COVID-19NCT05334615
COVID-19 Coagulopathy Extension Study
An observational study of COVID-19, run by University of Iowa at 1 site in United States.
Trial summary
At the University of Iowa, the investigators led a multicenter randomized clinical trial comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with COVID-19 (NCT04360824). Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- COVID-19
- How many people
- 180 participants
- Where
- 1 siteUnited States
- Study dates
- 21 Jan 2022to 31 Dec 2025
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Hospitalized patients with acute COVID-19 (laboratory-confirmed SARS-CoV-2 infection) Hospitalized patients with incidental COVID-19 (laboratory-confirmed SARS-CoV-2 infection) Hospitalized patients with acute influenza (laboratory confirmed infection with influenza A or influenza B)
Who may be able to join
- Subjects must meet all inclusion criteria in one of the following three categories:
- Acute COVID-19
- Hospital admission for management of symptoms related to COVID-19
- Laboratory confirmed infection with SARS-CoV-2 by either PCR or antigen testing within 4 weeks of hospital admission
- Age ≥18 years
- Incidental COVID-19
Show all 13Show fewer
- Hospital admission for indications unrelated to COVID-19 who are incidentally found to have infection with SARS-CoV-2
- Age ≥18 years
- Acute influenza
- Hospital admission for clinical management of symptoms related to influenza
- Laboratory confirmed infection with influenza A or influenza B within 4 weeks of hospital admission
- Negative testing for SARS-CoV-2
- Age ≥18 years
Who cannot join
- Current pregnancy
- Prisoner
- History of a bleeding disorder
- Active cancer
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Iowa Health Care
Iowa City, Iowa, 52242
Katina Wilson, +1 319 353-7102, katina-wilson@uiowa.edu
Andrew Goss, +1 319 356-0529, andrew-goss@uiowa.edu
About this study
Official title: Cellular Effects of SARS-CoV-2 in Mediating Thrombotic Susceptibility
At the University of Iowa, the investigators led a multicenter randomized clinical trial comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with COVID-19 (NCT04360824). As part of an exploratory biomarker component of this trial, blood samples were collected from hospitalized COVID-19 patients at enrollment and weekly for up to 30 days of hospitalization. The pilot results, as well as reports from other groups, demonstrate increased potential for thrombin generation in the plasma of COVID-19 patients. In particular, in the COVID-19 patient cohort enhanced thrombin generation potential persisted for at least 30 days of hospitalization. The investigators now propose to explore the mechanistic roles of activation of blood cells (such as platelets and neutrophils) and products of cellular activation as mediators of enhanced thrombin generation in patients with COVID-19. The study design will be a longitudinal cohort study, which will allow for the determination of the time course of enhanced thrombin generation potential in relation to clinical outcomes and changes in markers of cellular activation in serial samples obtained from COVID-19 patients for up to 3 years after infection with SARS-CoV-2. This study may provide clues to why a subset of COVID-19 patients present with late thrombotic complications even after apparent recovery from SARS-CoV-2 infection. An ongoing question in the field relates to the comparative prothrombotic effects of acute COVID-19 versus incidental SARS-CoV-2 infection versus acute infection with influenza viruses. Therefore, we will include three categories of hospitalized patients in this study: (1) acute COVID-19, (2) incidental COVID-19, and (3) acute influenza A or B. This project has a strong scientific rationale with direct clinical implications, especially given the emergence of SARS-CoV-2 variants such as delta and omicron that may prolong the pandemic and/or cause surges of COVID-19 in the coming months.
Read the detailed description
- Background and scientific rationale Infection with the novel coronavirus SARS-CoV-2, first identified in Wuhan, China in late 2019, has become a global pandemic affecting over 209 countries and territories. The illness caused by SARS-CoV-2 is classified as COVID-19. As of August 23rd, 2021, more than 212 million cases of COVID-19 had been reported in more than 220 countries, resulting in more than 4.4 million deaths. The U.S. has by far the largest number of total cases (>38 million) with a mortality rate of 1.67%. Although many patients may have only mild upper respiratory symptoms, some COVID-19 patients become severely ill with respiratory failure with risk of progression to multiple organ failure and development of systemic coagulopathy with features similar to disseminated intravascular coagulation (DIC).1 The pathophysiology of COVID-19-associated coagulopathy appears to be complex and multifactorial, involving both cellular and plasmatic elements of the hemostatic system. Development of coagulopathy is a predictor of mortality in patients with COVID-19.2 Still, there are no direct mechanistic links established between SARS-CoV-2 infection and coagulopathy or thrombosis. At the University of Iowa, we led a multicenter randomized clinical trial comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with COVID-19 (NCT04360824).3 As part of an exploratory biomarker component of this trial, we collected blood samples from hospitalized COVID-19 patients at enrollment and weekly for up to 30 days of hospitalization. Our pilot results, as well as reports from other groups, demonstrate increased potential for thrombin generation in the plasma of COVID-19 patients. In particular, in our COVID-19 patient cohort we observed that enhanced thrombin generation potential persisted for at least 30 days of hospitalization. We now propose to explore the mechanistic roles of activation of blood cells (such as platelets and neutrophils), microparticles, extracellular histones, interleukin-6 (IL6), and galectin-3 (Gal-3) as mediators of enhanced thrombin generation in patients with COVID-19. The study design will be a longitudinal cohort study, which will allow us to determine the time course of enhanced thrombin generation potential in relation to clinical outcomes and changes in markers of cellular activation in serial samples obtained from COVID-19 patients for up to 3 years after infection with SARS-CoV-2. This study may provide clues to why a subset of COVID-19 patients present with late thrombotic complications even after apparent recovery from SARS-CoV-2 infection.4 Thus, this project has a strong scientific rationale with direct clinical implications, especially given the emergence of SARS-CoV-2 variants such as delta and omicron that may prolong the pandemic and/or cause surges of COVID-19 in the coming months. An ongoing question in the field relates to the comparative prothrombotic effects of acute COVID-19 versus incidental SARS-CoV-2 infection versus acute infection with influenza viruses. Therefore, we will include three categories of hospitalized patients in this study: (1) acute COVID-19, (2) incidental COVID-19, and (3) acute influenza A or B. It is now recognized that SARS-CoV-2 infection can be associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed "postacute sequelae of SARS-CoV-2 infection" (PASC), also known as "long COVID" or "post-COVID condition" (PCC) or "postinfective fatigue syndrome" (PIFS).5 It is not known whether or not persistent coagulopathy is a feature of PASC. Therefore, we will include assessment of post-COVID symptoms in our longitudinal cohort study design, which will allow us to assess for PASC as defined by Thaweethai et al.,2023.5
- Objectives 2.1 Primary objectives 2.1.1 Determine the time course of enhanced thrombin generation potential in patients with COVID-19 or influenza. 2.1.2 Test the hypothesis that activation of platelets, neutrophils, and endothelial cells by plasma from COVID-19 patients is mediated by Gal-3, IL6, and/or histones. 2.1.3 Determine the roles of neutrophils, platelets and endothelial cells in mediating increased thrombin generation and whether targeting IL6, Gal-3, or histones decreases thrombin generation potential in plasma samples from patients with COVID-19 or influenza. 2.2 Secondary objectives 2.2.1 Determine time course of changes in plasma levels of IL6, sIL6R, H3Cit, and Gal-3 in patients with COVID-19 or influenza. 2.2.2 Determine the association of plasma levels of IL6, sIL6R, H3Cit, and Gal-3 with thrombin generation potential in patients with COVID-19 or influenza. 2.3 Exploratory objectives 2.3.1 Using mouse models of experimental venous thrombosis, determine if infusion of plasma or microvesicles isolated from COVID-19 patient plasma potentiates thrombosis and whether neutralizing histones is protective. 2.3.2 Determine whether plasma thrombin generation potential or plasma levels of IL6, sIL6R, Gal-3 or H3Cit predict clinical outcomes during up to 3 years following hospitalization with COVID-19.
- Study design 3.1. Single-center longitudinal cohort study of hospitalized patients with COVID-19 (laboratory-confirmed SARS-CoV-2 infection) or influenza (laboratory-confirmed infection with influenza virus A or B).
- Study procedures and evaluations 4.1 Screening and enrollment Potentially eligible patients will be identified by a healthcare professional per institutional policy on privacy. The healthcare professional will assess the eligibility of the patient by performing a chart review which will include laboratory results. Only patients meeting all inclusion and exclusion criteria will be asked to participate. After obtaining verbal consent from the patient to be contacted for the study, a member of the research staff will approach the patient to be part of the study. The research staff will obtain informed consent from the patient or legally authorized representative (LAR) before collecting any data and performing any procedures. 4.2 Blood sample collection Blood samples will be collected at baseline (within 24 hours of enrollment), weekly thereafter during up to 30 days of hospitalization, and once between 3-6 months after enrollment. If the patient is discharged before the baseline blood samples are collected, then an outpatient study visit can be scheduled to obtain blood samples within one week of hospital discharge. Annual telephonic follow-up and optional follow-up visits for blood sample collection will occur at 12, 24, and 36 months after enrollment (+/- 60 days).
- Each blood sample collection will include the following (total blood volume 21.8 mL):
- Four 2.7 mL citrate tubes
- Two 3.0 mL EDTA tubes
- One 5.0 mL serum separator tube
- All blood samples are processed within one hour of collection. One tube of citrated blood is centrifuged at 2000 g for 10 min and platelet poor plasma (PPP) is aliquoted and snap frozen immediately for assays of cytokines and markers of cellular activation. Samples of PPP designated for thrombin generation assays are centrifuged again at 10,000 g for 10 min, aliquoted, and snap frozen. Microvesicles are isolated from double centrifuged plasma by centrifugation at 20,000 g for 30 min. A tube of citrated blood will be used to isolate platelets. Blood collected in EDTA will be used to measure complete blood counts and isolate leukocytes. Serum samples will be used to measure immunoglobulins and other biomarkers. 4.3 Clinical data capture
- Clinical and demographic data will be collected by UIHC medical record review and patient interview at the time of enrollment and each follow-up visit, and entered into UIHC RedCap
- Data to be collected:
- Age
- Gender
- Race/ethnicity (self-reported)
- Height, weight, and body mass index
- COVID-19 vaccination history
- Medications
- Other medical conditions/past medical history
- History of thrombosis
- History of cigarette smoking
- Current symptoms Anosmia (partial or complete loss of sense of smell) Dysguesia (altered sense of taste) Postexertional malaise (symptoms that get worse after physical or mental effort) Chronic cough Difficulty thinking or concentrating ("brain fog") Thirst Palpitations (fast-beating or pounding heart) Chest pain Fatigue Decreased libido (sexual desire or capacity) Lightheadedness or dizziness Nausea Diarrhea Abnormal movements Fever Chills Headache Insomnia (sleep problems) Myalgia (muscle or body aches) Sensory neuropathy (numbness or pins and needles sensation) Dyspnea (shortness of breath) Other symptoms? Clinical outcomes of special interest: All-cause mortality Thrombosis
- Arterial thrombosis, confirmed with imaging
- Venous thromboembolism, confirmed with imaging Bleeding
- Major bleeding, defined according to ISTH criteria.6
- Minor bleeding, defined as a bleeding event that does not meet ISTH criteria for major bleeding
- Withdrawal or Termination Any participant who wishes to withdraw from the study may do so at any time. If a participant chooses to withdraw from the study, no new data about that participant will be collected for study purposes. A participant may also withdraw authorization for the researchers to use his or her data that has already been collected (other than data needed to keep track of the withdrawal, including demographic data), but the participant must do this in writing to the site principal investigator. The study may be terminated at any time by the Principal Investigator if it is deemed continuation of the protocol will not yield statistically or scientifically useful data.
- Statistical analysis Summary statistics will be provided for all laboratory measures. Categorical measures will be presented as counts and percentages. Continuous measure distributions will be assessed using the D'Agostino-Pearson omnibus test and displayed as means and standard deviations or medians and IQRs, depending on the normality of the distribution. Tests for differences between serial samples and baseline samples will follow Fisher's exact Student's t- or Mann-Whitney U-tests, depending on the variable type and distribution. Analyses over time will utilize the generalized linear mixed modeling (GLMM) framework, which accommodates repeated measures data and a variety of outcome variable distributions. All models will include time as a predictor to test for differences within and between groups. In addition to unadjusted assessments, modifying factors such as age and gender will be considered for inclusion in the models to identify the optimal predictor set. For each outcome, the multivariate model with the smallest Akaike information criterion (AIC) will be deemed the optimal predictor set. All tests for statistical significance of the optimal model main effects and interactions will be conducted at alpha = 0.05 and follow the Bonferroni adjustment based on number of model predictors to account for multiple comparisons. Based on our pilot data and assuming effect sizes of at least 1.54, a total of 46 subjects are needed to have >80% power when testing for differences in these measures at alpha = 0.00625 (Bonferroni correction, 0.05/8). Anticipating technical issues with some samples or discontinued participation of patients in the longitudinal sample collection, we propose to recruit 60 subjects in each category (section 4.1) to get technically adequate serial samples.
- Study Management It is expected that the IRB will have the proper representation and function in accordance with federally mandated regulations. The IRB should approve the consent form and protocol. In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) and to ethical principles that have their origin in the Declaration of Helsinki. Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study and will be given the opportunity to review the consent form. Each consent form must include all the relevant elements currently required by the FDA Regulations and local or state regulations. Once this essential information has been provided to the patient and the investigator is assured that the patient understands the implications of participating in the study, the patient will be asked to give consent to participate in the study by signing an IRB-approved consent form. Prior to a patient's participation in the trial, the written informed consent form should be signed and personally dated by the patient or the patient's legally acceptable representative, and by the person who conducted the informed consent discussion.
- Conditions
- COVID-19
- Keywords
- thrombosis, coagulopathy, influenza
- Medical subject headings
- COVID-19, Thrombosis, Hemostatic Disorders, Influenza, Human
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Acute COVID-19 | Hospital admission for management of symptoms related to COVID-19. Laboratory confirmed infection with SARS-CoV-2 by either PCR or antigen testing within 4 weeks of hospital admission. Age ≥18 years. | |
| Incidental COVID-19 | Hospital admission for indications unrelated to COVID-19 who are incidentally found to have infection with SARS-CoV-2. Age ≥18 years. | |
| Acute influenza | Hospital admission for clinical management of symptoms related to influenza. Laboratory confirmed infection with influenza A or influenza B within 4 weeks of hospital admission. Negative testing for SARS-CoV-2. Age ≥18 years. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Thrombin generation
Determine the time course of enhanced thrombin generation potential in patients with COVID-19 or influenza
Measured: 3 years
Blood cell activation
Test the hypothesis that activation of platelets, neutrophils, and endothelial cells by plasma from COVID-19 patients is mediated by Gal-3, IL6, and/or histones.
Measured: 3 years
Cellular mediators of thrombin generation
Determine the roles of neutrophils, platelets and endothelial cells in mediating increased thrombin generation and whether targeting IL6, Gal-3, or histones decreases thrombin generation potential in plasma samples from COVID-19 patients.
Measured: 3 years
Secondary outcomes (2)
Biomarkers
Determine time course of changes in plasma levels of IL6, sIL6R, H3Cit, and Gal-3 in patients with COVID-19.
Measured: 3 years
Association of biomarkers with thrombin generation
Determine the association of plasma levels of IL6, sIL6R, H3Cit, and Gal-3 with thrombin generation potential in patients with COVID-19.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Apr 2022
- Study start21 Jan 2022
- Primary completion31 Dec 2025 (estimated)
- Study completion31 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 180 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Iowa
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Steven Lentz, University of Iowa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05334615
- Sponsor's protocol ID
- 202112148
- Other IDs
- R01AI162778
- Status last verified
- Apr 2025
- First submitted
- 17 Apr 2022
- Last updated
- 6 Apr 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Perepu US, Chambers I, Wahab A, Ten Eyck P, Wu C, Dayal S, Sutamtewagul G, Bailey SR, Rosenstein LJ, Lentz SR. Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: A multi-center, open-label, randomized controlled trial. J Thromb Haemost. 2021 Sep;19(9):2225-2234. doi: 10.1111/jth.15450. Epub 2021 Jul 18.
PubMed 34236768
Study at a glance
From the registry record, last updated by the sponsor on 6 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cellular Effects of SARS-CoV-2 in Mediating Thrombotic Susceptibility
- ClinicalTrials.gov ID
- NCT05334615
- Acronym / sponsor ID
- 202112148
- Conditions
- COVID-19
- Keywords
- thrombosis, coagulopathy, influenza
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 180 participants (estimated)
- Lead sponsor
- University of IowaUniversity, hospital or other
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- 21 Jan 2022 (actual)
- Primary completion
- 31 Dec 2025 (estimated)
- Study completion
- 31 Dec 2025 (estimated)
- First posted
- 19 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
At the University of Iowa, the investigators led a multicenter randomized clinical trial comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with COVID-19 (NCT04360824). As part of an exploratory biomarker component of this trial, blood samples were collected from hospitalized COVID-19 patients at enrollment and weekly for up to 30 days of hospitalization. The pilot results, as well as reports from other groups, demonstrate increased potential for thrombin generation in the plasma of COVID-19 patients. In particular, in the COVID-19 patient cohort enhanced thrombin generation potential persisted for at least 30 days of hospitalization. The investigators now propose to explore the mechanistic roles of activation of blood cells (such as platelets and neutrophils) and products of cellular activation as mediators of enhanced thrombin generation in patients with COVID-19. The study design will be a longitudinal cohort study, which will allow for the determination of the time course of enhanced thrombin generation potential in relation to clinical outcomes and changes in markers of cellular activation in serial samples obtained from COVID-19 patients for up to 3 years after infection with SARS-CoV-2. This study may provide clues to why a subset of COVID-19 patients present with late thrombotic complications even after apparent recovery from SARS-CoV-2 infection. An ongoing question in the field relates to the comparative prothrombotic effects of acute COVID-19 versus incidental SARS-CoV-2 infection versus acute infection with influenza viruses. Therefore, we will include three categories of hospitalized patients in this study: (1) acute COVID-19, (2) incidental COVID-19, and (3) acute influenza A or B. This project has a strong scientific rationale with direct clinical implications, especially given the emergence of SARS-CoV-2 variants such as delta and omicron that may prolong the pandemic and/or cause surges of COVID-19 in the coming months.
Detailed description
- Background and scientific rationale Infection with the novel coronavirus SARS-CoV-2, first identified in Wuhan, China in late 2019, has become a global pandemic affecting over 209 countries and territories. The illness caused by SARS-CoV-2 is classified as COVID-19. As of August 23rd, 2021, more than 212 million cases of COVID-19 had been reported in more than 220 countries, resulting in more than 4.4 million deaths. The U.S. has by far the largest number of total cases (>38 million) with a mortality rate of 1.67%. Although many patients may have only mild upper respiratory symptoms, some COVID-19 patients become severely ill with respiratory failure with risk of progression to multiple organ failure and development of systemic coagulopathy with features similar to disseminated intravascular coagulation (DIC).1 The pathophysiology of COVID-19-associated coagulopathy appears to be complex and multifactorial, involving both cellular and plasmatic elements of the hemostatic system. Development of coagulopathy is a predictor of mortality in patients with COVID-19.2 Still, there are no direct mechanistic links established between SARS-CoV-2 infection and coagulopathy or thrombosis. At the University of Iowa, we led a multicenter randomized clinical trial comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with COVID-19 (NCT04360824).3 As part of an exploratory biomarker component of this trial, we collected blood samples from hospitalized COVID-19 patients at enrollment and weekly for up to 30 days of hospitalization. Our pilot results, as well as reports from other groups, demonstrate increased potential for thrombin generation in the plasma of COVID-19 patients. In particular, in our COVID-19 patient cohort we observed that enhanced thrombin generation potential persisted for at least 30 days of hospitalization. We now propose to explore the mechanistic roles of activation of blood cells (such as platelets and neutrophils), microparticles, extracellular histones, interleukin-6 (IL6), and galectin-3 (Gal-3) as mediators of enhanced thrombin generation in patients with COVID-19. The study design will be a longitudinal cohort study, which will allow us to determine the time course of enhanced thrombin generation potential in relation to clinical outcomes and changes in markers of cellular activation in serial samples obtained from COVID-19 patients for up to 3 years after infection with SARS-CoV-2. This study may provide clues to why a subset of COVID-19 patients present with late thrombotic complications even after apparent recovery from SARS-CoV-2 infection.4 Thus, this project has a strong scientific rationale with direct clinical implications, especially given the emergence of SARS-CoV-2 variants such as delta and omicron that may prolong the pandemic and/or cause surges of COVID-19 in the coming months. An ongoing question in the field relates to the comparative prothrombotic effects of acute COVID-19 versus incidental SARS-CoV-2 infection versus acute infection with influenza viruses. Therefore, we will include three categories of hospitalized patients in this study: (1) acute COVID-19, (2) incidental COVID-19, and (3) acute influenza A or B. It is now recognized that SARS-CoV-2 infection can be associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed "postacute sequelae of SARS-CoV-2 infection" (PASC), also known as "long COVID" or "post-COVID condition" (PCC) or "postinfective fatigue syndrome" (PIFS).5 It is not known whether or not persistent coagulopathy is a feature of PASC. Therefore, we will include assessment of post-COVID symptoms in our longitudinal cohort study design, which will allow us to assess for PASC as defined by Thaweethai et al.,2023.5
- Objectives 2.1 Primary objectives 2.1.1 Determine the time course of enhanced thrombin generation potential in patients with COVID-19 or influenza. 2.1.2 Test the hypothesis that activation of platelets, neutrophils, and endothelial cells by plasma from COVID-19 patients is mediated by Gal-3, IL6, and/or histones. 2.1.3 Determine the roles of neutrophils, platelets and endothelial cells in mediating increased thrombin generation and whether targeting IL6, Gal-3, or histones decreases thrombin generation potential in plasma samples from patients with COVID-19 or influenza. 2.2 Secondary objectives 2.2.1 Determine time course of changes in plasma levels of IL6, sIL6R, H3Cit, and Gal-3 in patients with COVID-19 or influenza. 2.2.2 Determine the association of plasma levels of IL6, sIL6R, H3Cit, and Gal-3 with thrombin generation potential in patients with COVID-19 or influenza. 2.3 Exploratory objectives 2.3.1 Using mouse models of experimental venous thrombosis, determine if infusion of plasma or microvesicles isolated from COVID-19 patient plasma potentiates thrombosis and whether neutralizing histones is protective. 2.3.2 Determine whether plasma thrombin generation potential or plasma levels of IL6, sIL6R, Gal-3 or H3Cit predict clinical outcomes during up to 3 years following hospitalization with COVID-19.
- Study design 3.1. Single-center longitudinal cohort study of hospitalized patients with COVID-19 (laboratory-confirmed SARS-CoV-2 infection) or influenza (laboratory-confirmed infection with influenza virus A or B).
- Study procedures and evaluations 4.1 Screening and enrollment Potentially eligible patients will be identified by a healthcare professional per institutional policy on privacy. The healthcare professional will assess the eligibility of the patient by performing a chart review which will include laboratory results. Only patients meeting all inclusion and exclusion criteria will be asked to participate. After obtaining verbal consent from the patient to be contacted for the study, a member of the research staff will approach the patient to be part of the study. The research staff will obtain informed consent from the patient or legally authorized representative (LAR) before collecting any data and performing any procedures. 4.2 Blood sample collection Blood samples will be collected at baseline (within 24 hours of enrollment), weekly thereafter during up to 30 days of hospitalization, and once between 3-6 months after enrollment. If the patient is discharged before the baseline blood samples are collected, then an outpatient study visit can be scheduled to obtain blood samples within one week of hospital discharge. Annual telephonic follow-up and optional follow-up visits for blood sample collection will occur at 12, 24, and 36 months after enrollment (+/- 60 days).
- Each blood sample collection will include the following (total blood volume 21.8 mL):
- Four 2.7 mL citrate tubes
- Two 3.0 mL EDTA tubes
- One 5.0 mL serum separator tube
- All blood samples are processed within one hour of collection. One tube of citrated blood is centrifuged at 2000 g for 10 min and platelet poor plasma (PPP) is aliquoted and snap frozen immediately for assays of cytokines and markers of cellular activation. Samples of PPP designated for thrombin generation assays are centrifuged again at 10,000 g for 10 min, aliquoted, and snap frozen. Microvesicles are isolated from double centrifuged plasma by centrifugation at 20,000 g for 30 min. A tube of citrated blood will be used to isolate platelets. Blood collected in EDTA will be used to measure complete blood counts and isolate leukocytes. Serum samples will be used to measure immunoglobulins and other biomarkers. 4.3 Clinical data capture
- Clinical and demographic data will be collected by UIHC medical record review and patient interview at the time of enrollment and each follow-up visit, and entered into UIHC RedCap
- Data to be collected:
- Age
- Gender
- Race/ethnicity (self-reported)
- Height, weight, and body mass index
- COVID-19 vaccination history
- Medications
- Other medical conditions/past medical history
- History of thrombosis
- History of cigarette smoking
- Current symptoms Anosmia (partial or complete loss of sense of smell) Dysguesia (altered sense of taste) Postexertional malaise (symptoms that get worse after physical or mental effort) Chronic cough Difficulty thinking or concentrating ("brain fog") Thirst Palpitations (fast-beating or pounding heart) Chest pain Fatigue Decreased libido (sexual desire or capacity) Lightheadedness or dizziness Nausea Diarrhea Abnormal movements Fever Chills Headache Insomnia (sleep problems) Myalgia (muscle or body aches) Sensory neuropathy (numbness or pins and needles sensation) Dyspnea (shortness of breath) Other symptoms? Clinical outcomes of special interest: All-cause mortality Thrombosis
- Arterial thrombosis, confirmed with imaging
- Venous thromboembolism, confirmed with imaging Bleeding
- Major bleeding, defined according to ISTH criteria.6
- Minor bleeding, defined as a bleeding event that does not meet ISTH criteria for major bleeding
- Withdrawal or Termination Any participant who wishes to withdraw from the study may do so at any time. If a participant chooses to withdraw from the study, no new data about that participant will be collected for study purposes. A participant may also withdraw authorization for the researchers to use his or her data that has already been collected (other than data needed to keep track of the withdrawal, including demographic data), but the participant must do this in writing to the site principal investigator. The study may be terminated at any time by the Principal Investigator if it is deemed continuation of the protocol will not yield statistically or scientifically useful data.
- Statistical analysis Summary statistics will be provided for all laboratory measures. Categorical measures will be presented as counts and percentages. Continuous measure distributions will be assessed using the D'Agostino-Pearson omnibus test and displayed as means and standard deviations or medians and IQRs, depending on the normality of the distribution. Tests for differences between serial samples and baseline samples will follow Fisher's exact Student's t- or Mann-Whitney U-tests, depending on the variable type and distribution. Analyses over time will utilize the generalized linear mixed modeling (GLMM) framework, which accommodates repeated measures data and a variety of outcome variable distributions. All models will include time as a predictor to test for differences within and between groups. In addition to unadjusted assessments, modifying factors such as age and gender will be considered for inclusion in the models to identify the optimal predictor set. For each outcome, the multivariate model with the smallest Akaike information criterion (AIC) will be deemed the optimal predictor set. All tests for statistical significance of the optimal model main effects and interactions will be conducted at alpha = 0.05 and follow the Bonferroni adjustment based on number of model predictors to account for multiple comparisons. Based on our pilot data and assuming effect sizes of at least 1.54, a total of 46 subjects are needed to have >80% power when testing for differences in these measures at alpha = 0.00625 (Bonferroni correction, 0.05/8). Anticipating technical issues with some samples or discontinued participation of patients in the longitudinal sample collection, we propose to recruit 60 subjects in each category (section 4.1) to get technically adequate serial samples.
- Study Management It is expected that the IRB will have the proper representation and function in accordance with federally mandated regulations. The IRB should approve the consent form and protocol. In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) and to ethical principles that have their origin in the Declaration of Helsinki. Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study and will be given the opportunity to review the consent form. Each consent form must include all the relevant elements currently required by the FDA Regulations and local or state regulations. Once this essential information has been provided to the patient and the investigator is assured that the patient understands the implications of participating in the study, the patient will be asked to give consent to participate in the study by signing an IRB-approved consent form. Prior to a patient's participation in the trial, the written informed consent form should be signed and personally dated by the patient or the patient's legally acceptable representative, and by the person who conducted the informed consent discussion.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Acute COVID-19 | – | –Hospital admission for management of symptoms related to COVID-19. Laboratory confirmed infection with SARS-CoV-2 by either PCR or antigen testing within 4 weeks of hospital admission. Age ≥18 years. |
| Incidental COVID-19 | – | –Hospital admission for indications unrelated to COVID-19 who are incidentally found to have infection with SARS-CoV-2. Age ≥18 years. |
| Acute influenza | – | –Hospital admission for clinical management of symptoms related to influenza. Laboratory confirmed infection with influenza A or influenza B within 4 weeks of hospital admission. Negative testing for SARS-CoV-2. Age ≥18 years. |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Hospitalized patients with acute COVID-19 (laboratory-confirmed SARS-CoV-2 infection) Hospitalized patients with incidental COVID-19 (laboratory-confirmed SARS-CoV-2 infection) Hospitalized patients with acute influenza (laboratory confirmed infection with influenza A or influenza B)
Key inclusion criteria (13 listed)
- Acute COVID-19
- Incidental COVID-19
- Acute influenza
Key exclusion criteria (4 listed)
- Current pregnancy
- Prisoner
- History of a bleeding disorder
- Active cancer
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Thrombin generation
Time frame: 3 years
Determine the time course of enhanced thrombin generation potential in patients with COVID-19 or influenza
Blood cell activation
Time frame: 3 years
Test the hypothesis that activation of platelets, neutrophils, and endothelial cells by plasma from COVID-19 patients is mediated by Gal-3, IL6, and/or histones.
Cellular mediators of thrombin generation
Time frame: 3 years
Determine the roles of neutrophils, platelets and endothelial cells in mediating increased thrombin generation and whether targeting IL6, Gal-3, or histones decreases thrombin generation potential in plasma samples from COVID-19 patients.
2 secondary outcomes
Biomarkers
Time frame: 3 years
Association of biomarkers with thrombin generation
Time frame: 3 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Apr 2025.
- Background: PubMed 34236768Perepu US, Chambers I, Wahab A, Ten Eyck P, Wu C, Dayal S, Sutamtewagul G, Bailey SR, Rosenstein LJ, Lentz SR. Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: A multi-center, open-label, randomized controlled trial. J Thromb Haemost. 2021 Sep;19(9):2225-2234. doi: 10.1111/jth.15450. Epub 2021 Jul 18.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of COVID-19, run by University of Iowa at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 6 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Steven Lentz, MD, PhD (+1 319 356 4048, steven-lentz@uiowa.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Thrombin generation (time frame: 3 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05334615, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2025.