Markers Of Hypercoagulability Research Articles

Plasma tissue factor pathway inhibitor levels in coronavirus disease 2019 patients: a systematic review and meta-analysis.

PROSPERO CRD42023437353.

Assessing hypercoagulability and VTE risk using thromboelastography and Khorana score in women with cancers receiving chemotherapy.

Venous thromboembolism (VTE) is a common occurrence in cancer and chemotherapy increases thrombosis risk. Current risk assessment models such as the Khorana score (KS) and its modifications have limitations in female cancers. We assessed the coagulation profile of a group of women cancer patients under chemotherapy using thromboelastography (TEG) to determine if this can inform VTE risk assessment. Cancer patients who planned to receive chemotherapy were recruited. Baseline demographics, cancer data, BMI, Khorana Score (KS), and VTE risk factors were recorded and patients were followed for 6 months, for any thrombotic events. A total of 36 patients aged 35-85 (18 breast, 11 endometrial, 7 ovarian cancer) were evaluated. Hypercoagulability was detected in 63% of patients post-chemo cycle 1 and 75% post-cycle 2, with a significant increase in MA (maximum amplitude) and CI (clotting index), reduction in R (reaction time), K (clot kinetics), and LY30 (lysis time after 30 min of MA). KS showed only 7% of patients were high risk, 23% were low, and 70% were intermediate risk. MA and CI significantly increased in patients with intermediate and high-risk KS when compared with the low-risk patients and MA was positively correlated with KS. Five patients developed actual VTE; 100% of the tested ones were hypercoagulable either post-cycle 1 or 2 and 80% were KS intermediate risk. TEG is a hypercoagulability marker and TEG-MA and CI can potentially assess VTE risk. Larger studies are needed to assess the utility of TEG as an adjuvant to KS to better predict VTE in specific female cancers.

ISCHEMIC STROKE AND HEMOSTASIS DISORDERS IN ONCOLOGICAL PROCESS: A LITERATURE REVIEW

Malignant neoplasms are associated with an increased risk of developing acute cerebrovascular accidents. This article provides a review of the literature on hemostatic disorders during oncological processes in patients with ischemic stroke. Cancer-associated stroke can develop for several reasons, including direct effects of the tumor, as well as indirectly through the development of blood coagulation disorders, concomitant infectious diseases, or complications of antitumor therapy. One of the most common pathogenetic mechanisms is cancer-associated coagulopathy. Trousseau syndrome is a variant of paraneoplastic syndrome, characterized by a state of hypercoagulability with the development of thrombosis that precedes the diagnosis of a malignant neoplasm or develops simultaneously with it. Cerebral ischemia in Trousseau’s syndrome is characterized by a multifocal pattern of lesions according to neuroimaging data. To date, there are no clear diagnostic criteria for cancer-associated stroke, which is often one of the first clinical manifestations of the oncological process. According to various studies, laboratory markers of hypercoagulability can serve as predictors of previously undiagnosed malignancy in patients with cryptogenic ischemic stroke. Currently, more and more attempts are being made to develop diagnostic scales based on clinical and neuroimaging characteristics of stroke to identify hidden oncological processes. Another important aspect of the issue remains the lack of evidence-based recommendations for the treatment of ischemic stroke associated with cancer. Given the prevalence of stroke in cancer patients, potentially poor functional prognosss, higher rates of post-stroke mortality and high relapse rates, further research into this issue is required.

A Retrospective Analysis of COVID-19 Coagulopathy in Hospitalized and Intensive Care Patients with Sickle Cell Disease

Purpose/Objective: The implications of COVID-19 induced hypercoagulability in patients with sickle cell disease (SCD) remain largely unknown. Both COVID-19 and SCD have independent pathophysiological mechanisms which impact each aspect of Virchow's triad to induce a hypercoagulable state (Saxena and Muthu., 2023), however the joint impact of COVID-19-SCD on venous thromboembolism (VTE) remains understudied. As such, our primary objective involved investigating the incidence of VTE events in SCD patients with COVID-19. Our secondary objective involved assessing parameters of COVID-19 infection severity in SCD patients. Methods: We conducted a retrospective cross-sectional study at New York City Health and Hospitals, Kings County involving SCD, sickle cell trait (SCT) and the general population of COVID-19 patients (non-sickle). Data was collected from the onset of the pandemic on March 1, 2020 to December 31, 2021 for hospitalized and intensive care patients. We collected information on incidence of VTE, type of VTE (deep vein thrombosis or pulmonary embolism), age, sex, comorbidities, VTE prophylaxis, D-dimer, ferritin, LDH, BMI, sickle cell phenotype, transfusion requirements, COVID-19 management, SCD management, and outcomes. Data was analyzed on GraphPad PRISM, using one-way ANOVA and odds ratios. A p-value of <0.05 was considered statistically significant. Results: The study included three patient cohorts, consisting of 24 SCT, 26 SCD and 675 non-sickle patients (non-SS) to study incidence of VTE. Additional information regarding infection parameters was obtained on 146 non-sickle patients, and all SCT and SCD patients. We found that there was no significant difference between VTE risk in the SCD and non-sickle patients (OR=0.3736, 95% CI 0.0223 to 6.2675) or SCT and SCD patients (OR=0.2956, 95% CI 0.0115 to 7.6121). There was no significant difference in mortality (OR=0.4909, 95% CI 0.0606 to 3.9736) or intensive care requirements (OR=0.4137, 95% CI 0.1171 to 1.4608) between SCD and non-SS patients (Table 1). We also investigated markers of infection and hypercoagulability and found that there was no significant difference between D-dimer or LDH levels between the three cohorts, however ferritin was significantly increased in the SCD group compared to the non-sickle cohort (Figure 1, p=0.0123). Conclusions/Implications: Current ASH guidelines recommend use of prophylactic dose anticoagulation for critically ill COVID-19 patients and therapeutic dose anticoagulation for acute, but not critically ill patients (Cuker et. al., 2022). There are currently no formal recommendations regarding VTE prevention for hospitalized SCD patients with COVID-19. Our data supports prior reports on VTE in SCD (Singh et. al., 2022) which note that SCD patients with COVID-19 do not have an increased risk of VTE compared with uninfected SCD patients. Similarly, our data suggests that there is no statistical difference in VTE incidence in SCD-COVID-19 patients compared to the general population affected by COVID-19. Given no differences in VTE incidence, we recommend that anticoagulation parameters for the general population of hospitalized and intensive care patients be applied to SCD patients.

PB0717 Urological Cancer Patients Display an Increase in Markers of Hypercoagulability and Inflammation

PB0717 Urological Cancer Patients Display an Increase in Markers of Hypercoagulability and Inflammation

PB0062 Extracellular Vesicles as Markers of Inflammation and Hypercoagulability during the First Month of Sars-COV-2 Infection in Outpatients and Hospitalized Patients

PB0062 Extracellular Vesicles as Markers of Inflammation and Hypercoagulability during the First Month of Sars-COV-2 Infection in Outpatients and Hospitalized Patients

Association between gut-derived endotoxins and porto-sinusoidal vascular disorder with portal hypertension.

Porto-sinusoidal vascular disorder (PSVD) is characterised by lesions involving portal veins and sinusoids in absence of cirrhosis with an unclear pathophysiology. However, its association with immunodeficiency, bowel disorders and abdominal bacterial infections supports the role of altered intestinal permeability and gut-derived endotoxins. The study aimed at assessing the association between serological markers of increased intestinal permeability, pro-aggregating/procoagulant state and liver injury in PSVD and portal hypertension. Thirty-three patients with biopsy-proven PSVD and portal hypertension and 33 healthy subjects were submitted to a venous blood sampling for the measurement of zonulin and lipopolysaccharides (LPS) as markers of intestinal permeability, of s-Glycoprotein VI, sP-selectin, ADAMTS13 and von Willebrand factor (vWF), as markers of platelet aggregation and microvascular inflammation, factor VIII and F1 + 2 as markers of hypercoagulability. In 17 PSVD patients, histomorphological and immunohistochemical study on liver biopsies was performed. Compared with controls, PSVD patients had higher levels of LPS, zonulin, vWF, factor VIII and sP-selectin, F1 + 2. ADAMTS13 was reduced. Serum LPS correlated with zonulin, sP-selectin, FVIII and vWF. At histological analysis, PSVD specimens had increased LPS localisation, toll-like receptor-4(TLR4)-positive macrophages and platelet number compared with samples from healthy liver donors. TLR4+ macrophage number correlated with portal inflammation and fibrosis. Sinusoid dilation and capillarisation were observed. PSVD biopsies showed signs of biliary damage and reduced ductular reaction without alteration in Sox9+ cell population. PSVD patients display an altered intestinal permeability and endotoxemia correlated to a pro-aggregating/procoagulant state; histologically, PSVD was associated with increased TLR4+ cell involvement and platelet clumps within sinusoids. Our study suggests that LPS-TLR4 pathway could contribute to the pathophysiological basis of PSVD with portal hypertension.

Association between the platelet/high-density lipoprotein cholesterol ratio and nonalcoholic fatty liver disease: results from NHANES 2017–2020

The platelet/high-density lipoprotein cholesterol ratio (PHR) is a novel inflammatory and hypercoagulability marker that represents the severity of metabolic syndrome. Liver metabolic syndrome is manifested by nonalcoholic fatty liver disease (NAFLD), which is associated with inflammation and hypercoagulability. This cross-sectional investigation aimed to identify the relationship between PHR and NAFLD. Participants in the National Health and Nutrition Examination Survey (NHANES) 2017–2020 were evaluated for hepatic steatosis and fibrosis using vibration-controlled transient elastography. The PHR was calculated as the ratio of platelets to high-density lipoprotein cholesterol. Increased PHR was associated with an increased incidence of NAFLD and hepatic fibrosis. Compared with patients in the first PHR quartile, after adjustment for clinical variables, the corresponding odds ratio (OR) for NAFLD in the fourth quartile was 2.36 (95% CI, 1.76 to 3.18) (p < 0.05); however, the OR for hepatic fibrosis was not statistically significant (p > 0.05). Furthermore, restricted cubic spline analyses showed an S-shaped association between PHR and NAFLD and an L-shaped relationship between PHR and hepatic fibrosis. The results support the effectiveness of PHR as a marker for NAFLD and hepatic fibrosis. Therefore, interventions to improve the PHR may be of benefit in reducing the incidence of both hepatic steatosis and fibrosis.

The immunology of long COVID.

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing-remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein-Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.

Risk factors for in-hospital mortality in patients with COVID-19

Objective — to determine the association of basic demographic, clinical, and routine laboratory characteristics with the risk of adverse outcomes in patients with COVID-19. Materials and methods. Data of 320 patients hospitalized in the City Clinical Hospital No. 21 named after Prof. Ye. G. Popkova with a diagnosis of coronavirus disease19 (SARS-CoV2+ RNA)) were studied. Women — 156 (48.8 %), men — 164 (51.2 %), the mean age of the patients — (60.3 ± 13.6) years. Patients were divided into 2 groups: Group I — 270 (84.4 %) people who were discharged from the hospital with recovery or significant improvement in their condition, Group II — 50 (15.6 %) patients who died as a result of the disease (p = 0.010). The average period from the onset of the disease to hospitalization was 9 (7; 11) days. Statistical processing of the research results was carried out using the Statistica v. 6.1 software package. Results and discussion. Most of the deceased patients were older than 60 years — 36 (72.0 %) (p &lt; 0.001). The maximum number of fatalities is in the age range of 60—69 years. Mortality among men was 1.5 times higher than among women — 30 (60.0 %) vs 20 (40.0 %) (p = 0.046). In the II group, the following were observed significantly more often: ischemic heart disease and hypertension — respectively 54.0 vs 20.7 % (p &lt; 0.001) and 70.0 vs 50.0 % (p = 0.009); other heart diseases (OR — 7.23, rv = 0.202, p &lt; 0.001), obesity (OR — 2.97, rv = 0.186, p &lt; 0.001), diabetes (OR — 2.38, rv = 0.146; p = 0.009).The risk of mortality increased in the presence of cough (OR — 11.87, p = 0.012), fever (OR — 3.44, p &lt; 0.001); lymphopenia (OR — 3.82, p &lt; 0.001); hyperglycemia (OR — 4.69, p &lt; 0.001); increased C-reactive protein (CRP) (OR — 5.96, p &lt; 0.001), especially above 100 mg/l (OR from 39.86 to 52.35 at p &lt; 0.01 and p &lt; 0.001). However, thrombocytosis and lymphomonocytosis were more often observed during the benign course of the disease (respectively: p &lt; 0.001, p = 0.051). A direct relationship between the probability of mortality and age (rs = 0.143, p = 0.011), respiratory rate (rs = 0.332, p &lt; 0.001) and heart rate (rs = 0.159, p = 0.004) was revealed; fever (rs = 0.152, p = 0.006), quantitative indicators: segmented neutrophils (rs = 0.275, p &lt; 0.001), urea (rs = 0.309, p &lt; 0.001), urea nitrogen (rs = 0.300, p &lt; 0.001), residual nitrogen (rs = 0.288, p &lt; 0.001), creatinine (rs = 0.111, p = 0.047), glucose (rs = 0.273, p &lt; 0.001), CRP (rs = 0.348, p &lt; 0.001), prothrombin time (rs = 0.149, p = 0.008), international normalized ratio (rs = 0.193, p = 0.001). A inverse relationship was determined with blood oxygen saturation (rs = – 0.431, p &lt; 0.001); levels of lymphocytes, bands, platelets and prothrombin index (respectively: rs = – 0.278, p &lt; 0.001; rs = – 0.118, p = 0.034; rs = – 0.223, p &lt; 0.001; rs = – 0.170, p = 0.002). Conclusions. The following are associated with in-hospital mortality in patients with COVID-19: older age, coronary heart disease, stage III hypertension, diabetes, stage III obesity, clinical and laboratory signs: fever, shortness of breath, cough, lymphopenia, CRP content in the blood more than 100 mg/l, hyperglycemia, increased markers of kidney damage and hypercoagulation. The obtained results may be useful for predicting the course of the coronavirus disease.

D ‐Dimer Level After Endovascular Treatment Can Help Predict Outcome of Acute Ischemic Stroke

Background d ‐Dimer level is a marker of hypercoagulability, which is associated with thrombus formation and resolution. We investigated the value of d ‐dimer levels in predicting outcomes of acute ischemic stroke in patients who underwent endovascular treatment (EVT). Methods We analyzed data of patients who underwent only EVT from the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) registry. d ‐Dimer levels were routinely measured in 10 of 15 participating hospitals. Patients were grouped into tertiles (tertile 1, tertile 2, and tertile 3) according to d ‐dimer levels (lowest, moderate, and highest, respectively). We compared serial scores on the National Institutes of Health Stroke Scale at baseline, on day 1 of hospitalization, and at discharge; functional outcome 3 months after EVT; and rate of mortality within 6 months after EVT. Results In the 170 patients, the median d ‐dimer level was 477 ng/mL (interquartile range, 249–988 ng/mL). In tertile 3, the National Institutes of Health Stroke Scale score was higher at discharge than on day 1 of hospitalization. Poor outcome 3 months after EVT (modified Rankin Scale score, ≥3) was more common with high d ‐dimer levels (26.3% of tertile 1, 57.1% of tertile 2, and 76.4% of tertile 3; P &lt;0.001). Multivariable analysis showed that a high d ‐dimer level was independently associated with poor outcome 3 months after EVT (odds ratio [OR], 4.399 [95% CI, 1.594–12.135]). Kaplan–Meier survival analysis showed that a high d ‐dimer level was independently associated with death within 6 months after EVT (OR, 5.441 [95% CI, 1.560–18.978]; log‐rank test, P &lt;0.001). The d ‐dimer effect showed no heterogeneity across the subgroups for poor outcome 3 months after EVT or death within 6 months after EVT. The direction of effect was unfavorable for tertile 3 across all demographic strata. Conclusions High plasma d ‐dimer levels were predictive of early neurologic worsening, poor functional outcome 3 months after EVT, and death within 6 months after EVT. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT02964052.

Relationship of the main indicators of systemic COVID-associated endotheliopathy with the morphofunctional state and hemodynamics of the retina and chorioid in the acute period of the disease

BACKGROUND: Nonspecific angio- and retinopathy is one of the clinical manifestations of a new coronavirus infection. The frequency of occurrence of these changes in people with severe COVID-19 does not exceed 55%. The causes, course and consequences of these microcirculatory disorders of the retina are currently not well understood.&#x0D; AIM: To study and compare of retinal morphometric parameters and systemic endothelial dysfunction markers, as well as the main clinical and laboratory parameters in patients with moderate and severe coronavirus infection during convalescence.&#x0D; MATERIALS AND METHODS: The study involved 44 patients (86 eyes) who had COVID-19 during the previous 3 months, who were divided into 2 groups: with moderate and severe disease. The control group consisted of 18 healthy volunteers (36 eyes). All patients underwent a standard ophthalmological examination and optical coherence tomography, which included an assessment of the choroidal thickness (CT) and measurement of the mean diameter of the peripapillary arteries (MAD) and veins (MVD). During hospitalization, all patients underwent a laboratory study of venous blood parameters, as well as an assessment of the microcirculation of the sublingual plexus by examining the density of the endothelial glycocalyx (PBR) using the GlycoCheck.&#x0D; RESULTS: In patients who underwent COVID-19, there was a significant increase in CT relative to the control group, amounting to 308, 344 and 392 m, respectively. The most pronounced difference was observed between MVD in patients with severe infection and the control group (119.1 m vs. 99.2 m). In patients with moderate and severe COVID-19, MAD and MVD were positively correlated with TC, with r = 0.389 and r = 0.584, respectively. MVD also correlated with the level of leukocytes (r = 0.504), the ESR value (r = 0.656). Correlations between MVD and data characterizing the state of the glycocalyx in the sublingual vascular plexus were revealed: the filling of small capillaries with erythrocytes (r = 0.587), as well as the marginal perfusion value in large capillaries 2025 m (r = 0.479) and PBR (r = 0.479). Only significant differences and correlations are shown (p 0.005).&#x0D; CONCLUSIONS: In patients who underwent moderate and severe COVID-19 during the convalescence period (up to 30 days), an increase in the diameter of peripapillary vessels and TC is observed, proportional to the severity of COVID-19, laboratory markers of systemic inflammation and hypercoagulation (the number of leukocytes, the ESR value, D-dimer and prothrombin), which indicates the inflammatory nature of the changes. The severity of postcovid retinal microangiopathy correlates with indicators detecting a decreasing of the endothelial glycocalyx thickness in the sublingual capillary plexus, which indirectly indicates a connection with systemic endotheliopathy.

Antithrombin Activity Is Associated with Persistent Thromboinflammation and Mortality in Patients with Severe COVID-19 Illness

Introduction: Severe COVID-19 illness can lead to thrombotic complications, organ failure, and death. Antithrombin (AT) regulates thromboinflammation and is a key component of chemical thromboprophylaxis. Our goal was to examine the link between AT activity and responsiveness to thromboprophylaxis, markers of hypercoagulability, and inflammation among severe COVID-19 patients. Methods: This was a single-center, prospective observational study enrolling SARS-CoV-2-positive patients admitted to the intensive care unit on prophylactic enoxaparin. Blood was collected daily for 7 days to assess AT activity and anti-factor Xa levels. Patient demographics, outcomes, and hospital laboratory results were collected. Continuous variables were compared using Mann-Whitney tests, and categorical variables were compared using χ2 tests. Multivariable logistic regression was used to determine the association between AT activity and mortality. Results: In 36 patients, 3 thromboembolic events occurred, and 18 (50%) patients died. Patients who died had higher fibrinogen, D-dimer, and C-reactive protein (CRP) levels and lower AT activity. Reduced AT activity was independently associated with mortality and correlated with both markers of hypercoagulability (D-dimer) and inflammation (CRP). Conclusion: Low AT activity is associated with mortality and persistent hypercoagulable and proinflammatory states in severe COVID-19 patients. The anti-thromboinflammatory properties of AT make it an appealing therapeutic target for future studies.

Association of D-dimer with estimated glomerular filtration rate in chronic kidney disease at different stages in Indian population

: Hyper-coagulability followed by cardiovascular disease is the most common cause of mortality in CKD (chronic kidney disease). Diagnostic usefulness of hypercoagulability marker at various stages of CKD needs to be assessed. : An observational cross-sectional study.: Dept of Biochemistry, Institute of Nephrourology, Bangalore, India from January 2022 to March 2022.Study population consists of CKD patients attending Nephrology outpatient for follow up. They were categorized into 5 stages using eGFR values. Laboratory test including D-Dimer was assayed in all the participants using Abbott Architect ci4100 analyzer. In our study, a peaked and statistically significant (P value = &amp;#60;0.0001) D-Dimer values were observed in stage 4&amp;5 (5.4 ±2.5) in comparison with stage 1, 2 &amp; 3 (0.9±0.2). D- Dimer had strong negative correlationR= - 0.79 with eGFR in stage 5 CKD. D-Dimer assay should be considered as a part of routine investigations in CKD patients especially in developing countries like India, where most of the patients reach hospital only at the later stages of the disease, in order to achieve a better follow-up and management of the disease.

Extracellular Vesicles As Markers of Inflammation and Hypercoagulability during the First Month of Sars-COV-2 Infection in Outpatients and Hospitalized Patients

During SARS-CoV-2 infection, a severe hypercoagulability state is observed due to the stimulus of multiple mechanisms of hemostasis, such as intrinsic and extrinsic coagulation pathways, activation of platelets, endothelial cells, monocytes and neutrophils endothelial and impaired fibrinolysis. As a consequence, thrombotic complications are common in the course of COVID-19. Microvesicles (MVs) are intracellular transmitters that participate in pathological conditions, such as inflammatory and infectious processes, and are capable of triggering prothrombotic mechanisms. Since MVs release is potentially associated with COVID-19-induced coagulopathy, our aim was to identify the moment during the time course of the disease when the stimulus for MVs release occurs and whether this was associated with adverse outcomes. Therefore, we evaluate changes in MVs markers levels during the first month of SARS-CoV-2 infection in patients with severe disease (patients hospitalized in an intensive care unit - ICU) as compared to outpatients. We also evaluated the association between MVs markers and: acute phase inflammatory biomarkers (C-reactive protein, CRP), hypercoagulability (D-dimer) and death. Blood samples of patients were collected on three occasions: before the 10th day of symptoms (6th to 10th day), in the third week of symptoms (16th to 20th) and in the fourth week of symptoms (21st to 25th day) for the quantification of the following MVs markers by flow cytometry: CD41A (platelet activation), CD162 (PSGL-1; leukocyte-platelet interaction), CD31 (endothelium-platelet interaction) and CD142 (tissue factor). Statistical tests of ANOVA with repeated measures, Mann-Whitney and regression methods were used. The population studied was 85 patients, 65 outpatients and 20 ICU patients. Forty-three were men (51%), with a median age of 41 years old. The concentration of MVs expressing CD31+, CD41+, CD162+ and CD142+ were persistently elevated in patients who required ICU compared to outpatients at the 3 moments studied, except for the levels of MVs-CD31+ and MVs-CD142+ that were similar between ICU and outpatients in the fourth week of symptoms. However, despite the differences between the groups, there were no significant changes in the concentration of MVs during the course of the disease within the groups. In subgroup analysis, we observed that increases in the levels of MVs-CD162+ and MVs-CD142+ in the third week of symptoms were associated with the risk of death (P=0.02 and P=0.06, respectively). We also observed that before the 10th day of symptoms there was no correlation between MVs markers, CRP and D dimer levels. However, throughout the course of the disease the association between MVs, coagulability and inflammation was evident. In the third week of symptoms, D-dimer levels were correlated with MV-CD31+ (r=0.52; P<0.0001), MV-CD162+ (r=0.35, P=0.001), MV-CD41A+ (r=0.44, P<0.0001) and MV-CD142+ (r=0.47, P<0.0001). In the fourth week of symptoms, these correlations remained unchanged. CRP values from the third week of symptoms were correlated with MV-CD31+ (r=0.56, P=<0.0001), MV-CD162+ (r=0.48, P<0.0001), MV-CD41A+ (r= 0.41, P=0.0001), and MV-CD142+ (r=0.56, P<0.0001). In the fourth week of symptoms, these correlations remained unchanged. In conclusion, MVs that express antigens related to platelet activation, leukocyte-platelet interaction and endothelium-platelet interaction, as well as those related to tissue factor are released during the course of COVID-19 in patients with severe disease. After the 4th week of symptoms, the release of these MVs was associated with signs of inflammation and hypercoagulability. Additionally, MVs that express tissue factor and leukocyte-platelet interaction antigens were particularly high among non-survivors, suggesting that these MVs may serve as markers of the risk of death. Finally, these findings suggest the participation of innate immunity and tissue factor pathways in the prognosis of COVID-19, and point towards a possible role of MVs as biomarkers of disease prognosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Global Hemostatic Assays for Risk Stratification of Thrombosis in Myeloproliferative Neoplasms (MPN): A Systematic Review and Meta-Analysis

Background: Arterial and venous thromboembolism are major complications of myeloproliferative neoplasms (MPN), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The pathogenesis of thrombosis in MPN is not fully understood. Global hemostatic assays, including thrombin generation assay (TGA), rotational thromboelastometry (ROTEM), and thromboelastography (TEG), have been evaluated as predictive markers of hypercoagulability in MPNs. However, validation of these and other laboratory surrogates is lacking. The objective of this systematic review is to summarize the literature and to examine the utility of global hemostatic assays as predictive markers for hypercoagulability and occurrence of thrombosis in MPNs. Methods: A systematic literature search was performed using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception to April 14, 2022, restricted to the English language. Criteria for eligible studies were studies that reported the results of TGA, ROTEM, and TEG in ET, PV, or PMF adult patients. Studies were required to have ≥10 subjects in each group. Two reviewers (A.T. and T.C.) independently searched the literature and extracted data from eligible studies. Disagreements were resolved by consensus or a third reviewer (C.K) when necessary. The methodological quality of included studies was appraised using the Newcastle - Ottawa Quality Assessment Scale (NOS) assessment tool. A meta-analysis was planned given sufficient data from included studies. The study protocol is available on PROSPERO (CRD42022325893). Results: A total of 815 records were retrieved from the literature search. After screening by title and abstract, 745 records were excluded. The remaining 70 references underwent full text review, 30 of which met eligibility criteria and were included in the analysis. These 30 studies (15 full-texts and 15 abstracts) collectively enrolled 926 controls, 700 ET, 556 PV, and 192 PMF patients. The number of studies that reported TGA, ROTEM, and TEG were 26, 3, and 3, respectively. The number of participants in each study ranged from 25 to 212 including the controls. Two studies originated from Oceania, 1 from North America, and 27 from Europe. JAK2 mutation was reported only in 15 studies and only two studies reported quantitative variant allele frequencies. There were 5 studies that did not have healthy controls. All of these studies were cross sectional analyses; no longitudinal prospective age/sex matched controlled studies have been published. Of the 26 TGA studies, comparison of TGA parameters were made between MPN vs. controls (15 studies), MPN with thrombosis vs. without thrombosis (3 studies), JAK2 positive vs. negative MPNs (11 studies), and MPN with vs. without treatment (6 studies). There is heterogeneity in the types of samples (platelet poor plasma or platelet rich plasma), trigger reagents (amounts of tissue factor, phospholipid, and thrombomodulin), and the automated platforms that were used. Significant differences in the endogenous thrombin potential (9 studies), peak height (10 studies), lag time (6 studies), and velocity index (3 studies) were found between MPN and controls. Thirteen studies reported rates of arterial and venous thrombotic outcomes in MPN patients, which ranged from 19 to 45%. Only 1 study found an association of TGA parameters and thrombosis. Two ROTEM studies showed ET having higher maximum clot firmness and shorter clot formation time compared to controls. Two TEG studies showed increased alpha angle between MPN and controls and between PV and controls. Risk of bias assessment with NOS showed summary scores ranging 1-3 for abstracts and 4-9 for full text studies. We were not able to perform meta-analysis due to insufficient data and the high heterogeneity in study objectives and laboratory methods. Conclusions: Studies were limited by small sample sizes and inconsistent results and do not comprehensively reflect the effects of treatment, duration of disease, or clonal status. The role of these global hemostatic assays in predicting thrombotic events remains inconclusive. Future studies are necessary to establish the usefulness and validity of these surrogate markers as predictors of thrombotic complications in the MPNs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

D-dimer, a predictor of bad outcome in gastric cancer patients undergoing radical resection

As a marker of hypercoagulability, plasma D-dimer is associated with progression of many cancers but remains controversial in gastric cancer (GC). We aim to investigate the predictive value of D-dimer for postoperative outcomes after radical gastrectomy of GC patients. We enrolled 903 consecutive patients with GC who underwent radical gastrectomy and the clinicopathological characteristics were compared. Risk factors for overall survival (OS) and disease-free survival (DFS) were determined using multivariate cox regression analysis. We also compared the survival difference based on Kaplan–Meier method after a one-to-one propensity score matching (PSM). Patients with elevated D-dimer had older age (p < 0.001), advanced TNM stage (p < 0.001), larger tumor size (p = 0.005), lower 5-year OS rate (32.8% vs 62.6%, p < 0.001) and DFS (29% vs 59.6%, p < 0.001). In multivariate analysis, elevated D-dimer was independently associated with shorter OS [hazard ratio (HR): 1.633, 95% confidence interval (CI) 1.178–2.264, p = 0.003] and DFS (HR: 1.58, 95% CI 1.151–2.169, P = 0.005). After PSM, the 5-year OS rate of patients with elevated D-dimer was still significantly lower than matched group (32.8% vs 40.6%, p = 0.005), so was DFS (29% vs 36.6%, p = 0.008). Preoperative elevated D-dimer is an independent risk factor for GC patients undergoing curative gastrectomy.

CORR Insights®: What Proportion of Patients With Musculoskeletal Tumors Demonstrate Thromboelastographic Markers of Hypercoagulability? A Pilot Study.

SELECTED PROCEEDINGS FROM THE 2021 MUSCULOSKELETAL TUMOR SOCIETY MEETING GUEST EDITOR H. THOMAS TEMPLE MD

P1683: PERSISTENT HYPERCOAGULABILITY, ENDOTHELIOPATHY AND INFLAMMATION IN COVID-19 PATIENTS APPROXIMATING 1 YEAR AFTER RECOVERY.

Background: Sustained hypercoagulability and endotheliopathy has been demonstrated in convalescent COVID-19 patients for up to 4 months from recovery in previous studies. Aims: We performed a prospective, observational study assessing for hypercoagulability, endotheliopathy and inflammation in recovered COVID-19 patients beyond 6 months of recovery. Methods: The haemostatic (coagulation tests, global haemostatic tests), endothelial function and inflammatory profiles of recovered COVID-19 patients were evaluated at least 6 months after diagnosis of COVID-19. 39 patients were reviewed at a mean of 12.7±3.6 months following recovery from SARS-CoV-2 infection. These values were compared with a control group of healthy volunteers (n=124) who did not have COVID-19. Results: Among the 39 patients (71.8% males, median age 43 years, 11 having asymptomatic COVID-19, 19 having mild to moderate COVID-19, 2 having severe COVID-19 and 7 having critical COVID-19 requiring ICU care), 2 patients had pulmonary embolism during acute SARS-CoV-2 infection, and 1 patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. COVID-19 patients had significantly higher biomarkers of hypercoagulability, endothelial dysfunction and inflammation as compared to controls (Figure 1). Elevated D-dimer and Factor VIII levels above the normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of COVID-19 patients respectively, with a higher median D-dimer 0.34 μg/mL (IQR 0.28, 0.46) (p < 0.001) and Factor VIII 150% (IQR 171, 203) (p=0.004), compared to controls. Thrombin generation (Thromboscreen) also showed higher median endogenous thrombin potential (ETP) 1352nM*min (IQR 1152, 1490)(p=0.002), peak height 221.4nM (IQR 170.2, 280.4)(p=0.01) and a delayed lag time 2.4min (1.42-2.97)(p=0.0002) compared to controls. Raised endothelial biomarkers such as von Willebrand factor antigen (VWF:Ag) and ICAM-1 were observed in 17.9% (7/39) and 7.7% (3/39) of COVID-19 patients respectively, with a higher median VWF:Ag 117%(IQR 86, 154)(p=0.02) and ICAM-1 54.1%(IQR 43.8, 64.1)(p=0.004) than controls. Interleukin-6 (IL-6) was noted to be raised in 35.9% (14/39) of recovered COVID-19 patients, with a higher median IL-6 of 1.5pg/ml (IQR 0.6, 3.0) compared to controls. Subgroup analysis stratifying COVID-19 patients by age (≥50 years old), COVID-19 mRNA vaccination before acquiring SARS-CoV-2 infection, or pre-existing cardiovascular risk factors did not show any statistically significant differences across haemostatic, endothelial or inflammatory parameters. Patients who had experienced mild or asymptomatic COVID-19 compared with moderate to severe COVID-19 also demonstrated raised markers of hypercoagulability, endothelial dysfunction and inflammation. Image:Summary/Conclusion: Persistent hypercoagulability, endotheliopathy and inflammation is still detectable approximately 1 year from recovery in COVID-19 patients, with prior COVID-19 mRNA vaccination not appearing to reduce this risk.

Fibrinolytic Proteins and Factor XIII as Predictors of Thrombotic and Hemorrhagic Complications in Hospitalized COVID-19 Patients.

IntroductionIn a prospective cohort of hospitalized COVID-19 patients, an extensive characterization of hemostatic alterations by both global and specific assays was performed to clarify mechanisms underlying the coagulopathy and identify predictive factors for thrombotic and hemorrhagic events during hospitalization.Materials and MethodsIntensive care unit (ICU; n = 46) and non-ICU (n = 55) patients were enrolled, and the occurrence of thrombotic and hemorrhagic events was prospectively monitored. At study inclusion, thromboelastometry together with the measurement of specific coagulation proteins and hypercoagulation markers was performed.ResultsPatients (median age 67 years) showed significantly shorter clot formation time together with greater maximum clot firmness by thromboelastometry, increased levels of F1 + 2 and D-dimer, as biomarkers of hypercoagulability, and of procoagulant factors V, VIII, IX, XI, and fibrinogen, while FXIII was significantly reduced. The concentration of fibrinolytic proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were elevated in the overall cohort of patients. Many of these hemostatic alterations were significantly greater in ICU compared to non-ICU subjects and, furthermore, they were associated with inflammatory biomarker elevation [i.e., interleukin 6 (IL-6), C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and procalcitonin]. After enrollment, 7 thrombosis and 14 major bleedings occurred. Analysis of clinical and biological data identified increased t-PA, PAI-1, and NLR values as independent predictive factors for thrombosis, while lower FXIII levels were associated with bleeding.ConclusionThis study demonstrates alterations in all different hemostatic compartments analyzed, particularly in severe COVID-19 conditions, that strongly correlated with the inflammatory status. A potential role of fibrinolytic proteins together with NLR and of FXIII as predictors of thrombotic and hemorrhagic complications, respectively, is highlighted.