Randomized trials of therapeutic heparin for COVID-19: A meta-analysis.

BACKGROUND: Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19. METHODS: We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs). RESULTS AND CONCLUSIONS: There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.

Anticoagulation practice patterns in COVID-19: A global survey.

Background: Best practice for prevention, diagnosis, and management of venous thromboembolism (VTE) in patients with coronavirus disease 2019 (COVID-19) is unknown due to limited published data in this population. Objectives: We aimed to assess current global practice and experience in management of COVID-19-associated coagulopathy to identify information to guide prospective and randomized studies. Methods: Physicians were queried about their current approach to prophylaxis, diagnosis, and treatment of VTE in patients with COVID-19 using an online survey tool distributed through multiple international organizations between April 10 and 14, 2020. Results: Five hundred fifteen physicians from 41 countries responded. The majority of respondents (78%) recommended prophylactic anticoagulation for all hospitalized patients with COVID-19, with most recommending use of low-molecular-weight heparin or unfractionated heparin. Significant practice variation was found regarding the need for dose escalation of anticoagulation outside the setting of confirmed or suspected VTE. Respondents reported the use of bedside testing when unable to perform standard diagnostic imaging for diagnosis of VTE. Two hundred ninety-one respondents reported observing thrombotic complications in their patients, with 64% noting that the complication was pulmonary embolism. Of the 44% of respondents who estimated incidence of thrombosis in patients with COVID-19 in their hospital, estimates ranged widely from 1% to 50%. One hundred seventy-four respondents noted bleeding complications (34% minor bleeding, 14% clinically relevant nonmajor bleeding, and 12% major bleeding). Conclusion: Well-designed epidemiologic studies are urgently needed to understand the incidence and risk factors of VTE and bleeding complications in patients with COVID-19. Randomized clinical trials addressing use of anticoagulation are also needed.

Case Report: Hypergranular Platelets in Vaccine-Induced Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination.

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) post SARS-CoV-2 vaccination is characterized by thrombocytopenia and severe thrombosis. Platelet function during patient recovery in the medium-/long-term has not been investigated fully. Here, we undertook a 3-month study, assessing the recovery of a VITT patient and assessing platelet morphology, granule content and dense-granule release at two distinct time points during recovery. CASE PRESENTATION: A 61 year-old female was admitted to hospital 15 days post ChAdOx1 nCov-19 vaccination. Hematological parameters and peripheral blood smears were monitored over 3 months. Platelet morphology and granule populations were assessed using transmission electron microscopy (TEM) at two distinct time points during recovery, as was agonist-induced platelet dense-granule release. Upon admission, the patient had reduced platelet counts, increased D-dimer and high anti-PF4 antibodies with multiple sites of cerebral venous sinus thrombosis (CVST). Peripheral blood smears revealed the presence of large, hypergranular platelets. Following treatment, hematological parameters returned to normal ranges over the study period. Anti-PF4 antibodies remained persistently high up to 90 days post-admission. Two days after admission, VITT platelets contained more granules per-platelet when compared to day 72 and healthy platelets. Additionally, maximal ATP release (marker of dense-granule release) was increased on day 2 compared to day 72 and healthy control platelets. CONCLUSION: This study highlights a previously unreported observation of platelet hypergranularity in VITT which may contribute to the thrombotic risk associated with VITT. Optimal approaches to monitoring recovery from VITT over time remains to be determined but our findings may help inform therapeutic decisions relating to anticoagulation treatment in this novel pathology.

Non-severe COVID-19 is associated with endothelial damage and hypercoagulability despite pharmacological thromboprophylaxis.

BACKGROUND: Hypercoagulability and endothelial dysfunction are hallmarks of coronavirus disease 2019 (COVID-19) and appear to predict disease severity. A high incidence of thrombosis despite thromboprophylaxis is reported in patients with moderate to severe COVID-19. Recent randomized clinical trials suggest that therapeutic-intensity heparin confers a survival benefit in moderate-severity COVID-19 compared to standard-intensity heparin, potentially by harnessing heparin-mediated endothelial-stabilizing and anti-inflammatory effects. OBJECTIVE: We hypothesized that patients with moderate-severity COVID-19 exhibit enhanced hypercoagulability despite standard-intensity thromboprophylaxis with low molecular weight heparin (LMWH) compared to non-COVID-19 hospitalized patients. METHODS: Patients with moderate COVID-19 and a control group (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]-negative hospitalized patients) receiving LMWH thromboprophylaxis were recruited. Markers of endothelial damage and plasma thrombin generation parameters were assessed. RESULTS: Tissue plasminogen activator levels were significantly increased in the COVID-19 group (8.3 ± 4.4 vs. 4.9 ± 2.4 ng/ml; P = .02) compared to non-COVID-19-hospitalized patients. Despite thromboprophylaxis, mean endogenous thrombin potential was significantly increased among COVID-19 patients (1929 ± 448 vs. 1528 ± 460.8 nM*min; P = .04) but lag time to thrombin generation was significantly prolonged (8.1 ± 1.8 vs. 6.2 ± 1.8 mins; P = .02). While tissue factor pathway inhibitor (TFPI) levels were similar in both groups, in the presence of an inhibitory anti-TFPI antibody, the difference in lag time between the groups was abrogated. CONCLUSIONS: Collectively, these data demonstrate that COVID-19 of moderate severity is associated with increased plasma thrombin generation and endothelial damage, and that hypercoagulability persists despite standard LMWH thromboprophylaxis. These findings may be of clinical interest given recent clinical trial data which suggest escalated heparin dosing in non-severe COVID-19 may be associated with improved clinical outcomes.

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.

Global reporting of pulmonary embolism-related deaths in the World Health Organization mortality database: Vital registration data from 123 countries.

INTRODUCTION: Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause-specific mortality in global reports. METHODS: We analyzed global PE-related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age-sex-specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE-related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization. RESULTS: We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper-middle income, 14 (12.1%) lower-middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE-related mortality rate increased with age in most countries. The reporting of PE-related deaths was heterogeneous, with an age-standardized mortality rate ranging from 0 to 24 deaths per 100 000 population-years. Income status only partially explained this heterogeneity. CONCLUSIONS: Reporting of PE-related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE-related mortality and provides a case for full recognition of PE and VTE as a primary cause of death.

Routine Hematological Parameters May Be Predictors of COVID-19 Severity.

To date, coronavirus disease 2019 (COVID-19) has affected over 100 million people globally. COVID-19 can present with a variety of different symptoms leading to manifestation of disease ranging from mild cases to a life-threatening condition requiring critical care-level support. At present, a rapid prediction of disease severity and critical care requirement in COVID-19 patients, in early stages of disease, remains an unmet challenge. Therefore, we assessed whether parameters from a routine clinical hematology workup, at the time of hospital admission, can be valuable predictors of COVID-19 severity and the requirement for critical care. Hematological data from the day of hospital admission (day of positive COVID-19 test) for patients with severe COVID-19 disease (requiring critical care during illness) and patients with non-severe disease (not requiring critical care) were acquired. The data were amalgamated and cleaned and modeling was performed. Using a decision tree model, we demonstrated that routine clinical hematology parameters are important predictors of COVID-19 severity. This proof-of-concept study shows that a combination of activated partial thromboplastin time, white cell count-to-neutrophil ratio, and platelet count can predict subsequent severity of COVID-19 with high sensitivity and specificity (area under ROC 0.9956) at the time of the patient's hospital admission. These data, pending further validation, indicate that a decision tree model with hematological parameters could potentially form the basis for a rapid risk stratification tool that predicts COVID-19 severity in hospitalized patients.

Platelets, extracellular vesicles and coagulation in pulmonary arterial hypertension.

Pulmonary arterial hypertension is a rare disease of the pulmonary vasculature, characterised pathologically by proliferation, remodelling and thrombosis in situ. Unfortunately, existing therapeutic interventions do not reverse these findings and the disease continues to result in significant morbidity and premature mortality. A number of haematological derangements have been described in pulmonary arterial hypertension which may provide insights into the pathobiology of the disease and opportunities to explore new therapeutic pathways. These include quantitative and qualitative platelet abnormalities, such as thrombocytopaenia, increased mean platelet volume and altered platelet bioenergetics. Furthermore, a hypercoagulable state and aberrant negative regulatory pathways can be observed, which could contribute to thrombosis in situ in distal pulmonary arteries and arterioles. Finally, there is increasing interest in the role of extracellular vesicle autocrine and paracrine signalling in pulmonary arterial hypertension, and their potential utility as biomarkers and novel therapeutic targets. This review focuses on the potential role of platelets, extracellular vesicles and coagulation pathways in the pathobiology of pulmonary arterial hypertension. We highlight important unanswered clinical questions and the implications of these observations for future research and pulmonary arterial hypertension-directed therapies.

COVID-19 induces a hyperactive phenotype in circulating platelets.

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.