Covid-19 Associated Coagulopathy

COVID-19-associated Coagulopathy: Safety and Efficacy of Prophylactic Anticoagulation Therapy in Hospitalized Adults With COVID-19

This prospective, randomized, open-label, multi-center interventional study is designed to compare the safety and efficacy of two LMWH dosing protocols in patients admitted to the University of Iowa Hospitals with COVID-19 who meet the modified ISTH Overt DIC criteria score ≥3. Patients will be randomized to standard prophylactic dose LMWH (standard of care arm) or intermediate-dose LMWH (intervention arm).

Study Overview

• Status: Completed
• Conditions: COVID 19 Associated Coagulopathy
• Intervention / Treatment: Drug: Standard of Care thromboprophylaxis; Drug: Intermediate dose thromboprophylaxis

Detailed Description

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 and weight as measured on admission to the hospital. 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/LAR before collecting any data and performing any procedures.

5.2 Trial interventions

As standard of care, hospitalized patients with confirmed COVID-19 will be monitored for coagulopathy. Daily blood tests for platelet count, prothrombin time, D-Dimer, and fibrinogen and weekly thromboelastography will be obtained, and a daily Modified ISTH Overt DIC score will be calculated (Exhibit 1). Only patients meeting all inclusion and exclusion criteria will be asked to participate in the trial. Patients will be randomized to one of two arms:

1. Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30 kg/m2; 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2).
2. Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI <30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30 kg/m2), with doses rounded up to the nearest dose syringe in hospitalized patients with laboratory confirmed SARS CoV-2 infection.

5.3 Dose Modifications

1. Enoxaparin will be held if platelets decrease to <25,000/mm3. Enoxaparin will resume once platelets increase to ≥25,000/ mm3.
2. Enoxaparin will be held if fibrinogen is <50 mg/dL. Enoxaparin will resume once fibrinogen increases to ≥50 mg/dL.
3. Enoxaparin will be held if estimated Creatinine clearance < 15 ml/min calculated by the modified Cockcroft and Gault formula and resumed once the Creatinine Clearance is ≥15 ml/min.
4. Enoxaparin will be held if there is a clinical suspicion for heparin induced thrombocytopenia.
5. Enoxaparin dose will be reduced by 25% if Creatinine Clearance ≥15 and <30 ml/min calculated by the modified Cockcroft and Gault formula and increased once the estimated Creatinine Clearance is ≥30 ml/min in both the arms.

All participating patients will continue the assigned doses of enoxaparin until hospital discharge or until a clinical event occurs requiring either discontinuation of anticoagulation therapy or full therapeutic dose anticoagulation therapy.

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Usha Perepu, MBBS; Phone Number: 319-356-2195; Email: usha-perepu@uiowa.edu
• Study Contact Backup: Name: Steven Lentz, MD, PhD; Phone Number: 319-356-2148; Email: steven-lentz@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Laboratory confirmed SARS-CoV-2 infection
• Age ≥18 years
• Requires hospital admission for further clinical management
• Modified ISTH Overt DIC score ≥ 3

Exclusion Criteria:

• Indication for full therapeutic-dose anticoagulation
• Acute venous thromboembolism (deep vein thrombosis or pulmonary embolism) within prior 3 months
• Acute cardiovascular event within prior 3 months
• Acute stroke (ischemic or hemorrhagic) within prior 3 months
• Active major bleeding
• Severe thrombocytopenia (<25,000/mm3)
• Increased risk of bleeding, as assessed by the investigator
• Acute or chronic renal insufficiency with Creatinine Clearance < 30 ml/min calculated by the modified Cockcroft and Gault formula
• Weight < 40 kg
• Known allergies to ingredients contained in enoxaparin, allergy to heparin products or history of heparin induced thrombocytopenia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care; 1) Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30kg/m2).	Drug: Standard of Care thromboprophylaxis; Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2).
Other: Interventional; 2) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI<30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2).	Drug: Intermediate dose thromboprophylaxis; 2) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI<30kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2).; Other Names: intermediate dose Enoxaparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	All-cause mortality	30 Days post intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Acute Kidney Injury	Defined as an estimated creatinine clearance <30 mL/min	30 days post intervention
Number of Participants With Arterial Thrombosis	Risk of ischemic stroke, myocardial infarction and/or limb ischemia	30 Days post intervention
Number of Participants With Venous Thrombosis	Those at risk of symptomatic venous thromboembolism, which is a blood clot in a vein.	30 Days post intervention
Number of Participants With Major Bleeding	Those at risk of ISTH defined major bleeding, such as fatal bleeding, or bleeding into a critical area or organ.	30 Days post intervention
Number of Participants With Minor Bleeding	Defined as a bleeding event that did not meet ISTH criteria for major bleeding.	30 Days post intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The endogenous thrombin potential will be determined within 24 hours of randomization and weekly for 30 days or until hospital discharge	Will be performed in stored plasma using Calibrated Automated Thrombogram. The endogenous thrombin potential will be calculated in units of nM.Min.	30 days post intervention
Plasma levels of cell-free DNA will be determined within 24 hours of randomization and weekly for 30 days or until hospital discharge	These assays will be performed in stored plasma. Quantification of cfDNA will be performed using Qubit dsDNA HS Assay kit. Histones H4, citrullinated-histone and DNA-myeloperoxidase will be measured using commercially available ELISA kit.	30 days post intervention
PAI-1	will be measured in stored plasma using a commercially available ELISA kit.	30 days post intervention

Collaborators and Investigators

• Sponsor: University of Iowa

Publications and helpful links

General Publications

• Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
• Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.
• Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
• Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.
• Lentz SR. Thrombosis in the setting of obesity or inflammatory bowel disease. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):180-187. doi: 10.1182/asheducation-2016.1.180.

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2020
• Primary Completion (Actual): April 16, 2021
• Study Completion (Actual): April 16, 2021

Study Registration Dates

• First Submitted: April 13, 2020
• First Submitted That Met QC Criteria: April 22, 2020
• First Posted (Actual): April 24, 2020

Study Record Updates

• Last Update Posted (Actual): March 1, 2023
• Last Update Submitted That Met QC Criteria: January 31, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Hematologic Diseases; Hemorrhagic Disorders; COVID-19; Hemostatic Disorders; Blood Coagulation Disorders; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: 202004235

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No individual participant data will be shared

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No