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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.

Platelet cytoskeletal reorganisation is a critical component of platelet activation and thrombus formation in haemostasis. The Rho GTPases RhoA, Rac1 and Cdc42 are the primary drivers in the dynamic reorganisation process, leading to the development of filopodia and lamellipodia which dramatically increase platelet surface area upon activation. Rho GTPases cycle between their active (GTP-bound) and inactive (GDP-bound) states through tightly regulated processes, central to which are the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs catalyse the dissociation of GDP by inducing changes in the nucleotide binding site, facilitating GTP binding and activating Rho GTPases. By contrast, while all GTPases possess intrinsic hydrolysing activity, this reaction is extremely slow. Therefore, GAPs catalyse the hydrolysis of GTP to GDP, reverting Rho GTPases to their inactive state. Our current knowledge of these proteins is constantly being updated but there is considerably less known about the functionality of Rho GTPase specific GAPs and GEFs in platelets. In the present review, we discuss GAP and GEF proteins for Rho GTPases identified in platelets, their regulation, biological function and present a case for their further study in platelets.

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.

Upon activation, platelets release a host of soluble and vesicular signals, collectively termed the “platelet releasate” (PR). The contents of this PR play a significant role in haemostasis, inflammation, and pathologic sequelae . Despite this, proteomic studies investigating the PR in coronary artery disease have not been performed. Here, we undertook a comparative label-free quantitative (LFQ) proteomic profiling of the 1 U/ml thrombin-induced PR from 13 acute coronary syndrome vs. 14 stable angina pectoris patients using a tandem mass spectrometry approach. Data are available via ProteomeXchange with identifier PXD009356. 318 PR proteins were identified across both cohorts with 9 proteins found to be differentially released, including tetranectin (CLEC3B), protein disulfide-isomerase-A3 (PDIA3), coagulation factor V (F5), and fibronectin (FN1). Strikingly, these 9 differential proteins were all associated with the gene ontology cellular component term “extracellular vesicle” and reduced levels of EVs were detected in the corresponding plasma of ST-segment elevation myocardial infarction (STEMI) patients. Network analysis revealed 3 proteins either reduced (F5; FN1) or absent (CLEC3B) in the PR of STEMI patients that are strongly connected to both the clotting cascade and major druggable targets on platelets. This moderated proteomic signature may prove useful for non-invasive risk assessment of the progression of coronary artery disease. These data further contribute to the growing evidence-base of using the platelet releasate as a predictor of pathological state and disease 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.

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. 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. 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.

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.

Filoviruses (Family Filoviridae genera Ebolavirus and Marburgvirus ) are negative-stranded RNA viruses that cause severe health effects in humans and non-human primates, including death. Except in outbreak settings, vaccines and other medical countermeasures against Ebola virus (EBOV) will require testing under the FDA Animal Rule. Multiple vaccine candidates have been evaluated using cynomolgus monkeys (CM) exposed to EBOV Kikwit strain. To the best of our knowledge, however, animal model development data supporting the use of CM in vaccine research have not been submitted to the FDA. This study describes a large CM database (122 CM, 62 female and 60 male, age 2 to 9 years) and demonstrates the consistency of the CM model through time to death models and descriptive statistics. CMs were exposed to EBOV doses of 0.1 to 100,000 PFU in 33 studies conducted at three Animal Biosafety Level 4 facilities, by three exposure routes. Time to death was modeled using Cox proportional hazards models with a frailty term that incorporated study-to-study variability. Despite significant differences attributed to exposure variables, all CMs exposed to the 100 to 1,000 pfu doses commonly used in vaccine studies died or met euthanasia criteria within 21 days of exposure, median 7 days, 93% between 5 and 12 days of exposure. Moderate clinical signs were observed 4 to 5 days after exposure and preceded death or euthanasia by approximately one day. Viremia was detected within a few days of infection. Hematology indices were indicative of viremia and the propensity for hemorrhage with progression of Ebola viremia. Changes associated with coagulation parameters and platelets were consistent with coagulation disruption. Changes in leukocyte profiles were indicative of an acute inflammatory response. Increased liver enzymes were observed shortly after exposure. Taken together, these factors suggest that the cynomolgus monkey is a reliable animal model for human disease.

The Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, recognizes that the evaluation of medical countermeasures under the Animal Rule requires well-characterized and reproducible animal models that are likely to be predictive of clinical benefit. Marburg virus (MARV), one of two members of the genus Marburgvirus, is characterized by a hemorrhagic fever and a high case fatality rate for which there are no licensed vaccines or therapeutics available. This natural history study consisted of twelve cynomolgus macaques challenged with 1000 PFU of MARV Angola and observed for body weight, temperature, viremia, hematology, clinical chemistry, and coagulation at multiple time points. All animals succumbed to disease within 8 days and exhibited signs consistent with those observed in human cases, including viremia, fever, systemic inflammation, coagulopathy, and lymphocytolysis, among others. Additionally, this study determined the time from exposure to onset of disease manifestations and the time course, frequency, and magnitude of the manifestations. This study will be instrumental in the design and development of medical countermeasures to Marburg virus disease.