VTE risk assessment, prevention and diagnosis in pregnancy.

Venous thromboembolism (VTE) is still reported as the leading cause of direct maternal death in pregnancy in serial international reports in developed countries. VTE risk is higher during pregnancy but is further increased by additional well-characterized risk factors. International guidelines recommend that formal VTE risk assessment should be conducted at least in early pregnancy, at delivery and when risk factors change. High quality data supporting optimal VTE prevention strategies are lacking, outside the setting of prevention of VTE recurrence. Moreover, recent high-quality studies have provided much-needed data on diagnostic strategies for pulmonary embolism (PE) in pregnancy. In this review, we summarize knowledge gaps and recently published data in the prevention and diagnosis of VTE in pregnancy. Moreover, we describe ongoing high-quality randomised trials and prospective clinical management studies in this area. High quality clinical studies and trials in pregnancy can be done and must be prioritised, through international network efforts and national funding advocacy. Ultimately, translation of study results to impact upon guidelines and policy will deliver better care to and will protect the lives and health of pregnant people and those contemplating pregnancy throughout the world.

The effect of UVA light/8-methoxypsoralen exposure used in Extracorporeal Photopheresis treatment on platelets and extracellular vesicles.

Extracorporeal Photopheresis (ECP) is a leukapheresis based treatment for Cutaneous T-Cell Lymphoma, which takes advantage of the cellular lethal effects of UVA light in combination with a photoactivated drug, 8-methoxypsoralen. 25% of patients treated with ECP do not respond to treatment, however the underlying mechanisms for this lack of response remain unknown. Platelets, a rich source of extracellular vesicles (EVs) and key mediators in thromboinflammatory oncological progression, as well as leukocytes, are both processed through ECP and are subsequently transfused back into the patient, delivering potent immunomodulation. The effect of exposing platelets and their EVs directly to Ultra Violet A light (UVA)/8-methoxypsoralen is currently unknown. Platelet-rich plasma (PRP) was isolated from healthy donors and exposed to UVA light and/or 8-methoxysporalen in vitro and platelet activation and aggregation was assessed. EV size and concentration were also characterised by Nanoparticle Tracking Analysis and Flow Cytometry. We found that UVA light and 8-methoxypsoralen treatment in vitro does not induce platelet aggregation or significantly alter levels of the platelet activation markers, soluble P-selectin or platelet factor 4, with circulating levels of small and large EV size and concentration remaining constant. Therefore, utilising the combination of UVA light and 8-methoxypsoralen used in ECP in vitro does not activate platelets or alter important circulating EVs. Further studies will be needed to validate if our observations are consistent in vivo.

Retrospective cross-sectional analysis of concurrent VTE diagnosis in hospitalised socially excluded individuals in Ireland.

OBJECTIVE: Social exclusion (such as that experienced by people who are homeless, incarcerated or use drugs) increases morbidity across a range of diseases but is poorly captured in routine data sets. The aim of this study was to use a novel composite variable in a national-level hospital usage dataset to identify social exclusion and to determine whether social exclusion is associated with concurrent venous thromboembolism (VTE) in hospitalised patients in Ireland. Identifying and characterising this association in people who are socially excluded will inform VTE prevention and treatment strategies. DESIGN: Retrospective cross-sectional study. SETTING: Irish Hospital Inpatient Enquiry (HIPE) system, which collects diagnostic information by International Classification of Diseases Tenth Revision code on all hospital admission episodes in the Ireland. PARTICIPANTS: All hospital admission episodes involving a VTE diagnosis (in a primary 'Dx 1' or secondary 'Dx 2-30' coding position) during a 12-month period in the Ireland were identified from consolidated, national-level datasets derived from the Irish HIPE system. Social exclusion was defined as the presence of one or more indicators of homelessness, drug use, incarceration, health hazards due to socioeconomic status or episodes of healthcare terminated prematurely. RESULTS: Of 5701 admission episodes involving a VTE diagnosis (in a primary or secondary position) during the study period, 271 (4.8%) related to an individual affected by social exclusion. Among hospitalised individuals identified as being socially excluded based on the novel composite variable, the likelihood of having a concurrent VTE diagnosis was over twofold greater than that observed in the general population (OR 2.14, 95% CI 1.79 to 2.26; p<0.001). CONCLUSION: These data suggest that VTE (primary and secondary) is over-represented in hospitalised socially excluded persons in Ireland and that the development of strategies to address this potentially life-threatening accompanying condition in this vulnerable patient group must be prioritised.

Proteomic analysis of extracellular vesicle cargoes mirror the cardioprotective effects of rivaroxaban in patients with venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality worldwide. Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties; yet, these remain poorly characterized. Extracellular vesicles (EVs) are considered proinflammatory messengers regulating a myriad of (patho)physiological processes and may be highly relevant to the pathophysiology of VTE. The effects of Rivaroxaban on circulating EVs in VTE patients remain unknown. We have established that differential EV biosignatures are found in patients with non-valvular atrial fibrillation anticoagulated with Rivaroxaban versus warfarin. Here, we investigated whether differential proteomic profiles of circulating EVs could also be found in patients with VTE. METHODS AND RESULTS: We performed comparative label-free quantitative proteomic profiling of enriched plasma EVs from VTE patients anticoagulated with either Rivaroxaban or warfarin using a tandem mass spectrometry approach. Of the 182 quantified proteins, six were found to be either exclusive to, or enriched in, Rivaroxaban-treated patients. Intriguingly, these proteins are involved in negative feedback regulation of inflammatory and coagulation pathways, suggesting that EV proteomic signatures may reflect both Rivaroxaban's anti-coagulatory and anti-inflammatory potential. CONCLUSIONS: These differences suggest Rivaroxaban may have pleiotropic effects, supporting the reports of its emerging anti-inflammatory and cardiovascular-protective characteristics relative to warfarin.

Prevention, diagnosis, and management of PE and DVT in pregnant women.

Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality worldwide. Despite the impact of VTE on pregnant and postpartum people and on society, guidelines addressing prevention, diagnosis, and management of VTE in pregnant and postpartum people frequently are based on recommendations from expert opinion and are extrapolated from data in nonpregnant populations. Pregnant individuals are frequently excluded from clinical trials, which is a barrier to providing safe, effective care. Anchoring to a case discussion, this review provides an update on recently published and ongoing randomized clinical trials (RCTs), prospective clinical management studies, and other research in this area. It highlights, in particular, the results of the Highlow RCT, which addresses optimal prevention of recurrence during pregnancy in people with prior VTE. Finally, we raise awareness of the impact of national and international clinical trial networks on the conduct of RCTs in pregnancy. We conclude, based on these data, that academic VTE clinical trials in pregnant women can and must be done.

Platelet proteo-transcriptomic profiling validates mediators of thrombosis and proteostasis in patients with myeloproliferative neoplasms.

Patients with chronic Myeloproliferative Neoplasms (MPN) including polycythemia vera (PV) and essential thrombocythemia (ET) exhibit unique clinical features, such as a tendency toward thrombosis and hemorrhage, and risk of disease progression to secondary bone marrow fibrosis and/or acute leukemia. Although an increase in blood cell lineage counts (quantitative features) contribute to these morbid sequelae, the significant qualitative abnormalities of myeloid cells that contribute to vascular risk are not well understood. Here, we address this critical knowledge gap via a comprehensive and untargeted profiling of the platelet proteome in a large (n= 140) cohort of patients (from two independent sites) with an established diagnosis of PV and ET (and complement prior work on the MPN platelet transcriptome from a third site). We discover distinct MPN platelet protein expression and confirm key molecular impairments associated with proteostasis and thrombosis mechanisms of potential relevance to MPN pathology. Specifically, we validate expression of high-priority candidate markers from the platelet transcriptome at the platelet proteome (e.g., calreticulin (CALR), Fc gamma receptor (FcγRIIA) and galectin-1 (LGALS1) pointing to their likely significance in the proinflammatory, prothrombotic and profibrotic phenotypes in patients with MPN. Together, our proteo-transcriptomic study identifies the peripherally-derived platelet molecular profile as a potential window into MPN pathophysiology and demonstrates the value of integrative multi-omic approaches in gaining a better understanding of the complex molecular dynamics of disease.

An optimized protocol to isolate quiescent washed platelets from human whole blood and generate platelet releasate under clinical conditions.

The contents of the platelet releasate (PR) play significant roles in hemostasis, inflammation, and pathologic sequelae. Careful platelet isolation to ensure quiescence and subsequent activation is key to the successful generation of PR. Here, we describe steps to isolate and aggregate quiescent washed platelets from whole blood of a clinical patient cohort. We then detail the generation of PR from isolated human washed platelets under clinical conditions. This protocol allows the investigation of platelet cargoes released through various activation pathways.

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.

The role of the calibrated automated thrombogram in neonates: describing mechanisms of neonatal haemostasis and evaluating haemostatic drugs.

Premature infants are at high risk of haemorrhage and thrombosis. Our understanding of the differences between the neonatal and adult haemostatic system is evolving. There are several limitations to the standard coagulation tests used in clinical practice, and there is currently a lack of evidence to support many of the transfusion practices in neonatal medicine. The evaluation of haemostasis is particularly challenging in neonates due to their limited blood volume. The calibrated automated thrombogram (CAT) is a global coagulation assay, first described in 2002, which evaluates both pro- and anti-coagulant pathways in platelet-rich or platelet-poor plasma. In this review, the current applications and limitations of CAT in the neonatal population are discussed.Conclusion: CAT has successfully elucidated several differences between haemostatic mechanisms in premature and term neonates compared with adults. Moreover, it has been used to evaluate the effect of a number of haemostatic drugs in a pre-clinical model. However, the lack of evidence of CAT as an accurate predictor of neonatal bleeding, blood volume required and the absence of an evidence-based treatment algorithm for abnormal CAT results limit its current application as a bedside clinical tool for the evaluation of sick neonates. What is Known: • The Calibrated automated thrombogram (CAT) is a global coagulation assay which evaluates pro- and anti-coagulant pathways. • CAT provides greater information than standard clotting tests and has been used in adults to evaluate bleeding risk. What is New: • This review summarises the physiological differences in haemostasis between neonates and adults described using CAT. • The haemostatic effect of several drugs has been evaluated in neonatal plasma using CAT.

Characteristics of chronic thromboembolic pulmonary hypertension in Ireland.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and under-recognised complication of acute pulmonary embolism. Information regarding the characteristics of CTEPH in Ireland is limited, and the aim of this retrospective cohort study was to address this knowledge gap. Seventy-two cases of CTEPH were diagnosed in the National Pulmonary Hypertension Unit (NPHU) in Ireland between 2010 and 2020. This accounted for 6% of all referrals to the unit and translates to an estimated annual incidence of 1.39 per million population (95% confidence interval, 0.33-2.46). The prevalence of diagnosed CTEPH in Ireland in 2020 was estimated at 12.05 per million population (95% CI 9.00-15.10). The average duration of symptoms prior to CTEPH diagnosis was 23 (±22) months. Patients with CTEPH were more likely to be male (n = 40, 56%), older (60 ± 17 years) and have identifiable risk factors for CTEPH (n = 61, 85%) at diagnosis. Regarding treatment, pulmonary hypertension (PH) vasodilator therapy was prescribed in 75% (n = 54) within 12 months of diagnosis, inferior vena cava filters were placed in 24% (n = 17) and 97% (n = 70) of cases were anticoagulated. Pulmonary endarterectomy was performed in 35% (n = 25), balloon pulmonary angioplasty in 6% (n = 4). One-, three- and five-year survival was 93%, 80% and 65% from the time of diagnosis, and this was significantly better in patients who underwent pulmonary endarterectomy (p = 0.01). This is the first study describing the characteristics of CTEPH in Ireland and highlights suboptimal disease recognition and referral for the assessment for pulmonary endarterectomy.

Haematological parameters and coagulation in umbilical cord blood following COVID-19 infection in pregnancy.

OBJECTIVE: The aim of this study was to evaluate infants, born to women with SARS-CoV-2 detected during pregnancy, for evidence of haematological abnormalities or hypercoagulability in umbilical cord blood. STUDY DESIGN: This was a prospective observational case-control study of infants born to women who had SARS-CoV-2 RNA detected by PCR at any time during their pregnancy (n = 15). The study was carried out in a Tertiary University Maternity Hospital (8,500 deliveries/year) in Ireland. This study was approved by the Hospital Research Ethics Committee and written consent was obtained. Umbilical cord blood samples were collected at delivery, full blood count and Calibrated Automated Thrombography were performed. Demographics and clinical outcomes were recorded. Healthy term infants, previously recruited as controls to a larger study prior to the outbreak of COVID-19, were the historical control population (n = 10). RESULTS: Infants born to women with SARS-CoV-2 had similar growth parameters (birth weight 3600 g v 3680 g, p = 0.83) and clinical outcomes to healthy controls, such as need for resuscitation at birth (2 (13.3%) v 1 (10%), p = 1.0) and NICU admission (1 (6.7%) v 2 (20%), p = 0.54). Haematological parameters (Haemoglobin, platelet, white cell and lymphocyte counts) in the COVID-19 group were all within normal neonatal reference ranges. Calibrated Automated Thrombography revealed no differences in any thrombin generation parameters (lag time (p = 0.92), endogenous thrombin potential (p = 0.24), peak thrombin (p = 0.44), time to peak thrombin (p = 0.94)) between the two groups. CONCLUSION: In this prospective study including eligible cases in a very large population of approximately 1500 women, there was no evidence of derangement of the haematological parameters or hypercoagulability in umbilical cord blood due to COVID-19. Further research is required to investigate the pathological placental changes, particularly COVID-19 placentitis and the impact of different strains of SARS-CoV-2 (particularly the B.1.1.7 and the emerging Delta variant) and the severity and timing of infection on the developing fetus.

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.

Nonvalvular atrial fibrillation patients anticoagulated with rivaroxaban compared with warfarin exhibit reduced circulating extracellular vesicles with attenuated pro-inflammatory protein signatures.

BACKGROUND: Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties; however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of atrial fibrillation as they reflect alterations in platelet and endothelial biology. However, the effects of rivaroxaban on circulating pro-inflammatory EVs remain unknown. OBJECTIVES: We hypothesized that rivaroxaban's anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs. METHODS: Differences in circulating EV profiles were assessed using a combination of single vesicle analysis by Nanoparticle Tracking Analysis and flow cytometry, and proteomics. RESULTS: We demonstrate, for the first time, that rivaroxaban-treated non-valvular atrial fibrillation (NVAF) patients (n=8) exhibit attenuated inflammation compared with matched warfarin controls (n=15). Circulating EV profiles were fundamentally altered. Moreover, quantitative proteomic analysis of enriched plasma EVs from six pooled biological donors per treatment group revealed a profound decrease in highly pro-inflammatory protein expression and complement factors, together with increased expression of negative regulators of inflammatory pathways. Crucially, a reduction in circulating levels of soluble P-selectin was observed in rivaroxaban-treated patients (compared with warfarin controls), which negatively correlated with the patient's time on treatment. CONCLUSION: Collectively, these data demonstrate that NVAF patients anticoagulated with rivaroxaban (compared with warfarin) exhibit both a reduced pro-inflammatory state and evidence of reduced endothelial activation. These findings are of translational relevance toward characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with rivaroxaban therapy.

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.

Which patients are at high risk of recurrent venous thromboembolism (deep vein thrombosis and pulmonary embolism)?

Recurrent venous thromboembolism (VTE, or deep vein thrombosis and pulmonary embolism) is associated with mortality and long-term morbidity. The circumstances in which an index VTE event occurred are crucial when personalized VTE recurrence risk is assessed. Patients who experience a VTE event in the setting of a transient major risk factor (such as surgery associated with general anesthesia for >30 minutes) are predicted to have a low VTE recurrence risk following discontinuation of anticoagulation, and limited-duration anticoagulation is generally recommended. In contrast, those patients whose VTE event occurred in the absence of risk factors or who have persistent risk factors have a higher VTE recurrence risk. Here, we review the literature surrounding VTE recurrence risk in a range of clinical conditions. We describe gender-specific risks, including VTE recurrence risk following hormone- and pregnancy-associated VTE events. Finally, we discuss how the competing impacts of VTE recurrence and bleeding have shaped international guideline recommendations.

Which patients are at high risk of recurrent venous thromboembolism (deep vein thrombosis and pulmonary embolism)?

Recurrent venous thromboembolism (VTE, or deep vein thrombosis and pulmonary embolism) is associated with mortality and long-term morbidity. The circumstances in which an index VTE event occurred are crucial when personalized VTE recurrence risk is assessed. Patients who experience a VTE event in the setting of a transient major risk factor (such as surgery associated with general anesthesia for >30 minutes) are predicted to have a low VTE recurrence risk following discontinuation of anticoagulation, and limited-duration anticoagulation is generally recommended. In contrast, those patients whose VTE event occurred in the absence of risk factors or who have persistent risk factors have a higher VTE recurrence risk. Here, we review the literature surrounding VTE recurrence risk in a range of clinical conditions. We describe gender-specific risks, including VTE recurrence risk following hormone- and pregnancy-associated VTE events. Finally, we discuss how the competing impacts of VTE recurrence and bleeding have shaped international guideline recommendations.

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.

Pathophysiology of the Venous Thromboembolism Risk in Preeclampsia.

Preeclampsia complicates up to 8% of pregnancies and is a leading cause of fetomaternal morbidity andmortality. Treatment options are limited, with supportive care and delivery of the placenta representing the cornerstone of current management strategies. Derangements in blood coagulation are wellrecognised in this disorder and appear to favour an increased risk of venous thromboembolism among affected women. This risk appears to be most significant in the postpartum period. The mechanisms underlying this increased thrombosis risk remain to be fully elucidated although increased expression of procoagulant factors, endothelial dysfunction, attenuation of endogenous anticoagulant activity and increased platelet activity have been implicated in the prothrombotic tendency. Preeclampsia is also occasionally complicated by life-threatening haemorrhagic events and current evidence suggests that in some severe manifestations of this disease a coagulopathy with a clinical bleeding tendency may be the predominant haemostatic abnormality. Identifying affected women at significant risk of thrombosis and managing the competing thrombotic and haemorrhagic risks continue to be a significant clinical challenge. Derangements in blood coagulation are also implicated in the pathogenesis of preeclampsia; however, the role of antiplatelet or anticoagulant drugs in the prevention and treatment of this disorder remains a source of considerable debate. In addition, the potential role of specific haemostatic markers as diagnostic or screening tools for preeclampsia has also yet to be determined. Further characterisation of the underlying molecular mechanisms would likely be of major translational relevance and could provide insights into the pathogenesis of this disease as well as the associated haemostatic dysfunction.