Publications by authors named "Elena Campello"

97 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

Determinants of increased thrombotic tendency in NASH cirrhosis: not there yet!

Transpl Int 2021 07 21;34(7):1325-1327. Epub 2021 May 21.

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

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http://dx.doi.org/10.1111/tri.13895DOI Listing
July 2021

Reply to "Acute kidney injury in patients with decompensated cirrhosis".

Dig Liver Dis 2021 Apr 27. Epub 2021 Apr 27.

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

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http://dx.doi.org/10.1016/j.dld.2021.03.034DOI Listing
April 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

Influence of Hepatocellular Carcinoma on Platelet Aggregation in Cirrhosis.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy.

Hyper-functional platelets are being proposed as a potential therapeutic target in multiple cancers. Whether this can be considered in patients with cirrhosis and hepatocellular carcinoma (HCC) is unknown as their platelet function has not yet been investigated. We evaluated platelet function in cirrhosis patients with HCC. Patients with cirrhosis with and without HCC were prospectively recruited. Platelet aggregation, a marker of platelet function, was assessed by impedance aggregometry with adenosine diphosphate (ADP), arachidonic acid (ASPI), and thrombin (TRAP) stimulation. Plasmatic levels of Von Willebrand factor antigen (VWF) were also determined. One-hundred patients were recruited (50 cirrhotics with and 50 without HCC). Cirrhosis severity by Child class and platelet count were comparable between cirrhotics with and without HCC. Cirrhotics with HCC had higher ADP- (45 vs. 28; < 0.001), ASPI- (47 vs. 28; < 0.001), and TRAP- (85 vs. 75; = 0.01) induced platelet aggregation than cirrhotics without HCC, all indicative of platelet hyper-function. The relatively increased platelet aggregation in patients with HCC was confirmed after adjusting the analysis for platelet count/severity of thrombocytopenia. Levels of VWF were higher in patients with vs. without HCC (348 vs. 267; = 0.006), particularly in compensated cirrhosis. In patients with cirrhosis, HCC is associated with increased platelet aggregation and higher VWF. The clinical implications of these findings deserve further investigation.
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http://dx.doi.org/10.3390/cancers13051150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962527PMC
March 2021

The risk of arterial thrombosis in carriers of natural coagulation inhibitors: a prospective family cohort study.

Intern Emerg Med 2021 Jun 22;16(4):997-1003. Epub 2021 Feb 22.

Chair of Internal Medicine, Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy.

Background: Whether the carriership of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiency increases the risk of arterial thromboembolic events (ATE) is controversial. This information has the potential to inform the management of family members of probands with inherited deficiency of natural anticoagulants.

Patients/methods: We conducted a large prospective family cohort study in 640 subjects (of whom 341 carriers and 299 non-carriers) belonging to 86 families with inherited deficiency of AT, PC, or PS.

Results: A total of 4240 and 3810 patient-years were available for carriers and non-carriers, respectively. Risk factors for atherosclerosis were similarly distributed in the two groups. Of the 26 ATE that were recorded, 19 occurred in carriers (5.6%), as compared to 7 in non-carriers (2.3%) [p = 0.07]. After adjusting for confounders, the hazard ratio (HR) for ATE was 4.9 (95% CI 1.5-16.3) in carriers as compared to non-carriers.

Conclusions: Among family members of probands with an inherited deficiency of natural anticoagulants, carriers exhibit a risk of ATE that is almost five times higher than in non-carriers.
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http://dx.doi.org/10.1007/s11739-021-02656-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195788PMC
June 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

Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: Risk Factors and Prevention.

Semin Thromb Hemost 2021 Jan 22. Epub 2021 Jan 22.

Department of Medicine, University Hospital of Padova, Padova, Italy.

Ambulatory cancer patients undergoing chemotherapy are at a substantial risk for venous thromboembolism (VTE) over the course of therapy and beyond it. Factors accounting for this risk include the activation of extrinsic and intrinsic coagulation pathways, platelet activation, impaired fibrinolysis, use of catheters, infusion of blood products, and thrombogenic potential of several chemotherapeutic drugs. A few stratification models can help identify patients at a higher risk of chemotherapy-associated VTE, who may benefit from preventive strategies. Although low-molecular-weight heparins (LMWHs) effectively reduce the risk of VTE, current guidelines recommend against their routine use. Based on the results of recent randomized controlled clinical trials, the administration of prophylactic doses of the novel direct oral anticoagulants (DOACs) to ambulatory cancer patients undergoing chemotherapy has the potential to offer an effective and safe protection against VTE, obviating the inconveniences of heparins. Except for patients in whom the novel drugs are unsuitable or are contraindicated, in all other patients LMWHs should be replaced by low-dose DOACs.
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http://dx.doi.org/10.1055/s-0040-1718927DOI Listing
January 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

Incidence of VTE in asymptomatic children with deficiencies of antithrombin, protein C, and protein S: a prospective cohort study.

Blood Adv 2020 11;4(21):5442-5448

General Internal Medicine and Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy; and.

Although antithrombin, protein C, and protein S defects are well-recognized inherited risk factors for venous thromboembolism (VTE) in adults, whether they predispose children to these vascular disorders as well is undefined. In a prospective cohort study, we assessed the incidence of spontaneous and risk period-related VTE in children who were family members of adults who, after an episode of symptomatic VTE, had then been identified as carriers of these abnormalities. A total of 134 children from 87 families were enrolled. Seventy (51.5%) of these children were carriers of an inherited defect, and the remaining 64 were not; the mean observation period was 4 years (range, 1-16 years) and 3.9 years (range, 1-13), respectively. Sixteen risk periods were experienced by carriers, and 9 by noncarriers. Six VTE occurred in the 70 carriers during 287 observation-years, accounting for an annual incidence of 2.09% patient-years (95% confidence interval, 0.8-4.5), compared with none in the 64 noncarriers during 248 observation-years. Of the 14 children with thrombophilia who experienced a risk period for thrombosis, 4 (28.6%) developed a VTE episode. The overall incidence of risk-related VTE was 25% per risk period (95% confidence interval, 6.8-64). In conclusion, the thrombotic risk in otherwise healthy children with severe inherited thrombophilia does not seem to differ from that reported for adults with the same defects. Screening for thrombophilia in children who belong to families with these defects seems justified to identify those who may benefit from thromboprophylaxis during risk periods for thrombosis.
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http://dx.doi.org/10.1182/bloodadvances.2020002781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656938PMC
November 2020

Viscoelastic testing in oncology patients (including for the diagnosis of fibrinolysis): Review of existing evidence, technology comparison, and clinical utility.

Transfusion 2020 10;60 Suppl 6:S86-S100

Department of Medical Affairs, Haemonetics Corporation, Boston, Massachusetts, USA.

The quantification of the coagulopathic state associated with oncologic and hematologic diseases is imperfectly assessed by common coagulation tests such as prothrombin time, activated partial thromboplastin time, fibrinogen levels, and platelet count. These tests provide a static representation of a component of hemostatic integrity, presenting an incomplete picture of coagulation in these patients. Viscoelastic tests (VETs), such as rotational thromboelastometry (ROTEM) and thromboelastography (TEG), as whole blood analyses, provide data related to the cumulative effects of blood components and all stages of the coagulation and fibrinolytic processes. The utility of VETs has been demonstrated since the late 1960s in guiding blood component therapy for patients undergoing liver transplantation. Since then, the scope of viscoelastic testing has expanded to become routinely used for cardiac surgery, obstetrics, and trauma. In the past decade, VETs' expanded usage has been most significant in trauma resuscitation. However, use of VETs for patients with malignancy-associated coagulopathy (MAC) and hematologic malignancies is increasing. For the purposes of this narrative review, we discuss the similarities between trauma-induced coagulopathy (TIC) and MAC. These similarities center on the thrombomodulin-thrombin complex as it switches between the thrombin-activatable fibrinolysis inhibitor coagulation pathway and activating the protein C anticoagulation pathway. This produces a spectrum of coagulopathy and fibrinolytic alterations ranging from shutdown to hyperfibrinolysis that are common to TIC, MAC, and hematologic malignancies. There is expanding literature regarding the utility of TEG and ROTEM to describe the hemostatic integrity of patients with oncologic and hematologic conditions, which we review here.
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http://dx.doi.org/10.1111/trf.16102DOI Listing
October 2020

Viscoelastic testing in benign hematologic disorders: Clinical perspectives and future implications of point-of-care testing to assess hemostatic competence.

Transfusion 2020 10;60 Suppl 6:S101-S121

Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana.

Viscoelastic tests (VETs) have been used routinely for liver transplantation, cardiac surgery, and trauma, but only recently have found clinical utility in benign hematologic disorders. Therefore, guidelines for diagnosis and treatment of these disorders based on viscoelastic variables have been adapted from the existing transplant, cardiothoracic surgery, and trauma resuscitation literature. As a result, diagnostic and therapeutic strategies for benign hematologic disorders utilizing VETs are not uniform. Accordingly, even though there has been a recent increase in the utilization of VET for the diagnosis and treatment of such disorders, the literature is still in its early stages. Analysis of point-of-care viscoelastic tracings from benign hematologic disorders has the potential to allow prompt recognition of disease and to guide patient-specific intervention. Here we present a review describing the application of VETs to benign hematologic disorders.
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http://dx.doi.org/10.1111/trf.16088DOI Listing
October 2020

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

Platelet-Derived Microparticles Bearing PF4 and Anti-GAGS Immunoglobulins in Patients with Sepsis.

Diagnostics (Basel) 2020 Aug 24;10(9). Epub 2020 Aug 24.

Department of Medicine DIMED, Padova University Medical School, 35100 Padova, Italy.

PF4 is a megakaryocyte-derived cationic chemokine that plays a part in innate immunity through its activity on the macrophages. In bacterial sepsis, PF4 binds to glycosaminoglycans (GAGs) on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of anti-PF4 IgG-IgA-IgM. This triggers the immune response in patients receiving heparin therapy who develop heparin-induced thrombocytopenia (HIT). These antibodies have also been identified in patients with chronic Gram-negative infections. Given the complexity of this innate immune response network, our study on 45 patients with sepsis focused on the immune response mediated by platelet PF4. We analyzed the role of IgG-IgA-IgM against PF4-GAGs, and the presence of specific PF4-bearing platelet microparticles (PMPs). Anti-GAGs/PF4 IgG-IgA-IgM levels were significantly higher in septic patients than in control groups (healthy controls or acute patients without sepsis, < 0.001). PF4-bearing PMP levels were only significantly higher in septic patients ( < 0.001). The occurrence of IgG-IgA-IgM against PF4-GAGs and PF4+ PMPs correlated with an improvement in patients' sepsis. In conclusion, we demonstrated that, in the course of bacterial sepsis, platelet activation leads to the formation of specific PF4-bearing PMPs. These specific microparticles bind to polyanionic sequences on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of IgG-IgA-IgM against PF4-GAGs as an innate immune response to infection.
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http://dx.doi.org/10.3390/diagnostics10090627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555115PMC
August 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

Acute Kidney Injury in Decompensated Cirrhosis Is Associated With Both Hypo-coagulable and Hyper-coagulable Features.

Hepatology 2020 10;72(4):1327-1340

Digestive Disease Section, Internal Medicine, Yale School of Medicine, New Haven, CT.

Background And Aims: Recent evidence suggests that acute kidney injury (AKI) is the main predictor of postparacentesis bleeding in patients with cirrhosis. To assess the factors responsible for bleeding tendency in AKI, we performed a prospective study comparing all three aspects of hemostasis (platelets, coagulation, and fibrinolysis) in patients with decompensated cirrhosis with and without AKI.

Approach And Results: Primary hemostasis assessment included platelet aggregation and secretion (platelet function markers) and von Willebrand factor. Secondary hemostasis assessment included pro-coagulant (factor VIII and factor XIII) and anti-coagulant (protein C, protein S, and antithrombin) factors and thrombin generation. Tertiary hemostasis assessment included fibrinolytic factors and plasmin-antiplasmin complex. Eighty patients with decompensated cirrhosis were recruited (40 each with and without AKI). Severity of cirrhosis and platelet count were comparable between groups. Median serum creatinine was 1.8 mg/dL and 0.8 mg/dL in patients with and without AKI, respectively. At baseline, patients with cirrhosis and AKI had lower platelet aggregation and secretion, indicative of impaired platelet function (increased bleeding tendency), without differences in von Willebrand factor. Regarding coagulation factors, factor VIII was higher, whereas protein C, protein S, and antithrombin were all lower, which, together with increased thrombin generation, indicate hypercoagulability. In contrast, factor XIII was lower in AKI (increased bleeding tendency). Finally, while both hypofibrinolytic and hyperfibrinolytic changes were present in AKI, a higher plasmin-antiplasmin complex indicated a hyperfibrinolytic state. After AKI resolution (n = 23 of 40), platelet function and coagulation improved to levels observed in patients with cirrhosis patients without AKI; however, fibrinolysis remained hyperactivated.

Conclusions: In patients with decompensated cirrhosis, AKI is associated with both hypocoagulable and hypercoagulable features that can potentially increase the risk of both bleeding and thrombosis.
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http://dx.doi.org/10.1002/hep.31443DOI Listing
October 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
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