Sex differences in D-dimer and critical illness in patients with COVID-19: A systematic review and meta-analysis.

Background: Observed sex differences in COVID-19 outcomes suggest that men are more likely to experience critical illness and mortality. Thrombosis is common in severe COVID-19, and D-dimer is a significant marker for COVID-19 severity and mortality. It is unclear whether D-dimer levels differ between men and women, and the effect of D-dimer levels on disease outcomes remains under investigation. Objectives: We aimed to evaluate the sex difference in the D-dimer level among hospitalized patients with COVID-19 and the effect of sex and D-dimer level on disease outcomes. Methods: We meta-analyzed articles reporting D-dimer levels in men and women hospitalized for COVID-19, until October 2021, using random effects. Primary outcomes were mortality, critical illness, and thrombotic complications. Results: In total, 11,682 patients from 10 studies were analyzed (N = 5606 men (55.7%), N = 5176 women (44.3%)). Men had significantly higher odds of experiencing mortality (odds ratios (OR) = 1.41, 95% CI: [1.25, 1.59], P ≤ .001, I2 = 0%) and critical illness (OR = 1.76, 95% CI: [1.43, 2.18], P ≤ .001, I2 = 61%). The mean D-dimer level was not significantly different between men and women (MD = 0.08, 95% CI: [-0.23, 0.40], P = .61, I2 = 52%). In the subgroup analysis, men had significantly higher odds of experiencing critical illness compared with women in both the "higher" (P = .006) and "lower" (P = .001) D-dimer subgroups. Conclusion: Men have significantly increased odds of experiencing poor COVID-19 outcomes compared with women. No sex difference was found in the D-dimer level between men and women with COVID-19. The diversity in D-dimer reporting impacts data interpretation and requires further attention.

COVID-19 Vaccine-Associated Immune Thrombosis and Thrombocytopenia (VITT): Diagnostic Discrepancies and Global Implications.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported in association with the coronavirus disease 2019 preventative adenovirus vector-based vaccines ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson) in hundreds of recipients across the globe. VITT is characterized by thrombosis, typically at unusual sites, low fibrinogen, and elevated plasma D-dimer, generally manifesting between 4 and 28 days following vaccination. Detection of anti-platelet factor antibodies using an enzyme-linked immunosorbent assay (ELISA) is often confirmatory. Although several similar principles subside in most diagnostic criteria for VITT, the presentation of a positive ELISA assay, use of expert hematology and neurology opinion, and exclusion of possible VITT cases outside the "standard" 4 to 28-day timeframe have contributed a lack of global standardization for defining VITT. Accordingly, the global and regional incidence of VITT differs according to the diagnostic pathway and case definition used. This has influenced the public perception of VITT's severity and the decision to use adenovirus vector-based vaccines for limiting severe acute respiratory syndrome coronavirus 2 infection. We hereby delineate the recognized pathogenic mechanisms, global incidence, discrepancies in diagnostic criteria, recommended treatments, and global implications to vaccine hesitancy from this coagulopathy.

Thrombocytopathy vs Platelet hyper-reactivity in COVID-19: diverse pathologies, disease outcomes and therapeutic implications.

Coagulopathy is an evident complication of COVID-19 with predominance of a prothrombotic state. Platelet activation plays a key role. The terms "hyper-reactivity" and "hyperactivity" used in recent literature may not be clear or sufficient to explain the pathological events involved in COVID-related thrombosis (CRT). Inflammation may play a bigger role compared to thrombosis in COVID-related mortality because a smaller percentage of patients with COVID-19 die due to direct effects of thrombosis. Not all COVID-19 patients have thrombocytopenia and a few show thrombocytosis. We believe the platelet pathology is more complex than just activation or hyper-activation, particularly due to the platelets' role in inflammation. Understanding the pathology and consequences of platelets' role may help optimize management strategies and diminish CRT-associated morbidity and mortality. In this viewpoint report, we examine the published evidence of platelet hyper-reactivity in COVID-19 with a focused analysis of the key pathologies, diverse alterations, disease outcomes, and therapeutic targets. We believe that COVID-19 is a disease of inflammation and pathologic platelets, and based on the complexity and diverse pathologies, we propose the term "thrombocytopathy" as a more reflective term of the platelets' involvement in COVID-19. In our opinion, thrombocytopathy is the unpredictable pathologic alterations of platelets in function, morphology and number, caused by different factors with a variety of presentations.

Harnessing Twitter to empower scientific engagement and communication: The ISTH 2020 virtual congress experience.

As a result of the coronavirus disease 2019 pandemic, the International Society on Thrombosis and Haemostasis (ISTH), like many societies around the world, canceled their in-person hematology congress planned for Milan, Italy, in July 2020. As a result, the first virtual ISTH congress in the organisation's 51-year history was delivered, inviting free registration from across the globe. As part of the social media support, marketing, and scientific dissemination efforts for the virtual congress, the ISTH assembled a group of official Twitter Ambassadors, which represented the broad and diverse ISTH community. Ambassadors were tasked to tweet daily throughout the congress and to share their commentary on the hematology research being presented with the "#ISTH2020" hashtag. Ambassadors were also supported by Twitter activities from the two official ISTH-affiliated journals: the Journal of Thrombosis and Haemostasis (JTH) and Research and Practice in Thrombosis and Haemostasis (RPTH). In this forum and through the Twitter ambassadors' lens, we present the Twitter Ambassadors' experience, reflect on the impact of social media on the ISTH 2020 congress, and share this experience with the wider scientific community. Specifically, we report on the role of Twitter communication for virtual meetings, discuss the pros and cons of the virtual congress, and offer Twitter-related recommendations for future virtual or blended congresses. We conclude that the ISTH Twitter Ambassador program broadened social media engagement and offers a novel route to improve social connectivity in the virtual research congress setting.

To clot or not to clot? Ad is the question-Insights on mechanisms related to vaccine-induced thrombotic thrombocytopenia.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) has caused global concern. VITT is characterized by thrombosis and thrombocytopenia following COVID-19 vaccinations with the AstraZeneca ChAdOx1 nCov-19 and the Janssen Ad26.COV2.S vaccines. Patients present with thrombosis, severe thrombocytopenia developing 5-24 days following first dose of vaccine, with elevated D-dimer, and PF4 antibodies, signifying platelet activation. As of June 1, 2021, more than 1.93 billion COVID-19 vaccine doses had been administered worldwide. Currently, 467 VITT cases (0.000024%) have been reported across the UK, Europe, Canada, and Australia. Guidance on diagnosis and management of VITT has been reported but the pathogenic mechanism is yet to be fully elucidated. Here, we propose and discuss potential mechanisms in relation to adenovirus induction of VITT. We provide insights and clues into areas warranting investigation into the mechanistic basis of VITT, highlighting the unanswered questions. Further research is required to help solidify a pathogenic model for this condition.

Physician experiences in management of COVID-19-associated coagulopathy in pregnancy: Communication from the ISTH SSC Subcommittee on Women's Health Issues in Thrombosis and Haemostasis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) occurs following infection with the potentially fatal, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Infection can be complicated by coagulopathy, at times featuring thrombocytopenia and thrombosis alongside other coagulation abnormalities, also termed COVID-19-associated coagulopathy (CAC). Data concerning CAC in pregnancy are limited. Better understanding of physician experiences is essential to identify current practice patterns and knowledge gaps. OBJECTIVES: To determine physician experiences and practice patterns regarding CAC in pregnancy. METHODS: Self-administered survey using the RedCap online platform; supported by the ISTH Subcommittee on Women's Health Issues in Thrombosis and Hemostasis. RESULTS: Seventy-five respondents fully or partially completed the survey. Of 1546 reported cases, disease severity was specified in 1298. Sixty-four percent of COVID-19 infections were mild, whereas 4% were severe. Of all cases, 1% developed CAC, with 65% classified as severe. The most frequent abnormalities included thrombocytopenia, elevated C-reactive protein, D-dimer, and lymphopenia. Low molecular weight heparin was the anticoagulant of choice in CAC and was provided by 77% of respondents, with 60% using standard prophylactic dosing. Thrombosis occurred in seven anticoagulated patients who were receiving standard prophylactic (four) or weight-based (three) dosing. Disease severity and additional thrombosis risk factors dictated anticoagulation duration. CONCLUSION: In the select population reported by our survey, CAC appears to be uncommon in pregnancy. Anticoagulation practices vary and may not reflect current guidelines. Venous thromboembolism was observed in some CAC patients despite prophylactic anticoagulation (including standard and weight-adjusted dosing). Urgent research is required to determine appropriate anticoagulant dosing and duration in pregnant women with COVID-19 infection.

Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis.

BACKGROUND: As pregnancy is a physiological prothrombotic state, pregnant women may be at increased risk of developing coagulopathic and/or thromboembolic complications associated with COVID-19. METHODS: Two biomedical databases were searched between September 2019 and June 2020 for case reports and series of pregnant women with a diagnosis of COVID-19 based either on a positive swab or high clinical suspicion where no swab had been performed. Additional registry cases known to the authors were included. Steps were taken to minimise duplicate patients. Information on coagulopathy based on abnormal coagulation test results or clinical evidence of disseminated intravascular coagulation (DIC), and on arterial or venous thrombosis, were extracted using a standard form. If available, detailed laboratory results and information on maternal outcomes were analysed. RESULTS: One thousand sixty-three women met the inclusion criteria, of which three (0.28, 95% CI 0.0 to 0.6) had arterial and/or venous thrombosis, seven (0.66, 95% CI 0.17 to 1.1) had DIC, and a further three (0.28, 95% CI 0.0 to 0.6) had coagulopathy without meeting the definition of DIC. Five hundred and thirty-seven women (56%) had been reported as having given birth and 426 (40%) as having an ongoing pregnancy. There were 17 (1.6, 95% CI 0.85 to 2.3) maternal deaths in which DIC was reported as a factor in two. CONCLUSIONS: Our data suggests that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Detection of the former may be useful in the identification of women at risk of deterioration.

COVID-19 susceptibility in pregnancy: Immune/inflammatory considerations, the role of placental ACE-2 and research considerations.

SARS-CoV-2 is a new virus, to which herd immunity has not yet developed and both molecular and serological testing are not without flaws. The virus evokes a state of severe and widespread inflammation, and stimulates both innate and adaptive immune response. The angiotensin-converting enzyme 2 (ACE2), which acts as the SARS-CoV-2 receptor, is present in endothelial cells and has been noted within the human placenta. There are questions about whether pregnancy would increase the susceptibility of pregnant women to COVID-19 and disease severity within this population. In this report, we highlight physiological and immune/inflammatory considerations that may explain the susceptibility and disease pathology in response to SARS CoV-2 during pregnancy, explore testing considerations in asymptomatic individuals, discuss the potential role and of placental ACE2 receptor in the pathogenesis of COVID-19 in pregnancy and in pregnancy outcomes, and finally share our perspective with respect to an urgently needed change concerning involvement of pregnant women in research addressing COVID-19.

COVID-19 coagulopathy in pregnancy: Critical review, preliminary recommendations, and ISTH registry-Communication from the ISTH SSC for Women's Health.

BACKGROUND: Novel coronavirus (SARS-CoV-2), which causes COVID-19, has thus far affected more than 15 million individuals, resulting in more than 600 000 deaths worldwide, and the number continues to rise. In a large systematic review and meta-analysis of the literature including 2567 pregnant women, 7% required intensive care admission, with a maternal mortality ~1% and perinatal mortality below 1%. There has been a rapid increase in publications on COVID-19-associated coagulopathy, including disseminated intravascular coagulopathy and venous thromboembolism, in the non-pregnant population, but very few reports of COVID-19 coagulopathy during pregnancy; leaving us with no guidance for care of this specific population. METHODS: This is a collaborative effort conducted by a group of experts that was reviewed, critiqued, and approved by the International Society on Thrombosis and Haemostasis Subcommittee for Women's Health Issues in Thrombosis and Hemostasis. A structured literature search was conducted, and the quality of current and emerging evidence was evaluated. Based on the published studies in the non-pregnant and pregnant population with a moderate to high risk of bias as assessed by Newcastle-Ottawa scale and acknowledging the absence of data from randomized clinical trials for management of pregnant women infected with SARS-CoV-2, a consensus in support of a guidance document for COVID-19 coagulopathy in pregnancy was identified. RESULTS AND CONCLUSIONS: Specific hemostatic issues during pregnancy were highlighted, and preliminary recommendations to assist in the care of COVID-19-affected pregnant women with coagulopathy or thrombotic complications were developed. An international registry to gather data to support the management of COVID-19 and associated coagulopathy in pregnancy was established.

Hemostatic laboratory derangements in COVID-19 with a focus on platelet count.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease in 2019 (COVID-19) which rapidly evolved from an outbreak in Wuhan, China into a pandemic that has resulted in over millions of infections and over hundreds of thousands of mortalities worldwide. Various coagulopathies have been reported in association with COVID-19, including disseminated intravascular coagulation (DIC), sepsis-induced coagulopathy (SIC), local microthrombi, venous thromboembolism (VTE), arterial thrombotic complications, and thrombo-inflammation. There is a plethora of publications and conflicting data on hematological and hemostatic derangements in COVID-19 with some data suggesting the link to disease progress, severity and/or mortality. There is also growing evidence of potentially useful clinical biomarkers to predict COVID-19 progression and disease outcomes. Of those, a link between thrombocytopenia and COVID-19 severity or mortality was suggested. In this opinion report, we examine the published evidence of hematological and hemostatic laboratory derangements in COVID-19 and the interrelated SARS-CoV-2 induced inflammation, with a focussed discussion on platelet count alterations. We explore whether thrombocytopenia could be a potential disease biomarker and we provide recommendations for future studies in this regard.