Publications by authors named "Paolo Simioni"

217 Publications

Global reporting of pulmonary embolism-related deaths in the World Health Organization mortality database: Vital registration data from 123 countries.

Res Pract Thromb Haemost 2021 Jul 15;5(5):e12520. Epub 2021 Jun 15.

Center for Thrombosis and Hemostasis University Medical Center Mainz Mainz Germany.

Introduction: Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause-specific mortality in global reports.

Methods: We analyzed global PE-related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age-sex-specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE-related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization.

Results: We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper-middle income, 14 (12.1%) lower-middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE-related mortality rate increased with age in most countries. The reporting of PE-related deaths was heterogeneous, with an age-standardized mortality rate ranging from 0 to 24 deaths per 100 000 population-years. Income status only partially explained this heterogeneity.

Conclusions: Reporting of PE-related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE-related mortality and provides a case for full recognition of PE and VTE as a primary cause of death.
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http://dx.doi.org/10.1002/rth2.12520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268665PMC
July 2021

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

Critical Review of the Evolution of Extracellular Vesicles' Knowledge: From 1946 to Today.

Int J Mol Sci 2021 Jun 15;22(12). Epub 2021 Jun 15.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy.

Extracellular vesicles (EVs) are a family of particles/vesicles present in blood and body fluids, composed of phospholipid bilayers that carry a variety of molecules that can mediate cell communication, modulating crucial cell processes such as homeostasis, induction/dampening of inflammation, and promotion of repair. Their existence, initially suspected in 1946 and confirmed in 1967, spurred a sharp increase in the number of scientific publications. Paradoxically, the increasing interest for EV content and function progressively reduced the relevance for a precise nomenclature in classifying EVs, therefore leading to a confusing scientific production. The aim of this review was to analyze the evolution of the progress in the knowledge and definition of EVs over the years, with an overview of the methodologies used for the identification of the vesicles, their cell of origin, and the detection of their cargo. The MISEV 2018 guidelines for the proper recognition nomenclature and ways to study EVs are summarized. The review finishes with a "more questions than answers" chapter, in which some of the problems we still face to fully understand the EV function and potential as a diagnostic and therapeutic tool are analyzed.
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http://dx.doi.org/10.3390/ijms22126417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232679PMC
June 2021

Comparison of fondaparinux and low molecular weight heparin in the treatment of portal vein thrombosis in cirrhosis.

Am J Med 2021 Jun 28. Epub 2021 Jun 28.

Unit of Internal Medicine and Hepatology Department of Medicine-DIMED, Padua University Hospital, Padua, Italy.

Background: Portal vein thrombosis is the most common thrombotic complication in cirrhosis. About 60% of anticoagulated patients can achieve recanalization. Despite fondaparinux (FPX) theoretical advantages, data are lacking regarding safety and efficacy for treatment of portal vein thrombosis in cirrhosis.

Methods: Cirrhotic patients with portal vein thrombosis treated with FPX or low molecular heparin (LMWH) were retrospectively included. The extension of thrombosis at baseline and its evolution during anticoagulant treatment were evaluated. Patients were treated with LMWH or FPX at therapeutic dosage and reduction was considered in selected cases.

Results: One-hundred and twenty-four patients were included. Main PV branch, splenic and superior mesenteric veins were involved in 84%, 13% and 36% of cases, respectively. Forty-one patients (33%) were treated with FPX and eighty-three (67%) with LMWH. The probability of resolution of thrombosis at 36 months was significantly higher in patients treated with FPX than in those treated with LMWH (77% vs 51%; p=0.001), particularly when prescribed at reduced dose. With multivariate analysis, the treatment with FPX (HR=2.38; p=0.002) and use of a full dose (HR=1.78; p=0.035) were independent predictors of portal vein full recanalization. Bleeding rate was higher in patients treated with FPX than in those treated with LMWH (27% vs 13%; p=0.06).

Conclusions: FPX appears to be more effective than LMWH in the treatment of portal vein thrombosis when used at reduced dose, also in complete thrombosis. FPX should be considered amongst possible treatments for portal vein thrombosis in cirrhosis.
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http://dx.doi.org/10.1016/j.amjmed.2021.05.013DOI Listing
June 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

PAR-4/Ca-calpain pathway activation stimulates platelet-derived microparticles in hyperglycemic type 2 diabetes.

Cardiovasc Diabetol 2021 04 3;20(1):77. Epub 2021 Apr 3.

Metabolic Disease Unit, Department of Medicine-DIMED, Via Giustiniani, 2, 35128, Padova, Italy.

Background: Patients with type 2 diabetes (T2DM) have a prothrombotic state that needs to be fully clarified; microparticles (MPs) have emerged as mediators and markers of this condition. Thus, we investigate, in vivo, in T2DM either with good (HbA1c ≤ 7.0%; GGC) or poor (HbA1c > 7.0%; PGC) glycemic control, the circulating levels of MPs, and in vitro, the molecular pathways involved in the release of MPs from platelets (PMP) and tested their pro-inflammatory effects on THP-1 transformed macrophages.

Methods: In 59 T2DM, and 23 control subjects with normal glucose tolerance (NGT), circulating levels of CD62E+, CD62P+, CD142+, CD45+ MPs were determined by flow cytometry, while plasma levels of ICAM-1, VCAM-1, IL-6 by ELISA. In vitro, PMP release and activation of isolated platelets from GGC and PGC were investigated, along with their effect on IL-6 secretion in THP-1 transformed macrophages.

Results: We found that MPs CD62P (PMP) and CD142 (tissue factor-bearing MP) were significantly higher in PGC T2DM than GGC T2DM and NGT. Among MPs, PMP were also correlated with HbA1c and IL-6. In vitro, we showed that acute thrombin exposure stimulated a significantly higher PMP release in PGC T2DM than GGC T2DM through a more robust activation of PAR-4 receptor than PAR-1 receptor. Treatment with PAR-4 agonist induced an increased release of PMP in PGC with a Ca-calpain dependent mechanism since this effect was blunted by calpain inhibitor. Finally, the uptake of PMP derived from PAR-4 treated PGC platelets into THP-1 transformed macrophages promoted a marked increase of IL-6 release compared to PMP derived from GGC through the activation of the NF-kB pathway.

Conclusions: These results identify PAR-4 as a mediator of platelet activation, microparticle release, and inflammation, in poorly controlled T2DM.
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http://dx.doi.org/10.1186/s12933-021-01267-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019350PMC
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

Reduced Clot Stability by Thromboelastography as a Potential Indicator of Procedure-Related Bleeding in Decompensated Cirrhosis.

Hepatol Commun 2021 Feb 12;5(2):272-282. Epub 2020 Dec 12.

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

In patients with decompensated cirrhosis, procedure-related bleeding is a potentially lethal complication. Routine coagulation tests such as international normalized ratio and platelet count do not predict bleeding risk. We investigated whether thromboelastography (TEG) can identify patients with cirrhosis who are at risk of procedure-related bleeding. As a part of a prospective study on hemostasis in decompensated cirrhosis, patients had TEG performed on admission and were followed prospectively during hospitalization for the development of procedure-related bleeding. Eighty patients with cirrhosis were included. Among the 72 who had procedures performed, 7 had procedure-related bleeding, which was major in three cases (two following paracentesis and one following thoracentesis). Conventional coagulation tests were comparable between bleeding and nonbleeding patients, whereas TEG parameters of k-time (4.5 minutes vs. 2.2 minutes;  = 0.02), α-angle (34° vs. 59°;  = 0.003), and maximum amplitude (37 mm vs. 50 mm;  = 0.004) were significantly different (all indicative of hypocoagulability). TEG maximum amplitude (MA), a marker of overall clot stability, accurately discriminated between patients who had major, life-threatening bleeding (all with MA < 30 mm) and those who had mild or no bleeding (all with MA > 30 mm), whereas a platelet count < 50 × 10/L could not discriminate between bleeding (minor or major) and nonbleeding patients. : In a prospective cohort of hospitalized patients with decompensated cirrhosis, TEG parameters associated with hypocoagulability appeared to predict procedure-related bleeding, particularly a TEG MA < 30 mm. If results are validated in a larger cohort, this could be a threshold to identify patients with decompensated cirrhosis at higher risk for procedure-related bleeding, in whom to consider preprocedural prophylaxis.
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http://dx.doi.org/10.1002/hep4.1641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850311PMC
February 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

Sounds Stimulation on In Vitro HL1 Cells: A Pilot Study and a Theoretical Physical Model.

Int J Mol Sci 2020 Dec 25;22(1). Epub 2020 Dec 25.

Department of Cardiac, Thoracic and Vascular Sciences, Padua University Medical School,35100 Padua, Italy.

Mechanical vibrations seem to affect the behaviour of different cell types and the functions of different organs. Pressure waves, including acoustic waves (sounds), could affect cytoskeletal molecules via coherent changes in their spatial organization and mechano-transduction signalling. We analyzed the sounds spectra and their fractal features. Cardiac muscle HL1 cells were exposed to different sounds, were stained for cytoskeletal markers (phalloidin, beta-actin, alpha-tubulin, alpha-actinin-1), and studied with multifractal analysis (using FracLac for ImageJ). A single cell was live-imaged and its dynamic contractility changes in response to each different sound were analysed (using Musclemotion for ImageJ). Different sound stimuli seem to influence the contractility and the spatial organization of HL1 cells, resulting in a different localization and fluorescence emission of cytoskeletal proteins. Since the cellular behaviour seems to correlate with the fractal structure of the sound used, we speculate that it can influence the cells by virtue of the different sound waves' geometric properties that we have photographed and filmed. A theoretical physical model is proposed to explain our results, based on the coherent molecular dynamics. We stress the role of the systemic view in the understanding of the biological activity.
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http://dx.doi.org/10.3390/ijms22010156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796405PMC
December 2020

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Blood Adv 2020 12;4(24):6250-6258

Bayer AG, Wuppertal, Germany.

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.
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http://dx.doi.org/10.1182/bloodadvances.2020003244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756994PMC
December 2020

Hepatic benefits of HCV cure: Don't forget coagulation!

J Hepatol 2021 Apr 16;74(4):967-968. Epub 2020 Dec 16.

Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.10.031DOI Listing
April 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

Microvesicles in bronchoalveolar lavage as a potential biomarker of COPD.

Am J Physiol Lung Cell Mol Physiol 2021 02 4;320(2):L241-L245. Epub 2020 Nov 4.

Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, University of Padova, Padua, Italy.

Microvesicles (MVs) released from almost all cells are recognized as cell communication tools. MVs have been investigated in several inflammatory diseases but poorly in biological fluids like bronchoalveolar lavage (BAL) of smokers. The purpose of this study was to investigate the presence and source of MVs in BAL of smokers with and without chronic obstructive pulmonary disease (COPD) compared with nonsmoking controls. Using flow cytometry in BAL, we detected endothelial and alveolar macrophage (AM)-derived MVs and found a higher number of AM-MVs in the BAL of smokers with COPD than in smokers without COPD and nonsmokers, which correlated with the pack-years ( = 0.46; = 0.05) and with the degree of airway obstruction measured by the forced expiratory volume in 1 s percent predicted ( = -0.56; = 0.01). Endothelial and alveolar macrophage-derived MVs are present and measurable in human BAL fluid. In response to smoking and to the development of COPD, inflammatory signals in AM-derived MVs can be quantified, and their numbers are related to the pack-years and the decrease in lung function. These results open the opportunity for future investigation of these microvesicles as biomarkers and possible mechanistic guides in COPD.
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http://dx.doi.org/10.1152/ajplung.00362.2020DOI Listing
February 2021

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

COVID-19-Associated Coagulopathy and Inflammatory Response: What Do We Know Already and What Are the Knowledge Gaps?

Anesth Analg 2020 11;131(5):1324-1333

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

Patients with coronavirus disease 2019 (COVID-19) frequently experience a coagulopathy associated with a high incidence of thrombotic events leading to poor outcomes. Here, biomarkers of coagulation (such as D-dimer, fibrinogen, platelet count), inflammation (such as interleukin-6), and immunity (such as lymphocyte count) as well as clinical scoring systems (such as sequential organ failure assessment [SOFA], International Society on Thrombosis and Hemostasis disseminated intravascular coagulation [ISTH DIC], and sepsis-induced coagulopathy [SIC] score) can be helpful in predicting clinical course, need for hospital resources (such as intensive care unit [ICU] beds, intubation and ventilator therapy, and extracorporeal membrane oxygenation [ECMO]) and patient's outcome in patients with COVID-19. However, therapeutic options are actually limited to unspecific supportive therapy. Whether viscoelastic testing can provide additional value in predicting clinical course, need for hospital resources and patient's outcome or in guiding anticoagulation in COVID-19-associated coagulopathy is still incompletely understood and currently under investigation (eg, in the rotational thromboelastometry analysis and standard coagulation tests in hospitalized patients with COVID-19 [ROHOCO] study). This article summarizes what we know already about COVID-19-associated coagulopathy and-perhaps even more importantly-characterizes important knowledge gaps.
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http://dx.doi.org/10.1213/ANE.0000000000005147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389937PMC
November 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
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