Publications by authors named "Luca Spiezia"

122 Publications

Absence of hypercoagulability after nCoV-19 vaccination: An observational pilot study.

Thromb Res 2021 Jun 25;205:24-28. Epub 2021 Jun 25.

Department of Medicine, General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, University of Padua Medical School, Padua, Italy. Electronic address:

Background: It is still unknown whether COVID-19 vaccines induce a prothrombotic state or increase the hypercoagulable condition in subjects with a predisposition to thrombosis.

Objectives: We evaluated the coagulation profile in a series of healthy subjects who received the first dose of the BNT162b2 or the ChAdOx1 vaccines and assessed whether hypercoagulability developed.

Patients/methods: Volunteers among the staff of the University of Padua or health care professionals in the Padua University Hospital who had received either the ChAdOx1 or BNT162b2 vaccine in the previous 10 ± 2 days were eligible. A cohort of unvaccinated volunteers among family members of the University staff acted as control group. Global coagulation monitoring was assessed by whole blood rotational thromboelastometry, whole blood impedance aggregometry and thrombin generation. Platelet count was also obtained.

Results: One hundred and ninety subjects were enrolled: 101 (53.2%) received the ChAdOx1 vaccine and 89 (46.8%) the BNT162b2 vaccine. Twenty-eight non-vaccinated subjects acted as controls. Thromboelastometry parameters were all comparable among groups. Thrombin receptor activating peptide (TRAP)-, ADP- and ASPI-induced platelet aggregation were similar among groups, as well as platelet count. Endogenous thrombin potential (ETP) was comparable among groups. The results were confirmed after controlling for age, gender and hormonal. Considering women taking combined oral contraceptives or thrombophilia carriers, no differences were detected in thromboelastometry or thrombin generation parameters between subjects who received ChAdOx1 vs. BNT162b2 vaccines.

Conclusions: No significant activation of fibrinogen-driven coagulation, plasma thrombin generation or clinically meaningful platelet aggregation after ChAdOx1 or BNT162b2 vaccination was observed.
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http://dx.doi.org/10.1016/j.thromres.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231699PMC
June 2021

Coagulopathy is not predictive of bleeding in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.

Liver Int 2021 Jul 5. Epub 2021 Jul 5.

Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Padova University Hospital, Padova, Italy.

Background & Aims: Understanding factors responsible for the increased bleeding tendency in acute-on-chronic liver failure (ACLF) would improve the management of these complications. We investigated coagulation alterations in ACLF and assessed whether they were predictive of bleeding.

Methods: Cirrhosis patients with ACLF (cases) and acute decompensation (AD, controls) were prospectively recruited and underwent an extensive haemostatic assessment including standard tests, pro and anticoagulant factors, thrombomodulin-modified thrombin generation (TG) and thromboelastometry (ROTEM ). In study part 1 (case-control), we compared coagulation in ACLF vs AD. In study part 2 (prospective), all patients were followed for bleeding, and predictors of outcome were assessed.

Results: Ninety-one patients were included (51 with ACLF, 40 with AD). Infections and ascites/renal dysfunction were the most common precipitating and decompensating events. Platelet count was lower while INR and activated partial thrombin time were longer in ACLF cohort vs AD. Regarding clotting factors, fibrinogen and factor VIII were comparable between groups while protein C and antithrombin were significantly reduced in ACLF. Endogenous thrombin potential by TG was comparable between groups. Clotting formation time and clot stability by ROTEM were significantly lower in ACLF, indicative of a more hypocoagulable state. No haemostasis alteration could discriminate between patients who had bleeding complications during hospitalization and those who did not.

Conclusion: We found coagulation changes in ACLF to largely overlap with that of AD and evidence of preserved coagulation capacity in both groups. ROTEM alterations were indicative of a more pronounced hypocoagulable state in ACLF; however, no correlation was found between such alterations and bleeding.
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http://dx.doi.org/10.1111/liv.15001DOI Listing
July 2021

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin.

Thromb Haemost 2021 Jun 15. Epub 2021 Jun 15.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.

Background:  Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation.

Methods:  Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca], aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed.

Results:  Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation.

Conclusion:  Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.
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http://dx.doi.org/10.1055/s-0041-1730312DOI Listing
June 2021

Use of Glucocorticoids and Risk of Venous Thromboembolism: A Narrative Review.

Semin Thromb Hemost 2021 Apr 23. Epub 2021 Apr 23.

Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.

Glucocorticoids are potent anti-inflammatory agents that are widely used for the treatment of many inflammatory, autoimmune, and neoplastic disorders. However, their beneficial effect is associated with several side effects, including an increased risk of cardiovascular complications, such as myocardial infarction and stroke. Whether their use also contributes to a procoagulant state, and therefore increases the risk of venous thromboembolism (VTE), is still a matter of debate. As an increased risk of venous thrombotic events is described in patients with Cushing's syndrome, which is characterized by endogenous hypercortisolism, it is reasonable to speculate that the chronic administration of glucocorticoids may induce a hypercoagulable state. However, it seems virtually impossible to separate the role of the drug from the underlying condition, which itself predisposes to the development of VTE. Actually, some evidence suggests that the use of exogenous glucocorticoids for the treatment of underlying disease and its exacerbations may further amplify the risk of VTE. Moreover, a procoagulant state has also been reported in healthy participants receiving oral glucocorticoids versus placebo. We have performed a concise narrative review on available data on the influence of exogenous glucocorticoids on hemostasis and their clinical impact on the risk of VTE.
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http://dx.doi.org/10.1055/s-0040-1722270DOI Listing
April 2021

More severe hypercoagulable state in acute COVID-19 pneumonia as compared to other pneumonia.

Mayo Clin Proc Innov Qual Outcomes 2021 Apr 12. Epub 2021 Apr 12.

General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy.

Objective: To conduct a comprehensive evaluation of coagulation profiles - via traditional and whole blood thromboelastometry tests - in COVID-19 positive vs. COVID-19 negative patients admitted to medical wards for acute pneumonia.

Patients And Methods: We enrolled all consecutive patients admitted to Internal Medicine wards of Padova University Hospital between 7 March and 30 April 2020 for COVID-19-related pneumonia (cases) vs. non-COVID-19 pneumonia (controls). A group of healthy subjects acted as baseline for thromboelastometry parameters.

Results: Fifty-six cases (mean age 64±15 yrs, M/F 37/19) and 56 controls (mean age 76±11 yrs, M/F 35/21) were enrolled. Cases and controls showed markedly hypercoagulable thromboelastometry profiles vs. healthy subjects, mainly characterized by a significantly shorter propagation phase of coagulation (Clot Formation Time, CFT) and significantly increased maximum clot firmness (MCF) (p <0.001 in all comparisons). COVID-19 patients with pneumonia had significantly shorter CFT and higher MCF (p <0.01 and <0.05, respectively in all comparisons) vs. controls.

Conclusion: Patients admitted to internal medicine wards for COVID-19 pneumonia presented a markedly prothrombotic state, which seems peculiar to COVID-19 rather than pneumonia itself.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041140PMC
April 2021

MAC Project-Monitoring Anticoagulant Therapy Observational Study: Rationale and Protocol.

Front Med (Lausanne) 2020 28;7:584459. Epub 2021 Jan 28.

General Medicine Unit & Thrombotic, and Haemorrhagic Disorders Unit, Department of Internal Medicine, University Hospital of Padua, Padua, Italy.

Real-life studies complement data from registrative trials. Because of the delayed registration of direct oral anticoagulants in Italy, scarce real-life data on such treatments is available for the Italian population. The aim of the MAC project is to collect real-life clinical information in unselected patients given oral anticoagulants for venous thromboembolism, during a 5-year follow-up period. This is a prospective-cohort, multi-center, observational study performed in four Italian centers. The estimated samples size is 4,000 patients. The efficacy outcomes are: incidence of symptomatic recurrent venous thromboembolism and of post-thrombotic syndrome. The safety outcomes are: incidence of major bleeding, clinically relevant non-major bleeding, minor bleeding, serious adverse events, and mortality. The MAC project has the potential to improve our understanding of the epidemiology and of the therapeutic strategies adopted in Italian patients with venous thromboembolism. : WWW.ClinicalTrials.Gov, identifier: NCT0432939.
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http://dx.doi.org/10.3389/fmed.2020.584459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876063PMC
January 2021

Thrombin generation in patients with COVID-19 with and without thromboprophylaxis.

Clin Chem Lab Med 2021 06 4;59(7):1323-1330. Epub 2021 Feb 4.

Department of Medicine, General Medicine and Thrombotic and Haemorrhagic Diseases Unit, Padova University Hospital, Padova, Italy.

Objectives: Thrombin generation (TG) with and without thrombomodulin (TM) was evaluated in COVID-19 patients with different disease severity and thromboprophylaxis regimen, in order to understand the prothrombotic profile.

Methods: We enrolled consecutive patients with confirmed diagnosis of COVID-19 admitted to Medical Departments (MD) or Intensive Care Units (ICU), and 54 healthy controls.

Results: Eighty-nine patients were included (mean age 60.4±16.1 years, 68.5% male); 33.7% admitted to ICU. Twenty-four patients (26.9%) were enrolled before thromboprophylaxis administration; 45 patients (50.6%) received standard and 20 (22.5%) intermediate sub-therapeutic dose thromboprophylaxis. Overall, patients with COVID-19 showed a TG profile comparable to that of healthy subjects (i.e. comparable peak height, endogenous thrombin potential [ETP] with and without TM). The only exception was lag time and time to peak, prolonged in COVID-19 patients vs. controls. MD patients showed a similar TG profile to healthy controls, and ICU patients showed significantly decrease ETP (p=0.030) compared to MD. As for thromboprophylaxis, TG profile was significantly increased in COVID-19 patients without thromboprophylaxis vs. controls and vs. those with thromboprophylaxis. In this latter group, ETP inhibition was significantly decreased (p=0.0003) and positively correlated with anti-Xa activity (r=0.49, p=0.0017). However, patients with thromboprophylaxis had similar TG profile vs. controls. Intermediate dose thromboprophylaxis more effectively inhibited TG in severe COVID-19 patients by increasing ETP inhibition via ETP with TM reduction vs. standard dose.

Conclusions: COVID-19 patients showed increased TG at diagnosis. Standard thromboprophylaxis reduced TG to levels of healthy controls. Intermediate sub-therapeutic thromboprophylaxis more effectively inhibited TG by decreasing ETP with TM.
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http://dx.doi.org/10.1515/cclm-2021-0108DOI Listing
June 2021

Cardiopulmonary bypass-induced coagulopathy in pediatric patients: The role of platelets in postoperative bleeding. A preliminary study.

Artif Organs 2021 Aug 13;45(8):852-860. Epub 2021 Feb 13.

Department of Medicine (DIMED), Anaesthesia and Intensive Care Unit, Padova University Hospital, Padova, Italy.

Pediatric patients are particularly prone to cardiopulmonary bypass (CPB)-induced coagulopathy mainly due to hemodilution, consumption of coagulation factors and hypothermia. The aim of the present study was to examine the possible role of platelet count and function as it relates to the bleeding risk after CPB in the pediatric population. All consecutive patients (age <13 years) scheduled for elective cardiac surgery between January 2019 and November 2019 were retrospectively considered for the study. We gathered demographic characteristics, perioperative laboratory data (mainly platelet count and function), transfusion requirements, and blood loss for each patient. Patients with a chest tube output during the first 24 hours after surgery >75th percentile were bleeders (cases). Controls were nonbleeders. A total of 31 patients were enrolled [median age 17 (4-57) months]. A significant postoperative reduction in platelet count (P < .001) and function either in ADP-test (P < .001), TRAP-test (P < .001) and ASPI-test (P < .001) was found, with positive correlations between chest tube output within the first 24 hours after surgery and postoperative impairment of platelet count (R = 0.553, P = .001), ADP-test (R = 0.543, P = .001), TRAP-test (R = 0.627, P < .001) and ASPI-test (R = 0.436, P = .014). Eight children (26%) experienced major postoperative bleeding. Bleeders were significantly younger (P = .015) and underwent longer CPB duration (P = .015). Despite no significant differences in postoperative platelet count and function between cases and controls, the postoperative reduction (Δ) in platelet count (P = .002) and function in ADP-test (P = .007), TRAP-test (P = .020) and ASPI-test (P = .042) was significantly greater in bleeders vs. nonbleeders. A ΔPLT >262 500 ×10 /L, a ΔADP-test >29 U, a ΔTRAP-test >44 U and a ΔASPI-test >26 U showed to be predictive of major postoperative bleeding. Postoperative bleeding in children undergoing cardiac surgery with CPB was linked to younger age, longer CPB duration, and significant postoperative reduction in platelet count and function. Larger studies are needed to confirm our results and define strategies to reduce postoperative bleeding in these patients.
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http://dx.doi.org/10.1111/aor.13912DOI Listing
August 2021

Acute kidney injury is associated with increased levels of circulating microvesicles in patients with decompensated cirrhosis.

Dig Liver Dis 2021 Jul 8;53(7):879-888. Epub 2021 Jan 8.

Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Padova University Hospital, Padova, Italy. Electronic address:

Background: Microvesicles (MVs) play a role in inflammation, coagulation, and vascular homeostasis in liver disease.

Aim: To characterize circulating plasma MVs profile in patients with decompensated cirrhosis and acute kidney injury (AKI).

Methods: We measured the levels of total, endothelial, platelet, tissue factor (TF)+, leukocyte and hepatocyte MVs by new generation flow-cytometry in a prospective cohort of patients with decompensated cirrhosis with and without AKI.

Results: Eighty patients with decompensated cirrhosis were recruited (40 each with and without AKI). Patients with cirrhosis with AKI had significantly higher calcein+ (total), endothelial, and platelet-MVs. Conversely, TF+, leukocyte, and hepatocyte-MVs were comparable between groups. Resolution of AKI was associated with significantly decreased total and endothelial-MVs that became comparable with those in patients without AKI. Platelet MVs significantly decreased but remained higher compared to patients without AKI. TF+MVs significantly decreased and became lower than patients without AKI. Leukocyte and hepatocyte-MVs remained unchanged. Creatinine (OR 4.3 [95%CI 1.8-10.7]), MELD (OR 1.13 [95%CI 1.02-1.27]), any bleeding (OR 9.07 [95%CI 2.02-40.6]), and hepatocyte-MVs (OR 1.04 [95%CI 1.02-1.07]) were independently associated with 30-day mortality.

Conclusion: AKI worsened vascular and cellular homeostasis in patients with cirrhosis, particularly by inducing endothelial dysfunction and platelet activation. AKI did not worsen systemic inflammation and hepatocytes activation.
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http://dx.doi.org/10.1016/j.dld.2020.12.118DOI Listing
July 2021

ABO blood groups and the risk of retinal vein occlusion.

Intern Emerg Med 2021 Aug 4;16(5):1387-1390. Epub 2021 Jan 4.

General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Via Giustiniani 2, 35128, Padova, Italy.

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http://dx.doi.org/10.1007/s11739-020-02608-5DOI Listing
August 2021

Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia.

Blood 2021 Apr;137(17):2383-2393

Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

High coagulation factor VIII (FVIII) levels comprise a common risk factor for venous thromboembolism (VTE), but the underlying genetic determinants are largely unknown. We investigated the molecular bases of high FVIII levels in 2 Italian families with severe thrombophilia. The proband of the first family had a history of recurrent VTE before age 50 years, with extremely and persistently elevated FVIII antigen and activity levels (>400%) as the only thrombophilic defects. Genetic analysis revealed a 23.4-kb tandem duplication of the proximal portion of the F8 gene (promoter, exon 1, and a large part of intron 1), which cosegregated with high FVIII levels in the family and was absent in 103 normal controls. Targeted screening of 50 unrelated VTE patients with FVIII levels ≥250% identified a second thrombophilic family with the same F8 rearrangement on the same genetic background, suggesting a founder effect. Carriers of the duplication from both families showed a twofold or greater upregulation of F8 messenger RNA, consistent with the presence of open chromatin signatures and enhancer elements within the duplicated region. Testing of these sequences in a luciferase reporter assay pinpointed a 927-bp region of F8 intron 1 associated with >45-fold increased reporter activity in endothelial cells, potentially mediating the F8 transcriptional enhancement observed in carriers of the duplication. In summary, we report the first thrombophilic defect in the F8 gene (designated FVIII Padua) associated with markedly elevated FVIII levels and severe thrombophilia in 2 Italian families.
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http://dx.doi.org/10.1182/blood.2020008168DOI Listing
April 2021

Direct Oral Anticoagulants in Patients With Inherited Thrombophilia and Venous Thromboembolism: A Prospective Cohort Study.

J Am Heart Assoc 2020 12 23;9(23):e018917. Epub 2020 Nov 23.

Thrombotic and Hemorrhagic Diseases Unit Department of Medicine Padova University Hospital Padova Italy.

Background In this prospective cohort study, we aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus heparin/vitamin K antagonists for the treatment of venous thromboembolism (VTE) in patients with inherited thrombophilia. Methods and Results We enrolled consecutive patients with acute VTE and inherited thrombophilia treated with DOACs (cases) or heparin/vitamin K antagonists (controls), matched for age, sex, ethnicity, and thrombophilia type. End points were VTE recurrence and bleeding complications; residual vein thrombosis and post-thrombotic syndrome; VTE recurrence after anticoagulant discontinuation. Two hundred fifty-five cases (age 52.4±17.3 years, Female 44.3%, severe thrombophilia 33.1%) and 322 controls (age 49.7±18.1 years, Female 50.3%, severe thrombophilia 35.1%) were included. The cumulative incidence of VTE recurrence during anticoagulation was 1.09% in cases versus 1.83%, adjusted hazard ratio (HR) 0.67 (95% CI, 0.16-2.77). The cumulative incidence of bleeding was 10.2% in cases versus 4.97%, HR 2.24 (95% CI 1.10-4.58). No major bleedings occurred in cases (versus 3 in controls). No significant differences regarding residual vein thrombosis and post-thrombotic syndrome. After anticoagulant discontinuation, DOACs yielded a significantly lower 2-year VTE recurrence risk versus traditional anticoagulants (HR, 0.61 [95% CI, 0.47-0.82]). Conclusions DOACs and heparin/vitamin K antagonists showed a similar efficacy in treating VTE in patients with thrombophilia. Although major bleeding episodes were recorded solely with heparin/vitamin K antagonists, we noted an overall increased bleeding rate with DOACs. The use of DOACs was associated with a lower 2-year risk of VTE recurrence after anticoagulant discontinuation.
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http://dx.doi.org/10.1161/JAHA.120.018917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763770PMC
December 2020

Are thromboelastometric and thromboelastographic parameters associated with mortality in septic patients? A systematic review and meta-analysis.

J Crit Care 2021 Feb 6;61:5-13. Epub 2020 Oct 6.

Anaesthesia and Intensive Care Unit, Padua University Hospital, Italy; Department of Medicine-DIMED, University of Padua, Italy.

Background: Thromboelastometry/elastography (ROTEM/TEG) showed promising results for diagnosis of sepsis-induced coagulopathy, but their association with the outcome is unclear. Our aim was to assess any difference in ROTEM/TEG measurements between septic survivors and non-survivors.

Methods: Pubmed, Web of Science, Embase and Cochrane Library databases were investigated. The research aimed to include any randomized or observational study: i) on septic adult patients admitted to Intensive Care Unit (ICU) or Emergency Department (ED); ii) including ROTEM/TEG; iii) assessing mortality.

Results: Seven prospective and four retrospective observational studies (952 patients) were included. According to the INTEM/kaolin-assay, clotting time (CT)/R (standardized mean difference(SMD) -0.29, 95% CI -0.49 to -0.09, p = 0.004) and clot formation time (CFT)/K (SMD -0.42, 95% CI -0.78 to -0.06, p = 0.02) were shorter in survivors. According to the EXTEM-assay, CT was shorter (MD -11.66 s, 95% CI -22.59 to -0.73, p = 0.04), while MCF was higher (MD 3.49 mm, 95% CI 0.43 to 6.55, p = 0.03) in survivors. A hypocoagulable profile was more frequent in non-survivors (OR 0.31, 95%CI 0.18 to 0.55, p < 0.0001). Overall, the risk of bias of the included studies was moderate and the quality of evidence low.

Conclusions: Hypocoagulability and lower MCF in EXTEM may be associated with higher mortality in sepsis.
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http://dx.doi.org/10.1016/j.jcrc.2020.09.034DOI Listing
February 2021

More Severe Hypercoagulable State in Acute COVID-19 Pneumonia as Compared With Other Pneumonia.

Mayo Clin Proc Innov Qual Outcomes 2020 Dec 1;4(6):696-702. Epub 2020 Oct 1.

General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy.

Objective: To conduct a comprehensive evaluation of coagulation profiles-via traditional and whole blood thromboelastometry tests-in coronavirus disease 2019 (COVID-19)-positive vs COVID-19-negative patients admitted to medical wards for acute pneumonia.

Patients And Methods: We enrolled all consecutive patients admitted to internal medicine wards of Padova University Hospital between 7 March and 30 April, 2020, for COVID-19-related pneumonia (cases) vs non-COVID-19 pneumonia (controls). A group of healthy individuals acted as baseline for thromboelastometry parameters.

Results: Fifty-six cases (mean age, 64±15 years; male/female, 37/19) and 56 controls (mean age, 76±11 years; male/female, 35/21) were enrolled. Cases and controls exhibited markedly hypercoagulable thromboelastometry profiles vs healthy individuals, mainly characterized by a significantly shorter propagation phase of coagulation (clot formation time) and significantly increased maximum clot firmness (<.001 for all comparisons). Patients with COVID-19 pneumonia had significantly shorter clot formation time and higher maximum clot firmness (<.01 and <.05, respectively, for all comparisons) than did controls.

Conclusion: Patients admitted to internal medicine wards for COVID-19 pneumonia presented a markedly prothrombotic state, which seems peculiar to COVID-19 rather than pneumonia itself.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528900PMC
December 2020

Post-operative hypercoagulable whole blood profiles in patients undergoing open thoracotomy vs video-assisted thoracoscopic surgery.

Blood Transfus 2021 03 6;19(2):144-151. Epub 2020 Aug 6.

Haemorrhagic and Thrombotic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy.

Background: Patients undergoing video-assisted thoracoscopic surgery (VATS) have a lower risk of thrombosis compared to those undergoing open thoracotomy (OT) which may be due to several post-operative factors such as early mobilisation, shorter hospital stays, lower transfusion rates and lower risk of infections. Whether the higher thrombotic risk after OT is also linked to a peri-operative hypercoagulable state is a matter of debate. We therefore conducted a case-control study to compare peri-operative coagulation profiles in patients with primary lung cancer undergoing VATS vs OT.

Materials And Methods: All consecutive patients undergoing VATS or OT for primary lung cancer at the Department of Thoracic Surgery of Padua University Hospital, Italy, between February and June 2018 were enrolled. Each patient provided a venous blood sample at least 30 min prior to surgical incision (T0) and 4±1 days after surgery (T1). Peri-operative coagulation profiles were assessed via traditional, viscoelastic whole blood (ROTEM [Instrumentation Laboratory-Werfen]) and impedance aggregometry (Multiplate Analyser [Roche Diagnostics]) tests.

Results: We enrolled 65 patients (males 43, females 22; mean age 65±13 years) of whom 35 (54%) underwent VATS and 30 (46%) underwent OT. Compared to healthy controls, the surgical group (VATS and OT patients) had a significantly shorter clot formation time and higher alpha angle and maximum clot firmness values, as well as increased mean platelet function. In the post-operative period, patients who underwent OT had a significantly shorter clot formation time, higher alpha angle and maximum clot firmness values and higher mean platelet function vs VATS patients.

Discussion: Whole blood ROTEM profiles and Multiplate aggregometry identified a more hypercoagulable post-operative state in patients who underwent OT than in those who underwent VATS. Larger studies are warranted to confirm our results and ascertain whether the observed hypercoagulability might promote post-operative thrombosis.
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http://dx.doi.org/10.2450/2020.0040-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925226PMC
March 2021

COVID-19 and Venous Thromboembolism in Intensive Care or Medical Ward.

Clin Transl Sci 2020 11 23;13(6):1108-1114. Epub 2020 Oct 23.

General Internal Medicine and Thrombotic and Haemorrhagic Diseases Unit, Department of Internal Medicine, Padua University Hospital, Padua, Italy.

Despite thromboprophylaxis, patients with coronavirus disease 2019 (COVID-19) exhibit hypercoagulability and higher venous thromboembolic risk, although its real incidence is still unknown. The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with COVID-19 admitted to both intensive care units (ICUs) and medical wards (MWs). Consecutive patients admitted for COVID-19 to the MW and the ICU at Padua University Hospital, all receiving thromboprophylaxis, underwent systematic ultrasonography of the internal jugular, and the upper and lower limbs veins every 7 days (± 1 day) after the admission; and, if negative, once-weekly until discharge or death. In case of suspected pulmonary embolism, a multidetector computed tomographic angiography was performed. The primary outcome was the proportion of any deep-vein thrombosis (DVT) and symptomatic pulmonary embolism in both groups. An extended blood coagulative test was performed as well. From March 4 to April 30, 2020, a total of 85 patients were investigated, 44 (52%) in MWs and 41 (48%) in the ICU. Despite thromboprophylaxis, VTE occurred in 12 patients in the MWs (27.3%) and 31 patients in the ICU (75.6%) with an odds ratio of 9.3 (95% confidence interval (CI) 3.5-24.5; P < 0.001). Multiple-site DVT occurred in 55.6% of patients (95% CI 39.6-70.5). Increased D-dimer levels significantly correlated with VTE (P = 0.001) and death (P = 0.015). Summarizing, patients with COVID-19 admitted to the MW or ICU showed a high frequency of venous thromboembolism, despite standard-dose or high-dose thromboprophylaxis. Whether thrombosis, particularly asymptomatic events, may play a role in the morbidity and mortality of patients with COVID-19 remain to be clarified.
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http://dx.doi.org/10.1111/cts.12907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567296PMC
November 2020

Correction to: Acute pulmonary embolism in COVID-19 related hypercoagulability.

J Thromb Thrombolysis 2021 Feb;51(2):559

General Internal Medicine and Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padua, Italy.

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http://dx.doi.org/10.1007/s11239-020-02284-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505938PMC
February 2021

Acquired haemophilia A, concomitant acute myocardial infarction and urgent major surgery: How to successfully treat a critical patient with rpFVIII (Obizur®).

Thromb Res 2020 11 9;195:125-127. Epub 2020 Jul 9.

Centre for Haemorrhagic and Thrombotic Diseases, Department of Medicine, University Hospital of Padua, Italy.

Association of acute myocardial infarction (AMI) and acquired haemophilia A (AHA) is extremely rare, and very difficult to treat, if the patient then presents several serious comorbidities and must undergo an urgent major surgery, the correct choice of haemostatic therapy is essential to avoid potentially life-threatening adverse events for the patient. The recombinant porcine FVIII (rpFVIII) is considered, together with the bypassing agents, as first-line therapy for the AHA, but compared to these it presents a reduced thromboembolic risk which makes it safer in patients who already present at the onset of haemorrhagic event an underlying cardiovascular disease. Haemorrhagic and thrombotic events are always to be taken into consideration in the case of surgery, but in the case of patients with concomitant acquired haemophilia the risk of having serious bleeding has further increase. Today there have been no reports of surgeries carried out under Obizur® coverage. We are reporting the successful case of an elderly critical patient with acquired haemophilia A and concomitant myocardial infarction, treated with rpFVIII and in which an urgent major surgery under coverage of this dug was performed for the first time.
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http://dx.doi.org/10.1016/j.thromres.2020.07.012DOI Listing
November 2020

Platelet-primed interactions of coagulation and anticoagulation pathways in flow-dependent thrombus formation.

Sci Rep 2020 07 17;10(1):11910. Epub 2020 Jul 17.

Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

In haemostasis and thrombosis, platelet, coagulation and anticoagulation pathways act together to produce fibrin-containing thrombi. We developed a microspot-based technique, in which we assessed platelet adhesion, platelet activation, thrombus structure and fibrin clot formation in real time using flowing whole blood. Microspots were made from distinct platelet-adhesive surfaces in the absence or presence of tissue factor, thrombomodulin or activated protein C. Kinetics of platelet activation, thrombus structure and fibrin formation were assessed by fluorescence microscopy. This work revealed: (1) a priming role of platelet adhesion in thrombus contraction and subsequent fibrin formation; (2) a surface-independent role of tissue factor, independent of the shear rate; (3) a mechanism of tissue factor-enhanced activation of the intrinsic coagulation pathway; (4) a local, suppressive role of the anticoagulant thrombomodulin/protein C pathway under flow. Multiparameter analysis using blood samples from patients with (anti)coagulation disorders indicated characteristic defects in thrombus formation, in cases of factor V, XI or XII deficiency; and in contrast, thrombogenic effects in patients with factor V-Leiden. Taken together, this integrative phenotyping approach of platelet-fibrin thrombus formation has revealed interaction mechanisms of platelet-primed key haemostatic pathways with alterations in patients with (anti)coagulation defects. It can help as an important functional add-on whole-blood phenotyping.
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http://dx.doi.org/10.1038/s41598-020-68438-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368055PMC
July 2020

How haemophilia A impacts severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) treatment: a case report.

J Thromb Thrombolysis 2020 Nov 16;50(4):795-798. Epub 2020 Jul 16.

Centre for Haemorrhagic and Thrombotic Diseases, Medicine Department, Padua University Hospital, Padua, Italy.

The typical symptoms of COVID-19 mimic those of the common season flu. In addition, several changes in the coagulation processes have been observed. To date, it's not fully clear how COVID-19 may affect patients with hereditary bleeding disorders. Anticoagulation in patients with haemophilia is still debated, but in this case could be needed. We are reporting a case of an elderly patient with mild haemophilia A hospitalized for Sars-Cov-2. On the 15th day of hospitalization, we observed an increase of all coagulation parameters. An antithrombotic prophylaxis at low dosage was immediately started, then increased at prophylactic dosage. Even if much more data are needed to ascertain the real thrombotic risk of haemophilia A in COVID-19 patients, it's clear that the FVIII and vWF should be strictly monitored in order to promptly establish an adequate treatment and avoid the onset of thromboembolic events, even fatal, causing many deaths in COVID-19 patients.
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http://dx.doi.org/10.1007/s11239-020-02227-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364750PMC
November 2020

Endothelial Damage of the Portal Vein is Associated with Heparin-Like Effect in Advanced Stages of Cirrhosis.

Thromb Haemost 2020 Aug 30;120(8):1173-1181. Epub 2020 Jun 30.

Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy.

Background:  Portal vein thrombosis (PVT) is the most common thrombotic complication in cirrhosis; however, local risk factors involved in its pathogenesis are still not fully investigated. The aim of the study was to evaluate hemostasis and endothelial damage in the portal vein in patients with cirrhosis and portal hypertension.

Methods:  Adult cirrhotics undergoing transjugular intrahepatic portosystemic shunt were consecutively enrolled. Rotational thromboelastometry (ROTEM), dosage of total circulating glycosaminoglycans (GAGs), and endotoxemia levels (lipopolysaccharide [LPS]), along with evaluation of endothelial dysfunction by quantification of circulating endothelial microparticles (MPs), were performed on citrated peripheric and portal venous blood samples from each enrolled patient.

Results:  Forty-five cirrhotics were enrolled. ROTEM analysis revealed the presence of a significant heparin-like effect in portal blood (median ɑ angle NATEM 50° vs. HEPTEM 55°,  = 0.027; median coagulation time NATEM 665 s vs. HEPTEM 585 s,  = 0.006), which was not detected in peripheral blood, and was associated with a higher concentration of circulating GAGs. Even though total annexin V-MP circulating MPs were less concentrated in the splanchnic district, the proportion of MPs of endothelial origin, with respect to annexin V-MP, was significantly increased in the portal district ( = 0.036). LPS concentration was higher in portal (197 pg/mL) compared with peripheral blood (165 pg/mL) ( < 0.001).

Conclusion:  Evidences of a damage of glycocalyx along with increased concentration of endothelial MPs suggest the presence of a significant endothelial alteration in the portal vein with respect to peripheral veins. Portal site-specific endothelial damage could hamper its antithrombotic properties and may represent an important local risk factor in the pathogenesis of PVT.
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http://dx.doi.org/10.1055/s-0040-1713169DOI Listing
August 2020

Acute pulmonary embolism in COVID-19 related hypercoagulability.

J Thromb Thrombolysis 2020 Jul;50(1):223-226

General Internal Medicine and Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padua, Italy.

Since December 2019, a novel Coronavirus (SARS-CoV-2) was confirmed as the etiologic agent of a worldwide outbreak of a pneumonia that can result in severe respiratory failure. This clinical entity seems to be associated with a marked hypercoagulable state that causes both arterial and venous thromboembolic complications. Therefore, an adequate anti-thrombotic prophylaxis is recommended in hospitalized COVID-19 patients. Although rapidly worsening respiratory symptoms in a patient with SARS-CoV-2 respiratory infection may correlate with worsening pneumonia itself, it may also mask a pulmonary embolism. We report the case of a 50-year-old man affected by SARS-CoV-2 pneumonia, who developed acute pulmonary embolism.
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http://dx.doi.org/10.1007/s11239-020-02160-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260472PMC
July 2020

COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure.

Thromb Haemost 2020 Jun 21;120(6):998-1000. Epub 2020 Apr 21.

General Internal Medicine and Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy.

In late December 2019 an outbreak of a novel coronavirus (SARS-CoV-2) causing severe pneumonia (COVID-19) was reported in Wuhan, Hubei Province, China. A common finding in most COVID-19 patients is high D-dimer levels which are associated with a worse prognosis. We aimed to evaluate coagulation abnormalities via traditional tests and whole blood thromboelastometry profiles in a group of 22 (mean age 67 ± 8 years, M:F 20:2) consecutive patients admitted to the Intensive Care Unit of Padova University Hospital for acute respiratory failure due to COVID-19. Cases showed significantly higher fibrinogen and D-dimer plasma levels versus healthy controls ( < 0.0001 in both comparisons). Interestingly enough, markedly hypercoagulable thromboelastometry profiles were observed in COVID-19 patients, as reflected by shorter Clot Formation Time (CFT) in INTEM ( = 0.0002) and EXTEM ( = 0.01) and higher Maximum Clot Firmness (MCF) in INTEM, EXTEM and FIBTEM ( < 0.001 in all comparisons). In conclusion, COVID-19 patients with acute respiratory failure present a severe hypercoagulability rather than consumptive coagulopathy. Fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome.
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http://dx.doi.org/10.1055/s-0040-1710018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295272PMC
June 2020

Dengue fever as a rare cause of pulmonary embolism.

J Thromb Thrombolysis 2020 May;49(4):690-693

Universita degli Studi di Padova Dipartimento di Medicina, Padua, Italy.

Dengue fever is a clinical entity well known for its haemorrhagic complications whose pathophysiology, though not completely understood, may be linked to a systemic inflammatory state caused by the infection itself. Even if rarely described, inflammation may lead as well to thromboembolic manifestations, as in the case we report here.
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http://dx.doi.org/10.1007/s11239-020-02082-yDOI Listing
May 2020

Thrombotic risk following video-assisted thoracoscopic surgery versus open thoracotomy: a systematic review and meta-analysis.

Interact Cardiovasc Thorac Surg 2020 04;30(4):573-581

Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine - DIMED, Padova University Hospital, Padova, Italy.

Objectives: There is no consensus on the risk of thrombotic events following video-assisted thoracoscopic surgery (VATS) versus open thoracotomy (OT), despite multiple studies. In fact, the estimates for the overall thrombotic risk for VATS versus OT are inconclusive. In this systematic review and meta-analysis, we endeavoured to ascertain the best estimate of thrombotic risk in VATS versus OT.

Methods: Relevant studies were searched through PubMed and Cochrane Library database. Outcomes of interests were myocardial infarction (MI), pulmonary embolism (PE) and deep vein thrombosis (DVT). Data were pooled using random-effects model. The results were presented as odds ratio (OR) with the corresponding 95% confidence interval (CI).

Results: Nineteen studies were meta-analysed: 17 observational studies and 2 randomized controlled trials. Using propensity-matched data, in comparison with OT, VATS was associated with a statistically significant, postoperative reduction in MI (OR 0.60, 95% CI 0.39-0.91; P = 0.017), DVT/PE (OR 0.52, 95% CI 0.44-0.61; P < 0.001), PE (OR 0.59, 95% CI 0.43-0.82; P = 0.001) and DVT (OR 0.47, 95% CI 0.35-0.64; P < 0.001). Unadjusted data showed no statistical differences for all outcomes. The risk of DVT/PE (OR 0.55, 95% CI 0.42-0.72; P < 0.001), but not the other outcomes, remained significantly lower following the exclusion of the sole large study. There is no significant statistical heterogeneity between the included studies.

Conclusions: Overall, the postoperative thrombotic risk following VATS is significantly lower than OT. Further prospective randomized controlled trials with large sample sizes are warranted to corroborate our findings.
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http://dx.doi.org/10.1093/icvts/ivz321DOI Listing
April 2020

Thrombin generation and thromboelastometry in monitoring the in-vitro reversal of warfarin: a comparison between 3-factor and 4-factor prothrombin complex concentrates.

Blood Coagul Fibrinolysis 2020 Mar;31(2):127-131

Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy.

: The efficacy of three-factor prothrombin complex concentrates (PCCs) in the reversal of vitamin K antagonists is still a matter of debate. We compared the 'in-vitro' effect of three PCCs (one three-factor and two four-factor) on international normalized ratio (INR), thrombin generation and thromboelastometry of patients at different degrees of anticoagulation with vitamin K antagonist. We tested three concentrations of PCC (0.5, 1 and 1.5 U/ml) in six patients: three (INR 2.0-2.9) and three (INR 3.0-4.0). In this preliminary phase, we determined the lowest effective dose for a target INR less than 1.5 and to normalize endogenous thrombin potential and clotting time in EXTEM assay. In the validation phase, we tested the effect of the newly determined lowest effective PCC dose on samples of 40 (INR 2.0-2.9) and 20 (INR 3.0-4.0) patients. The minimum efficacious dosage to achieve the target INR with three-factor PCC (3-PCC) was 0.5 (INR 2.0-2.9) and 1.5 U/ml (INR 3.0-4.0). Four-factor PCCs (4-PCCs) achieved target INR with the lowest dose (0.5 U/ml) independently of baseline INR. Thrombin generation endogenous thrombin potential and EXTEM clotting time achieved normal values with the lowest dose (0.5 U/ml) of either 3-PCC or 4-PCC independently of baseline INR. Data observed in the preliminary phase were confirmed in the validation phase. 3-PCC appears to be as effective as 4-PCC in reversing oral anticoagulant treatment based on thrombin generation and EXTEM data, but not INR data, at least in the range of INR considered in our study. Further studies are needed to address the clinical implications of our results.
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http://dx.doi.org/10.1097/MBC.0000000000000887DOI Listing
March 2020

Whole-blood hypocoagulable profile correlates with a greater risk of death within 28 days in patients with severe sepsis.

Korean J Anesthesiol 2020 06 7;73(3):224-231. Epub 2020 Jan 7.

Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padua, Italy.

Background: Hypocoagulability and impaired platelet function have been associated with a high risk of death in sepsis. The aim of this cohort study was to determine whether sepsis-induced hypocoagulability and platelet dysfunction (assessed by ROTEM® and MULTIPLATE®, respectively) are increased in sepsis patients who died within 28 days after diagnosis compared with patients who died between 29 and 90 days after diagnosis.

Methods: Consecutive patients admitted to the intensive care unit of Padova University Hospital from March 2015 to March 2018 for severe sepsis were considered. We collected blood samples from all patients to determine ROTEM® and MULTIPLATE® parameters. Each enrolled patient underwent a 90-day follow-up and the mortality rate was recorded.

Results: Of 120 patients, 36 (30%) died within 28 days post-diagnosis (Group A), 23 (19%) died between days 29 and 90 post-diagnosis (Group B), and 61 (51%) were alive after 90 days (survivors). The clotting time in the ROTEM® test and clot formation time in the EXTEM test were significantly more prolonged in Group A than in B. Both groups showed a significantly higher hypocoagulability than survivors in the EXTEM test. MULTIPLATE® platelet function analysis showed that platelet function was significantly lower in Group A than in Group B.

Conclusions: The present study showed that the combination of thromboelastometry and impedance aggregometry may help identifying sepsis patients at high risk of short-term death. Larger studies are warranted to corroborate our results.
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http://dx.doi.org/10.4097/kja.19396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280891PMC
June 2020

Changes in plasma circulating microvesicles in patients with HCV-related cirrhosis after treatment with direct-acting antivirals.

Liver Int 2020 04 10;40(4):913-920. Epub 2019 Sep 10.

Department of Medicine, Thrombotic and Haemorrhagic Diseases Unit, Padova University Hospital, Padova, Italy.

Background & Aims: The eradication of Hepatitis C (HCV) infection by direct-acting antiviral (DAAs) agents has been linked to an amelioration of liver synthesis and regression of fibrosis. Although changes in number and type of circulating microvesicles (MVs) have been reported in cirrhosis, conclusive data on the effect of DAAs treatment on MVs profile in HCV cirrhotic patients remain scarce.

Methods: We measured the levels of endothelial, platelet and hepatocyte MVs, as well as MVs-expressing versican core protein (VCAN+) in patients with HCV-related cirrhosis at baseline, end of treatment (EOT), at 12, 24 and 48 weeks (W) after EOT by new generation flow cytometry.

Results: Fifty-eight patients were enrolled (86% Child's A). MVs were increased at EOT vs baseline, though only platelet MVs revealed a statistically significant difference (P < .01). MV levels did not change significantly after EOT notwithstanding a steady downward trend towards baseline levels. Conversely, VCAN + MVs dropped significantly at EOT (P < .001) and remained low throughout the follow-up. Hepatocyte MVs significantly correlated with liver stiffness (r = .40, P = .0021). Eight composite outcomes occurred during the 1-year follow-up: three portal vein thromboses (PVTs), two hepatocellular carcinomas (HCCs) and three liver decompensation. Child's B, the presence of F2 oesophageal varices (OR for interaction 19.2 [95% CI 1.45-253.7], P = .023) and platelet MVs (OR 1.026 [95% CI 1.00-1.05, P = .023) correlated significantly with clinical outcomes.

Conclusions: VCAN + MVs appear to mirror the profibrotic status of the cirrhotic disease; hepatocyte MVs correlate with liver stiffness and increased platelet MV levels could be associated with a worse clinical outcome.
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http://dx.doi.org/10.1111/liv.14234DOI Listing
April 2020

The prognostic role of ThromboDynamic Index in patients with severe sepsis.

Intern Emerg Med 2020 01 2;15(1):163-168. Epub 2019 Jul 2.

Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine-DIMED, Padova University Hospital, 105, Via Ospedale Civile, 35100, Padua, Italy.

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http://dx.doi.org/10.1007/s11739-019-02137-wDOI Listing
January 2020
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