bone marrow failure. There is a lack of established clinical guidance on the screening, diagnosis and manage-ment of PNH in Singapore. A relatively low level of awareness among healthcare professionals regarding PNH manifestations further contributes to diagnostic delays. Additionally, limited access to complement inhibitors, like eculizumab, may delay treatment and impact patient outcomes. Method: Nine haematologists from different institu-tions in Singapore convened to formulate evidence-based consensus recommendations for optimising the diagnosis and management of patients with PNH and improving access to novel treatments. The experts reviewed the existing literature and international guidelines published from January 2010 to July 2023, focusing on 7 clinical questions spanning PNH screening, diagnostic criteria, investigations, treatment and monitoring of subclinical and classic disease, PNH with underlying bone marrow disorders, and PNH in pregnancy. A total of 181 papers were reviewed to formulate the statements. All experts voted on the statements via 2 rounds of Delphi and convened for an expert panel discussion to finetune the recommendations. Results: Sixteen statements have been formulated for optimising the screening, diagnosis and management of PNH. Upon confirmation of PNH diagnosis, individuals with active haemolysis and/or thrombosis should be considered for anti-complement therapy, with eculizumab being the only approved drug in Singapore. Conclusion: The current recommendations aim to guide the clinicians in optimising the screening, diagnosis and management of PNH in Singapore.

Coagulation factors II, V, VII, IX, X and XI and mortality - a cohort study.

Background: Elevated levels of coagulation factors (F) II (FII), FV, FVII, FIX, FX, and FXI have often been related with coronary heart disease, ischemic stroke, and venous thrombosis (VT). However, there are few studies on their associations with all-cause mortality. Objective: We explored whether elevated levels of FII, FV, FVII, FIX, FX, and FXI are associated with an increased risk of death in patients who had VT and in individuals from the general population. Methods: We followed 1919 patients with previous VT and 2800 age- and sex-matched community controls in whom coagulation factor levels were measured. A high coagulation factor was defined as the >90th percentile of normal in the controls. Cox regression analyses were adjusted for age and sex and for being a patient with VT or being a control subject. Results: The median age at time of enrolment was 48 years for both patients and controls, and slightly more women than men were followed. Over a median follow-up of 6.1 years for patients and 5.0 years for controls, there were 79 and 60 deaths in patient and controls respectively. There was no association of FII, FV, FVII, FIX, FX, and FXI with all-cause mortality in patients or in control individuals. Conclusions: Elevated levels of FII, FV, FVII, FIX, FX, and FXI levels may not be associated with an increased risk of all-cause mortality. Only for cardiac death, an association with high FX and FXI was found, which confirms the findings of previous studies, but numbers were small.

Procoagulant factors and future risk of arterial cardiovascular disease in patients with prior venous thrombosis: A cohort study.

Patients with venous thrombosis (VT) are at increased risk of future arterial cardiovascular disease (CVD) (i.e., myocardial infarction, ischemic stroke or peripheral artery disease). We investigated whether shared risk factors for VT and CVD are associated with the levels of procoagulant factors (fibrinogen, factor VIII, and von Willebrand factor), and whether the relationship between these risk factors and subsequent CVD was mediated through these procoagulant factors in patients with VT. In a follow-up study consisting of 4956 patients with VT, 2176 patients (44%) provided blood samples and were linked to the Dutch Hospital registry of Statistics Netherlands to identify hospital admissions or procedures for subsequent CVD. In total, 52 CVD events occurred over a follow-up of 11,124 years, with an incidence rate of 4.7 per 1000 patient years (95% confidence intervals 3.5-6.1). Increasing age, male sex, smoking history, major illnesses, dyslipidemia, and impaired fasting glucose levels were associated with increased CVD risk. Procoagulant factor levels were also associated with CVD risk. When adjusted for these procoagulant factors, the association between the risk factors and CVD attenuated partially. This study provides evidence that procoagulant factors can partially explain the association between increased risks of subsequent CVD in patients with previous VT.

Venous thromboembolism in an Asian COVID-19 cohort across 3 infection waves-a retrospective observational study.

Background: A high incidence of venous thromboembolism (VTE) in COVID-19 has led to international recommendations for thromboprophylaxis. With limited data on Asian patients with COVID-19, the role of thromboprophylaxis remains unclear. Objectives: To investigate the in-hospital incidence of VTE in an Asian COVID-19 cohort, describe the VTE trend through successive COVID-19 waves (wild-type, delta, and omicron), and characterize the risk factors for VTE. Methods: We performed a retrospective observational cohort study of hospitalized COVID-19 adults from January 2020 to February 2022. Objectively confirmed VTE were reviewed to obtain VTE incidence and trend. Subset analysis of critical (intensive care), moderate (oxygen supplementation), and mild cases hospitalized ≥5 days was performed to investigate risk factors and in-hospital hazards of VTE. Results: Sixteen VTE events occurred among 3574 patients. Overall, VTE incidence was 0.45%, or 0.21% in mild, 3.60% in moderate, and 5.38% in critical infection. The maximum cumulative risk of VTE was 1.14% at 14 days for mild, 8.13% at 21 days for moderate, and 11.55% at 35 days for critical infection. Thromboprophylaxis use in mild, moderate, and critical cases was 5.7%, 28.8%, and 81.7%, respectively. In multivariable analysis, the severity of infection remained the strongest independent predictor of VTE. Compared with mild infection, the relative risk was 8.26 (95% CI, 2.26-30.16) for critical infection and 6.29 (95% CI, 1.54-25.67) for moderate infection. Conclusion: Overall, VTE incidence in Asian patients with COVID-19 is <1% across successive waves. Patients with moderate and critical infections are at greater risk for VTE and should be considered for routine thromboprophylaxis.

Extrapulmonary manifestations and complications of severe acute respiratory syndrome coronavirus-2 infection: a systematic review.

Introduction: We aimed to describe the extrapulmonary manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, including their frequency, onset with respect to respiratory symptoms, pathogenesis and association with disease severity. Methods: We searched the MEDLINE and Embase databases for SARS-CoV-2-related studies. Meta-analysis, observational studies, case series and case reports published in English or Chinese between 1 January 2020 and 1 May 2020 were included. Reports with only paediatric or obstetric cases were excluded. Results: 169 articles were included. Early manifestations (preceding respiratory symptoms until Day 6 of onset) included olfactory and gustatory disturbance (self-reported in up to 68% and 85% of cases, respectively), gastrointestinal symptoms (up to 65.9%) and rash (up to 20.4%). From Day 7 onwards, hypercytokinaemia, paralleled multi-organ complications including acute cardiac injury (pooled incidence of 17.7% in 1,412 patients, mostly with severe disease and 17.4% mortality), kidney and liver injury (up to 17% and 33%, respectively) and thrombocytopenia (up to 30%). Hypercoagulability resulted in venous thromboembolic events in up to 31% of all patients. Uncommon disease presentation and complications comprised Guillain-Barré syndrome, rhabdomyolysis, otitis media, meningoencephalitis and spontaneous pneumomediastinum. Conclusion: Although the systemic manifestations of SARS-CoV-2 infection are variegated, they are deeply interwoven by shared mechanisms. Two phases of extrapulmonary disease were identified: (a) an early phase with possible gastrointestinal, ocular and cutaneous involvement; and (b) a late phase characterised by multiorgan dysfunction and clinical deterioration. A clear, multidisciplinary consensus to define and approach thromboinflammation and cytokine release syndrome in SARS-CoV-2 is needed.