[Coagulopathy in COVID-19: pathophysiology]. / La coagulopatia nel COVID-19: basi fisiopatologiche.

On March 11, 2020, just after 2 months from the first cases of coronavirus disease 2019 (COVID-19) in China, the Director-General of the World Health Organization stated that COVID-19 has to be considered as a pandemic. Italian doctors were the first protagonists, after the Chinese ones, in the management of this disease. Clinical observations showed that, in addition to the respiratory infection, a systemic inflammatory response occurs, which leads to coagulation disorders and consequent venous thromboembolism as well as other thrombotic complications. We here review the available literature on this issue to better understand the pathophysiological mechanisms of coagulopathy useful to draw future clinical and therapeutic conclusions.

Steady-State Serum T3 Concentrations for 48 Hours Following the Oral Administration of a Single Dose of 3,5,3'-Triiodothyronine Sulfate (T3S).

OBJECTIVE: Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T3) sulfate (T3S) in rats. The present study investigated whether T3S is absorbed after oral administration in humans and if it represents a source of T3. METHODS: Twenty-eight hypothyroid patients (7 men and 21 women; mean age, 44 ± 11 years) who had a thyroidectomy for thyroid carcinoma were enrolled. Replacement thyroid hormone therapy was withdrawn (42 days for thyroxine, 14 days for T3) prior to 131I remnant ablation. A single oral dose of 20, 40, 80 (4 patients/group), or 160 µg (16 patients/group) of T3S was administered 3 days before the planned administration of 131I. Blood samples for serum T3S and total T3 (TT3) concentrations were obtained at various times up to 48 hours after T3S administration. RESULTS: At all T3S doses, serum T3S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T3S maximum concentration (Cmax) and area under the 0- to 48-hour concentration-time curve (AUC0-48h) were directly and significantly related to the administered dose. An increase in serum TT3 concentration was observed (significant after 1 hour), and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T3S administration. There was a significant direct correlation between the TT3 AUC0-48h and the administered dose of T3S. No changes in serum free thyroxine (T4) concentrations during the entire study period were observed, whereas serum thyroid-stimulating hormone levels increased slightly at 48 hours, but this was not related to the dose of T3S. No adverse events were reported. CONCLUSION: (1) T3S is absorbed following oral administration in hypothyroid humans; (2) after a single oral dose, T3S is converted to T3 in a dose-dependent manner, resulting in steady-state serum T3 concentrations for 48 hours; (3) T3S may represent a new agent in combination with T4 in the therapy of hypothyroidism, if similar conversion of T3S to T3 can be demonstrated in euthyroid patients who are already taking T4.

Dynamic contrast enhanced ultrasound assessment of the vascular effects of novel therapeutics in early stage trials.

Imaging is key in the accurate monitoring of response to cancer therapies targeting tumour vascularity to inhibit its growth and dissemination. Dynamic contrast enhanced ultrasound (DCE ultrasound) is a quantitative method with the advantage of being non-invasive, widely available, portable, cost effective, highly sensitive and reproducible using agents that are truly intravascular. Under the auspices of the initiative of the Experimental Cancer Medicine Centre Imaging Network, bringing together experts from the UK, Europe and North America for a 2-day workshop in May 2010, this consensus paper aims to provide guidance on the use of DCE ultrasound in the measurement of tumour vascular support in clinical trials. Key Points • DCE ultrasound can quantify and extract specific blood flow parameters, such as flow velocity, relative vascular volume and relative blood flow rate. • DCE ultrasound can be performed repeatedly and is therefore ideally suited for pharmacokinetic and pharmacodynamic studies evaluating vascular-targeted drugs. • DCE ultrasound provides a reproducible method of assessing the vascular effects of therapy in pre-clinical and early clinical trials, which is easily translatable into routine clinical practice.

BR38, a new ultrasound blood pool agent.

OBJECTIVE: : To evaluate BR38, a new microbubble-based blood pool agent for contrast-enhanced ultrasound imaging. MATERIALS AND METHODS: : The size characteristics of BR38 microbubbles were measured by Coulter counting. The backscatter and attenuation coefficients were determined as a function of frequency. Additional measurements included the surface charge, osmolality, viscosity, and resistance to hydrostatic pressure. Extensive pharmacological and toxicological studies were conducted on the final formulation in rats and dogs. The blood levels and elimination of the gaseous component C4F10 were determined in the rabbit. Contrast-enhanced echographic examinations were performed in pigs focusing on the myocardium and the liver. Finally, safety testing and preliminary imaging experiments were performed in a Phase I clinical study in human volunteers. RESULTS: : BR38 suspensions are isotonic, nonviscous, and show a high resistance to hydrostatic pressure. Their backscatter coefficient is high at ≥ 2 MHz and attenuation shows a maximum at 4 MHz, slowly decreasing at higher frequencies. The no adverse effect levels of 1 µL/kg (rats) and 5 µL/kg (dogs) expressed as microbubble gas volume, observed in repeated toxicology studies, correspond to 50 and 250 times the expected imaging dose in human beings (0.02 µL/kg), respectively. No effects on cardiovascular and respiratory parameters were observed in rats and dogs. C4F10 is eliminated within minutes from blood and excreted in expired air. Imaging experiments showed strong and persistent enhancement of the myocardium and the liver. A late phase was observed in the liver, in animals and in human volunteers. No serious adverse events and no significant changes in vital signs, electrocardiographs, and laboratory tests were observed in Phase I human volunteers. CONCLUSIONS: : BR38 shows a very good safety profile. It is characterized by a long persistence and low shadowing. BR38 is a promising ultrasound blood pool agent for noncardiac and cardiac applications including myocardial perfusion imaging.

CEUS in abdominal trauma: multi-center study.

The objective of this study was to evaluate the concordance of US and contrast-enhanced US (CEUS) with CT in the assessment of solid organ injury following blunt trauma. Patients underwent complete US examination, including free fluid search and solid organ analysis. CEUS followed, using low-mechanical index techniques and SonoVue. CT was performed within 1 h. Among 156 enrolled patients, 91 had one or more abnormalities (n = 107) at CT: 26 renal, 38 liver, 43 spleen. Sensitivity, specificity, and accuracy for renal trauma at baseline US were 36%, 98%, and 88%, respectively, after CEUS values increased to 69%, 99%, and 94%. For liver baseline US values were 68%, 97%, and 90%; after CEUS were 84%, 99%, and 96%. For spleen, results were 77%, 96%, and 91% at baseline US and 93%, 99%, and 97% after CEUS. Per patient evaluation gave the following results in terms of sensitivity, specificity and accuracy: 79%, 82%, 80% at baseline US; 94%, 89%, and 92% following CEUS. CEUS is more sensitive than US in the detection of solid organ injury, potentially reducing the need for further imaging. False negatives from CEUS are due to minor injuries, without relevant consequences for patient management and prognosis.

The use of contrasted transvaginal sonography in the diagnosis of gynecologic diseases: a preliminary study.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of a new contrast-dedicated ultrasound technology, contrast-tuned imaging (CnTI), implemented on an endovaginal probe and using the second-generation contrast agent SonoVue (Bracco International BV, Amsterdam, the Netherlands), compared with the standard ultrasound examination in different gynecologic diseases. METHODS: Eighty-nine patients were enrolled in the study in 4 different clinical centers. The study included 40 patients with uncertain pelvic adnexal masses, 10 patients with pelvic masses indicative of recurrences of gynecologic tumors, 26 patients with uterine pathologic features, and 13 patients with cervical lesions. RESULTS: Application of CnTI technology after the SonoVue injection gave a picture of the intralesional microvascularization dramatically different from that obtained during color Doppler examination. Of the 40 pelvic masses, 15 (37.5%) were considered benign and 25 (62.5%) were considered malignant at B-mode and color Doppler examinations. Contrast-enhanced sonography showed no intralesional contrast perfusion in 11 (73%) of 15 cases, and all these were benign at final diagnosis. Of the 4 (27%) cases that had perfusion, 2 were malignant. Conversely, of the 25 cases with positive findings at color Doppler examination and therefore expected to show the appearance of contrast tissue-filling morphologic characteristics, 13 (52%) were malignant at final diagnosis. For evaluation of uterine pathologic features, the CnTI-SonoVue technology did not appear to be superior to the B-mode and color Doppler examinations; however, for the evaluation of cervical cancer, CnTI-SonoVue technology revealed a better definition of the margins of the neoplastic lesions in 4 (40%) of 10 cases. CONCLUSIONS: In the evaluation of uncertain pelvic masses, the CnTI technology led to an improvement in the ability of the practitioner to differentiate benign from malignant adnexal lesions.